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Sample records for paclitaxel

  1. Paclitaxel Injection

    MedlinePLUS

    ... other medications. Paclitaxel injection manufactured with polyoxyethylated castor oil is used to treat ovarian cancer (cancer that ... and lung cancer. Paclitaxel injection with polyoxyethylated castor oil is also used to treat Kaposi's sarcoma (a ...

  2. Possible Side Effects of Paclitaxel

    Cancer.gov

    Page of 1Possible Side Effects of Paclitaxel (Table Version Date: August 23, 2013) COMMON, SOME MAY BE SERIOUS In 100 people receiving Paclitaxel, more than 20 and up to 100 may have: Anemia which may cause tiredness, or may require blood transfusions Infection,

  3. Possible Side Effects of Carboplatin and Paclitaxel

    Cancer.gov

    Page of 1Possible Side Effects of Carboplatin and Paclitaxel (Table Version Date: October 8, 2013) COMMON, SOME MAY BE SERIOUS In 100 people receiving Carboplatin and Paclitaxel, more than 20 and up to 100 may have: Hair loss Infection, especially when

  4. How Taxol/paclitaxel kills cancer cells

    PubMed Central

    Weaver, Beth A.

    2014-01-01

    Taxol (generic name paclitaxel) is a microtubule-stabilizing drug that is approved by the Food and Drug Administration for the treatment of ovarian, breast, and lung cancer, as well as Kaposi's sarcoma. It is used off-label to treat gastroesophageal, endometrial, cervical, prostate, and head and neck cancers, in addition to sarcoma, lymphoma, and leukemia. Paclitaxel has long been recognized to induce mitotic arrest, which leads to cell death in a subset of the arrested population. However, recent evidence demonstrates that intratumoral concentrations of paclitaxel are too low to cause mitotic arrest and result in multipolar divisions instead. It is hoped that this insight can now be used to develop a biomarker to identify the ?50% of patients that will benefit from paclitaxel therapy. Here I discuss the history of paclitaxel and our recently evolved understanding of its mechanism of action. PMID:25213191

  5. Paclitaxel alters sensory nerve biomechanical properties.

    PubMed

    Bober, Brian G; Shah, Sameer B

    2015-10-15

    Paclitaxel is an effective chemotherapeutic that, despite its common use, frequently causes debilitating peripheral sensory neuropathy. Paclitaxel binds to and stabilizes microtubules, and through unknown mechanisms, causes abnormal microtubule aggregation. Given that microtubules contribute to the mechanical properties of cells, we tested the hypothesis that paclitaxel treatment would alter the stiffness of sensory nerves. Rat sural nerves were excised and soaked in Ringer's solution with or without paclitaxel. Nerves were secured between a force transducer and actuator, and linearly strained. Stress-strain curves were generated, from which elastic moduli were calculated. Paclitaxel treated nerves exhibited significantly higher moduli in both linear and transition regions of the curve. A composite-tissue model was then generated to estimate the stiffness increase in the cellular fraction of the nerve following paclitaxel treatment. This model was supported experimentally by data on mechanical properties of sural nerves stripped of their epineurium, and area fractions of the cellular and connective tissue components of the rat sural nerve, calculated from immunohistochemical images. Model results revealed that the cellular components of the nerve must stiffen 12x to 115x, depending on the initial axonal modulus assumed, in order to achieve the observed tissue level mechanical changes. Consistent with such an increase, electron microscopy showed increased microtubule aggregation and cytoskeletal packing, suggestive of a more cross-linked cytoskeleton. Overall, our data suggests that paclitaxel treatment induces increased microtubule bundling in axons, which leads to alterations in tissue-level mechanical properties. PMID:26321364

  6. Paclitaxel Albumin-stabilized Nanoparticle Formulation

    Cancer.gov

    This page contains brief information about paclitaxel albumin-stabilized nanoparticle formulation and a collection of links to more information about the use of this drug, research results, and ongoing clinical trials.

  7. Synthesis of paclitaxel-BGL conjugates.

    PubMed

    Nemoto, Hisao; Katagiri, Ayato; Kamiya, Masaki; Kawamura, Tomoyuki; Matsushita, Tsuyoshi; Matsumura, Kosuke; Itou, Tomohiro; Hattori, Hatsuhiko; Tamaki, Miho; Ishizawa, Keisuke; Miyamoto, Licht; Abe, Shinji; Tsuchiya, Koichiro

    2012-09-15

    Four kinds of symmetrically branched oligoglyceryl trimeric (BGL003)-paclitaxel conjugates and a corresponding heptameric (BGL007) conjugate were synthesized. Molecular weights of all the compounds were less than two times that of paclitaxel. The anti-tumor activity of the most water-soluble BGL003 conjugate was examined and found to be preserved in spite of the chemical modification that is displacement of the N3'-debenzoyl residue with the BGL003 succinyl residue. PMID:22892212

  8. Albumin-bound Paclitaxel: in metastatic breast cancer.

    PubMed

    Robinson, Dean M; Keating, Gillian M

    2006-01-01

    A new formulation of paclitaxel, 130-nanometre albumin-bound paclitaxel (nab-paclitaxel), solubilises hydrophobic paclitaxel and may increase paclitaxel delivery to tumour cells. Intravenous nab-paclitaxel 260 mg/m(2) had a higher maximum whole-blood concentration, shorter time to peak concentration, larger distribution volume and greater clearance than a 175 mg/m(2) dose of a conventional polyoxyethylated castor oil (Cremophor EL) solublised paclitaxel (CrEL-paclitaxel). The reconciled target-lesion response rate was significantly higher in patients receiving intravenous nab-paclitaxel 260 mg/m(2) once every 3 weeks than in those receiving CrEL-paclitaxel 175 mg/m(2) once every 3 weeks (21.5% vs 11.1%) in a randomised, nonblind, phase III trial in 454 patients with metastatic breast cancer. The objective response rate (ORR) was also significantly greater in nab-paclitaxel than in CrEL-paclitaxel recipients (33% vs 19%). In noncomparative phase II trials, ORRs of 48% and 51% were observed in patients receiving nab-paclitaxel 175 or 300 mg/m(2) once every 3 weeks. nab-Paclitaxel 260 mg/m(2) caused less grade 4 neutropenia than CrEL-paclitaxel 175 mg/m(2). The incidence of grade 3 sensory neuropathy was higher in nab-paclitaxel recipients, reflecting the higher dosage of nab-paclitaxel, and improved with treatment interruption. Despite the absence of corticosteroid and antihistamine premedication, no severe hypersensitivity reactions were reported. PMID:16740010

  9. Possible Side Effects of Cyclophosphamide, Doxorubicin, and Paclitaxel

    Cancer.gov

    Page of 1Possible Side Effects of Cyclophosphamide, Doxorubicin, and Paclitaxel (Table Version Date: October 8, 2013) COMMON, SOME MAY BE SERIOUS In 100 people receiving Cyclophosphamide, Doxorubicin, and Paclitaxel, more than 20 and up to 100 may have: Hair

  10. Nab-Paclitaxel Plus Gemcitabine for Metastatic Pancreatic Cancer

    Cancer.gov

    A summary of results from a phase III trial that compared the combination of albumin-bound paclitaxel (nab-paclitaxel [Abraxane®]) and gemcitabine (Gemzar®) versus gemcitabine alone in patients with metastatic pancreatic cancer.

  11. A MATHEMATICAL MODEL FOR THE TRANSPORT OF PACLITAXEL (TAXOL)

    E-print Network

    A MATHEMATICAL MODEL FOR THE TRANSPORT OF PACLITAXEL (TAXOL) ACROSS THE BLOOD-BRAIN BARRIER S that is successfully used in the fight against many different types of cancers. However, exclusion of paclitaxel from the central nervous system by the blood-brain barrier is a major obstacle for paclitaxel-based treat- ment

  12. Combining Paclitaxel with ABT-263 Has a Synergistic Effect on Paclitaxel Resistant Prostate Cancer Cells

    PubMed Central

    Wang, Chihuei; Huang, Shih-Bo; Yang, Min-Chi; Lin, Yi-Tsen; Chu, I-Hung; Shen, Ya-Ni; Chiu, Yueh-Ho; Hung, Shao-Hung; Kang, Lin; Hong, Yi-Ren; Chen, Chung-Hwan

    2015-01-01

    We assessed the capability of paclitaxel, one of the taxanes, to induce death in two prostate cancer lines, LNCaP and PC3. Paclitaxel drove an apoptotic pathway in LNCaP, but not in PC3 cells, in response to G2/M arrest. An examination of the levels of anti-apoptotic proteins revealed that Bcl-xl was much higher in PC3 cells than in LNCaP cells and Bcl2 could be detected only in PC3 cells, not in LNCaP cells. Knocking down Bcl-xl enhanced paclitaxel-induced apoptosis in LNCaP cells, while we were unable to knock down Bcl-xl efficiently in PC3 cells. Significantly, a comparison of ABT-263, a specific inhibitor of Bcl2 and Bcl-xl, with ABT-199, a Bcl2 selective inhibitor, disclosed that only ABT-263, not ABT-199, could induce apoptosis in LNCaP and PC3 cells. The results indicate that Bcl-xl has a protective role against paclitaxel-induced apoptosis in LNCaP and PC3 cells, and its overexpression causes the paclitaxel resistance seen in PC3 cells. Interestingly, combined paclitaxel with ABT-263 to treat LNCaP and PC3 cells demonstrated synergistic apoptosis activation, indicating that ABT-263 could enhance paclitaxel-induced apoptosis in LNCaP cells and overcome Bcl-xl overexpression to trigger paclitaxel-induced apoptosis in PC3 cells. We also observed that the activation of apoptosis in LNCaP cells was more efficient than in PC3 cells in response to paclitaxel plus ABT-263 or to ABT-263 alone, suggesting that the apoptosis pathway in PC3 cells might have further differences from that in LNCaP cells even after Bcl-xl overexpression is accounted for. PMID:25811469

  13. Albumin-bound paclitaxel: a next-generation taxane.

    PubMed

    Gradishar, William J

    2006-06-01

    Taxanes are standard treatment for metastatic breast cancer; however, the solvents used as vehicles in these formulations cause severe toxicities. The FDA recently approved a solvent-free formulation of paclitaxel for the treatment of metastatic breast cancer that utilises 130-nanometer albumin-bound (nab) technology (Abraxane; nab-paclitaxel) to circumvent the requirement for solvents. nab-Paclitaxel utilises the natural properties of albumin to reversibly bind paclitaxel, transport it across the endothelial cell and concentrate it in areas of tumour. The proposed mechanism of drug delivery involves, in part, glycoprotein 60-mediated endothelial cell transcytosis of paclitaxel-bound albumin and accumulation in the area of tumour by albumin binding to SPARC (secreted protein, acidic and rich in cysteine). Clinical studies have shown that nab-paclitaxel is significantly more effective than paclitaxel formulated as Cremophor EL (CrEL, Taxol, CrEL-paclitaxel), with almost double the response rate, increased time to disease progression and increased survival in second-line patients. The absence of CrEL from the formulation is associated with decreased neutropenia and rapid improvement of peripheral neuropathy with nab-paclitaxel, compared with CrEL-paclitaxel. For these reasons, nab-paclitaxel can be administered using higher doses of paclitaxel than that achievable with CrEL-paclitaxel, with shorter infusion duration and without the requirement for corticosteroid and antihistamine premedication to reduce the risk of solvent-mediated hypersensitivity reactions. Taken together, these studies have demonstrated that nab technology has increased the therapeutic index of paclitaxel compared with the conventional, solvent-based formulation. PMID:16722814

  14. Prolonged remission of recurrent cervical carcinoma following paclitaxel and carboplatin chemotherapy with paclitaxel maintenance chemotherapy.

    PubMed

    Micha, John P; Sassoon, Aaron F; Wong, Humberto; Goldstein, Bram H

    2015-08-01

    Cervical cancer recurs in ~30% of cases, for which a favorable prognosis is often unattainable. We describe a cervical cancer patient who developed metastatic disease ~5 years after her initial diagnosis. She was subsequently treated with six cycles of paclitaxel (175?mg/m) and carboplatin area under the curve (AUC) 5 chemotherapy every 21 days, and paclitaxel (135?mg/m) maintenance therapy every 21 days; the patient has remained in clinical remission after more than 5 years of follow-up. Chemotherapy has not historically been effective in managing recurrent, persistent, or metastatic cervical cancer. However, our case study involving paclitaxel and carboplatin chemotherapy with maintenance chemotherapy represents one of the longest documented remission rates in association with the management of recurrent cervical cancer. PMID:25933247

  15. Stathmin Potentiates Vinflunine and Inhibits Paclitaxel Activity

    PubMed Central

    Malesinski, Soazig; Tsvetkov, Philipp O.; Kruczynski, Anna; Peyrot, Vincent; Devred, François

    2015-01-01

    Cell biology and crystallographic studies have suggested a functional link between stathmin and microtubule targeting agents (MTAs). In a previous study we showed that stathmin increases vinblastine (VLB) binding to tubulin, and that conversely VLB increases stathmin binding to tubulin. This constituted the first biochemical evidence of the direct relationship between stathmin and an antimitotic drug, and revealed a new mechanism of action for VLB. The question remained if the observed interaction was specific for this drug or represented a general phenomenon for all MTAs. In the present study we investigated the binding of recombinant stathmin to purified tubulin in the presence of paclitaxel or another Vinca alkaloid, vinflunine, using Isothermal Titration Calorimetry (ITC). These experiments revealed that stathmin binding to tubulin is increased in the presence of vinflunine, whereas no signal is observed in the presence of paclitaxel. Further investigation using turbidity and co-sedimentation showed that stathmin inhibited paclitaxel microtubule-stabilizing activity. Taken together with the previous study using vinblastine, our results suggest that stathmin can be seen as a modulator of MTA activity and binding to tubulin, providing molecular explanation for multiple previous cellular and in vivo studies showing that stathmin expression level affects MTAs efficiency. PMID:26030092

  16. Possible Side Effects of 5-Fluorouracil, Oxaliplatin, Paclitaxel

    Cancer.gov

    Page of 2Possible Side Effects of 5-Fluorouracil, Oxaliplatin, Paclitaxel (Table Version Date: October 8, 2013) COMMON, SOME MAY BE SERIOUS In 100 people receiving 5-Fluorouracil, Oxaliplatin, Paclitaxel, more than 20 and up to 100 may have: Hair loss Redness,

  17. Possible Side Effects of Carboplatin, 5-Fluorouracil, and Paclitaxel

    Cancer.gov

    Page of 1Possible Side Effects of Carboplatin, 5-Fluorouracil, and Paclitaxel (Table Version Date: October 8, 2013) COMMON, SOME MAY BE SERIOUS In 100 people receiving Carboplatin, 5-Fluorouracil, and Paclitaxel, more than 20 and up to 100 may have: Hair

  18. Possible Side Effects of Cisplatin, 5-Fluorouracil, and Paclitaxel

    Cancer.gov

    Page of 1Possible Side Effects of Cisplatin, 5-Fluorouracil, and Paclitaxel (Table Version Date: October 8, 2013) COMMON, SOME MAY BE SERIOUS In 100 people receiving Cisplatin, 5-Fluorouracil, and Paclitaxel, more than 20 and up to 100 may have: Diarrhea,

  19. Possible Side Effects of Paclitaxel Protein-Bound Particles

    Cancer.gov

    Page of 1Possible Side Effects of Paclitaxel Protein-Bound Particles (Table Version Date: October 24, 2013) COMMON, SOME MAY BE SERIOUS In 100 people receiving Paclitaxel protein-bound particles, more than 20 and up to 100 may have: Anemia, which may

  20. Combinatorial influences of paclitaxel and strain on axonal transport.

    PubMed

    Bober, Brian G; Gutierrez, Edgar; Plaxe, Steven; Groisman, Alex; Shah, Sameer B

    2015-09-01

    Paclitaxel is an effective chemotherapeutic agent that, despite its common use, often causes peripheral sensory neuropathy. In neurons, paclitaxel binds to and stabilizes microtubules, and through unknown mechanisms, bundles microtubules and disrupts their organization. Because microtubules serve as tracks on which a variety of axonal cargoes are transported, a leading hypothesis for the etiology of paclitaxel-induced neuropathy is that these changes to microtubule organization impair axonal transport. In addition to supporting transport, microtubules also serve a structural role, accommodating axonal extension occurring during axonal growth or joint movement. In light of this dual role for microtubules, we tested the hypothesis that axonal stretch amplified the effects of paclitaxel on axonal transport. Embryonic rat dorsal root ganglia were cultured on stretchable silicone substrates, and parameters describing the axonal transport of three distinct cargoes--mitochondria, synaptophysin, and actin--were measured with and without paclitaxel treatment and axonal strain. Paclitaxel treatment, particularly in combination with stretch, led to severe perturbations in several transport parameters, including the number, velocity, and travel distance of cargoes in the axon. Our results suggest that mechanical loading of neurons can exacerbate transport deficits associated with paclitaxel treatment, raising the interesting possibility that paclitaxel influences neuronal function in a multi-factorial manner. PMID:26143110

  1. Development and Evaluation of Transferrin-Stabilized Paclitaxel Nanocrystal Formulation

    PubMed Central

    Lu, Ying; Wang, Zhao-hui; Li, Tonglei; McNally, Helen; Park, Kinam; Sturek, Michael

    2014-01-01

    The aim of the present study was to prepare and evaluate a paclitaxel nanocrystal-based formulation stabilized by serum protein transferrin in a non-covalent manner. The pure paclitaxel nanocrystals were first prepared using an antisolvent precipitation method augmented by sonication. The serum protein transferrin was selected for use after evaluating the stabilizing effect of several serum proteins including albumin and immunoglobulin G. The formulation contained approximately 55~60% drug and was stable for at least 3 months at 4 °C. In vivo antitumor efficacy studies using mice inoculated with KB cells demonstrate significantly higher tumor inhibition rate of 45.1% for paclitaxel-transferrin formulation compared to 28.8% for paclitaxel nanosuspension treatment alone. Interestingly, the Taxol® formulation showed higher antitumor activity than the paclitaxel-transferrin formulation, achieving a 93.3% tumor inhibition rate 12 days post initial dosing. However, the paclitaxel-transferrin formulation showed a lower level of toxicity, which is indicated by steady increase in body weight of mice over the treatment period. In comparison, treatment with Taxol® resulted in toxicity issues as body weight decreased. These results suggest the potential benefit of using a serum protein in a non-covalent manner in conjunction with paclitaxel nanocrystals as a promising drug delivery model for anticancer therapy. PMID:24378441

  2. [Study of bioavailability of paclitaxel after sublingual administration].

    PubMed

    Samsonia, M; Lesiovskaia, E; Ghibradze, O; Kandelaki, M

    2015-05-01

    The bioavailability of sublingual form of paclitaxel, developed in the pharmacology laboratory of pharmaceutical company - Legion "Provisus" is studied. Sublingual form of paclitaxel is an alcoholic solution of paclitaxel (1 mg/ml) with penetrator - dimethyl sulfoxide (DMSO) addition. Experiments were performed on 180 white mongrel male mice each of 25-30 g. The animals were divided into three groups. The first group served for control. 10 mg/kg of taxol was injected (once) in the lateral tail vein of the first group animals. A solution was prepared by diluting taxol with physiological sodium chloride solution until to a final concentration of paclitaxel to 1 mg/ml. The dose of 10 mg/kg (single dose) was applied under the tongue of the second group animals. Paclitaxel (substance) was extracted with dichloromethane - Taxol (by liquid-liquid extraction) for the manufacturing of a sublingual form. Unlike the second group, the third group animals took the same dose of sublingual form of paclitaxel orally (by gavage). The concentration of paclitaxel in plasma was studied by reversed-phase HPLC with spectrophotometric detection at ? = 227 nm by Woo JS et al. (2003) method. Bioavailability was determined by comparing the concentration of paclitaxel in blood after sublingual and intravenous use of Taxol (as an area under the curve of concentration versus time). It is established that the bioavailability of sublingual forms of paclitaxel was 42.4%, Cmax = 615 ± 73 ng × ml(-1) and tmax = 30-35 min. The value of the initial volume of distribution of paclitaxel (Vd = 3,14 ± 0,85 l × kg(-1)) also shows its intensive penetration to the organs and tissues. The half-life of the drug on the terminal segment of concentration-time curve was averaged 1,06 ± 0,21 h. The results create the preconditions for further preclinical study of sublingual form of paclitaxel, as the bioavailability of paclitaxel after sublingual application allows to have a systemic effect on the tumor process. PMID:26042449

  3. Paclitaxel-carboplatin induced radiation recall colitis.

    PubMed

    Kundak, Isil; Oztop, Ilhan; Soyturk, Mujde; Ozcan, Mehmet Ali; Yilmaz, Ugur; Meydan, Nezih; Gorken, Ilknur Bilkay; Kupelioglu, Ali; Alakavuklar, Mehmet

    2004-01-01

    Some chemotherapeutic agents can "recall" the irradiated volumes by skin or pulmonary reactions in cancer patients who previously received radiation therapy. We report a recall colitis following the administration of paclitaxel-containing regimen in a patient who had been irradiated for a carcinoma of the uterine cervix. A 63-year-old woman underwent a Wertheim operation because of uterine cervix carcinoma. After 8 years of follow-up, a local recurrence was observed and she received curative external radiotherapy (45 Gy) to the pelvis. No significant adverse events were observed during the radiotherapy. Approximately one year later, she was hospitalized because of metastatic disease with multiple pulmonary nodules, and a chemotherapy regimen consisting of paclitaxel and carboplatin was administered. The day after the administration of chemotherapy the patient had diarrhea and rectal bleeding. Histological examination of the biopsy taken from rectal hyperemic lesions showed a radiation colitis. The symptoms reappeared after the administration of each course of chemotherapy and continued until the death of the patient despite the interruption of the chemotherapy. In conclusion, the probability of recall phenomena should be kept in mind in patients who received previously with pelvic radiotherapy and treated later with cytotoxic chemotherapy. PMID:15237594

  4. Design, synthesis and applications of hyaluronic acid-paclitaxel bioconjugates.

    PubMed

    Leonelli, Francesca; La Bella, Angela; Migneco, Luisa Maria; Bettolo, Rinaldo Marini

    2008-01-01

    Paclitaxel (1a), a well known antitumor agent adopted mainly for the treatment of breast and ovarian cancer, suffers from significant disadvantages such as low solubility, certain toxicity and specific drug-resistance of some tumor cells. To overcome these problems extensive research has been carried out. Among the various proposed strategies, the conjugation of paclitaxel (1a) to a biocompatible polymer, such as hyaluronic acid (HA, 2), has also been considered. Coupling a bioactive compound to a biocompatible polymer offers, in general, many advantages such as better drug solubilization, better stabilization, specific localization and controlled release. Hereafter the design, synthesis and applications of hyaluronic acid-paclitaxel bioconjugates are reviewed. An overview of HA-paclitaxel combinations is also given. PMID:18305424

  5. Paclitaxel uptake and transport in Taxus cell suspension cultures

    PubMed Central

    Naill, Michael C.; Kolewe, Martin E.; Roberts, Susan C.

    2012-01-01

    The transport of paclitaxel in Taxus canadensis suspension cultures was studied with a fluorescence analogue of paclitaxel (Flutax-2®) in combination with flow cytometry detection. Experiments were carried out using both isolated protoplasts and aggregated suspension cell cultures. Flutax-2® was shown to be greater than 90% stable in Taxus suspension cultures over the required incubation time (24 hours). Unlabeled paclitaxel was shown to inhibit the cellular uptake of Flutax-2®, although structurally similar taxanes such as cephalomannine, baccatin III, and 10-deacetylbaccatin III did not inhibit Flutax-2® uptake. Saturation kinetics of Flutax-2® uptake was demonstrated. These results indicate the presence of a specific transport system for paclitaxel. Suspension cells elicited with methyl jasmonate accumulated 60% more Flutax-2® than unelicited cells, possibly due to an increased cellular storage capacity following methyl jasmonate elicitation. The presence of a specific mechanism for paclitaxel transport is an important first result that will provide the basis of more detailed studies as well as the development of targeted strategies for increased paclitaxel secretion to the extracellular medium. PMID:23180977

  6. Paclitaxel inhibits mRNA transport in axons.

    PubMed

    Bobylev, Ilja; Joshi, Abhijeet R; Barham, Mohammed; Ritter, Christian; Neiss, Wolfram F; Höke, Ahmet; Lehmann, Helmar C

    2015-10-01

    Paclitaxel is an integral component of solid tumor treatment. This chemotherapeutic agent provokes an often irreversible peripheral sensory neuropathy with pathological features of distal axonal degeneration. Current pathological concepts assume that polymerization of axonal microtubules and mitochondrial dysfunction contributes to the development of paclitaxel-induced peripheral neuropathy. The relationship, however, between microtubule stabilization, mitotoxicity and axonal degeneration is still not completely understood. To explore the function of axonal mitochondria we treated transgenic mice that harbor cyan fluorescent protein (CFP)-labeled neuronal mitochondria with repeated doses of paclitaxel and assessed neuropathic changes by nerve conduction and histological studies. In addition, mitochondrial content and morphology was determined by ex vivo imaging of axons containing CFP-labeled mitochondria. Using quantitative RT-PCR and fluorescence-labeled mRNA we determined axonal mRNA transport of nuclear encoded mitochondrial proteins. Prolonged treatment with high doses of paclitaxel-induced a predominant sensory neuropathy in mice. Although mitochondrial velocity in axons per se was not altered, we observed significant changes in mitochondrial morphology, suggesting that paclitaxel treatment impairs the dynamics of axonal mitochondria. These changes were caused by decreased levels of nuclear encoded mRNA, including the mitochondrial fusion/fission machinery. Moreover, impaired axonal mRNA transport in vitro resulted in mitochondrial dysfunction and subsequent axonal degeneration. Taken together, our experiments provide evidence that disrupted axonal transport of nuclear derived mRNA plays a crucial role in the pathogenesis of paclitaxel-induced sensory neuropathy. PMID:26188177

  7. Albumin-Bound Paclitaxel: A Review in Non-Small Cell Lung Cancer.

    PubMed

    Blair, Hannah A; Deeks, Emma D

    2015-11-01

    Nanoparticle albumin-bound paclitaxel (Abraxane(®)) [hereafter referred to as nab-paclitaxel] is a taxane developed to avoid some of the toxicities associated with solvent-bound (sb) paclitaxel. Nab-paclitaxel, in combination with carboplatin, is indicated for the first-line treatment of non-small cell lung cancer (NSCLC) in patients who are not candidates for curative surgery and/or radiation therapy. This article summarizes pharmacological, efficacy and tolerability data relevant to the use of nab-paclitaxel in this indication. Compared with sb-paclitaxel plus carboplatin, nab-paclitaxel plus carboplatin significantly improved the objective response rate (ORR), but did not prolong progression-free survival or overall survival (OS), in the overall population of patients with advanced NSCLC in a multinational phase III trial. The nab-paclitaxel regimen also provided benefit over the sb-paclitaxel regimen in certain patient subgroups, including patients with squamous cell histology (in terms of ORR) and patients who were elderly (in terms of OS). Nab-paclitaxel plus carboplatin had a manageable tolerability profile with some benefits over sb-paclitaxel plus carboplatin, including lower rates of grade ?3 neutropenia, peripheral neuropathy, arthralgia and myalgia, although was associated with more grade ?3 anaemia and thrombocytopenia. Given its efficacy and tolerability, intravenous nab-paclitaxel plus carboplatin is a valuable first-line treatment option for patients with advanced NSCLC. PMID:26541764

  8. Lipophilic prodrug of paclitaxel: interaction with a dimyristoylphosphatidylcholine monolayer.

    PubMed

    Giuffrida, Maria Chiara; Dosio, Franco; Castelli, Francesco; Sarpietro, Maria Grazia

    2014-11-20

    Interactions between paclitaxel and its squalenoyl prodrug with dimyristoylphosphatidylcholine (DMPC) monolayer at the air/water interface were studied. Paclitaxel is an antineoplastic drug, largely used as anti-cancer agents. Because its low aqueous solubility, Cremophor EL is used as excipient for its formulation. However, it has been shown that Cremophor causes serious side effects. Several attempts have been made to develop a safer formulation such as the synthesis of lipophilic prodrug. In particular we have synthesized a paclitaxel prodrug obtained by conjugation with 1,1,2-trisnorsqualenoic acid to improve the physico-chemical properties of this antineoplastic drug. The miscibility of these compounds with DMPC monolayer were studied analyzing thermodynamic properties as well as excess Gibbs free energies, compressibility modulus and mixed monolayer isotherms. The results allowed to evaluate the spatial organization of the compounds and suggested that the prodrug can efficiently be incorporated in the DMPC monolayer. PMID:25234865

  9. Paclitaxel Enhances Carboplatin-DNA Adduct Formation and Cytotoxicity.

    PubMed

    Jiang, Shuai; Pan, Amy W; Lin, Tzu-Yin; Zhang, Hongyong; Malfatti, Michael; Turteltaub, Kenneth; Henderson, Paul T; Pan, Chong-Xian

    2015-12-21

    This rapid report focuses on the pharmacodynamic mechanism of the carboplatin/paclitaxel combination and correlates it with its cytotoxicity. Consistent with the synergistic to additive antitumor activity (the combination index ranging from 0.53 to 0.94), cells exposed to this combination had significantly increased carboplatin-DNA adduct formation when compared to that of carboplatin alone (450 ± 30 versus 320 ± 120 adducts per 10(8) nucleotides at 2 h, p = 0.004). Removal of paclitaxel increased the repair of carboplatin-DNA adducts: 39.4 versus 33.1 adducts per 10(8) nucleotides per hour in carboplatin alone (p = 0.021). This rapid report provides the first pharmacodynamics data to support the use of carboplatin/paclitaxel combination in the clinic. PMID:26544157

  10. Self-Assembled Poly(butadiene)-b-Poly(ethylene oxide) Polymersomes as Paclitaxel Carriers

    PubMed Central

    Li, Shuliang; Byrne, Belinda; Welsh, JoEllen; Palmer, Andre F.

    2008-01-01

    In this work, self-assembled poly(butadiene)-b-poly(ethylene oxide) (PB-PEO) polymersomes (polymer vesicles) and worm micelles were evaluated as paclitaxel carriers. Paclitaxel was successfully incorporated into PB-PEO polymersomes and worm micelles. The loading capacity of paclitaxel inside PB-PEO colloids ranged from 6.7-13.7% w/w, depending on the morphology of copolymer colloids and the molecular weight of diblock copolymer. Paclitaxel loaded OB4 (PB219-PEO121) polymersome formulations were colloidally stable for 4 months at 4 °C, and exhibited slow steady release of paclitaxel over a 5 week period at 37 °C. Evaluation of the in vitro cytotoxicity of paclitaxel-polymersome formulations showed that the ability of paclitaxel-loaded polymersomes to inhibit proliferation of MCF-7 human breast cancer cells was less compared to paclitaxel alone. By increasing the concentration of paclitaxel in polymersomes from 0.02 ?g/mL to 0.2 ?g/mL, paclitaxel-polymersome formulations showed comparable activity in inhibiting the growth of MCF-7 cells. Taken together, these results demonstrate that paclitaxel-polymersomes have desirable restrained release profile and exhibit long-term stability. PMID:17269699

  11. Sunitinib Plus Paclitaxel Versus Bevacizumab Plus Paclitaxel for First-Line Treatment of Patients With Advanced Breast Cancer: A Phase III, Randomized, Open-Label Trial

    PubMed Central

    Robert, Nicholas J.; Saleh, Mansoor N.; Paul, Devchand; Generali, Daniele; Gressot, Laurent; Copur, Mehmet S.; Brufsky, Adam M.; Minton, Susan E.; Giguere, Jeffrey K.; Smith, John W.; Richards, Paul D.; Gernhardt, Diana; Huang, Xin; Liau, Katherine F.; Kern, Kenneth A.; Davis, John

    2015-01-01

    Introduction A multicenter, open-label phase III study was conducted to test whether sunitinib plus paclitaxel prolongs progression-free survival (PFS) compared with bevacizumab plus paclitaxel as first-line treatment for patients with HER2? advanced breast cancer. Patients and Methods Patients with HER2? advanced breast cancer who were disease free for ? 12 months after adjuvant taxane treatment were randomized (1:1; planned enrollment 740 patients) to receive intravenous (I.V.) paclitaxel 90 mg/m2 every week for 3 weeks in 4-week cycles plus either sunitinib 25 to 37.5 mg every day or bevacizumab 10 mg/kg I.V. every 2 weeks. Results The trial was terminated early because of futility in reaching the primary endpoint as determined by the independent data monitoring committee during an interim futility analysis. At data cutoff, 242 patients had been randomized to sunitinib-paclitaxel and 243 patients to bevacizumab-paclitaxel. Median PFS was shorter with sunitinib-paclitaxel (7.4 vs. 9.2 months; hazard ratio [HR] 1.63 [95% confidence interval (CI), 1.18–2.25]; 1-sided P = .999). At a median follow-up of 8.1 months, with 79% of sunitinib-paclitaxel and 87% of bevacizumab-paclitaxel patients alive, overall survival analysis favored bevacizumab-paclitaxel (HR 1.82 [95% CI, 1.16–2.86]; 1-sided P = .996). The objective response rate was 32% in both arms, but median duration of response was shorter with sunitinib-paclitaxel (6.3 vs. 14.8 months). Bevacizumab-paclitaxel was better tolerated than sunitinib-paclitaxel. This was primarily due to a high frequency of grade 3/4, treatment-related neutropenia with sunitinib-paclitaxel (52%) precluding delivery of the prescribed doses of both drugs. Conclusion The sunitinib-paclitaxel regimen evaluated in this study was clinically inferior to the bevacizumab-paclitaxel regimen and is not a recommended treatment option for patients with advanced breast cancer. PMID:21569994

  12. Formulation and pharmacokinetic evaluation of a paclitaxel nanosuspension for intravenous delivery

    PubMed Central

    Wang, Yonglu; Li, Xueming; Wang, Liyao; Xu, Yuanlong; Cheng, Xiaodan; Wei, Ping

    2011-01-01

    Paclitaxel is a diterpenoid isolated from Taxus brevifolia. It is effective for various cancers, especially ovarian and breast cancer. Due to its aqueous insolubility, it is administered dissolved in ethanol and Cremophor® EL (BASF, Ludwigshafen, Germany), which can cause serious allergic reactions. In order to eliminate Cremophor EL, paclitaxel was formulated as a nanosuspension by high-pressure homogenization. The nanosuspension was lyophilized to obtain the dry paclitaxel nanoparticles (average size, 214.4 ± 15.03 nm), which enhanced both the physical and chemical stability of paclitaxel nanoparticles. Paclitaxel dissolution was also enhanced by the nanosuspension. Differential scanning calorimetry showed that the crystallinity of paclitaxel was preserved during the high-pressure homogenization process. The pharmacokinetics and tissue distribution of paclitaxel were compared after intravenous administration of paclitaxel nanosuspension and paclitaxel injection. In rat plasma, paclitaxel nanosuspension exhibited a significantly (P < 0.01) reduced area under the concentration curve (AUC)0–? (20.343 ± 9.119 ?g · h · mL?1 vs 5.196 ± 1.426 ?g · h · mL?1), greater clearance (2.050 ± 0.616 L · kg?1 · h?1 vs 0.556 ± 0.190 L · kg?1 · h?1), and shorter elimination half-life (5.646 ± 2.941 vs 3.774 ± 1.352 hours) compared with the paclitaxel solution. In contrast, the paclitaxel nanosuspension resulted in a significantly greater AUC0–? in liver, lung, and spleen (all P < 0.01), but not in heart or kidney. PMID:21796250

  13. Paclitaxel-induced peripheral neuropathy increases substance P release in rat spinal cord.

    PubMed

    Chiba, Terumasa; Oka, Yusuke; Kambe, Toshie; Koizumi, Naoya; Abe, Kenji; Kawakami, Kazuyoshi; Utsunomiya, Iku; Taguchi, Kyoji

    2016-01-01

    Peripheral neuropathy is a common adverse effect of paclitaxel treatment. The major dose-limiting side effect of paclitaxel is peripheral sensory neuropathy, which is characterized by painful paresthesia of the hands and feet. To analyze the contribution of substance P to the development of paclitaxel-induced mechanical hyperalgesia, substance P expression in the superficial layers of the rat spinal dorsal horn was analyzed after paclitaxel treatment. Behavioral assessment using the von Frey test and the paw thermal test showed that intraperitoneal administration of 2 and 4mg/kg paclitaxel induced mechanical allodynia/hyperalgesia and thermal hyperalgesia 7 and 14 days after treatment. Immunohistochemistry showed that paclitaxel (4mg/kg) treatment significantly increased substance P expression (37.6±3.7% on day 7, 43.6±4.6% on day 14) in the superficial layers of the spinal dorsal horn, whereas calcitonin gene-related peptide (CGRP) expression was unchanged. Moreover, paclitaxel (2 and 4mg/kg) treatment significantly increased substance P release in the spinal cord on day 14. These results suggest that paclitaxel treatment increases release of substance P, but not CGRP in the superficial layers of the spinal dorsal horn and may contribute to paclitaxel-induced painful peripheral neuropathy. PMID:26658369

  14. Label-free detection of anticancer drug paclitaxel in living cells by confocal Raman microscopy

    NASA Astrophysics Data System (ADS)

    Salehi, H.; Derely, L.; Vegh, A.-G.; Durand, J.-C.; Gergely, C.; Larroque, C.; Fauroux, M.-A.; Cuisinier, F. J. G.

    2013-03-01

    Confocal Raman microscopy, a non-invasive, label-free, and high spatial resolution imaging technique is employed to trace the anticancer drug paclitaxel in living Michigan Cancer Foundation-7 (MCF-7) cells. The Raman images were treated by K-mean cluster analysis to detect the drug in cells. Distribution of paclitaxel in cells is verified by calculating the correlation coefficient between the reference spectrum of the drug and the whole Raman image spectra. A time dependent gradual diffusion of paclitaxel all over the cell is observed suggesting a complementary picture of the pharmaceutical action of this drug based on rapid binding of free tubulin to crystallized paclitaxel.

  15. Paclitaxel stimulates chromosomal fusion and instability in cells with dysfunctional telomeres: Implication in multinucleation and chemosensitization

    SciTech Connect

    Park, Jeong-Eun; Woo, Seon Rang; Department of Biochemistry, College of Medicine, Korea University, Seoul 136-705 ; Kang, Chang-Mo; Juhn, Kyoung-Mi; Ju, Yeun-Jin; Shin, Hyun-Jin; Joo, Hyun-Yoo; Park, Eun Ran; Park, In-chul; Hong, Sung Hee; Hwang, Sang-Gu; Lee, Jung-Kee; Kim, Hae Kwon; Cho, Myung-Haing; Park, Gil Hong; Lee, Kee-Ho

    2011-01-14

    Research highlights: {yields} Paclitaxel serves as a stimulator of chromosomal fusion in cells in which telomeres are dysfunctional. {yields} Typical fusions involve p-arms, but paclitaxel-induced fusions occur between both q- and p-arms. {yields} Paclitaxel-stimulated fusions in cells in which telomeres are dysfunctional evoke prolonged G2/M cell cycle arrest and delay multinucleation. {yields} Upon telomere erosion, paclitaxel promotes chromosomal instability and subsequent apoptosis. {yields} Chromosomal fusion enhances paclitaxel chemosensitivity under telomere dysfunction. -- Abstract: The anticancer effect of paclitaxel is attributable principally to irreversible promotion of microtubule stabilization and is hampered upon development of chemoresistance by tumor cells. Telomere shortening, and eventual telomere erosion, evoke chromosomal instability, resulting in particular cellular responses. Using telomerase-deficient cells derived from mTREC-/-p53-/- mice, here we show that, upon telomere erosion, paclitaxel propagates chromosomal instability by stimulating chromosomal end-to-end fusions and delaying the development of multinucleation. The end-to-end fusions involve both the p- and q-arms in cells in which telomeres are dysfunctional. Paclitaxel-induced chromosomal fusions were accompanied by prolonged G2/M cell cycle arrest, delayed multinucleation, and apoptosis. Telomere dysfunctional cells with mutlinucleation eventually underwent apoptosis. Thus, as telomere erosion proceeds, paclitaxel stimulates chromosomal fusion and instability, and both apoptosis and chemosensitization eventually develop.

  16. Paclitaxel-coated balloons and aneurysm formation in peripheral vessels.

    PubMed

    Diamantopoulos, Athanasios; Gupta, Yuri; Zayed, Hany; Katsanos, Konstantinos

    2015-11-01

    We report two cases of early aneurysmal vessel dilatation after a paclitaxel-coated balloon (PCB) was used for angioplasty of the peripheral vessels. The first case refers to a failing vein bypass with a tight proximal anastomotic stenosis, whereas the second refers to a distal tibial artery occlusion. A PCB was used to treat both patients. Aneurysmal dilatation of the previously treated segment was noted in both patients during subsequent follow-up imaging. In the absence of other causal factors, we attribute both cases to PCB application. The aneurysms that formed had no detrimental effect on the patients' health and required no further treatment; however, it is important to bear in mind this potential risk of presumed paclitaxel toxicity. PMID:24801552

  17. PEGylated Nanoparticles Obtained through Emulsion Polymerization as Paclitaxel Carriers.

    PubMed

    Colombo, Claudio; Morosi, Lavinia; Bello, Ezia; Ferrari, Raffaele; Licandro, Simonetta Andrea; Lupi, Monica; Ubezio, Paolo; Morbidelli, Massimo; Zucchetti, Massimo; D'Incalci, Maurizio; Moscatelli, Davide; Frapolli, Roberta

    2016-01-01

    Polymer nanoparticles (NPs) represent a promising way to deliver poorly water-soluble anticancer drugs without the use of unwanted excipients, whose presence can be the cause of severe side effects. In this work, a Cremophor-free formulation for paclitaxel (PTX) has been developed by employing PEGylated polymer nanoparticles (NPs) as drug delivery carriers based on modified poly(?-caprolactone) macromonomers and synthesized through free radical emulsion polymerization. Paclitaxel was loaded in the NPs in a postsynthesis process which allowed to obtain a drug concentration suitable for in vivo use. In vivo experiments on drug biodistribution and therapeutic efficacy show comparable behavior between the NPs and the Cremophor formulation, also showing good tolerability of the new formulation proposed. PMID:26623665

  18. CYP3A4*22 genotype and systemic exposure affect paclitaxel-induced neurotoxicity

    PubMed Central

    de Graan, Anne-Joy M.; Elens, Laure; Sprowl, Jason A.; Sparreboom, Alex; Friberg, Lena E.; van der Holt, Bronno; de Raaf, Pleun J.; de Bruijn, Peter; Engels, Frederike K.; Eskens, Ferry A.L.M.; Wiemer, Erik A.C.; Verweij, Jaap; Mathijssen, Ron H.J.; van Schaik, Ron H.N.

    2013-01-01

    PURPOSE Paclitaxel is used for the treatment of several solid tumors and displays a high inter-individual variation in exposure and toxicity. Neurotoxicity is one of the most prominent side-effects of paclitaxel. This study explores potential predictive pharmacokinetic and pharmacogenetic determinants for the onset and severity of neurotoxicity. EXPERIMENTAL DESIGN In an exploratory cohort of patients (n=261) treated with paclitaxel, neurotoxicity incidence and severity, pharmacokinetic parameters and pharmacogenetic variants were determined. Paclitaxel plasma concentrations were measured by HPLC or LC-MS/MS, and individual pharmacokinetic parameters were estimated from previously developed population pharmacokinetic models by non-linear mixed effects modeling (NONMEM). Genetic variants of paclitaxel pharmacokinetics tested were CYP3A4*22, CYP2C8*3, CYP2C8*4, and ABCB1 3435 C>T. The association between CYP3A4*22 and neurotoxicity observed in the exploratory cohort was validated in an independent patient cohort (n=239). RESULTS Exposure to paclitaxel (logAUC) was correlated with severity of neurotoxicity (P <0.00001). Female CYP3A4*22 carriers were at increased risk of developing neurotoxicity (P = 0.043) in the exploratory cohort. CYP3A4*22 carrier status itself was not associated with pharmacokinetic parameters (CL, AUC, Cmax, or T>0.05) of paclitaxel in males or females. Other genetic variants displayed no association with neurotoxicity. In the subsequent independent validation cohort, CYP3A4*22 carriers were at risk of developing grade 3 neurotoxicity (odds ratio = 19.1; P = 0.001). CONCLUSIONS Paclitaxel exposure showed a relationship with the severity of paclitaxel-induced neurotoxicity. In this study, female CYP3A4*22 carriers had increased risk of developing severe neurotoxicity during paclitaxel therapy. These observations may guide future individualization of paclitaxel treatment. PMID:23640974

  19. Effect of paclitaxel (TAXOL) alone and in combination with radiation on the gastrointestinal mucosa

    SciTech Connect

    Mason, K.A.; Milas, L.; Peters, L.J.

    1995-07-30

    Paclitaxel is a potentially useful drug for augmenting the cytotoxic action of radiotherapy because it has independent cytotoxic activity against certain cancers and blocks cells in the radiosensitive mitotic phase of the cell cycle. However, all rapidly proliferating tissues, both normal and neoplastic, may be affected by this therapeutic strategy. The aim of this study was to define the in vivo response of rapidly dividing cells of the small bowel mucosa in mice to paclitaxel given alone and in combination with radiation. Paclitaxel blocked jejunal crypt cells in mitosis and induced apoptosis in a dose-dependent manner. Fractionating the paclitaxel dose over 1-4 days did not result in any greater accumulation of mitotically blocked cells than did a single dose. Mitosis peaked 2-4 h after paclitaxel and returned to near normal by 24 h. Apoptosis lagged several hours behind mitosis and peaked about 6 h later than mitosis. Despite these kinetic perturbations, there was little or no enhancement of radiation effect when single doses were delivered 2-4 h after paclitaxel administration. The maximum sensitizer enhancement ratio of 1.07 observed after a single paclitaxel dose of 40 mg/kg is consistent with independent crypt cell killing. Conversely, when radiation was given 24 h after paclitaxel, a significant protective effect of the drug (SER 0.89-0.92), most probably due to a regenerative overshoot induced by paclitaxel, was observed. Stem cells of the jejunal mucosa determining radiation response were not radiosensitized by paclitaxel with the drug concentrations and dose deliver schedules used, although additive cytotoxicity was observed with the highest drug dose. A radioprotective effect was observed when radiation was given 24 h after paclitaxel administration. 33 refs., 4 figs., 3 tabs.

  20. Paclitaxel Induces Apoptosis in Breast Cancer Cells through Different Calcium—Regulating Mechanisms Depending on External Calcium Conditions

    PubMed Central

    Pan, Zhi; Avila, Andrew; Gollahon, Lauren

    2014-01-01

    Previously, we reported that endoplasmic reticulum calcium stores were a direct target for paclitaxel initiation of apoptosis. Furthermore, the actions of paclitaxel attenuated Bcl-2 resistance to apoptosis through endoplasmic reticulum-mediated calcium release. To better understand the calcium-regulated mechanisms of paclitaxel-induced apoptosis in breast cancer cells, we investigated the role of extracellular calcium, specifically; whether influx of extracellular calcium contributed to and/or was necessary for paclitaxel-induced apoptosis. Our results demonstrated that paclitaxel induced extracellular calcium influx. This mobilization of extracellular calcium contributed to subsequent cytosolic calcium elevation differently, depending on dosage. Under normal extracellular calcium conditions, high dose paclitaxel induced apoptosis-promoting calcium influx, which did not occur in calcium-free conditions. In the absence of extracellular calcium an “Enhanced Calcium Efflux” mechanism in which high dose paclitaxel stimulated calcium efflux immediately, leading to dramatic cytosolic calcium decrease, was observed. In the absence of extracellular calcium, high dose paclitaxel’s stimulatory effects on capacitative calcium entry and apoptosis could not be completely restored. Thus, normal extracellular calcium concentrations are critical for high dose paclitaxel-induced apoptosis. In contrast, low dose paclitaxel mirrored controls, indicating that it occurs independent of extracellular calcium. Thus, extracellular calcium conditions only affect efficacy of high dose paclitaxel-induced apoptosis. PMID:24549172

  1. A tubulin-based fluorescent polarization assay for paclitaxel Sergi Morais,a

    E-print Network

    Chen, Wilfred

    A tubulin-based fluorescent polarization assay for paclitaxel Sergi Morais,a Sean OÕMalley on the binding interaction of paclitaxel to tubulin, the re- ceptor protein on which this drug acts. The bioassay (Rh-Tx) competed for tubulin binding, causing a change in fluorescence polarization, which

  2. Tumor-selective peptide-carrier delivery of Paclitaxel increases in vivo activity of the drug

    PubMed Central

    Brunetti, Jlenia; Pillozzi, Serena; Falciani, Chiara; Depau, Lorenzo; Tenori, Eleonora; Scali, Silvia; Lozzi, Luisa; Pini, Alessandro; Arcangeli, Annarosa; Menichetti, Stefano; Bracci, Luisa

    2015-01-01

    Taxanes are highly effective chemotherapeutic drugs against proliferating cancer and an established option in the standard treatment of ovarian and breast cancer. However, treatment with paclitaxel is associated with severe side effects, including sensory axonal neuropathy, and its poor solubility in water complicates its formulation. In this paper we report the in vitro and in vivo activity of a new form of paclitaxel, modified for conjugation with a tumor-selective tetrabranched peptide carrier (NT4). NT4 selectively targets tumor cells by binding to membrane sulfated glycosaminoglycans (GAG) and to endocytic receptors, like LRP1 and LRP6, which are established tumor markers. Biological activity of NT4-paclitaxel was tested in vitro on MDA-MB 231 and SKOV-3 cell lines, representing breast and ovarian cancer, respectively, and in vivo in an orthotopic mouse model of human breast cancer. Using in vivo bioluminescence imaging, we found that conjugation of paclitaxel with the NT4 peptide led to increased therapeutic activity of the drug in vivo. NT4-paclitaxel induced tumor regression, whereas treatment with unconjugated paclitaxel only produced a reduction in tumor growth. Moreover, unlike paclitaxel, NT4-paclitaxel is very hydrophilic, which may improve its pharmacokinetic profile and allow the use of less toxic dilution buffers, further decreasing its general chemotherapic toxicity. PMID:26626158

  3. Tumor-selective peptide-carrier delivery of Paclitaxel increases in vivo activity of the drug.

    PubMed

    Brunetti, Jlenia; Pillozzi, Serena; Falciani, Chiara; Depau, Lorenzo; Tenori, Eleonora; Scali, Silvia; Lozzi, Luisa; Pini, Alessandro; Arcangeli, Annarosa; Menichetti, Stefano; Bracci, Luisa

    2015-01-01

    Taxanes are highly effective chemotherapeutic drugs against proliferating cancer and an established option in the standard treatment of ovarian and breast cancer. However, treatment with paclitaxel is associated with severe side effects, including sensory axonal neuropathy, and its poor solubility in water complicates its formulation. In this paper we report the in vitro and in vivo activity of a new form of paclitaxel, modified for conjugation with a tumor-selective tetrabranched peptide carrier (NT4). NT4 selectively targets tumor cells by binding to membrane sulfated glycosaminoglycans (GAG) and to endocytic receptors, like LRP1 and LRP6, which are established tumor markers. Biological activity of NT4-paclitaxel was tested in vitro on MDA-MB 231 and SKOV-3 cell lines, representing breast and ovarian cancer, respectively, and in vivo in an orthotopic mouse model of human breast cancer. Using in vivo bioluminescence imaging, we found that conjugation of paclitaxel with the NT4 peptide led to increased therapeutic activity of the drug in vivo. NT4-paclitaxel induced tumor regression, whereas treatment with unconjugated paclitaxel only produced a reduction in tumor growth. Moreover, unlike paclitaxel, NT4-paclitaxel is very hydrophilic, which may improve its pharmacokinetic profile and allow the use of less toxic dilution buffers, further decreasing its general chemotherapic toxicity. PMID:26626158

  4. Restoration of paclitaxel resistance by CDK1 intervention in drug-resistant ovarian cancer.

    PubMed

    Bae, Taejeong; Weon, Kwon-Yeon; Lee, Jeong-Won; Eum, Ki-Hwan; Kim, Sungchul; Choi, Jin Woo

    2015-12-01

    Epithelial ovarian cancer (EOC) commonly acquires resistance to chemotherapy, and this is the major obstacle to the better prognosis. Elucidating the molecular targets altered by chemotherapy is critically required to understand and overcome drug resistance. As a drug combination including paclitaxel is a prevalent prescription for treatment of EOC, to uncover gene expression altered in paclitaxel-resistant EOC, we analyzed multidirectional microarray profiles in both EOC cell lines and patients with paclitaxel resistance. Cyclin-dependent kinase 1 (CDK1) was found to be a potential target of transcription factors to regulate paclitaxel resistance. As a result of the subsequent pharmacogenomics analysis, CDK1 inhibitor alsterpaullone was also indicated as a promising chemical that may be used in combinatorial therapies to reverse paclitaxel-induced chemoresistance. Although a CDK1 inhibitor has the potential to kill cancer cells, short-term treatment over 2 weeks at sublethal doses effectively induced cell death only upon additional treatment with paclitaxel. A prominent reduction in the tumor growth rate was observed upon paclitaxel subsequent to alsterpaullone treatment in EOC xenograft model. Thus, we suggest that inhibition of CDK1 with alsterpaullone may be a novel therapeutic method to reverse paclitaxel-induced resistance in ovarian cancer cells. PMID:26442525

  5. Paclitaxel Drug-Eluting Stents in Peripheral Arterial Disease: A Health Technology Assessment

    PubMed Central

    2015-01-01

    Background Peripheral arterial disease is a condition in which atherosclerotic plaques partially or completely block blood flow to the legs. Although percutaneous transluminal angioplasty and metallic stenting have high immediate success rates in treating peripheral arterial disease, long-term patency and restenosis rates in long and complex lesions remain unsatisfactory. Objective The objective of this analysis was to evaluate the clinical effectiveness, safety, cost-effectiveness and budget impact of Zilver paclitaxel self-expanding drug-eluting stents for the treatment of de novo or restenotic lesions in above-the-knee peripheral arterial disease. Data Sources Literature searches were performed using Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid Embase, EBSCO Cumulative Index to Nursing & Allied Health Literature (CINAHL), and EBM Reviews. For the economic review, a search filter was applied to limit search results to economics-related literature. Data sources for the budget impact analysis included expert opinion, published literature, and Ontario administrative data. Review Methods Systematic reviews, meta-analyses, randomized controlled trials, and observational studies were included in the clinical effectiveness review, and full economic evaluations were included in the economic literature review. Studies were included if they examined the effect of Zilver paclitaxel drug-eluting stents in de novo or restenotic lesions in above-the-knee arteries. For the budget impact analysis, 3 scenarios were constructed based on different assumptions. Results One randomized controlled trial reported a significantly higher patency rate with Zilver paclitaxel drug-eluting stents for lesions ? 14 cm than with angioplasty or bare metal stents. One observational study showed no difference in patency rates between Zilver paclitaxel drug-eluting stents and paclitaxel drug-coated balloons. Zilver paclitaxel drug-eluting stents were associated with a significantly higher event-free survival rate than angioplasty, but the event-free survival rate was similar for Zilver paclitaxel drug-eluting stents and paclitaxel drug-coated balloons. No economic evaluations compared Zilver paclitaxel drug-eluting stents with bare metal stents or angioplasty for peripheral arterial disease. A budget impact analysis showed that the cost savings associated with funding of Zilver paclitaxel drug-eluting stents would be $470,000 to $640,000 per year, assuming that the use of the Zilver paclitaxel drug-eluting stent was associated with a lower risk of subsequent revascularization. Conclusions Based on evidence of low to moderate quality, Zilver paclitaxel drug-eluting stents were associated with a higher patency rate than angioplasty or bare metal stents, and with fewer adverse events than angioplasty. The effectiveness and safety of Zilver paclitaxel drug-eluting stents and paclitaxel drug-coated balloons were similar. PMID:26719778

  6. Development of an oral solid dispersion formulation for use in low-dose metronomic chemotherapy of paclitaxel.

    PubMed

    Moes, Johannes; Koolen, Stijn; Huitema, Alwin; Schellens, Jan; Beijnen, Jos; Nuijen, Bastiaan

    2013-01-01

    For the clinical development of low-dose metronomic (LDM) chemotherapy of paclitaxel, oral administration is vital. However, the development of an oral formulation is difficult due to paclitaxel's low oral bioavailability, caused by its low permeability and low solubility. We increased the oral bioavailability of paclitaxel by combining a pharmacokinetic booster, ritonavir, with a new oral solid dispersion formulation of paclitaxel. The combined use of Hansen solubility parameters and dissolution experiments resulted in the development of a solid dispersion formulation containing 1/11 w/w paclitaxel, 9/11 w/w polyvinylpyrrolidone (PVP) K30, and 1/11 w/w sodium lauryl sulfate (SLS). Analysis of the solid dispersion formulation by X-ray diffraction, Fourier transform infrared (FT-IR) spectroscopy, and modulated differential scanning calorimetry (mDSC) confirmed the amorphous nature of paclitaxel and the fine dispersion of paclitaxel in the matrix of PVP-K30 and SLS. Furthermore, in vitro tests showed a major increase in the apparent solubility and dissolution rate of paclitaxel. To test the clinical significance of these findings, the solid dispersion formulation of paclitaxel (ModraPac001 10mg capsule) was compared to the paclitaxel premix solution in four patients with advanced cancer. Although the mean systemic exposure to paclitaxel after oral administration of the solid dispersion formulation was slightly lower compared to the paclitaxel premix solution (190±63.1ng/mLh for vs. 247±100ng/mLh), the systemic exposure to paclitaxel is clinically relevant [1,2]. In addition to this, the favorable pharmaceutical characteristics, for example, neutral taste, dosing accuracy, and the 2-year ambient shelf life, make the ModraPac001 10mg capsule an attractive candidate for oral paclitaxel chemotherapy. Currently, the ModraPac001 formulation is applied in the first clinical trial with oral LDM chemotherapy of paclitaxel. PMID:23085332

  7. Pharmacological Modulation of the Mitochondrial Electron Transport Chain in Paclitaxel-Induced Painful Peripheral Neuropathy

    PubMed Central

    Griffiths, Lisa A.; Flatters, Sarah J.L.

    2015-01-01

    Paclitaxel is an effective first-line chemotherapeutic with the major dose-limiting side effect of painful neuropathy. Mitochondrial dysfunction and oxidative stress have been implicated in paclitaxel-induced painful neuropathy. Here we show the effects of pharmacological modulation of mitochondrial sites that produce reactive oxygen species using systemic rotenone (complex I inhibitor) or antimycin A (complex III inhibitor) on the maintenance and development of paclitaxel-induced mechanical hypersensitivity in adult male Sprague Dawley rats. The maximally tolerated dose (5 mg/kg) of rotenone inhibited established paclitaxel-induced mechanical hypersensitivity. However, some of these inhibitory effects coincided with decreased motor coordination; 3 mg/kg rotenone also significantly attenuated established paclitaxel-induced mechanical hypersensitivity without any motor impairment. The maximally tolerated dose (.6 mg/kg) of antimycin A reversed established paclitaxel-induced mechanical hypersensitivity without any motor impairment. Seven daily doses of systemic rotenone or antimycin A were given either after paclitaxel administration or before and during paclitaxel administration. Rotenone had no significant effect on the development of paclitaxel-induced mechanical hypersensitivity. However, antimycin A significantly inhibited the development of paclitaxel-induced mechanical hypersensitivity when given before and during paclitaxel administration but had no effect when given after paclitaxel administration. These studies provide further evidence of paclitaxel-evoked mitochondrial dysfunction in vivo, suggesting that complex III activity is instrumental in paclitaxel-induced pain. Perspective This study provides further in vivo evidence that mitochondrial dysfunction is a key contributor to the development and maintenance of chemotherapy-induced painful neuropathy. This work also indicates that selective modulation of the electron transport chain can induce antinociceptive effects in a preclinical model of paclitaxel-induced pain. PMID:26142652

  8. In vitro and in vivo targeting effect of folate decorated paclitaxel loaded PLA–TPGS nanoparticles

    PubMed Central

    Thu, Ha Phuong; Nam, Nguyen Hoai; Quang, Bui Thuc; Son, Ho Anh; Toan, Nguyen Linh; Quang, Duong Tuan

    2015-01-01

    Paclitaxel is one of the most effective chemotherapeutic agents for treating various types of cancer. However, the clinical application of paclitaxel in cancer treatment is considerably limited due to its poor water solubility and low therapeutic index. Thus, it requires an urgent solution to improve therapeutic efficacy of paclitaxel. In this study, folate decorated paclitaxel loaded PLA–TPGS nanoparticles were prepared by a modified emulsification/solvent evaporation method. The obtained nanoparticles were characterized by Field Emission Scanning Electron Microscopy (FESEM), Fourier Transform Infrared (FTIR) and Dynamic Light Scattering (DLS) method. The spherical nanoparticles were around 50 nm in size with a narrow size distribution. Targeting effect of nanoparticles was investigated in vitro on cancer cell line and in vivo on tumor bearing nude mouse. The results indicated the effective targeting of folate decorated paclitaxel loaded copolymer nanoparticles on cancer cells both in vitro and in vivo. PMID:26702264

  9. Gemcitabine plus paclitaxel versus carboplatin plus either gemcitabine or paclitaxel in advanced non-small-cell lung cancer: a literature-based meta-analysis.

    PubMed

    Li, Chenguang; Sun, Yihua; Pan, Yunjian; Wang, Qifeng; Yang, Shu; Chen, Haiquan

    2010-10-01

    The combination of gemcitabine plus paclitaxel has been proposed as an alternative to the platinum-based combinations for treatment of advanced non-small-cell lung cancer (NSCLC). However, conflicting results have been reported. This meta-analysis was performed to compare the activity, efficacy, and toxicity of gemcitabine plus paclitaxel versus carboplatin plus either gemcitabine or paclitaxel in patients with untreated advanced NSCLC. Randomized phase II and phase III clinical trials comparing gemcitabine plus paclitaxel with carboplatin plus gemcitabine or paclitaxel were collected from electronic databases (Medline, EMBASE, and the Cochrane Central Register of Controlled Trials), relevant reference lists, and abstract books. The published languages and years were not limited. Pooled odds ratios (ORs) were calculated for the 1-year survival rate (1-year SR), the overall response rate (ORR), and grade 3 and grade 4 toxicities. Four randomized controlled trials (2186 patients) were identified from 2051 reports. They were all published as full-text articles. No significant heterogeneity was detected in these studies. A significant difference in ORR favoring gemcitabine plus paclitaxel over carboplatin-based doublets was observed [OR = 1.20; 95% confidence interval (95% CI) = 1.02-1.42; P = 0.03], whereas the trend toward an improved 1-year SR was not significant (OR = 1.07; 95% CI = 0.91-1.26; P = 0.41). An increased risk of grade 3-4 toxicities for patients receiving carboplatin-based chemotherapy was statistically demonstrated. The gemcitabine plus paclitaxel combination showed an improved ORR and a better toxicity profile but a similar 1-year SR compared to carboplatin-based doublets. For nonplatinum-based chemotherapy, gemcitabine plus paclitaxel is a useful alternative. PMID:20703493

  10. Inhibition of Spleen Tyrosine Kinase Potentiates Paclitaxel-Induced Cytotoxicity in Ovarian Cancer Cells by Stabilizing Microtubules.

    PubMed

    Yu, Yu; Gaillard, Stephanie; Phillip, Jude M; Huang, Tai-Chung; Pinto, Sneha M; Tessarollo, Nayara G; Zhang, Zhen; Pandey, Akhilesh; Wirtz, Denis; Ayhan, Ayse; Davidson, Ben; Wang, Tian-Li; Shih, Ie-Ming

    2015-07-13

    Resistance to chemotherapy represents a major obstacle for long-term remission, and effective strategies to overcome drug resistance would have significant clinical impact. We report that recurrent ovarian carcinomas after paclitaxel/carboplatin treatment have higher levels of spleen tyrosine kinase (SYK) and phospho-SYK. In vitro, paclitaxel-resistant cells expressed higher SYK, and the ratio of phospho-SYK/SYK positively associated with paclitaxel resistance in ovarian cancer cells. Inactivation of SYK by inhibitors or gene knockdown sensitized paclitaxel cytotoxicity in vitro and in vivo. Analysis of the phosphotyrosine proteome in paclitaxel-resistant tumor cells revealed that SYK phosphorylates tubulins and microtubule-associated proteins. Inhibition of SYK enhanced microtubule stability in paclitaxel-resistant tumor cells that were otherwise insensitive. Thus, targeting SYK pathway is a promising strategy to enhance paclitaxel response. PMID:26096845

  11. Potentiation of paclitaxel activity by curcumin in human breast cancer cell by modulating apoptosis and inhibiting EGFR signaling.

    PubMed

    Zhan, Yingzhuan; Chen, Yinnan; Liu, Rui; Zhang, Han; Zhang, Yanmin

    2014-08-01

    It has been suggested that combined effect of natural products may improve the treatment effectiveness in combating proliferation of cancer cells. Here, we examined the combined anticancer activities of compounds of three natural origin including baicalein, curcumin, and resveratrol with chemotherapy drug paclitaxel respectively, which showed that combination of paclitaxel with curcumin exhibited synergistic growth inhibition and induced significant apoptosis in MCF-7 cell lines. Treatment of MCF-7 cell lines with paclitaxel and curcumin induced the apoptosis of regulatory protein Bcl-2 but decreased Bax expression. In addition, simultaneous treatment with paclitaxel and curcumin strongly inhibited paclitaxel-induced activities of EGFR signaling. Furthermore, the combination of paclitaxel and curcumin exerted increased anti-tumor efficacy on mouse models. Overall, our data described the promising therapeutic potential and underlying mechanisms of combining paclitaxel with curcumin in treating breast cancer. PMID:24318305

  12. Orally Bioavailable Tubulin Antagonists for Paclitaxel-Refractory Cancer

    PubMed Central

    Li, Chien-Ming; Lu, Yan; Chen, Jianjun; Costello, Terrence A.; Narayanan, Ramesh; Dalton, Mara N.; Snyder, Linda M.; Ahn, Sunjoo; Li, Wei; Miller, Duane D.; Dalton, James T.

    2013-01-01

    Purpose To evaluate the efficacy and oral activity of two promising indoles, (2-(1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone [compound II] and (2-(1H-indol-5-ylamino)-thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone [compound IAT], in paclitaxel- and docetaxel-resistant tumor models in vitro and in vivo. Methods The in vitro drug-like properties, including potency, solubility, metabolic stability, and drug-drug interactions were examined for our two active compounds. An in vivo pharmacokinetic study and antitumor efficacy study were also completed to compare their efficacy with docetaxel. Results Both compounds bound to the colchicine-binding site on tubulin, and inhibited tubulin polymerization, resulting in highly potent cytotoxic activity in vitro. While the potency of paclitaxel and docetaxel was compromised in a multidrug-resistant cell line that overexpresses P-glycoprotein, the potency of compounds II and IATwas maintained. Both compounds had favorable drug-like properties, and acceptable oral bioavailability (21–50%) in mice, rats, and dogs. Tumor growth inhibition of greater than 100% was achieved when immunodeficient mice with rapidly growing paclitaxel-resistant prostate cancer cells were treated orally at doses of 3–30 mg/kg of II or IAT. Conclusions These studies highlight the potent and broad anticancer activity of two orally bioavailable compounds, offering significant pharmacologic advantage over existing drugs of this class for multidrug resistant or taxane-refractory cancers. PMID:22760659

  13. Rescue of tau-induced synaptic transmission pathology by paclitaxel

    PubMed Central

    Erez, Hadas; Shemesh, Or A.; Spira, Micha E.

    2014-01-01

    Behavioral and electrophysiological studies of Alzheimer’s disease (AD) and other tauopathies have revealed that the onset of cognitive decline correlates better with synaptic dysfunctions than with hallmark pathologies such as extracellular amyloid-? plaques, intracellular hyperphosphorylated tau or neuronal loss. Recent experiments have also demonstrated that anti-cancer microtubule (MT)-stabilizing drugs can rescue tau-induced behavioral decline and hallmark neuron pathologies. Nevertheless, the mechanisms underlying tau-induced synaptic dysfunction as well as those involved in the rescue of cognitive decline by MTs-stabilizing drugs remain unclear. Here we began to study these mechanisms using the glutaminergic sensory-motoneuron synapse derived from Aplysia ganglia, electrophysiological methods, the expression of mutant-human tau (mt-htau) either pre or postsynaptically and the antimitotic drug paclitaxel. Expression of mt-htau in the presynaptic neurons led to reduced excitatory postsynaptic potential (EPSP) amplitude generated by rested synapses within 3 days of mt-htau expression, and to deeper levels of homosynaptic depression. mt-htau-induced synaptic weakening correlated with reduced releasable presynaptic vesicle pools as revealed by the induction of asynchronous neurotransmitter release by hypertonic sucrose solution. Paclitaxel totally rescued tau-induced synaptic weakening by maintaining the availability of the presynaptic vesicle stores. Postsynaptic expression of mt-htau did not impair the above described synaptic-transmission parameters for up to 5 days. Along with earlier confocal microscope observations from our laboratory, these findings suggest that tau-induced synaptic dysfunction is the outcome of impaired axoplasmic transport and the ensuing reduction in the releasable presynaptic vesicle stores rather than the direct effects of mt-htau or paclitaxel on the synaptic release mechanisms. PMID:24574970

  14. Microwave-assisted efficient conjugation of nanodiamond and paclitaxel.

    PubMed

    Hsieh, Yi-Han; Liu, Kuang-Kai; Sulake, Rohidas S; Chao, Jui-I; Chen, Chinpiao

    2015-05-15

    Nanodiamond has recently received considerable attention due to the various possible applications in medical field such as drug delivery and bio-labeling. For this purpose suitable and effective surface functionalization of the diamond material are required. A versatile and reproducible surface modification method of nanoscale diamond is essential for functionalization. We introduce the input of microwave energy to assist the functionalization of nanodiamond surface. The feasibility of such a process is illustrated by comparing the biological assay of ND-paclitaxel synthesized by conventional and microwave irradiating. Using a microwave we manage to have approximately doubled grafted molecules per nanoparticle of nanodiamond. PMID:25890802

  15. Synthesis and preclinical characterization of a paclitaxel prodrug with improved antitumor activity and water solubility.

    PubMed

    Niethammer, A; Gaedicke, G; Lode, H N; Wrasidlo, W

    2001-01-01

    The development of novel chemotherapy strategies based on prodrugs remains a major challenge for effective treatment of malignancies. We tested the hypothesis that this can be achieved by a prodrug of paclitaxel where one biologically active center, represented by the C7 hydroxyl group, was blocked by a dihydroxypropyl side chain which can be hydrolytically cleaved by a pH-dependent, slow-release mechanism. The prodrug was synthesized by condensation of solketal chloroformate with the C7 hydroxyl group of paclitaxel followed by a ring-opening reaction to the dihydroxyl derivative. The cytotoxicity of the prodrug was similar to paclitaxel, when tested in vitro against a variety of human tumor cell lines. In vitro cell cycle analysis indicated that concentrations within the micromolar range of both drug and prodrug are required to induce sufficient G2M arrest. The hydrophilic paclitaxel prodrug proved to be more than 50-fold more water soluble than the parental drug and effectively converted to paclitaxel by pH dependent hydrolysis. Importantly, the prodrug could be used at a 3-fold higher maximum tolerated dose (MTD) and revealed a markedly improved antitumor activity in mice compared to paclitaxel. Taken together, our results demonstrate, that a hydrolytically activated paclitaxel prodrug exhibits greater water solubility and superior antitumor activity than the parental drug. PMID:11353540

  16. Development of New Lipid-Based Paclitaxel Nanoparticles Using Sequential Simplex Optimization

    PubMed Central

    Dong, Xiaowei; Mattingly, Cynthia A.; Tseng, Michael; Cho, Moo; Adams, Val R.; Mumper, Russell J.

    2008-01-01

    The objective of these studies was to develop Cremophor-free lipid-based paclitaxel (PX) nanoparticle formulations prepared from warm microemulsion precursors. To identify and optimize new nanoparticles, experimental design was performed combining Taguchi array and sequential simplex optimization. The combination of Taguchi array and sequential simplex optimization efficiently directed the design of paclitaxel nanoparticles. Two optimized paclitaxel nanoparticles (NPs) were obtained: G78 NPs composed of glyceryl tridodecanoate (GT) and polyoxyethylene 20-stearyl ether (Brij 78), and BTM NPs composed of Miglyol 812, Brij 78 and D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS). Both nanoparticles successfully entrapped paclitaxel at a final concentration of 150 ?g/ml (over 6% drug loading) with particle sizes less than 200 nm and over 85% of entrapment efficiency. These novel paclitaxel nanoparticles were stable at 4°C over three months and in PBS at 37°C over 102 hours as measured by physical stability. Release of paclitaxel was slow and sustained without initial burst release. Cytotoxicity studies in MDA-MB-231 cancer cells showed that both nanoparticles have similar anticancer activities compared to Taxol®. Interestingly, PX BTM nanocapsules could be lyophilized without cryoprotectants. The lyophilized powder comprised only of PX BTM NPs in water could be rapidly rehydrated with complete retention of original physicochemical properties, in-vitro release properties, and cytotoxicity profile. Sequential Simplex Optimization has been utilized to identify promising new lipid-based paclitaxel nanoparticles having useful attributes. PMID:19111929

  17. High energy shock waves (HESW) enhance paclitaxel cytotoxicity in MCF-7 cells.

    PubMed

    Frairia, Roberto; Catalano, Maria G; Fortunati, Nicoletta; Fazzari, Annamaria; Raineri, Mariangela; Berta, Laura

    2003-09-01

    High energy shock waves (HESW) produced by a piezoelectric generator were studied for their effect on human breast cancer cell (MCF-7) viability and sensitivity to paclitaxel. A dose-dependent impairment of cell viability was observed after HESW treatment (250-2000 shock waves, rate = 4/s, energy flux density = 0.25 mJ/mm2). Single treatment with shock waves produced no significant growth inhibition. Combined exposure to paclitaxel (ranging 0.1 nM to 20 microM) and shock waves (100, 500 and 1000 shots, respectively) resulted in a significant reduction of MCF-7 cell proliferation at day 3 after treatment in respect with cells treated with paclitaxel alone. Notably, a cell viability reduction of about 50% was obtained after combined treatment with HESW and 10 nM paclitaxel, in front of a reduction of only 40% using 10 microM paclitaxel alone. Moreover, an earlier induction as well as an enhancement of apoptotis was observed in cells subjected to combined treatment with shock waves and paclitaxel (200 nM; 20 microM). In conclusion, HESW can enhance paclitaxel cytotoxicity in MCF-7 cells, thus allowing the treatment with lower doses of drug. PMID:14531493

  18. Intraplantar injection of linalool reduces paclitaxel-induced acute pain in mice.

    PubMed

    Katsuyama, Soh; Kuwahata, Hikari; Yagi, Tomomi; Kishikawa, Yukinaga; Komatsu, Takaaki; Sakurada, Tsukasa; Nakamura, Hitoshi

    2012-06-01

    Linalool is the principal component of many essential oils known to possess biological activities. We previously reported that intraplantar injection of linalool reduces the nociceptive response as assayed by the capsaicin test. In this study, we sought to determine whether intraplantar injection of linalool could influence the induction of acute pain (allodynia and hyperalgesia) by paclitaxel in mice. Paclitaxel is widely used in cancer chemotherapy for the treatment of solid tumors, but it sometimes induces moderate to severe acute pain. Paclitaxel administered intraperitoneally as a single dose of 5, 10 or 20 mg/kg produced mechanical allodynia and hyperalgesia in mice. Paclitaxel-induced mechanical allodynia and hyperalgesia began 1 day after administration of paclitaxel and resolved within 7 days. Linalool injected into the hindpaw caused a significant reduction in paclitaxel-induced mechanical allodynia and hyperalgesia. Pretreatment with naloxone hydrochloride, an opioid receptor antagonist, or naloxone methiodide, a peripherally acting µ-opioid receptor-preferring antagonist, significantly reversed linalool-induced antiallodynia and antihyperalgesia. Our results provide evidence for the involvement of peripheral opioids in antiallodynia and antihyperalgesia induced by linalool. These results suggest that activation of peripheral opioid receptors may play an important role in reducing paclitaxel-induced mechanical allodynia and hyperalgesia. PMID:22790217

  19. Efficient purification of paclitaxel from yews using high-performance displacement chromatography technique.

    PubMed

    Watchueng, Jean; Kamnaing, Pierre; Gao, Jin-Ming; Kiyota, Taira; Yeboah, Faustinus; Konishi, Yasuo

    2011-05-20

    Paclitaxel was purified using high-performance displacement chromatography (HPDC) technique, but not by the mechanism of HPDC. On small scale, paclitaxel was extracted with methanol from dry needles of Taxus canadensis and was enriched by extracting with chloroform after removing water-soluble hydrophilic components and hexane-soluble hydrophobic components. Then, 93-99% purity of paclitaxel was obtained using the HPDC technique. On large scale, taxanes were enriched by solvent partitioning between acetic acid/MeOH/H(2)O and hexane and extracted with CH(2)Cl(2). Taxanes except paclitaxel were further removed by extracting with methanol-water-trifluoroacetic acid (1.0:98.9:0.1, v/v/v). Applying HPDC technique to water-insoluble substances is problematic as this method requires a highly aqueous solvent system. In order to overcome this incompatibility, a system was set up where paclitaxel, although in low concentration, was extracted by methanol-water-trifluoroacetic acid (10.0:89.9:0.1, v/v/v). Recycling the extracting solvent to ensure minimal volume, the extracted paclitaxel was adsorbed on a C(18) trap column. A C(18) column of 4.6mm internal diameter was then connected to the trap column. The HPDC technique was thus carried out using an isocratic acetonitrile-water-trifluoroacetic acid (30.0:69.9:0.1, v/v/v) mobile phase consisting of a displacer cetylpyridinium trifluoroacetate (3mg/mL). Paclitaxel was co-eluted with the displacer and spontaneously crystallized. The crystal (114mg) showed 99.4% purity and only 10% of paclitaxel in the starting crude extract was lost during the enrichment/purification processes. This large scale purification method was successfully applied to purify paclitaxel from Chinese yew in small scale, suggesting general applicability of the method. This is the first report of purifying a water-insoluble natural product using HPDC technique. PMID:21457989

  20. A Review of Paclitaxel and Novel Formulations Including Those Suitable for Use in Dogs.

    PubMed

    Khanna, C; Rosenberg, M; Vail, D M

    2015-01-01

    Paclitaxel is a commonly used chemotherapeutic agent with a broad spectrum of activity against cancers in humans. In 1992, paclitaxel was approved by the U.S. Food and Drug Administration (FDA) as Taxol(®) for use in advanced ovarian cancer. Two years later, it was approved for the treatment of metastatic breast cancer. Paclitaxel was originally isolated from the bark of the Pacific yew tree, Taxus brevifolia in 1971. Taxanes are a family of microtubule inhibitors. As a member of this family, paclitaxel suppresses spindle microtubule dynamics. This activity results in the blockage of the metaphase-anaphase transitions, and ultimately in the inhibition of mitosis, and induction of apoptosis in a wide spectrum of cancer cells. Additional anticancer activities of paclitaxel have been defined that are independent of these effects on the microtubules and may include the suppression of cell proliferation as well as antiangiogenic effects. Based on its targeting of a fundamental feature of the cancer phenotype, the mitotic complex, it is not surprising that paclitaxel has been found to be active in a wide variety of cancers in humans. This review summarizes the evidence in support of paclitaxel's broad anticancer activity and introduces the rationale for, and the progress in development of novel formulations of paclitaxel that may preferentially target cancers and that are not associated with the risks for hypersensitivity in dogs. Of note, a novel nanoparticle formulation of paclitaxel that substantially limits hypersensitivity was recently given conditional approval by the FDA Center for Veterinary Medicine for use in dogs with resectable and nonresectable squamous cell carcinoma and nonresectable stage III, IV and V mammary carcinoma. PMID:26179168

  1. Nanoparticle albumin bound Paclitaxel in the treatment of human cancer: nanodelivery reaches prime-time?

    PubMed

    Cucinotto, Iole; Fiorillo, Lucia; Gualtieri, Simona; Arbitrio, Mariamena; Ciliberto, Domenico; Staropoli, Nicoletta; Grimaldi, Anna; Luce, Amalia; Tassone, Pierfrancesco; Caraglia, Michele; Tagliaferri, Pierosandro

    2013-01-01

    Nanoparticle albumin bound paclitaxel (nab-paclitaxel) represents the first nanotechnology-based drug in cancer treatment. We discuss the development of this innovative compound and report the recent changing-practice results in breast and pancreatic cancer. A ground-breaking finding is the demonstration that nab-paclitaxel can not only enhance the activity and reduce the toxicity of chromophore-diluted compound, but also exert activity in diseases considered refractory to taxane-based treatment. This is the first clinical demonstration of major activity of nanotechnologically modified drugs in the treatment of human neoplasms. PMID:23738077

  2. Nanoparticle Albumin Bound Paclitaxel in the Treatment of Human Cancer: Nanodelivery Reaches Prime-Time?

    PubMed Central

    Cucinotto, Iole; Fiorillo, Lucia; Gualtieri, Simona; Arbitrio, Mariamena; Ciliberto, Domenico; Staropoli, Nicoletta; Grimaldi, Anna; Luce, Amalia; Tassone, Pierfrancesco; Caraglia, Michele; Tagliaferri, Pierosandro

    2013-01-01

    Nanoparticle albumin bound paclitaxel (nab-paclitaxel) represents the first nanotechnology-based drug in cancer treatment. We discuss the development of this innovative compound and report the recent changing-practice results in breast and pancreatic cancer. A ground-breaking finding is the demonstration that nab-paclitaxel can not only enhance the activity and reduce the toxicity of chromophore-diluted compound, but also exert activity in diseases considered refractory to taxane-based treatment. This is the first clinical demonstration of major activity of nanotechnologically modified drugs in the treatment of human neoplasms. PMID:23738077

  3. Paclitaxel loaded PEGylated gleceryl monooleate based nanoparticulate carriers in chemotherapy.

    PubMed

    Jain, Vikas; Swarnakar, Nitin K; Mishra, Prabhat R; Verma, Ashwni; Kaul, Ankur; Mishra, Anil K; Jain, Narendra K

    2012-10-01

    A PEGylated drug delivery system of paclitaxel (PTX), based on glyceryl monooleate (GMO) was prepared by optimizing various parameters to explore its potential in anticancer therapy. The prepared system was characterized through polarized light microscopy, TEM, AFM and SAXS to reveal its liquid crystalline nature. As GMO based LCNPs exhibit high hemolytic toxicity and faster release of entrapped drug (66.2 ± 2.5% in 24 h), PEGylation strategy was utilized to increase the hemocompatibility (reduction in hemolysis from 60.3 ± 10.2 to 4.4 ± 1.3%) and control the release of PTX (43.6 ± 3.2% released in 24 h). The cytotoxic potential and cellular uptake was assessed in MCF-7 cell lines. Further, biodistribution studies were carried out in EAT (Ehrlich Ascites tumor) bearing mice using (99m)Tc-(Technetium radionuclide) labeled formulations and an enhanced circulation time and tumor accumulation (14 and 8 times, respectively) were observed with PEGylated carriers over plain ones, at 24 h. Finally, tumor growth inhibition experiment was performed and after 15 days, control group exhibited 15 times enhancement in tumor volume, while plain and PEGylated systems exhibited only 8 and 4 times enhancement, respectively, as compared to initial tumor volume. The results suggest that PEGylation enhances the hemocompatibility and efficacy of GMO based system that may serve as an efficient i.v. delivery vehicle for paclitaxel. PMID:22809646

  4. Poly-cyclodextrin and poly-paclitaxel nano-assembly for anticancer therapy

    NASA Astrophysics Data System (ADS)

    Namgung, Ran; Mi Lee, Yeong; Kim, Jihoon; Jang, Yuna; Lee, Byung-Heon; Kim, In-San; Sokkar, Pandian; Rhee, Young Min; Hoffman, Allan S.; Kim, Won Jong

    2014-05-01

    Effective anticancer therapy can be achieved by designing a targeted drug-delivery system with high stability during circulation and efficient uptake by the target tumour cancer cells. We report here a novel nano-assembled drug-delivery system, formed by multivalent host-guest interactions between a polymer-cyclodextrin conjugate and a polymer-paclitaxel conjugate. The multivalent inclusion complexes confer high stability to the nano-assembly, which efficiently delivers paclitaxel into the targeted cancer cells via both passive and active targeting mechanisms. The ester linkages between paclitaxel and the polymer backbone permit efficient release of paclitaxel within the cell by degradation. This novel targeted nano-assembly exhibits significant antitumour activity in a mouse tumour model. The strategy established in this study also provides knowledge for the development of advanced anticancer drug delivery.

  5. A phase II study of paclitaxel in heavily pretreated patients with small-cell lung cancer.

    PubMed Central

    Smit, E. F.; Fokkema, E.; Biesma, B.; Groen, H. J.; Snoek, W.; Postmus, P. E.

    1998-01-01

    The purpose of the study was to delineate the efficacy and toxicity of paclitaxel (Taxol, Bristol Myers Squibb) in the treatment of drug resistant small-cell lung cancer (SCLC). Patients with SCLC relapsing within 3 months of cytotoxic therapy received paclitaxel 175 mg m(-2) intravenously over 3 h every 3 weeks. The dose of paclitaxel was adjusted to the toxicity encountered in the previous cycle. Of 24 patients entered into the study, 24 and 21 were assessable for response and toxicity respectively. There were two early deaths and two toxic deaths. No complete and seven partial responses (29%) (95%CI 12-51%) were observed and five patients had disease stabilization. The median survival (n = 21) was 100 days. Life-threatening toxicity occurred in four patients; in others (non)-haematological toxicity was manageable. Paclitaxel is active in drug-resistant SCLC. Further investigation in combination with other active agents in this poor prognosis group is appropriate. PMID:9461009

  6. Genomic signatures for paclitaxel and gemcitabine resistance in breast cancer derived by machine learning.

    PubMed

    Dorman, Stephanie N; Baranova, Katherina; Knoll, Joan H M; Urquhart, Brad L; Mariani, Gabriella; Carcangiu, Maria Luisa; Rogan, Peter K

    2016-01-01

    Increasingly, the effectiveness of adjuvant chemotherapy agents for breast cancer has been related to changes in the genomic profile of tumors. We investigated correspondence between growth inhibitory concentrations of paclitaxel and gemcitabine (GI50) and gene copy number, mutation, and expression first in breast cancer cell lines and then in patients. Genes encoding direct targets of these drugs, metabolizing enzymes, transporters, and those previously associated with chemoresistance to paclitaxel (n = 31 genes) or gemcitabine (n = 18) were analyzed. A multi-factorial, principal component analysis (MFA) indicated expression was the strongest indicator of sensitivity for paclitaxel, and copy number and expression were informative for gemcitabine. The factors were combined using support vector machines (SVM). Expression of 15 genes (ABCC10, BCL2, BCL2L1, BIRC5, BMF, FGF2, FN1, MAP4, MAPT, NFKB2, SLCO1B3, TLR6, TMEM243, TWIST1, and CSAG2) predicted cell line sensitivity to paclitaxel with 82% accuracy. Copy number profiles of 3 genes (ABCC10, NT5C, TYMS) together with expression of 7 genes (ABCB1, ABCC10, CMPK1, DCTD, NME1, RRM1, RRM2B), predicted gemcitabine response with 85% accuracy. Expression and copy number studies of two independent sets of patients with known responses were then analyzed with these models. These included tumor blocks from 21 patients that were treated with both paclitaxel and gemcitabine, and 319 patients on paclitaxel and anthracycline therapy. A new paclitaxel SVM was derived from an 11-gene subset since data for 4 of the original genes was unavailable. The accuracy of this SVM was similar in cell lines and tumor blocks (70-71%). The gemcitabine SVM exhibited 62% prediction accuracy for the tumor blocks due to the presence of samples with poor nucleic acid integrity. Nevertheless, the paclitaxel SVM predicted sensitivity in 84% of patients with no or minimal residual disease. PMID:26372358

  7. Effect of Paclitaxel on Antitumor Activity of Cyclophosphamide: Study on Two Transplanted Tumors in Mice.

    PubMed

    Kaledin, V I; Nikolin, V P; Popova, N A; Pyshnaya, I A; Bogdanova, L A; Morozkova, T S

    2015-11-01

    Antitumor effect of paclitaxel used as the monotherapy or in combination with cyclophosphamide was studied on CBA/LacSto mice with transplanted LS and RLS tumors characterized by high (LS) and low (RLS) sensitivity to cyclophosphamide. The therapeutic effects of cyclophosphamide and paclitaxel were summed in animals with drug-resistant RLS tumor, while combined use of these drugs in LS tumor highly sensitive to the apoptogenic effect of cyclophosphamide was no more effective than cyclophosphamide alone. PMID:26597686

  8. Synergistic Antitumor Effects of Novel HDAC Inhibitors and Paclitaxel In Vitro and In Vivo

    PubMed Central

    Zuco, Valentina; De Cesare, Michelandrea; Cincinelli, Raffaella; Nannei, Raffaella; Pisano, Claudio; Zaffaroni, Nadia; Zunino, Franco

    2011-01-01

    Preclinical studies support the therapeutic potential of histone deacetylases inhibitors (HDACi) in combination with taxanes. The efficacy of combination has been mainly ascribed to a cooperative effect on microtubule stabilization following tubulin acetylation. In the present study we investigated the effect of paclitaxel in combination with two novel HDACi, ST2782 or ST3595, able to induce p53 and tubulin hyperacetylation. A synergistic effect of the paclitaxel/ST2782 (or ST3595) combination was found in wild-type p53 ovarian carcinoma cells, but not in a p53 mutant subline, in spite of a marked tubulin acetylation. Such a synergistic interaction was confirmed in additional human solid tumor cell lines harboring wild-type p53 but not in those expressing mutant or null p53. In addition, a synergistic cytotoxic effect was found when ST2782 was combined with the depolymerising agent vinorelbine. In contrast to SAHA, which was substantially less effective in sensitizing cells to paclitaxel-induced apoptosis, ST2782 prevented up-regulation of p21WAF1/Cip1 by paclitaxel, which has a protective role in response to taxanes, and caused p53 down-regulation, acetylation and mitochondrial localization of acetylated p53. The synergistic antitumor effects of the paclitaxel/ST3595 combination were confirmed in two tumor xenograft models. Our results support the relevance of p53 modulation as a major determinant of the synergistic interaction observed between paclitaxel and novel HDACi and emphasize the therapeutic interest of this combination. PMID:22194993

  9. Vaginal delivery of paclitaxel via nanoparticles with non-mucoadhesive surfaces suppresses cervical tumor growth

    PubMed Central

    Yang, Ming; Yu, Tao; Wang, Ying-Ying; Lai, Samuel K.; Zeng, Qi; Miao, Bolong; Tang, Benjamin C.; Simons, Brian W.; Ensign, Laura; Liu, Guanshu; Chan, Kannie W. Y.; Juang, Chih-Yin; Mert, Olcay; Wood, Joseph; Fu, Jie; McMahon, Michael T.; Wu, T.-C.; Hung, Chien-Fu; Hanes, Justin

    2014-01-01

    Local delivery of chemotherapeutics in the cervicovaginal tract using nanoparticles may reduce adverse side effects associated with systemic chemotherapy, while improving outcomes for early stage cervical cancer. We hypothesize drug-loaded nanoparticles must rapidly penetrate cervicovaginal mucus (CVM) lining the female reproductive tract to effectively deliver their payload to underlying diseased tissues in a uniform and sustained manner. We develop paclitaxel-loaded nanoparticles, composed entirely of polymers used in FDA-approved products, which rapidly penetrate human CVM and provide sustained drug release with minimal burst effect. We further employ a mouse model with aggressive cervical tumors established in the cervicovaginal tract to compare paclitaxel-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (conventional particles , or CP) and similar particles coated with Pluronic® F127 (mucus-penetrating particles , or MPP). CP are mucoadhesive and, thus, aggregated in mucus, while MPP achieve more uniform distribution and close proximity to cervical tumors. Paclitaxel-MPP suppress tumor growth more effectively and prolong median survival of mice compared to free paclitaxel or paclitaxel-CP. Histopathological studies demonstrate minimal toxicity to the cervicovaginal epithelia, suggesting paclitaxel-MPP may be safe for intravaginal use. These results demonstrate for the first time the in vivo advantages of polymer-based MPP for treatment of tumors localized to a mucosal surface. PMID:24339398

  10. A Rare Case of Paclitaxel and/or Trastuzumab Induced Acute Hepatic Necrosis

    PubMed Central

    Mandaliya, Hiren; Baghi, Pinky; Prawira, Amy; George, Mathew K.

    2015-01-01

    Paclitaxel induced mild derangement of liver functions including bilirubin, alkaline phosphatase, and AST has been infrequently noticed in clinical trials. Contrary to Paclitaxel, hepatocellular injury, hepatitis, and liver tenderness are common laboratory and clinical findings with Trastuzumab. However, hepatic failure/necrosis secondary to Paclitaxel or Trastuzumab has never been reported in literature. A 62-year-old lady, previously healthy, was treated with adjuvant therapy for left breast stage II, high grade invasive ductal carcinoma which was node negative, oestrogen receptor negative, progesterone receptor positive, and HER2 receptor positive. After modified radical mastectomy and axillary clearance, she finished four cycles of Doxorubicin/Cyclophosphamide chemotherapy and then commenced on Paclitaxel/Trastuzumab combination chemotherapy. Within twelve hours of first dose of Paclitaxel/Trastuzumab therapy, patient required hospital admission for acute onset respiratory failure. Patient died within 36 hours of therapy and autopsy was suggestive of acute hepatic necrosis without any other significant findings. Detailed investigations were not carried out as event was quick with rapid deterioration. There was no history of prior liver pathology/injury and preliminary investigations for major organ involvement were unremarkable. As per our knowledge, Paclitaxel and/or Trastuzumab induced acute hepatic necrosis has never been reported in literature before, hence difficult to predict.

  11. Nanosuspension delivery of paclitaxel to xenograft mice can alter drug disposition and anti-tumor activity

    PubMed Central

    2014-01-01

    Paclitaxel is a common chemotherapeutic agent that is effective against various cancers. The poor aqueous solubility of paclitaxel necessitates a large percentage of Cremophor EL:ethanol (USP) in its commercial formulation which leads to hypersensitivity reactions in patients. We evaluate the use of a crystalline nanosuspension versus the USP formulation to deliver paclitaxel to tumor-bearing xenograft mice. Anti-tumor efficacy was assessed following intravenous administration of three 20 mg/kg doses of paclitaxel. Paclitaxel pharmacokinetics and tissue distribution were evaluated, and differences were observed between the two formulations. Plasma clearance and tissue to plasma ratio of mice that were dosed with the nanosuspension are approximately 33- and 11-fold higher compared to those of mice that were given the USP formulation. Despite a higher tumor to plasma ratio for the nanosuspension treatment group, absolute paclitaxel tumor exposure was higher for the USP group. Accordingly, a higher anti-tumor effect was observed in the xenograft mice that were dosed with the USP formulation (90% versus 42% tumor growth inhibition). This reduction in activity of nanoparticle formulation appeared to result from a slower than anticipated dissolution in vivo. This study illustrates a need for careful consideration of both dose and systemic solubility prior utilizing nanosuspension as a mode of intravenous delivery. PMID:24685243

  12. Cost-Benefit Analysis of Nanoparticle Albumin-Bound Paclitaxel versus Solvent-Based Paclitaxel for the Treatment of Metastatic Breast Cancer in the United States

    NASA Astrophysics Data System (ADS)

    Vichansavakul, Kittaya

    Breast cancer is the second leading cause of death among women in the US. Although early detection and treatment help to increase survival rates, some unfortunate patients develop metastatic breast cancer that has no cure. Palliative treatment is the main objective in this group of patients in order to prolong life and reduce toxicities from interventions. In the advancement of treatment for metastatic breast cancer, solvent-based paclitaxel has been widely used. However, solvent-based paclitaxel often causes adverse reactions. Therefore, researchers have developed a new chemotherapy based on nanotechnology. One of these drugs is the Nanoparticle albumin-bound Paclitaxel. This nanodrug aims to increase therapeutic index by reducing adverse reactions from solvents and to improve efficacy of conventional cytotoxic chemotherapy. Breast cancer is a disease with high epidemiological and economic burden. The treatment of metastatic breast cancer has not only high direct costs but also high indirect costs. Breast cancer affects mass populations, especially women younger than 50 years of age. It relates to high indirect costs due to lost productivity and premature death because the majority of these patients are in the workforce. Because of the high cost of breast cancer therapies and short survival rates, the question is raised whether the costs and benefits are worth paying or not. Due to the rising costs in healthcare and new financing policies that have been developed to address this issue, economic evaluation is an important aspect of the development and use of any new interventions. To guide policy makers on how to allocate limited healthcare resources in the most efficient and effective manner, many economic evaluation methods can be used to measure the costs, benefits, and impacts of healthcare innovations. Currently, economic evaluation and health outcomes studies have focused greatly on cost-effectiveness and cost-utility analysis. However, the previous studies had some limitations because they were conducted from a narrow perspective such as payer and provider point of views. The studies also considered only direct costs in their analysis. In fact, conducting economic evaluations from a narrow perspective and leaving out indirect costs might undermine the true benefit of the interventions for society. A cost-benefit analysis measures all costs and benefits in monetary units. It incorporates both health outcomes gained from individuals and the value gained to society in order to maximize the usage of resources effectively. This thesis conducted a cost-benefit analysis to compare nab-paclitaxel and generic paclitaxel in treating metastatic breast cancer from a societal perspective in the United States. The results showed that nab-paclitaxel is a cost-benefit strategy regardless of the different costs and benefits due to the extra 3 years of living it provides. In all models, when nab-paclitaxel was compared to generic paclitaxel, nab-paclitaxel showed cost-benefit to society. However, the results of generic paclitaxel were dependent on the total medical costs. Performing a cost-benefit analysis of nab-paclitaxel from a societal perspective is important to understand the true benefit of interventions. Furthermore, considering both direct and indirect costs, as well as benefits, of this drug is vital because the economic profile of nab-paclitaxel would be improved.

  13. Phase I feasibility study of intraperitoneal cisplatin and intravenous paclitaxel followed by intraperitoneal paclitaxel in untreated ovarian, fallopian tube, and primary peritoneal carcinoma: A Gynecologic Oncology Group Study

    PubMed Central

    Dizon, Don S.; Sill, Michael W.; Gould, Natalie; Rubin, Stephen C.; Yamada, S. Diane; DeBernardo, Robert L.; Mannel, Robert S.; Eisenhauer, Eric L.; Duska, Linda R.; Fracasso, Paula M.

    2011-01-01

    Purpose Intraperitoneal chemotherapy has shown a survival advantage over intravenous chemotherapy for women with newly diagnosed optimally debulked epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. However, significant toxicity has limited its acceptance. In an effort to reduce toxicity, the Gynecologic Oncology Group conducted a Phase I study to evaluate the feasibility of day 1 intravenous (IV) paclitaxel and intraperitoneal (IP) cisplatin followed by day 8 IP paclitaxel on an every 21-day cycle. Methods Patients with Stage IIB-IV epithelial ovarian, fallopian tube, primary peritoneal carcinomas or carcinosarcoma received paclitaxel 135 mg/m2 IV over 3 hours followed by cisplatin 75 mg/m2 IP on day 1 and paclitaxel 60 mg/m2 IP on day 8 of a 21 day cycle with 6 cycles planned. Dose-limiting toxicity (DLT) was defined as febrile neutropenia or dose-delay of greater than 2 weeks due to failure to recover counts, or Grade 3-5 non-hematologic toxicity occurring within the first 4 cycles of treatment. Results Twenty of 23 patients enrolled were evaluable and nineteen (95%) completed all six cycles of therapy. Three patients experienced a DLT consisting of infection with normal absolute neutrophil count, grade 3 hyperglycemia, and grade 4 abdominal pain. Conclusions This modified IP regimen which administers both IV paclitaxel and IP cisplatin on day one, followed by IP paclitaxel on day eight, of a twenty-one day cycle appears feasible and is an attractive alternative to the intraperitoneal treatment regimen administered in GOG-0172. PMID:21820161

  14. Reversible Posterior Leukoencephalopathy Syndrome Due to Carboplatin and Paclitaxel Therapy

    PubMed Central

    Kandemir, Melek; Küçükkaya, Belgin; Tepe, Muzaffer Sava?; Yalç?ner, Zehra Betül; Salepçi, Nedret Taflan

    2015-01-01

    Background: Reversible posterior leukoencephalopathy syndrome (RPLS) is a clinicoradiologic syndrome characterized by headache, decreased alertness, seizures, visual abnormalities, and white matter changes indicative of cerebral edema. Although the pathogenesis remains poorly understood, several etiological causes have been described. RPLS is a common complication of chemotherapeutics because of its toxic effect on the central nervous system. This syndrome is frequently associated with seizures but rarely seen with status epilepticus and periodic lateralized epileptiform discharges (PLEDs). Case Report: We present a case with metastatic lung cancer that developed RPLS after carboplatin and paclitaxel therapy. Our case was admitted to the hospital with status epilepticus and her electroencephalography showed PLEDs. Conclusion: It is important to closely monitor blood pressure and electrolyte levels in patients who take chemotherapeutic agents, especially when there is no previous history of hypertension. It should be kept in mind that RPLS is a causative factor of status epilepticus and PLEDs.

  15. Rationalization of paclitaxel insensitivity of yeast ?-tubulin and human ?III-tubulin isotype using principal component analysis

    PubMed Central

    2012-01-01

    Background The chemotherapeutic agent paclitaxel arrests cell division by binding to the hetero-dimeric protein tubulin. Subtle differences in tubulin sequences, across eukaryotes and among ?-tubulin isotypes, can have profound impact on paclitaxel-tubulin binding. To capture the experimentally observed paclitaxel-resistance of human ?III tubulin isotype and yeast ?-tubulin, within a common theoretical framework, we have performed structural principal component analyses of ?-tubulin sequences across eukaryotes. Results The paclitaxel-resistance of human ?III tubulin isotype and yeast ?-tubulin uniquely mapped on to the lowest two principal components, defining the paclitaxel-binding site residues of ?-tubulin. The molecular mechanisms behind paclitaxel-resistance, mediated through key residues, were identified from structural consequences of characteristic mutations that confer paclitaxel-resistance. Specifically, Ala277 in ?III isotype was shown to be crucial for paclitaxel-resistance. Conclusions The present analysis captures the origin of two apparently unrelated events, paclitaxel-insensitivity of yeast tubulin and human ?III tubulin isotype, through two common collective sequence vectors. PMID:22849332

  16. Combinatorial TGF-? attenuation with paclitaxel inhibits the epithelial-to-mesenchymal transition and breast cancer stem-like cells.

    PubMed

    Park, So-Yeon; Kim, Min-Jin; Park, Sang-A; Kim, Jung-Shin; Min, Kyung-Nan; Kim, Dae-Kee; Lim, Woosung; Nam, Jeong-Seok; Sheen, Yhun Yhong

    2015-11-10

    Distant relapse after chemotherapy is an important clinical issue for treating breast cancer patients and results from the development of cancer stem-like cells (CSCs) during chemotherapy. Here we report that blocking epithelial-to-mesenchymal transition (EMT) suppresses paclitaxel-induced CSCs properties by using a MDA-MB-231-xenografted mice model (in vivo), and breast cancer cell lines (in vitro). Paclitaxel, one of the cytotoxic taxane-drugs such as docetaxel, increases mesenchymal markers (Vimentin and Fibronectin) and decreases an epithelial marker (Zo-1). Blocking TGF-? signaling with the TGF-? type I receptor kinase (ALK5) inhibitor, EW-7197, suppresses paclitaxel-induced EMT and CSC properties such as mammosphere-forming efficiency (MSFE), aldehyde dehydrogenase (ALDH) activity, CD44+/CD24- ratio, and pluripotency regulators (Oct4, Nanog, Klf4, Myc, and Sox2). The combinatorial treatment of EW-7197 improves the therapeutic effect of paclitaxel by decreasing the lung metastasis and increasing the survival time in vivo. We confirmed that Snail is increased by paclitaxel-induced intracellular reactive oxygen species (ROS) and EW-7197 suppresses the paclitaxel-induced Snail and EMT by attenuating paclitaxel-induced intracellular ROS. Knock-down of SNAI1 suppresses paclitaxel-induced EMT and CSC properties. These data together suggest that blocking the Snail-induced EMT with the ALK5 inhibitor attenuates metastasis after paclitaxel-therapy and that this combinatorial approach could prove useful in treating breast cancer. PMID:26462028

  17. A novel biosensor for quantitative monitoring of on-target activity of paclitaxel

    NASA Astrophysics Data System (ADS)

    Townley, H. E.; Zheng, Y.; Goldsmith, J.; Zheng, Y. Y.; Stratford, M. R. L.; Dobson, P. J.; Ahmed, A. A.

    2014-12-01

    This study describes a system for quantifying paclitaxel activity using the C-terminus of ?-tubulin as a biomarker. Following stabilization of microtubules with paclitaxel, a specific detyrosination reaction occurs at the C-terminus of ?-tubulin which could be used to assess efficacy. A fluorescence resonance energy transfer (FRET) based biosensor was synthesized comprising a short peptide that corresponded to the C-terminus of ?-tubulin, a fluorophore (Abz), and a quencher (Dnp). The fluorophore added to the end of the peptide can be released upon enzymatic detyrosination. In addition, a single fluorophore-tagged peptide was also conjugated to mesoporous silica nanoparticles to examine the feasibility of combining the drug with the peptide biomarker. As a proof of concept, we found that the degree of peptide cleavage, and therefore enzymatic activity, was directly correlated with exogenous bovine carboxypeptidase (CPA) an enzyme that mimics endogenous detyrosination. In addition, we show that cell lysates obtained from paclitaxel-treated cancer cells competed with exogenous CPA for biosensor cleavage in a paclitaxel dose-dependent manner. Our work provides strong evidence for the feasibility of combining paclitaxel with a novel biosensor in a multi-load nanoparticle.This study describes a system for quantifying paclitaxel activity using the C-terminus of ?-tubulin as a biomarker. Following stabilization of microtubules with paclitaxel, a specific detyrosination reaction occurs at the C-terminus of ?-tubulin which could be used to assess efficacy. A fluorescence resonance energy transfer (FRET) based biosensor was synthesized comprising a short peptide that corresponded to the C-terminus of ?-tubulin, a fluorophore (Abz), and a quencher (Dnp). The fluorophore added to the end of the peptide can be released upon enzymatic detyrosination. In addition, a single fluorophore-tagged peptide was also conjugated to mesoporous silica nanoparticles to examine the feasibility of combining the drug with the peptide biomarker. As a proof of concept, we found that the degree of peptide cleavage, and therefore enzymatic activity, was directly correlated with exogenous bovine carboxypeptidase (CPA) an enzyme that mimics endogenous detyrosination. In addition, we show that cell lysates obtained from paclitaxel-treated cancer cells competed with exogenous CPA for biosensor cleavage in a paclitaxel dose-dependent manner. Our work provides strong evidence for the feasibility of combining paclitaxel with a novel biosensor in a multi-load nanoparticle. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr01105h

  18. The enhanced longevity and liver targetability of Paclitaxel by hybrid liposomes encapsulating Paclitaxel-conjugated gold nanoparticles.

    PubMed

    Bao, Quan-Ying; Zhang, Ning; Geng, Dong-Dong; Xue, Jing-Wei; Merritt, Mackenzie; Zhang, Can; Ding, Ya

    2014-12-30

    Organic and inorganic drug delivery systems both demonstrate their own advantages and challenges in practical applications. Combining these two drug delivery strategies in one system is expected to solve their current issues and achieve desirable functions. In this paper, gold nanoparticles (GNPs) and liposomes have been chosen as the model systems to construct a hybrid system and investigate its performance for the tumor therapy of Paclitaxel (PTX). The thiol-terminated polyethylene glycol (PEG400)-PTX derivative has been covalently modified on the surface of GNPs, followed by the encapsulation of PTX-conjugated GNPs (PTX-PEG400@GNPs) in liposomes. The hybrid liposomes solve the solubility and stability problems of gold conjugates and show high drug loading capacity. In vitro PTX release from the hybrid system maintains the similar sustained behavior demonstrated in its conjugates. Under the protection of a biocompatible liposome shell, encapsulated PTX shows enhanced circulation longevity and liver targetability compared to Taxol(®) and PTX-PEG400@GNPs suspension in the pharmacokinetic and biodistribution studies. These indicate that encapsulating drug-conjugated inorganic nanoparticles inside organic carriers maintains the superiority of both vehicles and improves the performance of hybrid systems. Although these attributes of hybrid liposomes lead to a better therapeutic capacity in a murine liver cancer model than that of the comparison groups, it shows no significant difference from Taxol(®) and conjugate suspension. This result could be due to the delayed and sustained drug release from the system. However, it indicates the promising potential for these hybrid liposomes will allow further construction of a compound preparation with improved performance that is based on their enhanced longevity and liver targetability of Paclitaxel. PMID:25455782

  19. Co-administration of GF120918 significantly increases the systemic exposure to oral paclitaxel in cancer patients

    PubMed Central

    Malingré, M M; Beijnen, J H; Rosing, H; Koopman, F J; Jewell, R C; Paul, E M; Huinink, W W Ten Bokkel; Schellens, J H M

    2001-01-01

    Oral bioavailability of paclitaxel is very low, which is due to efficient transport of the drug by the intestinal drug efflux pump P-glycoprotein (P-gp). We have recently demonstrated that the oral bioavailability of paclitaxel can be increased at least 7-fold by co-administration of the P-gp blocker cyclosporin A (CsA). Now we tested the potent alternative orally applicable non-immunosuppressive P-gp blocker GF120918. Six patients received one course of oral paclitaxel of 120 mg/m2 in combination with 1000 mg oral GF120918 (GG918, GW0918). Patients received intravenous (i.v.) paclitaxel 175 mg/m2 as a 3-hour infusion during subsequent courses. The mean area under the plasma concentration–time curve (AUC) of paclitaxel after oral drug administration in combination with GF120918 was 3.27 ± 1.67 ?M.h. In our previously performed study of 120 mg/m2 oral paclitaxel in combination with CsA the mean AUC of paclitaxel was 2.55 ± 2.29 ?M.h. After i.v. administration of paclitaxel the mean AUC was 15.92?± 2.46 ?M.h. The oral combination of paclitaxel with GF120918 was well tolerated. The increase in systemic exposure to paclitaxel in combination with GF120918 is of the same magnitude as in combination with CsA. GF120918 is a good and safe alternative for CsA and may enable chronic oral therapy with paclitaxel. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11139311

  20. Paclitaxel-induced endothelial dysfunction in living rats is prevented by nicorandil via reduction of oxidative stress.

    PubMed

    Serizawa, Ken-Ichi; Yogo, Kenji; Aizawa, Ken; Tashiro, Yoshihito; Takahari, Yoko; Sekine, Kaori; Suzuki, Toshihiko; Ishizuka, Nobuhiko; Ishida, Hideyuki

    2012-01-01

    Paclitaxel-eluting stents dramatically reduce rates of in-stent restenosis; however, paclitaxel is known to lead to endothelial dysfunction. Protective effects of nicorandil on paclitaxel-induced endothelial dysfunction by examining flow-mediated dilation (FMD) were investigated in anesthetized rats. After 7-day osmotic infusion of paclitaxel (5 mg/kg per day), FMD was measured by high-resolution ultrasound in the femoral artery of living rats. Paclitaxel significantly reduced FMD (21.6% ± 3.2% to 7.1% ± 1.7%); this reduction was prevented by co-treatment with nicorandil (15 mg/kg per day), while paclitaxel did not affect nitroglycerin-induced vasodilation. Diazoxide and tempol, but not isosorbide dinitrate, had an effect similar to nicorandil in preventing paclitaxel-induced decrease in FMD. Nicorandil significantly prevented paclitaxel-induced reduction in acetylcholine-induced vasodilation. On the underling mechanisms, paclitaxel increased reactive oxygen species (ROS) production (dihydrorhodamine 123, DCF fluorescence intensity) and NADPH oxidase (p47(phox), gp91(phox) mRNA) in arteries and human coronary artery endothelial cells (HCAECs), while paclitaxel reduced nitric oxide (NO) release (DAF-2 fluorescence intensity), but not endothelial NO synthase (eNOS) phosphorylation in HCAECs. Nicorandil prevented the increased ROS production in arteries and HCAECs, which was 5-hydroxydecanoate (5-HD)-sensitive but 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ)-resistant, without significant effect on the reduced NO release. In conclusion, nicorandil prevents paclitaxel-induced endothelial dysfunction, which may be brought by improved NO bioavailability due to the reduction of oxidative stress via K(ATP) channel activation. PMID:22850598

  1. Gene and microRNA expression reveals sensitivity to paclitaxel in laryngeal cancer cell line.

    PubMed

    Xu, Cheng-Zhi; Xie, Jin; Jin, Bin; Chen, Xin-Wei; Sun, Zhen-Feng; Wang, Bao-Xing; Dong, Pin

    2013-01-01

    Paclitaxel is a widely used chemotherapy drug for advanced laryngeal cancer patients. However, the fact that there are 20-40% of advanced laryngeal cancer patients do not response to paclitaxel makes it necessary to figure out potential biomarkers for paclitaxel sensitivity prediction. In this work, Hep2, a laryngeal cancer cell line, untreated or treated with lower dose of paclitaxel for 24 h, was applied to DNA microarray chips for gene and miR expression profile analysis. Expression of eight genes altered significantly following paclitaxel treatment, which was further validated by quantitative real-time PCR. Four up-regulated genes were ID2, BMP4, CCL4 and ACTG2, in which ID2 and BMP4 were implicated to be involved in several drugs sensitivity. While the down-regulated four genes, MAPK4, FASN, INSIG1 and SCD, were mainly linked to the endoplasmic reticulum and fatty acid biosynthesis, these two cell processes that are associated with drug sensitivity by increasing evidences. After paclitaxel treatment, expression of 49 miRs was significantly altered. Within these miRs, the most markedly expression-changed were miR-31-star, miR-1264, miR-3150b-5p and miR-210. While the miRs putatively modulated the mRNA expression of the most significantly expression-altered genes were miR-1264, miR-130a, miR-27b, miR-195, miR-1291, miR-214, miR-1277 and miR-1265, which were obtained by miR target prediction and miRNA target correlation. Collectively, our study might provide potential biomarkers for paclitaxel sensitivity prediction and drug resistance targets in laryngeal cancer patients. PMID:23826416

  2. Gene and microRNA expression reveals sensitivity to paclitaxel in laryngeal cancer cell line

    PubMed Central

    Xu, Cheng-Zhi; Xie, Jin; Jin, Bin; Chen, Xin-Wei; Sun, Zhen-Feng; Wang, Bao-Xing; Dong, Pin

    2013-01-01

    Paclitaxel is a widely used chemotherapy drug for advanced laryngeal cancer patients. However, the fact that there are 20-40% of advanced laryngeal cancer patients do not response to paclitaxel makes it necessary to figure out potential biomarkers for paclitaxel sensitivity prediction. In this work, Hep2, a laryngeal cancer cell line, untreated or treated with lower dose of paclitaxel for 24 h, was applied to DNA microarray chips for gene and miR expression profile analysis. Expression of eight genes altered significantly following paclitaxel treatment, which was further validated by quantitative real-time PCR. Four up-regulated genes were ID2, BMP4, CCL4 and ACTG2, in which ID2 and BMP4 were implicated to be involved in several drugs sensitivity. While the down-regulated four genes, MAPK4, FASN, INSIG1 and SCD, were mainly linked to the endoplasmic reticulum and fatty acid biosynthesis, these two cell processes that are associated with drug sensitivity by increasing evidences. After paclitaxel treatment, expression of 49 miRs was significantly altered. Within these miRs, the most markedly expression-changed were miR-31-star, miR-1264, miR-3150b-5p and miR-210. While the miRs putatively modulated the mRNA expression of the most significantly expression-altered genes were miR-1264, miR-130a, miR-27b, miR-195, miR-1291, miR-214, miR-1277 and miR-1265, which were obtained by miR target prediction and miRNA target correlation. Collectively, our study might provide potential biomarkers for paclitaxel sensitivity prediction and drug resistance targets in laryngeal cancer patients. PMID:23826416

  3. A painful peripheral neuropathy in the rat produced by the chemotherapeutic drug, paclitaxel.

    PubMed

    Polomano, R C; Mannes, A J; Clark, U S; Bennett, G J

    2001-12-01

    Paclitaxel, an effective anti-neoplastic agent in the treatment of solid tumors, produces a dose-limiting painful peripheral neuropathy in a clinically significant number of cancer patients. Prior work has demonstrated paclitaxel-induced neurodegeneration and sensory loss in laboratory rodents. We describe here an experimental paclitaxel-induced painful peripheral neuropathy. Adult male rats were given four intraperitoneal injections on alternate days of vehicle or 0.5, 1.0, or 2.0 mg/kg of paclitaxel (Taxol). Behavioral tests for pain using mechanical and thermal stimuli applied to the tail and hind paws, and tests for motor performance, were taken before, during and after dosing for 22-35 days. All three doses of paclitaxel caused heat-hyperalgesia, mechano-allodynia, mechano-hyperalgesia, and cold-allodynia, but had no effect on motor performance. Neuropathic pain began within days and lasted for several weeks. We did not detect any dose-response relationship. Tests at the distal, mid, and proximal tail failed to show evidence of a length-dependent neuropathy. Vehicle control injections had no effect on any measure. No significant systemic toxicities were noted in the paclitaxel-treated animals. Light-microscopic inspection of the sciatic nerve (mid-thigh level), L4-L5 dorsal root ganglia, and dorsal and ventral roots, and the gray and white matter of the L4-L5 spinal cord, showed no structural abnormalities. Electron microscopic examination of the sciatic nerve (mid-thigh level) and the L4-L5 dorsal root ganglia and dorsal horns demonstrated no degeneration of myelinated and unmyelinated axons in the sciatic nerve and roots, but revealed endoneurial edema. This model may be useful in understanding a significant source of pain in cancer patients, and in finding ways to avoid the neurotoxicity that limits paclitaxel therapy. PMID:11731066

  4. Quantitative proteomic analysis of mitochondria from human ovarian cancer cells and their paclitaxel-resistant sublines

    PubMed Central

    Chen, Ming; Huang, Hong; He, Haojie; Ying, Wantao; Liu, Xin; Dai, Zhiqin; Yin, Jie; Mao, Ning; Qian, Xiaohong; Pan, Lingya

    2015-01-01

    Paclitaxel resistance is a major obstacle for the treatment of ovarian cancer. The chemoresistance mechanisms are partly related to the mitochondria. Identification of the relevant proteins in mitochondria will help in clarifying the possible mechanisms and in selecting effective chemotherapy for patients with paclitaxel resistance. In the present study, mitochondria from two paclitaxel-sensitive human ovarian cancer cell lines (SKOV3 and A2780) and their corresponding resistant cell lines (SKOV3-TR and A2780-TR) were isolated. Guanidine-modified acetyl-stable isotope labeling and liquid chromatography-hybrid linear ion trap Fourier-transform ion cyclotron resonance mass spectrometry (LC-FTICR MS) were performed to find the expressed differential proteins. Comparative proteomic analysis revealed eight differentially expressed proteins in the ovarian cancer cells and their paclitaxel-resistant sublines. Among them, mimitin and 14-3-3 ?/? were selected for further research. The effects of mimitin and 14-3-3 ?/? were explored using specific siRNA interference in ovarian cancer cell lines and immunohistochemistry in human tissue specimens. The downregulation of mimitin and 14-3-3 ?/? using specific siRNA in paclitaxel-resistant ovarian cancer cells led to an increase in the resistance index to paclitaxel. Multivariate analyses demonstrated that lower expression levels of the mimitin and 14-3-3 ?/? proteins were positively associated with shorter progression-free survival (PFS) and overall survival (OS) in patients with primary ovarian cancer (mimitin: PFS: P = 0.041, OS: P = 0.003; 14-3-3 ?/?: PFS: P = 0.031, OS: P = 0.011). Mimitin and 14-3-3 protein ?/? are potential markers of paclitaxel resistance and prognostic factors in ovarian cancer. PMID:26033570

  5. Dasatinib enhances antitumor activity of paclitaxel in ovarian cancer through Src signaling

    PubMed Central

    XIAO, JUAN; XU, MANMAN; HOU, TENG; HUANG, YONGWEN; YANG, CHENLU; LI, JUNDONG

    2015-01-01

    Src family tyrosine kinase (SFK) activation is associated with ovarian cancer progression. Therefore, SFKs are targets for the development of potential treatments of ovarian cancer. Dasatinib is a tyrosine kinase inhibitor that targets SFK activity, and is used for the treatment of B cell and Abelson lymphomas. At the present time, the potential effect of dasatinib on ovarian cancer is not clear. The aim of the present study was to investigate the antitumor activity of dasatinib, alone and in combination with paclitaxel, in ovarian cancer in vitro and in vivo. In the present study, the expression of Src and phospho-Src-Y416 (p-Src) was measured in six ovarian cancer cell lines using western blotting and immunohistochemistry. In addition, cell viability and apoptosis were measured using an MTT assay and annexin V-fluorescein isothiocyanate staining. An ovarian cancer murine xenograft model was established, in order to evaluate the antitumor effect of dasatinib alone and in combination with paclitaxel in ovarian cancer. High levels of p-Src protein expression were observed in all cell lines, as compared with healthy cells, which indicated activation of the Src signaling pathway. p-Src expression increased in ovarian cancer cells following paclitaxel treatment. Dasatinib treatment demonstrated anti-ovarian cancer properties, by downregulating p-Src expression and by inducing cancer cell apoptosis. Combined treatment with dasatinib and paclitaxel markedly inhibited proliferation and promoted apoptosis of ovarian cancer cells, compared with control cells. Combined dasatinib and paclitaxel treatment exhibited antitumor activities in vivo and in vitro (combination indices, 0.25–0.93 and 0.31–0.75; and tumor growth inhibitory rates, 76.7% and 58.5%, in A2780 and HO8910 cell lines, respectively), compared with paclitaxel treatment alone. Dasatinib monotherapy demonstrated anti-ovarian cancer activities. The effects of dasatinib and paclitaxel treatments on ovarian cancer cells appeared to be mediated by the Src pathway. PMID:25975261

  6. The small molecule tyrosine kinase inhibitor NVP-BHG712 antagonizes ABCC10-mediated paclitaxel resistance: a preclinical and pharmacokinetic study

    PubMed Central

    Anreddy, Nagaraju; Chen, Kang; Patel, Atish; Alqahtani, Saeed; Zhang, Yun-Kai; Wang, Yi-Jun; Sodani, Kamlesh; Kaddoumi, Amal; Ashby, Charles R.; Chen, Zhe-Sheng

    2015-01-01

    Paclitaxel exhibits clinical activity against a wide variety of solid tumors. However, resistance to paclitaxel significantly attenuates the response to chemotherapy. The ABC transporter subfamily C member 10 (ABCC10), also known as multi-drug resistance protein 7 (MRP7) efflux transporter, is a major mediator of paclitaxel resistance. Here, we determine the effect of NVP-BHG712, a specific EphB4 receptor inhibitor, on 1) paclitaxel resistance in HEK293 cells transfected with ABCC10, 2) the growth of tumors in athymic nude mice that received NVP-BHG712 and paclitaxel systemically and 3) the pharmacokinetics of paclitaxel in presence or absence of NVP-BHG712. NVP-BHG712 (0.5 ?M), in HEK293/ABCC10 cells, significantly enhanced the intracellular accumulation of paclitaxel by inhibiting the efflux activity of ABCC10 without altering the expression level of the ABCC10 protein. Furthermore, NVP-BHG712 (25 mg/kg, p.o., q3d × 6), in combination with paclitaxel (15 mg/kg, i.p., q3d × 6), significantly inhibited the growth of ABCC10-expressing tumors in athymic nude mice. NVP-BHG712 administration significantly increased the levels of paclitaxel in the tumors but not in plasma compared to paclitaxel alone. The combination of NVP-BHG712 and paclitaxel could serve as a novel and useful therapeutic strategy to attenuate paclitaxel resistance mediated by the expression of the ABCC10 transporter. PMID:25402202

  7. The small molecule tyrosine kinase inhibitor NVP-BHG712 antagonizes ABCC10-mediated paclitaxel resistance: a preclinical and pharmacokinetic study.

    PubMed

    Kathawala, Rishil J; Wei, Liuya; Anreddy, Nagaraju; Chen, Kang; Patel, Atish; Alqahtani, Saeed; Zhang, Yun-Kai; Wang, Yi-Jun; Sodani, Kamlesh; Kaddoumi, Amal; Ashby, Charles R; Chen, Zhe-Sheng

    2015-01-01

    Paclitaxel exhibits clinical activity against a wide variety of solid tumors. However, resistance to paclitaxel significantly attenuates the response to chemotherapy. The ABC transporter subfamily C member 10 (ABCC10), also known as multi-drug resistance protein 7 (MRP7) efflux transporter, is a major mediator of paclitaxel resistance. Here, we determine the effect of NVP-BHG712, a specific EphB4 receptor inhibitor, on 1) paclitaxel resistance in HEK293 cells transfected with ABCC10, 2) the growth of tumors in athymic nude mice that received NVP-BHG712 and paclitaxel systemically and 3) the pharmacokinetics of paclitaxel in presence or absence of NVP-BHG712. NVP-BHG712 (0.5 ?M), in HEK293/ABCC10 cells, significantly enhanced the intracellular accumulation of paclitaxel by inhibiting the efflux activity of ABCC10 without altering the expression level of the ABCC10 protein. Furthermore, NVP-BHG712 (25 mg/kg, p.o., q3d x 6), in combination with paclitaxel (15 mg/kg, i.p., q3d x 6), significantly inhibited the growth of ABCC10-expressing tumors in athymic nude mice. NVP-BHG712 administration significantly increased the levels of paclitaxel in the tumors but not in plasma compared to paclitaxel alone. The combination of NVP-BHG712 and paclitaxel could serve as a novel and useful therapeutic strategy to attenuate paclitaxel resistance mediated by the expression of the ABCC10 transporter. PMID:25402202

  8. Pharmacokinetic and efficacy study of cisplatin and paclitaxel formulated in a new injectable poly(sebacic-co-ricinoleic acid) polymer.

    PubMed

    Levy-Nissenbaum, Etgar; Khan, Wahid; Pawar, Rajendra P; Tabakman, Rinat; Naftali, Esmira; Winkler, Ilan; Kaufman, Olga; Klapper, Leah; Domb, Abraham J

    2012-09-01

    Injectable biodegradable polymer poly(sebacic-co-ricinoleic acid), P(SA-RA) is currently under development for intratumoral (IT) delivery of drugs for treating solid tumors. This study presents formulation development, pharmacokinetic and efficacy studies of two anticancer drugs (cisplatin and paclitaxel) formulated with P(SA-RA) polymer. In pharmacokinetic study, systemic exposure and pharmacokinetic parameters of cisplatin/paclitaxel following single intravenous (IV) or subcutaneous (SC) doses of cisplatin/paclitaxel was compared with intramuscular (IM) or SC doses of cisplatin/paclitaxel formulated with P(SA-RA) polymer in male CD rat. Simultaneously, the tumor reduction effect and toxicity for these formulations were evaluated in human FaDu head and neck tumor xenograft subcutaneous nude mouse model. Pharmacokinetic data reflect the lower maximal concentrations and sustained release of polymer-cisplatin/paclitaxel formulations compared to standard cisplatin/paclitaxel administration. Regarding efficacy study, a single IT or near the tumor injection (NT) of polymer-paclitaxel or polymer-cisplatin formulation significantly reduced the tumor size, compared to the standard paclitaxel or cisplatin treatments. No death or toxicity and no effect on body weight as well as macroscopic and/or microscopic changes in or near the injected area were observed, proving biocompatibility and acceptability of polymer-formulations. In conclusion, the developed formulation demonstrated controlled release and significant efficacy in delivering these agents and exhibit potential for further clinical development. PMID:22732267

  9. IRAK1 is a therapeutic target that drives breast cancer metastasis and resistance to paclitaxel

    PubMed Central

    Wee, Zhen Ning; Yatim, Siti Maryam J. M.; Kohlbauer, Vera K; Feng, Min; Goh, Jian Yuan; Yi, Bao; Lee, Puay Leng; Zhang, Songjing; Wang, Pan Pan; Lim, Elgene; Tam, Wai Leong; Cai, Yu; Ditzel, Henrik J; Hoon, Dave S. B.; Tan, Ern Yu; Yu, Qiang

    2015-01-01

    Metastatic tumour recurrence due to failed treatments remains a major challenge of breast cancer clinical management. Here we report that interleukin-1 receptor-associated kinase 1 (IRAK1) is overexpressed in a subset of breast cancers, in particular triple-negative breast cancer (TNBC), where it acts to drive aggressive growth, metastasis and acquired resistance to paclitaxel treatment. We show that IRAK1 overexpression confers TNBC growth advantage through NF-?B-related cytokine secretion and metastatic TNBC cells exhibit gain of IRAK1 dependency, resulting in high susceptibility to genetic and pharmacologic inhibition of IRAK1. Importantly, paclitaxel treatment induces strong IRAK1 phosphorylation, an increase in inflammatory cytokine expression, enrichment of cancer stem cells and acquired resistance to paclitaxel treatment. Pharmacologic inhibition of IRAK1 is able to reverse paclitaxel resistance by triggering massive apoptosis at least in part through inhibiting p38-MCL1 pro-survival pathway. Our study thus demonstrates IRAK1 as a promising therapeutic target for TNBC metastasis and paclitaxel resistance. PMID:26503059

  10. Paclitaxel reduces formation of hypertrophic scars in the rabbit ear model

    PubMed Central

    Huang, Li-ping; Wang, Guo-qi; Jia, Zi-shan; Chen, Jing-wen; Wang, Gang; Wang, Xing-lin

    2015-01-01

    Background and objective The onset and progression of pathological scarring involves multiple cytokines and complex mechanisms. However, hyperplasia of fibroblasts and neovascularization plays important roles, which can be inhibited by paclitaxel. The aim of this study was to investigate the efficacy of paclitaxel in the treatment of hypertrophic scars on rabbit ears. Methods Rabbit ear models of hypertrophic scars were established to observe the therapeutic effects of paclitaxel at different concentrations (12 mg/L, 24 mg/L, 48 mg/L, 96 mg/L, 18 mg/L, 54 mg/L, 162 mg/L, 486 mg/L, 30 mg/L, 150 mg/L, 750 mg/L, 3,750 mg/L). The outcome measures included hypertrophic index (HI), density of fibroblasts, density of collagenous fibers, and microvessel density. Results In comparison with the control group, the concentrations of 96 mg/L, 150 mg/L, and 162 mg/L significantly reduce the formation of hypertrophic scars in the rabbit ear models. However, local necrosis was found in the rabbit ear models treated with paclitaxel solution >400 mg/L. Conclusion Paclitaxel has strong inhibitory effects on the hyperplasia of fibroblasts, deposition of collagen, and microangiogenesis in hypertrophic scars on rabbit ears within the concentration range from 48 mg/L to 162 mg/L, without causing local necrosis. PMID:26251604

  11. Characterization of PEG-iron oxide hydrogel nanocomposites for dual hyperthermia and paclitaxel delivery.

    PubMed

    Meenach, Samantha A; Shapiro, Jenna M; Hilt, J Zach; Anderson, Kimberly W

    2013-01-01

    Hyperthermia, the heating of tissue from 41 to 45?°C, has been shown to improve the efficacy of cancer therapy when used in conjunction with irradiation and/or chemotherapy. In this work, hydrogel nanocomposites have been developed that can control the delivery of both heat and a chemotherapeutic agent (e.g. paclitaxel). The nanocomposites studied involve a stealth, poly(ethylene glycol) (PEG)-based system comprised of PEG (n?=?1000) methyl ether methacrylate and PEG (n?=?400) dimethacrylate with iron oxide nanoparticles physically entrapped within the hydrogel matrices. The capability of the hydrogel nanocomposites to be heated in an alternating magnetic field was demonstrated. The heating of the hydrogel systems was dependent on the crosslinking of the hydrogel network where hydrogels with lower swelling ratios were found to heat to a greater extent than those with higher ratios. In addition, paclitaxel was shown to exhibit non-Fickian release from the hydrogel systems, with the amount of drug released dependent on the hydrogel network structure. Three cell lines: M059K (glioblastoma), MDA MB 231 (breast carcinoma), and A549 (lung adenocarcinoma) were exposed to paclitaxel only, hyperthermia only, and both paclitaxel and hyperthermia to determine if a synergistic cytotoxic effect was possible for these cell lines. The efficacy of paclitaxel was greater with hyperthermia for the A549 cells; however, the M059K and MDA MB 231 did not show the same response. PMID:23683041

  12. Paclitaxel sensitivity in relation to ABCB1 expression, efflux and single nucleotide polymorphisms in ovarian cancer

    PubMed Central

    Gao, Bo; Russell, Amanda; Beesley, Jonathan; Chen, Xiao Qing; Healey, Sue; Henderson, Michelle; Wong, Mark; Emmanuel, Catherine; Galletta, Laura; Johnatty, Sharon E.; Bowtell, David; Bowtell, David; Chenevix-Trench, Georgia; deFazio, Anna; Gertig, Dorota; Green, Adle; Webb, Penelope; Hung, Jillian; Moore, Sue; Traficante, Nadia; Fereday, Sian; Harrap, Karen; Sadkowsky, Troy; Pandeya, Nirmala; Stuart-Harris, Robin; Kirsten, Fred; Rutovitz, Josie; Clingan, Peter; Glasgow, Amanda; Proietto, Anthony; Braye, Stephen; Otton, Greg; Shannon, Jennifer; Bonaventura, Tony; Stewart, James; Begbie, Stephen; Friedlander, Michael; Bell, David; Baron-Hay, Sally; Ferrier, Alan; Gard, Greg; Nevell, David; Pavlakis, Nick; Valmadre, Sue; Young, Barbara; Camaris, Catherine; Crouch, Roger; Edwards, Lyndal; Hacker, Neville; Marsden, Donald; Robertson, Greg; Beale, Phillip; Beith, Jane; Carter, Jonothan; Dalrymple, Chris; Hamilton, Anne; Houghton, Roger; Russell, Peter; Links, Matthew; Grygiel, John; Hill, Jane; Brand, Alison; Byth, Karen; Jaworski, Richard; Harnett, Paul; Sharma, Raghwa; Achen, Anita; Wain, Gerard; Ward, Bruce; Papadimos, David; Crandon, Alex; Cummings, Margaret; Horwood, Ken; Obermair, Andreas; Perrin, Lew; Wyld, David; Nicklin, Jim; Davy, Margaret; Oehler, Martin K; Hall, Chris; Dodd, Tom; Healy, Tabitha; Pittman, Ken; Henderson, Doug; Miller, John; Pierdes, John; Blomfield, Penny; Challis, David; McIntosh, Robert; Parker, Andrew; Brown, Bob; Rome, Robert; Allen, David; Grant, Peter; Hyde, Simon; Laurie, Rohan; Robbie, Melissa; Healy, David; Jobling, Tom; Manolitsas, Tom; McNealage, Jane; Rogers, Peter; Susil, Beatrice; Sumithran, Eric; Simpson, Ian; Phillips, Kelly; Rischin, Danny; Fox, Stephen; Johnson, Daryl; Waring, Paul; Lade, Stephen; Loughrey, Maurice; O’Callaghan, Neil; Murray, William; Billson, Virginia; Pyman, Jan; Neesham, Debra; Quinn, Michael; Underhill, Craig; Bell, Richard; Ng, Leong-Fook; Blum, Robert; Ganju, Vinod; Hammond, Ian; Leung, Yee; McCartney, Anthony; Buck, Martin; Haviv, Izak; Purdie, David; Whiteman, David; Zeps, Nikolajs; Malt, Mary-Rose; Mellon, Anne; Robertson, Randall; Bergh, Trish Vanden; Jones, Marian; Mackenzie, Patricia; Maidens, Jane; Nattress, Kath; Chiew, Yoke-Eng; Stenlake, Annie; Sullivan, Helen; Alexander, Barbara; Ashover, Pat; Brown, Sue; Corrish, Tracy; Green, Lyn; Jackman, Leah; Ferguson, Kaltin; Martin, Karen; Martyn, Adam; Ranieri, Barbara; White, Jo; Jayde, Victoria; Bowes, Leanne; Mamers, Pamela; Galletta, Laura; Giles, Debra; Hendley, Joy; Alsop, Katherine; Schmidt, Trudy; Shirley, Helen; Ball, Colleen; Young, Cherry; Viduka, Suzanna; Tran, Hoa; Bilic, Sanela; Glavinas, Lydia; Brooks, Julia; Haber, Michelle; Norris, Murray; Harnett, Paul; Chenevix-Trench, Georgia; Balleine, Rosemary L.; deFazio, Anna

    2014-01-01

    ABCB1 (adenosine triphosphate-binding cassette transporter B1) mediates cellular elimination of many chemotherapeutic agents including paclitaxel, which is commonly used to treat ovarian cancer. A significant association between common single nucleotide polymorphisms (SNPs) in ABCB1 and progression-free survival has been reported in patients with ovarian cancer. Variable paclitaxel clearance due to genotype specific differences in ABCB1 activity in cancer cells and/or normal tissues may underlie the association. Using cell-based models, we evaluated the correlations between ABCB1 expression, polymorphisms, transporter activity and paclitaxel sensitivity in ovarian cancer (n = 10) and lymphoblastoid (n = 19) cell lines. Close associations between ABCB1 expression, transporter function and paclitaxel sensitivity were found in lymphoblastoid cell lines, although we could not demonstrate an association with common SNPs. In ovarian cancer cell lines, ABCB1 expression was low and the association between expression and function was lost. These results suggest that ABCB1 related survival difference in ovarian cancer patients is more likely to be due to differential whole body paclitaxel clearance mediated by normal cells rather than a direct effect on cancer cells. PMID:24810093

  13. A novel biosensor for quantitative monitoring of on-target activity of paclitaxel.

    PubMed

    Townley, H E; Zheng, Y; Goldsmith, J; Zheng, Y Y; Stratford, M R L; Dobson, P J; Ahmed, A A

    2015-01-21

    This study describes a system for quantifying paclitaxel activity using the C-terminus of ?-tubulin as a biomarker. Following stabilization of microtubules with paclitaxel, a specific detyrosination reaction occurs at the C-terminus of ?-tubulin which could be used to assess efficacy. A fluorescence resonance energy transfer (FRET) based biosensor was synthesized comprising a short peptide that corresponded to the C-terminus of ?-tubulin, a fluorophore (Abz), and a quencher (Dnp). The fluorophore added to the end of the peptide can be released upon enzymatic detyrosination. In addition, a single fluorophore-tagged peptide was also conjugated to mesoporous silica nanoparticles to examine the feasibility of combining the drug with the peptide biomarker. As a proof of concept, we found that the degree of peptide cleavage, and therefore enzymatic activity, was directly correlated with exogenous bovine carboxypeptidase (CPA) an enzyme that mimics endogenous detyrosination. In addition, we show that cell lysates obtained from paclitaxel-treated cancer cells competed with exogenous CPA for biosensor cleavage in a paclitaxel dose-dependent manner. Our work provides strong evidence for the feasibility of combining paclitaxel with a novel biosensor in a multi-load nanoparticle. PMID:25483994

  14. Elevated MARCKS phosphorylation contributes to unresponsiveness of breast cancer to paclitaxel treatment.

    PubMed

    Chen, Ching-Hsien; Cheng, Chun-Ting; Yuan, Yuan; Zhai, Jing; Arif, Muhammad; Fong, Lon Wolf R; Wu, Reen; Ann, David K

    2015-06-20

    Accumulating evidence has suggested that myristoylated alanine-rich C-kinase substrate (MARCKS) is critical for regulating multiple pathophysiological processes. However, the molecular mechanism underlying increased phosphorylation of MARCKS at Ser159/163 (phospho-MARCKS) and its functional consequence in neoplastic disease remain to be established. Herein, we investigated how phospho-MARCKS is regulated in breast carcinoma, and its role in the context of chemotherapy. In a screen of patients with breast tumors, we find that the abundance of phospho-MARCKS, not MARCKS protein per se, increased in breast cancers and positively correlated with tumor grade and metastatic status. Among chemotherapeutic agents, mitotic inhibitors, including paclitaxel, vincristine or eribulin, notably promoted phospho-MARCKS accumulation in multiple breast cancer cells. We further show that phospho-MARCKS acted upstream of Src activation upon paclitaxel exposure. Reduction of phospho-MARCKS by knockdown of MARCKS or pharmacological agents increased paclitaxel sensitivity. Particularly, a known phospho-MARCKS inhibitor, MANS peptide, was demonstrated to increase paclitaxel efficacy and attenuate angiogenesis/metastasis of xenografted breast cancer cells by decreasing abundance of phospho-MARCKS and messages of inflammatory mediators. Our data suggest that unresponsiveness of breast cancer to paclitaxel treatment is, at least in part, mediated by phospho-MARCKS and also provide an alternative therapeutic strategy against breast cancer by improving taxanes sensitivity. PMID:26015406

  15. Paclitaxel-loaded poly(D,L-lactide-co-glycolide) nanoparticles for radiotherapy in hypoxic human tumor cells in vitro.

    PubMed

    Jin, Cheng; Bai, Ling; Wu, Hong; Liu, Junye; Guo, Guozhen; Chen, Jingyuan

    2008-06-01

    Radioresistant hypoxic cells may contribute to the failure of radiation therapy in controlling certain tumors. Some studies have suggested the radiosensitizing effect of paclitaxel. The poly (D,L-lactide-co-glycolide)(PLGA) nanoparticles containing paclitaxel were prepared by o/w emulsification-solvent evaporation method. The physicochemical characteristics of the nanoparticles (i.e., encapsulation efficiency, particle size distribution, morphology, in vitro release) were studied. The morphology of the two human tumor cell lines: a carcinoma cervicis (HeLa) and a hepatoma (HepG(2)), treated with paclitaxel-loaded nanoparticles was photomicrographed. Flow cytometry was used to quantify the number of the tumor cells held in the G(2)/M phase of the cell cycle. The cellular uptake of nanoparticles was evaluated by transmission electronic microscopy. Cell viability was determined by the ability of single cell to form colonies in vitro. The prepared nanoparticles were spherical in shape with size between 200 nm and 800 nm. The encapsulation efficiency was 85.5%. The release behaviour of paclitaxel from the nanoparticles exhibited a biphasic pattern characterised by a fast initial release during the first 24 h, followed by a slower and continuous release. Co-culture of the two tumor cell lines with paclitaxel-loaded nanoparticles demonstrated that the cell morphology was changed and the released paclitaxel retained its bioactivity to block cells in the G(2)/M phase. The cellular uptake of nanoparticles was observed. The free paclitaxel and paclitaxel-loaded nanoparticles effectively sensitized hypoxic HeLa and HepG(2) cells to radiation. Under this experimental condition, the radiosensitization of paclitaxel-loaded nanoparticles was more significant than that of free paclitaxel. PMID:18367873

  16. Programmed Hydrolysis in Designing Paclitaxel Prodrug for Nanocarrier Assembly.

    PubMed

    Fu, Q; Wang, Y; Ma, Y; Zhang, D; Fallon, J K; Yang, X; Liu, D; He, Z; Liu, F

    2015-01-01

    Nanocarriers delivering prodrugs are a way of improving in vivo effectiveness and efficiency. For therapeutic efficacy, the prodrug must hydrolyze to its parent drug after administration. Based on the fact that the hydrolysis is impeded by steric hindrance and improved by sufficient polarity, in this study, we proposed the PTX-S-S-VE, the conjugation of paclitaxel (PTX) to vitamin E (VE) through a disulfide bridge. This conjugate possessed the following advantages: first, it can be encapsulated in the VE/VE2-PEG2000/water nanoemulsions because of favorable hydrophobic interactions; second, the nanoemulsions had a long blood circulation time; finally, the concentrated glutathione in the tumor microenvironment could cleave the disulfide bond to weaken the steric hindrance and increase the polarity, promoting the hydrolysis to PTX and increasing the anticancer activity. It was demonstrated in vitro that the hydrolysis of PTX-S-S-VE was enhanced and the cytotoxicity was increased. In addition, PTX-S-S-VE had greater anticancer activity against the KB-3-1 cell line tumor xenograft and the tumor size was smaller after the 4(th) injection. The present result suggests a new way, use of reduction, to improve the in vivo anticancer activity of a prodrug for nanocarrier delivery by unshielding the ester bond and taking off the steric block. PMID:26166066

  17. Programmed Hydrolysis in Designing Paclitaxel Prodrug for Nanocarrier Assembly

    PubMed Central

    Fu, Q.; Wang, Y.; Ma, Y.; Zhang, D.; Fallon, J. K.; Yang, X.; Liu, D.; He, Z.; Liu, F.

    2015-01-01

    Nanocarriers delivering prodrugs are a way of improving in vivo effectiveness and efficiency. For therapeutic efficacy, the prodrug must hydrolyze to its parent drug after administration. Based on the fact that the hydrolysis is impeded by steric hindrance and improved by sufficient polarity, in this study, we proposed the PTX-S-S-VE, the conjugation of paclitaxel (PTX) to vitamin E (VE) through a disulfide bridge. This conjugate possessed the following advantages: first, it can be encapsulated in the VE/VE2-PEG2000/water nanoemulsions because of favorable hydrophobic interactions; second, the nanoemulsions had a long blood circulation time; finally, the concentrated glutathione in the tumor microenvironment could cleave the disulfide bond to weaken the steric hindrance and increase the polarity, promoting the hydrolysis to PTX and increasing the anticancer activity. It was demonstrated in vitro that the hydrolysis of PTX-S-S-VE was enhanced and the cytotoxicity was increased. In addition, PTX-S-S-VE had greater anticancer activity against the KB-3-1 cell line tumor xenograft and the tumor size was smaller after the 4th injection. The present result suggests a new way, use of reduction, to improve the in vivo anticancer activity of a prodrug for nanocarrier delivery by unshielding the ester bond and taking off the steric block. PMID:26166066

  18. Molecular analysis of interactions between a PAMAM dendrimer-paclitaxel conjugate and a biomembrane.

    PubMed

    He, XiaoCong; Lin, Min; Lu, TianJian; Qu, ZhiGuo; Xu, Feng

    2015-11-28

    Understanding the underlying mechanism of nanomedicine-biomembrane interactions is important for the design and optimization of payload delivery systems. This study investigates the interactions between polyamidoamine (PAMAM) dendrimer-paclitaxel conjugates and biomembranes using coarse-grained molecular dynamics simulations. We found that acidic conditions (e.g., pH ? 5) and membrane asymmetry can improve the conjugate penetration. Paclitaxel (PTX) distributions on a G4 PAMAM dendrimer can affect interactions via the penetration mechanism, although they have no significant effect on interactions via the adsorption mechanism. The random distribution of PTX can enhance the ability of PTX molecules to pass through asymmetric membranes. Furthermore, the penetration process becomes more difficult with increasing paclitaxel loading ratios. These results provide molecular insights into the precise translocation mechanism of dendrimer-drug conjugates and thus provide suggestions for drug design and delivery. PMID:26256278

  19. Dermatomyositis and Paclitaxel-Induced Cutaneous Drug Eruption Associated with Metastatic Breast Cancer

    PubMed Central

    Kim, Youngji; Jung, Woojin

    2015-01-01

    Dermatomyositis (DM) is an idiopathic autoimmune connective disease characterized by muscles and skin inflammation of and a well-recognized association with several human malignancies, especially breast cancer. Paclitaxel is a taxane antineoplastic agent with therapeutic effects against a wide range of cancers including breast cancer. This drug is well known for neurotoxicity and hypersensitivity reactions. However, cutaneous drug eruptions, especially those of grade III or higher, are not frequent. Here, we describe the case of a 55-year-old woman with metastatic breast cancer who developed paraneoplastic DM and a paclitaxel-induced exanthematous drug eruption. This case report emphasizes the importance of evaluating internal malignancies, such as advanced breast cancer, in newly developed DM patients. In addition, it presents a rare case of paclitaxel-induced exanthematous drug eruption. The purpose of this case report highlights the immunological pathogenic mechanism of DM and drug eruption in underlying advanced breast cancer. PMID:26155297

  20. Joint Surface-Active Phospholipid-Mimetic Liposomes for Intra-Articular Delivery of Paclitaxel.

    PubMed

    Dyondi, Deepti; Sarkar, Amrita; Banerjee, Rinti

    2015-07-01

    Synovial inflammation, angiogenesis and joint degradation are the hallmarks of inflammatory arthritis progression. Angiostatic targeting is an extensively studied potential therapeutic option for inflammatory arthritis. Studies have confirmed that surface-active phospholipids (SAPLs), predominantly phosphatidylcholines (PCs), are responsible for the lubricating properties of lubricin in joints. Paclitaxel, a potent antineoplastic agent in cancer chemotherapy, has been shown to inhibit several processes associated with arthritis development such as angiogenesis, neutrophil activation and collagenase expression but is limited by systemic toxicity. This study was aimed at designing a surface-active phospholipid mimetic nanocarrier system and assessing its efficacy for intra-articular delivery of paclitaxel in rat joints. Dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) liposomes were prepared using a thin-film hydration method and characterized for size, morphology, drug encapsulation and in vitro release. DPPC liposomes of a size of 311 ± 57 nm and 92 ± 0.6% paclitaxel encapsulation were developed. In vitro release studies showed a short initial burst phase and a sustained release profile with a cumulative release of 18 ± 0.36% of the drug by 60 h in phosphate-buffered saline (PBS). The efficacy of the intra-articular formulation was evaluated in antigen-induced arthritic rat models and compared with direct injections of paclitaxel. After a 28-day period, intra-articular paclitaxel delivered in liposomes led to a significant improvement in gait scores and synovial inflammation in rats compared to the control, as seen in histopathology studies. Reduction in inflammation in the experimental group was confirmed by evaluating TNF? levels in serum samples. This study suggests feasibility of using surface-active phospholipid based carriers for local, intra-articular therapy of paclitaxel in arthritis. PMID:26307845

  1. Lipid-dendrimer hybrid nanosystem as a novel delivery system for paclitaxel to treat ovarian cancer.

    PubMed

    Liu, Yuanjie; Ng, Yiwei; Toh, Ming R; Chiu, Gigi N C

    2015-12-28

    Combining lipids and dendrimers into one formulation is an emerging platform in the drug delivery field. This study aims to (i) develop and characterize a lipid-dendrimer hybrid (LDH) nanosystem for the hydrophobic anticancer drug paclitaxel, and (ii) evaluate its in vitro and in vivo anti-cancer activity in ovarian cancer models. The LDH nanosystems were prepared from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and poly (amidoamine) (PAMAM) G4.0. The size and zeta potential of the LDH nanosystem were 37.6±6.1nm and +2.9±0.1mV, respectively, with vesicular morphology observed under cryo-TEM. The encapsulation efficiency of paclitaxel in the LDH system was 78.0±2.1%. The potency of paclitaxel could be significantly improved by 37-fold when presented in the LDH nanosystem as compared to free drug, whereby paclitaxel and PAMAM G4.0 acted synergistically in killing the ovarian cancer cells. As shown by fluorescence confocal microscopy, majority of the lipids in the LDH nanosystem were located in the plasma membrane, while the dendrimers were distributed intracellularly upon uptake. Despite the use of a 10-fold lower paclitaxel dose, the survival of IGROV-1 ovarian tumor-bearing animals could be significantly prolonged by the paclitaxel-loaded LDH nanosystem, as reflected by a 50% increase in the median survival time. Such hybrid nanosystem emerged from combining two established drug delivery platforms could pave way for the development of multifunctional delivery systems for potential theranostic applications. PMID:26551345

  2. Fatal outcome of a hypersensitivity reaction to paclitaxel: a critical review of premedication regimens.

    PubMed

    Kloover, J S; den Bakker, M A; Gelderblom, H; van Meerbeeck, J P

    2004-01-26

    Hypersensitivity reactions (HSRs) to paclitaxel are frequently encountered in patients receiving this antitumour drug. Administration of histamine H1- and H2-receptor antagonists and corticosteroids has been shown to reduce significantly the risk of developing an HSR in patients receiving taxanes. In this case report, we describe the fatal outcome of an HSR in a patient receiving paclitaxel despite short-course premedication. The level of evidence supporting the short-course i.v. premedication schedule is challenged, as it is not compatible with the pharmacokinetic properties of dexamethasone. PMID:14974481

  3. Multimodal imaging in paclitaxel-induced macular edema: the microtubule disfunction.

    PubMed

    Freitas-da-Costa, Paulo; Brandão, Elisete; Bragança, Teresa; Falcão-Reis, Fernando; Carneiro, Angela

    2015-12-01

    Taxanes are a rare cause of macular edema. A 63-year-old female, under paclitaxel treatment, was observed with progressively bilateral visual acuity loss and an apparently normal fundus. Optical coherence tomography revealed a bilateral cystoid macular edema with a late petaloid pooling on fluorescein angiography. Fundus autofluorescence exhibited a foveal hiperautofluorescent pattern. There was a great improvement of visual acuity and macular thickness after 5 months of drug withdrawal. Paclitaxel maculopathy diagnosis requires a high degree of suspicion. The pathophysiology remains unclear. PMID:25597372

  4. Therapeutic efficacy of paclitaxel and carboplatin via arterial or venous perfusion in rabbits with VX-2 tongue cancer

    PubMed Central

    Zhang, Ni-Ni; Zhang, Li-Gang; Liu, Ze-Nian; Huang, Gui-Lin; Zhang, Lin; Yi, Jie; Yao, Li; Hu, Xiao-Hua

    2015-01-01

    Objective: This study aimed to investigate the therapeutic efficacy of paclitaxel in combination with carboplatin in different ways in rabbits with VX-2 tongue cancer. Methods: Rabbit VX-2 tongue cancer model was established and animals were then divided into 6 groups, in which animals received perfusion with paclitaxel liposome and carboplatin via the lingual artery, with free paclitaxel and carboplatin via the lingual artery, with 5% glucose via the lingual artery, with paclitaxel liposome and carboplatin via ear vein, with free paclitaxel and carboplatin via the ear vein and with 5% glucose via the ear vein independently. When the maximum diameter of cervical lymph nodes was larger than 5 mm, chemotherapy was initiated. Seven days later, flow cytometry and immunohistochemistry were performed to detect the apoptosis of VX-2 cells and P53 expression in the primary cancer and metastatic lymph nodes. Results: Targeted arterial perfusion with paclitaxel liposome in combination with carboplatin was more effective to induce the apoptosis of cancer cells in the primary cancer and metastatic lymph nodes and inhibit their proliferation. Conclusion: Targeted arterial perfusion with paclitaxel liposome in combination with carboplatin is effective to reduce tumor size, attenuate the surgery induced injury and improve the post-operative quality of life of oral cancer patients. PMID:26131070

  5. Up-regulation of miR-877 induced by paclitaxel inhibits hepatocellular carcinoma cell proliferation though targeting FOXM1

    PubMed Central

    Huang, Xinli; Qin, Jianjie; Lu, Sen

    2015-01-01

    Paclitaxel is an effective chemotherapeutic agent for treatment of cancer patients, and frequently, clinical outcome is influenced by paclitaxel sensitivity. Despite this, our understanding of the molecular basis of paclitaxel response is incomplete. Recently, it has been shown that microRNAs (miRNAs) influence messenger RNA (mRNA) transcriptional control and can contribute to human carcinogenesis. In the present study, our objective was to identify miR-877 associated with HCC cell lines response to paclitaxel and to evaluate these miRNAs as therapeutic targets to increase paclitaxel sensitivity. We measured the expression of miR-877 in paclitaxel-treated HCC cell lines. We verified that miR-877 was up-regulated in paclitaxel-induced HCC cells by real-time PCR. We further investigated the role and mechanisms of miR-877. Over-expression of miR-877 in HCC cells partially restores paclitaxel sensitivity. The proliferation activity and the colony formation activity of HCC cells were both inhibited after transfected with miR-877. MiRNA targets prediction algorithms imply FOXM1 serves as a target gene for miR-877. A fluorescent reporter assay confirmed that miR-877 binds specifically to the predicted site of the FOXM1 mRNA 3’-untranslated region (3’UTR). When miR-877 was overexpressed in HCC cells, the protein levels of FOXM1 was downregulated. These results indicate that miR-877 could influence the sensitivity of paclitaxel treatment in hepatocellular carcinoma cell lines by targeting FOXM1. PMID:25973036

  6. The ABCB1 3435 T allele does not increase the risk of paclitaxel-induced neurotoxicity

    PubMed Central

    ÖFVERHOLM, ANNA; EINBEIGI, ZAKARIA; MANOUCHEHRPOUR, SHOKOUFEH; ALBERTSSON, PER; SKRTIC, STANKO; ENERBÄCK, CHARLOTTA

    2010-01-01

    Paclitaxel is a frequently used anticancer drug with considerable inter-individual variability in terms of drug efficiency and toxicity. The reasons for this variability have not been fully explained. The purpose of this study was to evaluate the possible relationship between paclitaxel-induced neurotoxicity and the distribution of genetic variations with reported functional significance in the ABCB1, CYP2C8 and CYP3A4 genes that are all implicated in taxol metabolism. Women (n=36) experiencing paclitaxel-induced neurotoxicity were included in the study, and the ABCB1 G2677A/T and C3435T as well as CYP2C8*3 and CYP3A4*1b allele frequencies were determined using PCR-RFLP and DNA sequence analysis. We showed that the ABCB1 3435T allele, previously reported as a risk allele for neurotoxicity, did not correlate with the occurrence of neurotoxicity in our patient sample (Chi-square test, p=0.61). Furthermore, we showed that neither the CYP2C8*3 nor CYP3A4*1b alleles, that both lead to diminished enzyme activity, correlated with paclitaxel-induced neurotoxicity. The occurrence and variation in severity of neurotoxicity in our Swedish patient sample could therefore not be explained by the reported functional polymorphisms in the ABCB1, CYP2C8 and CYP3A4 genes. PMID:22966274

  7. Chemotherapy with cisplatin and paclitaxel in patients with locally advanced, recurrent or metastatic oesophageal cancer.

    PubMed Central

    Petrasch, S.; Welt, A.; Reinacher, A.; Graeven, U.; König, M.; Schmiegel, W.

    1998-01-01

    Single-agent therapy with paclitaxel is effective against both squamous cell carcinoma and adenocarcinoma of the oesophagus. However, only limited data are available on the combination of paclitaxel with other cytotoxic drugs in this entity. Patients with unresectable stage III, recurrent or metastatic tumours were treated in a multicentre setting with paclitaxel 90 mg m(-2) given over 3 h intravenously, followed by cisplatin 50 mg m(-2). The courses were repeated every 14 days. Twenty patients with squamous cell carcinoma or adenocarcinoma of the oesophagus were evaluable for response. The overall remission rate was 40% (8/20), including 15% (3/20) clinically complete responses. Clinical benefit response, defined as relief of dysphagia and/or significant gain in weight, was achieved in 70% of the patients. Neutropenia of CTC grade 3 occurred only in 10% of the patients; no grade 4 neutropenia and no severe thrombocytopenia was encountered. CTC grade 4 neurotoxicity was seen in 5% of patients. Cisplatin/paclitaxel administered every 14 days, was effective in patients with poor prognosis oesophageal cancer and toxicity was acceptable. PMID:9716036

  8. Tumor-targeted delivery of paclitaxel using low density lipoprotein-mimetic solid lipid nanoparticles.

    PubMed

    Kim, Jin-Ho; Kim, Youngwook; Bae, Ki Hyun; Park, Tae Gwan; Lee, Jung Hee; Park, Keunchil

    2015-04-01

    Water-insoluble anticancer drugs, including paclitaxel, present severe clinical side effects when administered to patients, primarily associated with the toxicity of reagents used to solubilize the drugs. In efforts to develop alternative formulations of water-insoluble anticancer drugs suitable for intravenous administration, we developed biocompatible anticancer therapeutic solid lipid nanoparticles (SLNs), mimicking the structure and composition of natural particles, low-density lipoproteins (LDLs), for tumor-targeted delivery of paclitaxel. These therapeutic nanoparticles contained water-insoluble paclitaxel in the core with tumor-targeting ligand covalently conjugated on the polyethylene glycol (PEG)-modified surface (targeted PtSLNs). In preclinical human cancer xenograft mouse model studies, the paclitaxel-containing tumor-targeting SLNs exhibited pronounced in vivo stability and enhanced biocompatibility. Furthermore, these SLNs had superior antitumor activity to in-class nanoparticular therapeutics in clinical use (Taxol and Genexol-PM) and yielded long-term complete responses. The in vivo targeted antitumor activities of the SLN formulations in a mouse tumor model suggest that LDL-mimetic SLN formulations can be utilized as a biocompatible, tumor-targeting platform for the delivery of various anticancer therapeutics. PMID:25686010

  9. Formulation, characterization and hypersensitivity evaluation of an intravenous emulsion loaded with a paclitaxel-cholesterol complex.

    PubMed

    Xia, Xue-Jun; Guo, Rui-Fang; Liu, Yu-Ling; Zhang, Peng-Xiao; Zhou, Cui-Ping; Jin, Du-Jia; Wang, Ren-Yun

    2011-01-01

    The objective of this paper was to develop a novel Cremophor-free, autoclave stable, intravenous emulsion for paclitaxel (PACE). A paclitaxel-cholesterol complex was used as the drug carrier to improve the solubility of paclitaxel in the oil phase of emulsions. The complex and PACE were prepared by rotary evaporation and high-pressure homogenization, respectively. Effects of oil phases, emulsifiers and pH values on the characteristics of PACE were investigated. PACE was characterized with regard to its appearance, morphology, osmolality, pH value, particle size, zeta potential, encapsulation efficiency and stability. Hypersensitivity was evaluated by guinea pig hypersensitivity reaction. The final formulation was composed of the complex, soybean oil, medium-chain triglyceridel, soybean lecithin, poloxamer 188 and glycerol. The resulting PACE had an encapsulation efficiency of 97.3% with a particle size of 135 nm and a zeta potential of -38.3 mV. Osmolality and pH of the formulation were 383 mOsmol/kg and 4.5, respectively. The formulation survived autoclaving at 115 °C for 30 min and remained stable for at least 12 months at 6 °C. PACE also exhibited a better tolerance than an equal dose of Cremophor-based paclitaxel injection in guinea pigs, as no obvious hypersensitivity reaction was observed. These results suggested that PACE has a great potential for industrial-scale production and clinical applications. PMID:21372412

  10. Gemcitabine in combination with paclitaxel for advanced soft-tissue sarcomas

    PubMed Central

    SONNENBLICK, AMIR; ELEYAN, FERAS; PERETZ, TAMAR; OSPOVAT, INNA; MERIMSKY, OFER; SELLA, TAMAR; PEYLAN-RAMU, NILI; KATZ, DANIELA

    2015-01-01

    A limited number of chemotherapeutic agents have been found to be active against advanced soft-tissue sarcomas (STSs), particularly sarcomas that have progressed following doxorubicin treatment. The aim of this retrospective study was to determine the response to treatment with gemcitabine plus paclitaxel in patients with STSs. Data were collected on all patients with advanced non-resectable STS who were treated with a fixed dose 700 mg/m2 gemcitabine in combination with 70 mg/m2 paclitaxel on days 1 and 8 every 3 weeks. A total of 30 patients were included, with a median age of 56.4 years (range, 40–70 years). The gemcitabine/paclitaxel combination was well tolerated, with an overall response in 27% and a clinical benefit in 57% of the patients. The median progression-free survival was 6.1 months and the overall survival was 14.3 months. In conclusion, gemcitabine plus paclitaxel was found to be tolerable and effective in patients with advanced STSs. PMID:26171190

  11. Hybrid films from blends of chitosan and egg phosphatidylcholine for localized delivery of paclitaxel.

    PubMed

    Grant, J; Blicker, M; Piquette-Miller, M; Allen, C

    2005-07-01

    Chitosan and egg phosphatidylcholine (ePC) were used as a unique combination to prepare composite films for localized drug delivery. In comparison to other phospholipids analyzed, ePC was found to produce chitosan-based films with minimal swelling and a high degree of stability. The properties of the chitosan-ePC films were characterized and found to be dependent on the ratio of chitosan:ePC present. FTIR analysis of chitosan-ePC films revealed that their high stability may be attributed to interactions present between these two biomaterials. In vitro evaluation of the cytotoxicity and protein adsorption properties of the films were used to provide a preliminary indication of their biocompatibility. The chitosan-ePC film was also evaluated as a matrix for the localized delivery of the anti-cancer agent, paclitaxel. Nanoparticles containing paclitaxel were dispersed throughout the chitosan-ePC film to result in a drug:material ratio of 1:8 (wt/wt). The film was found to provide a sustained release of paclitaxel over a 4-month period in biologically relevant media. The biological activity of paclitaxel loaded in the chitosan-ePC film was confirmed in SKOV-3 human ovarian cancer cells. PMID:15920770

  12. A Novel Technique for Loading of Paclitaxel-PLGA Nanoparticles onto ePTFE Vascular Grafts

    E-print Network

    Park, Jong-Sang

    A Novel Technique for Loading of Paclitaxel-PLGA Nanoparticles onto ePTFE Vascular Grafts Hyun Jung and spin penetration techniques. Scanning electron microscope (SEM) images of various stages of Ptx, there are no effective therapeutic interventions for HVAD to date (5). At the histological level, neointimal hyperplasia

  13. Safety and pharmacology of paclitaxel in patients with impaired liver function: a population pharmacokinetic–pharmacodynamic study

    PubMed Central

    Joerger, M; Huitema, A D R; Huizing, M T; Willemse, P H B; de Graeff, A; Rosing, H; Schellens, J H M; Beijnen, J H; Vermorken, J B

    2007-01-01

    What is already known about this subject There are few data about the safety of paclitaxel in patients with clinically significant liver impairment. A study by Venook and colleagues (J Clin Oncol 1998; 16: 1811–19) studied paclitaxel pharmacokinetics (PK) and pharmacodynamics (PD) in patients with liver impairment. The results were mainly descriptive, as detailed PK–PD data were available for only a subgroup of patients. Another study by Wilson and colleagues found a correlation between tumour involvement of the liver, aspartate aminotransferase and total bilirubin concentrations and reduced paclitaxel clearance in 48 patients with advanced breast cancer in an early combined Phase I/II study (J Clin Oncol 1994; 12: 1621–9). Finally, the study by Huizing and colleagues (Ann Oncol 1995; 6: 699–704) described two advanced breast cancer patients with liver impairment who experienced higher paclitaxel AUC concentrations and more severe neuropathywhen exposed to paclitaxel 250 mg m?2 as a 3-h infusion. Liver impairment has been studied as a covariate within population models of paclitaxel in patients with normal or mildly impaired liver function (Henningsson et al. Eur JCancer 2003; 39: 1105–14; Joerger et al. Clin Cancer Res 2006; 12: 2150–7). Both studies found a negative correlation between total bilirubin concentrations and paclitaxel elimination. What this study adds A direct relationship between liver impairment, paclitaxel elimination and susceptibility to neutropenia/thrombopenia. As a result of PK–PD simulations, suggestions could be made for (further) dose adaptations for patients with more severe liver impairment. Aims To assess quantitatively the safety and pharmacology of paclitaxel in patients with moderate to severe hepatic impairment. Methods Solid tumour patients were enrolled into five liver function cohorts as defined by liver transaminase and total bilirubin concentrations. Paclitaxel was administered as a 3-h intravenous infusion at doses ranging from 110 to 175 mg m?2, depending on liver impairment. Covariate and semimechanistic pharmacokinetic–pharmacodynamic (PK–PD) population modelling was used to describe the impact of liver impairment on the pharmacology and safety of paclitaxel. Results Thirty-five patients were included in the study, and PK data were assessed for 59 treatment courses. Most patients had advanced breast cancer (n = 22). Objective responses to paclitaxel were seen in four patients (11%). Patients in higher categories of liver impairment had a significantly lower paclitaxel elimination capacity (R2 = ?0.38, P = 0.05), and total bilirubin was a significant covariate to predict decreased elimination capacity with population modelling (P = 0.002). Total bilirubin was also a significant predictor of increased haematological toxicity within the integrated population PK–PD model (P < 10?4). Data simulations were used to calculate safe initial paclitaxel doses, which were lower than the administered doses for liver impairment cohorts III–V. Conclusions Total bilirubin is a good predictor of paclitaxel elimination capacity and of individual susceptibility to paclitaxel-related myelosuppression in cancer patients with moderate to severe liver impairment. The proposed, adapted paclitaxel doses need validation in prospective trials. PMID:17935602

  14. Polymeric nanoparticles for the intracellular delivery of paclitaxel in lung and breast cancer

    NASA Astrophysics Data System (ADS)

    Zubris, Kimberly Ann Veronica

    Nanoparticles are useful for addressing many of the difficulties encountered when administering therapeutic compounds. Nanoparticles are able to increase the solubility of hydrophobic drugs, improve pharmacokinetics through sustained release, alter biodistribution, protect sensitive drugs from low pH environments or enzymatic alteration, and, in some cases, provide targeting of the drug to the desired tissues. The use of functional nanocarriers can also provide controlled intracellular delivery of a drug. To this end, we have developed functional pH-responsive expansile nanoparticles for the intracellular delivery of paclitaxel. The pH-responsiveness of these nanoparticles occurs due to a hydrophobic to hydrophilic transition of the polymer occurring under mildly acidic conditions. These polymeric nanoparticles were systematically evaluated for the delivery of paclitaxel in vitro and in vivo to improve local therapy for lung and breast cancers. Nanoparticles were synthesized using a miniemulsion polymerization process and were subsequently characterized and found to swell when exposed to acidic environments. Paclitaxel was successfully encapsulated within the nanoparticles, and the particles exhibited drug release at pH 5 but not at pH 7.4. In addition, the uptake of nanoparticles was observed using flow cytometry, and the anticancer efficacy of the paclitaxel-loaded nanoparticles was measured using cancer cell lines in vitro. The potency of the paclitaxel-loaded nanoparticles was close to that of free drug, demonstrating that the drug was effectively delivered by the particles and that the particles could act as an intracellular drug depot. Following in vitro characterization, murine in vivo studies demonstrated the ability of the paclitaxel-loaded responsive nanoparticles to delay recurrence of lung cancer and to prevent establishment of breast cancer in the mammary fat pads with higher efficacy than paclitaxel alone. In addition, the ability of nanoparticles to migrate up to 40 cm through lymphatic channels to local lymph nodes was demonstrated using near infrared imaging in a large animal model. Continued investigation of functional nanoparticles, like the system described here for lung and breast cancer, will facilitate the development of new materials that meet the varied and demanding needs in chemotherapy, and may afford new treatment options for the local and metastatic control of many forms of cancer.

  15. Comparative Effects of Ibandronate and Paclitaxel on Immunocompetent Bone Metastasis Model

    PubMed Central

    Chung, Yoon-Sok; Kang, Ho Chul

    2015-01-01

    Purpose Bone metastasis invariably increases morbidity and mortality. This study compares the effects of ibandronate and paclitaxel on bone structure and its mechanical properties and biochemical turnover in resorption markers using an immunocompetent Walker 256-Sprague-Dawley model, which was subjected to tumor-induced osteolysis. Materials and Methods Seventy rats were divided equally into 4 groups: 1) sham group (SHAM), 2) tumor group (CANC), 3) ibandronate treated group (IBAN), and 4) paclitaxel treated group (PAC). Morphological indices [bone volume fraction (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), trabecular separation (Tb.Sp)] and mechanical properties (failure load, stiffness) were evaluated after thirty days of treatment period. Bone resorption rate was analysed using serum deoxypyridinoline (Dpd) concentrations. Results Morphological indices showed that ibandronate (anti-resorptive drug) had a better effect in treating tumor-induced architectural changes in bone than paclitaxel (chemotherapeutic drug). The deterioration in bone architecture was reflected in the biomechanical properties of bone as studied with decreased failure load (Fx) and stiffness (S) of the bone on the 30th day post-surgery. Dpd concentrations were significantly lower in the IBAN group, indicating successful inhibition of bone resorption and destruction. Conclusion Ibandronate was found to be as effective as higher doses of paclitaxel in maintaining stiffness of bone. Paclitaxel treatment did not appear to inhibit osteoclast resorption, which is contrary to earlier in-vitro literature. Emphasis should be placed on the use of immunocompetent models for examining drug efficacy since it adequately reflects bone metastasis in clinical scenarios. PMID:26446649

  16. Carboxymethyl-chitosan-tethered lipid vesicles: hybrid nanoblanket for oral delivery of paclitaxel.

    PubMed

    Joshi, Nitin; Saha, Rama; Shanmugam, Thanigaivel; Balakrishnan, Biji; More, Prachi; Banerjee, Rinti

    2013-07-01

    We describe the development and evaluation of a hybrid lipopolymeric system comprising carboxymethyl chitosan (CMC), covalently tethered to phosphatidylethanolamine units on the surface of lipid nanovesicles, for oral delivery of paclitaxel. The bioploymer is intended to act as a blanket, thereby shielding the drug from harsh gastrointestinal conditions, whereas the lipid nanovesicle ensures high encapsulation efficiency of paclitaxel and its passive targeting to tumor. CMC-tethered nanovesicles (LN-C-PTX) in the size range of 200-300 nm improved the gastrointestinal resistance and mucoadhesion properties as compared with unmodified lipid nanovesicles (LN-PTX). Conjugation of CMC did not compromise the cytotoxic potential of paclitaxel yet facilitated the interaction and uptake of the nanovesicles by murine melanoma (B16F10) cells through an ATP-dependent process. CMC-conjugated nanovesicles, upon oral administration in rats, improved the plasma concentration profile of paclitaxel, with 1.5 fold increase in its bioavailability and 5.5 folds increase in elimination half life in comparison with Taxol. We also found that CMC in addition to providing a gastric resistant coating also imparted stealth character to the nanovesicles, thereby reducing their reticuloendothelial system (RES)-mediated uptake by liver and spleen and bypassing the need for PEGylation. In vivo efficacy in subcutaneous model of B16F10 showed significantly improved tumor growth inhibition and survival with CMC-tethered nanovesicles as compared with unmodified nanovesicles, both administered orally. LN-C-PTX exhibited therapeutic efficacy comparable to Taxol and Abraxane and also showed reduced toxicity and improved survival. Overall, these results suggest the therapeutic potential of CMC tethered nanovesicles as a platform for oral administration of paclitaxel and also unravel the ability of CMC to impart stealth character to the nanoparticles, thereby preventing their RES clearance. PMID:23721348

  17. Identification of transcription factors controlling the expression of paclitaxel biosynthesis genes in cambial meristematic cells of Taxus cuspidata 

    E-print Network

    Yan, Zejun Jun

    2013-11-28

    Paclitaxel is an antitumor diterpene from Taxus spp. that binds tubulin, stabilizes microtubules and induces apoptosis in dividing human cells. It was originally isolated from the bark of Taxus brevifolia and approved ...

  18. Everolimus-Eluting versus Paclitaxel-Eluting Stents in Percutaneous Coronary Intervention: Meta-Analysis of Randomized Trials

    PubMed Central

    Alazzoni, Ashraf; Al-Saleh, Ayman; Jolly, Sanjit S.

    2012-01-01

    Background. Individual randomized trials have suggested that everolimus-eluting stents may have improved clinical outcomes compared to paclitaxel-eluting stents, but individual trials are underpowered to examine outcomes such as mortality and very late stent thrombosis. Methods. Medline, Cochrane, and conference proceedings were searched for randomized trials comparing everolimus versus paclitaxel-eluting stents for percutaneous coronary intervention. Results. 6792 patients were included from 4 randomized controlled trials. Stent thrombosis was reduced with everolimus stents versus paclitaxel stents (0.7% versus 2.3%; OR: 0.32; CI: 0.20–0.51; P < 0.00001). The reductions in stent thrombosis were observed in (i) early stent thrombosis (within 30 days) (0.2% versus 0.9%; OR: 0.24; P = 0.0005), (ii) late (day 31–365) (0.2% versus 0.6%; OR: 0.32; P = 0.01), and (iii) very late stent thrombosis (>365 days) (0.2% versus 0.8%; OR: 0.34; P = 0.009). The rates of cardiovascular mortality were 1.2% in everolimus group and 1.6% in paclitaxel group (OR: 0.85; P = 0.43). Patients receiving everolimus-eluting stents had significantly lower myocardial infarction events and target vessel revascularization as compared to paclitaxel-eluting stents. Interpretation. Everolimus compared to paclitaxel-eluting stents reduced the incidence of early, late, and very late stent thrombosis as well as target vessel revascularization. PMID:22655192

  19. Everolimus-Eluting versus Paclitaxel-Eluting Stents in Percutaneous Coronary Intervention: Meta-Analysis of Randomized Trials.

    PubMed

    Alazzoni, Ashraf; Al-Saleh, Ayman; Jolly, Sanjit S

    2012-01-01

    Background. Individual randomized trials have suggested that everolimus-eluting stents may have improved clinical outcomes compared to paclitaxel-eluting stents, but individual trials are underpowered to examine outcomes such as mortality and very late stent thrombosis. Methods. Medline, Cochrane, and conference proceedings were searched for randomized trials comparing everolimus versus paclitaxel-eluting stents for percutaneous coronary intervention. Results. 6792 patients were included from 4 randomized controlled trials. Stent thrombosis was reduced with everolimus stents versus paclitaxel stents (0.7% versus 2.3%; OR: 0.32; CI: 0.20-0.51; P < 0.00001). The reductions in stent thrombosis were observed in (i) early stent thrombosis (within 30 days) (0.2% versus 0.9%; OR: 0.24; P = 0.0005), (ii) late (day 31-365) (0.2% versus 0.6%; OR: 0.32; P = 0.01), and (iii) very late stent thrombosis (>365 days) (0.2% versus 0.8%; OR: 0.34; P = 0.009). The rates of cardiovascular mortality were 1.2% in everolimus group and 1.6% in paclitaxel group (OR: 0.85; P = 0.43). Patients receiving everolimus-eluting stents had significantly lower myocardial infarction events and target vessel revascularization as compared to paclitaxel-eluting stents. Interpretation. Everolimus compared to paclitaxel-eluting stents reduced the incidence of early, late, and very late stent thrombosis as well as target vessel revascularization. PMID:22655192

  20. The ClC-3 chloride channel associated with microtubules is a target of paclitaxel in its induced-apoptosis

    PubMed Central

    Zhang, Haifeng; Li, Huarong; Yang, Lili; Deng, Zhiqin; Luo, Hai; Ye, Dong; Bai, Zhiquan; Zhu, Linyan; Ye, Wencai; Wang, Liwei; Chen, Lixin

    2013-01-01

    Recent evidences show that cationic fluxes play a pivotal role in cell apoptosis. In this study, the roles of Cl? channels in paclitaxel-induced apoptosis were investigated in nasopharyngeal carcinoma CNE-2Z cells. Chloride current and apoptosis were induced by paclitaxel and inhibited by chloride channel blockers. Paclitaxel-activated current possessed similar properties to volume-activated chloride current. After ClC-3 was knocked-down by ClC-3-siRNA, hypotonicity-activated and paclitaxel-induced chloride currents were obviously decreased, indicating that the chloride channel involved in paclitaxel-induced apoptosis may be ClC-3. In early apoptotic cells, ClC-3 was up-regulated significantly; over-expressed ClC-3 was accumulated in cell membrane to form intercrossed filaments, which were co-localized with ?-tubulins; changes of ultrastructures and decrease of flexibility in cell membrane were detected by atomic force microscopy. These suggest that ClC-3 is a critical target of paclitaxel and the involvement of ClC-3 in apoptosis may be associated with its accumulation with membrane microtubules and its over activation. PMID:24026363

  1. A combination of the telomerase inhibitor, BIBR1532, and paclitaxel synergistically inhibit cell proliferation in breast cancer cell lines.

    PubMed

    Shi, Yi; Sun, Lin; Chen, Ge; Zheng, Dongyan; Li, Li; Wei, Wanguo

    2015-12-01

    Breast cancer is one of the most significant causes of female cancer death worldwide. Paclitaxel, an extensively used breast cancer chemotherapeutic has limited success due to drug resistance. 2-[(E)-3-naphtalen-2-yl-but-2-enoylamino]-benzoic acid (BIBR1532), a small molecule pharmacological inhibitor of telomerase activity, can inhibit human cancer cell proliferation as well. Thus, to enhance breast cancer treatment efficacy, we studied the combination of BIBR1532 and paclitaxel in breast cancer cell lines. Cell viability assays revealed that BIBR1532 or paclitaxel alone inhibited proliferation in a dose-dependent manner, and combining the drugs synergistically induced growth inhibition in all breast cell lines tested independent of their p53, ER, and HER2 status. The drug combination also synergistically inhibited colony formation of MCF-7 cells in a dose-dependent manner. Annexin V-PI staining and Western blot assays on PARP cleavage and caspase-8 and caspase-3 revealed that BIBR1532 in combination with paclitaxel was more potent than either agent alone in promoting MCF-7 cell apoptosis. Cell cycle analysis indicated that BIBR1532 induced a G1 phase arrest and paclitaxel arrested cells at the G2/M phase. The drug combination dramatically blocked S cells from entering the G2/M phase. Our results suggest the potential of telomerase inhibition as an effective breast cancer treatment and that used in conjunction with paclitaxel; it may potentiate tumor cytotoxicity. PMID:25916999

  2. Paclitaxel induces apoptosis and reduces proliferation by targeting epidermal growth factor receptor signaling pathway in oral cavity squamous cell carcinoma

    PubMed Central

    HU, JING; ZHANG, NA; WANG, RONGLIN; HUANG, FEI; LI, GUANG

    2015-01-01

    Oral cavity cancer is common worldwide. Furthermore, the epidermal growth factor receptor (EGFR) signaling pathway is considered to be constitutively activated in oral cancers. Paclitaxel is widely accepted as an antitumor drug as it effectively inhibits the cell cycle. This study predominantly explores the possible molecule mechanism of paclitaxel on oral cancer treatment. Cell viability was first detected using an MTT assay. Cell apoptosis was examined by Hoechst staining and flow cytometry using an annexin-V and propidium iodide kit. Specific EGFR signaling pathways were further explored through western blot analysis. Abnormal protein expression levels were determined via immunofluoresence. Additionally, the protein levels of matrix metalloproteinase (MMP)-2 and 9 were determined using ELISA. Paclitaxel significantly inhibited oral cancer cell viability in a time- and dose-dependent manner. Paclitaxel also enhanced oral cancer cell apoptosis via increased Bim and Bid protein expression. Furthermore, paclitaxel was observed to inhibit oral cancer cell proliferation through increased MMP-2 and MMP-9 protein levels. Paclitaxel inhibited the growth of the oral cancer cell line, tea8113 malignant proliferation and enhanced tea8113 cell apoptosis through inhibiting the EGFR signaling pathway.

  3. Elevated AKAP12 in Paclitaxel-Resistant Serous Ovarian Cancer Cells is Prognostic and Predictive of Poor Survival in Patients

    PubMed Central

    Bateman, Nicholas W.; Jaworski, Elizabeth; Ao, Wei; Wang, Guisong; Litzi, Tracy; Dubil, Elizabeth; Marcus, Charlotte; Conrads, Kelly A.; Teng, Pang-ning; Hood, Brian L.; Phippen, Neil T.; Vasicek, Lisa A.; McGuire, William P.; Paz, Keren; Sidransky, David; Hamilton, Chad A.; Maxwell, G. Larry; Darcy, Kathleen M.; Conrads, Thomas P.

    2015-01-01

    A majority of high-grade (HG) serous ovarian cancer (SOC) patients develop resistant disease despite high initial response rates to platinum/paclitaxel-based chemotherapy. We identified shed/secreted proteins in preclinical models of paclitaxel-resistant human HGSOC models and correlated these candidate proteins with patient outcomes using public data from HGSOC patients. Proteomic analyses of a HGSOC cell line secretome was compared to those from a syngeneic paclitaxel-resistant variant and from a line established from an intrinsically chemorefractory HGSOC patient Associations between the identified candidate proteins and patient outcome were assessed in a discovery cohort of 545 patients and two validation cohorts totaling 795 independent SOC patients. Among the 81 differentially abundant proteins identified (q < 0.05) from paclitaxel-sensitive vs -resistant HGSOC cell secretomes, AKAP12 was verified to be elevated in all models of paclitaxel-resistant HGSOC. Furthermore, elevated AKAP12 transcript expression was associated with worse progression-free and overall survival. Associations with outcome were observed in three independent cohorts and remained significant after adjusted multivariate modeling. We further provide evidence to support that differential gene methyktion status is associated with elevated expression of AKAP12 in taxol-resistant ovarian cancer cells and ovarian cancer patient subsets. Elevated expression and shedding/secretion of AKAP12 is characteristic of paclitaxel-resistant HGSOC cells, and elevated AKAP12 transcript expression is a poor prognostic and predictive marker for progression-free and overall survival in SOC patients. PMID:25748058

  4. Paclitaxel-incorporated nanoparticles using block copolymers composed of poly(ethylene glycol)/poly(3-hydroxyoctanoate)

    PubMed Central

    2014-01-01

    Block copolymers composed of poly(3-hydroxyoctanoate) (PHO) and methoxy poly(ethylene glycol) (PEG) were synthesized to prepare paclitaxel-incorporated nanoparticle for antitumor drug delivery. In a 1H-NMR study, chemical structures of PHO/PEG block copolymers were confirmed and their molecular weight (M.W.) was analyzed with gel permeation chromatography (GPC). Paclitaxel as a model anticancer drug was incorporated into the nanoparticles of PHO/PEG block copolymer. They have spherical shapes and their particle sizes were less than 100 nm. In a 1H-NMR study in D2O, specific peaks of PEG solely appeared while peaks of PHO disappeared, indicating that nanoparticles have core-shell structures. The higher M.W. of PEG decreased loading efficiency and particle size. The higher drug feeding increased drug contents and average size of nanoparticles. In the drug release study, the higher M.W. of PEG block induced the acceleration of drug release rate. The increase in drug contents induced the slow release rate of drug. In an antitumor activity study in vitro, paclitaxel nanoparticles have practically similar anti-proliferation activity against HCT116 human colon carcinoma cells. In an in vivo animal study using HCT116 colon carcinoma cell-bearing mice, paclitaxel nanoparticles have enhanced antitumor activity compared to paclitaxel itself. Therefore, paclitaxel-incorporated nanoparticles of PHO/PEG block copolymer are a promising vehicle for antitumor drug delivery. PMID:25288916

  5. [A Case of Recurrent Breast Cancer with Carcinomatous Pleurisy Successfully Treated with Paclitaxel and Bevacizumab after Radical Mastectomy].

    PubMed

    Sakaguchi, Nanae; Moriya, Tomoyuki; Yamazaki, Tamio; Yamagishi, Youji; Hasegawa, Shou; Tsuda, Hitoshi; Hase, Kazuo; Yamamoto, Junji

    2015-06-01

    A 61-year-old postmenopausal woman with breast cancer and carcinomatous pleurisy was successfully treated with bevacizumab and paclitaxel. In December 2008, after receiving preoperative chemotherapy consisting of q3w 4 cycles of EC (E: 90 mg/m2, C: 600 mg/m2) and 12 cycles of weekly paclitaxel (80 mg/m2), the patient underwent modified radical mastectomy with axillary lymph node dissection for right breast cancer. Pathological examination showed residual tumor cells and lymph node metastasis (pT4bN2M0, Stage III b). In July 2012, 3 and a half years later, she complained of a cough and dyspnea. Chest X-ray and computed tomography scans showed a pleural effusion involving the entire left thoracic cavity, indicating carcinomatous pleurisy. Bevacizumab and paclitaxel therapy was initiated. Soon thereafter, the pleural fluid disappeared, tumor marker levels decreased, and symptoms were ameliorated. After 6 cycles of bevacizumab and paclitaxel therapy, the patient continuously received 3 cycles of weekly paclitaxel (80 mg/m2). Two years and 4 months since the diagnosis, she has remained free of carcinomatous pleurisy recurrence. She is currently receiving hormone therapy on an outpatient basis. Bevacizumab and paclitaxel therapy is potentially effective for the treatment of patients with carcinomatous pleurisy, providing a chance for long-term survival. PMID:26199251

  6. Paclitaxel suppresses the viability of breast tumor MCF7 cells through the regulation of EF1? and FOXO3a by AMPK signaling.

    PubMed

    Kim, Ji Hae; Lee, Jung Ok; Kim, Nami; Lee, Hye Jeong; Lee, Yong Woo; Kim, Hyung Ip; Kim, Su Jin; Park, Sun Hwa; Kim, Hyeon Soo

    2015-11-01

    Paclitaxel (Taxol), a potent drug of natural origin isolated from the bark of the Pacific yew, is widely used for treating ovarian, lung and breast cancers. Currently, there is little information regarding the specific mechanism underlying the anticancer activity of paclitaxel. In the present study, we found that 5-amino-1-?-D-ribofuranosyl-imidazole?4?carboxamide (AICAR), a well-known activator of adenosine monophosphate (AMP)-activated protein kinase (AMPK), downregulated the protein and mRNA levels of elongation factor 1 ? (EF1?) in breast cancer MCF7 cells. Paclitaxel increased the phosphorylation of AMPK and also downregulated the expression of EF1? in MCF7 cells. In addition, paclitaxel increased the expression, as well as the phosphorylation of forkhead box O3a (FOXO3a). Phosphorylation of FOXO3a was suppressed in the presence of compound C, a specific AMPK inhibitor, suggesting the involvement of AMPK in paclitaxel-induced FOXO3a phosphorylation. The induction and phosphorylation of FOXO3a by paclitaxel were not observed in EF1? and AMPK knockdown cells. Co-treatment with AICAR resulted in increased susceptibility of cancer cells to paclitaxel-induced suppression of their viability and further enhanced paclitaxel?induced FOXO3a phosphorylation. These results suggest that the antitumor effects of paclitaxel in breast cancer are mediated by activation of the AMPK/EF1?/FOXO3a signaling pathway. PMID:26397839

  7. Nab-paclitaxel-associated photosensitivity: report in a woman with non-small cell lung cancer and review of taxane-related photodermatoses

    PubMed Central

    Beutler, Bryce D.; Cohen, Philip R.

    2015-01-01

    Background: Taxanes [paclitaxel, nab-paclitaxel (Abraxane, Celgene Corp, USA), and docetaxel]—used in the treatment of lung, breast, and head and neck cancers—have been associated with cutaneous adverse effects, including photodermatoses. Purpose: We describe a woman with non-small cell lung cancer who developed a photodistributed dermatitis associated with her nab-paclitaxel therapy and review photodermatoses in patients receiving taxanes. Materials and methods: The features of a woman with a nab-paclitaxel-associated photodistributed dermatitis are presented and the literature on nab-paclitaxel-associated photosensitivity is reviewed. Results: Our patient developed nab-paclitaxel-associated photodistributed dermatitis on the sun-exposed surfaces of her upper extremities, which was exacerbated with each course of nab-paclitaxel. Biopsies revealed an interface dermatitis and laboratory studies were negative for lupus erythematosus and dermatomyositis. Her condition improved following topical corticosteroid cream application and strict avoidance of sunlight. Conclusion: Chemotherapy can be associated with adverse mucocutaneous events, including dermatoses on sun-exposed areas of the skin. Paclitaxel and nab-paclitaxel have both been associated with photodermatoses, including dermatitis, erythema multiforme, onycholysis, and subacute cutaneous lupus erythematosus. Strict avoidance of sun exposure, topical or oral corticosteroids, and/or discontinuation of the drug results in improvement with progressive resolution of symptoms and skin lesions. Development of photodermatoses is not an absolute contraindication to continuing chemotherapy, provided that the cutaneous condition resolves with dermatosis-directed treatment and the patient avoids sun exposure. PMID:26114068

  8. Peptidergic intraepidermal nerve fibers in the skin contribute to the neuropathic pain in paclitaxel-induced peripheral neuropathy.

    PubMed

    Ko, Miau-Hwa; Hu, Ming-E; Hsieh, Yu-Lin; Lan, Chyn-Tair; Tseng, To-Jung

    2014-06-01

    Paclitaxel in chemotherapy-induced peripheral neuropathy (CIPN) is predominantly with a dose-limiting effect on neuropathic pain in clinical strategy. In the present study, the relationship between the neuropathic pain and nerve degeneration in paclitaxel CIPN was investigated. Adult male Sprague-Dawley (SD) rats were divided into three paclitaxel groups (0.5, 1.0, 2.0mg/kg) and a vehicle group with four intraperitoneal (i.p.) injections on alternating days. Our results demonstrated that the paclitaxel groups significantly exhibited the reductions of thermal hyperalgesia and mechanical allodynia. The neurotoxicity of paclitaxel conveyed the degeneration of intraepidermal nerve fibers (IENFs) in hindpaw glabrous skin. Nevertheless, the influence of paclitaxel to the peptidergic IENFs are even unknown. The skin innervation of protein gene product 9.5 (PGP 9.5)-immunoreactive (IR) IENFs in paclitaxel groups revealed the decreasing levels of density (73.54±0.72%, 63.17±1.77%, 61.79±2.68%, respectively; vs. vehicle group, p<0.05) throughout the entire experimental period. Additionally, the diminishing levels of density for peptidergic substance P (SP)-IR IENFs in paclitaxel groups were significantly shown (48.84±1.74%, 30.02±1.69%, 30.14±0.37%, respectively; vs. vehicle group, p<0.05). On the contrary, the density for peptidergic calcitonin gene-related peptide (CGRP)-IR IENFs in paclitaxel groups were revealed the similar decreasing levels (82.75±0.91%, 84.34±3.20%, 81.99±0.25%, respectively; vs. vehicle group, p<0.05). Linear regression analyses exhibited that densities of IENFs for PGP 9.5, SP, CGRP were correlated with withdrawal latencies (r(2)=0.77, p<0.0001; r(2)=0.75, p<0.0001; r(2)=0.28, p=0.0001, respectively) and mechanical thresholds (r(2)=0.43, p<0.0001; r(2)=0.73, p<0.0001; r(2)=0.40, p<0.0001, respectively). Therefore, the present results suggested that the development of neuropathic pain following paclitaxel injection induced the progressive degeneration of IENFs in skin and gave the evidence that the peptidergic IENFs may play an important role in therapeutic strategy of paclitaxe CIPN. PMID:24630273

  9. 2’-Behenoyl-Paclitaxel Conjugate Containing Lipid Nanoparticles for the Treatment of Metastatic Breast Cancer

    PubMed Central

    Ma, Ping; Benhabbour, S. Rahima; Feng, Lan; Mumper, Russell J

    2012-01-01

    The aim of these studies was to develop a novel 2’-behenoyl-paclitaxel (C22-PX) conjugate nanoparticle (NP) formulation for the treatment of metastatic breast cancer. A lipophilic paclitaxel derivative C22-PX was synthesized and incorporated into lipid-based NPs. Free C22-PX and its NP formulation were evaluated in a series of in-vitro and in-vivo studies. The results demonstrated that C22-PX NPs were much better tolerated and had significantly higher plasma and tumor AUCs compared to Taxol at the maximum tolerated dose (MTD) in a subcutaneous 4T1 mouse mammary carcinoma model. These benefits resulted in significantly improved antitumor efficacy with the NP-based formulation. PMID:22902506

  10. Study of Paclitaxel-Treated HeLa Cells by Differential Electrical Impedance Flow Cytometry

    PubMed Central

    Kirkegaard, Julie; Clausen, Casper Hyttel; Rodriguez-Trujillo, Romen; Svendsen, Winnie Edith

    2014-01-01

    This work describes the electrical investigation of paclitaxel-treated HeLa cells using a custom-made microfluidic biosensor for whole cell analysis in continuous flow. We apply the method of differential electrical impedance spectroscopy to treated HeLa cells in order to elucidate the changes in electrical properties compared with non-treated cells. We found that our microfluidic system was able to distinguish between treated and non-treated cells. Furthermore, we utilize a model for electrical impedance spectroscopy in order to perform a theoretical study to clarify our results. This study focuses on investigating the changes in the electrical properties of the cell membrane caused by the effect of paclitaxel. We observe good agreement between the model and the obtained results. This establishes the proof-of-concept for the application in cell drug therapy. PMID:25587422

  11. Study of Paclitaxel-Treated HeLa Cells by Differential Electrical Impedance Flow Cytometry.

    PubMed

    Kirkegaard, Julie; Clausen, Casper Hyttel; Rodriguez-Trujillo, Romen; Svendsen, Winnie Edith

    2014-09-01

    This work describes the electrical investigation of paclitaxel-treated HeLa cells using a custom-made microfluidic biosensor for whole cell analysis in continuous flow. We apply the method of differential electrical impedance spectroscopy to treated HeLa cells in order to elucidate the changes in electrical properties compared with non-treated cells. We found that our microfluidic system was able to distinguish between treated and non-treated cells. Furthermore, we utilize a model for electrical impedance spectroscopy in order to perform a theoretical study to clarify our results. This study focuses on investigating the changes in the electrical properties of the cell membrane caused by the effect of paclitaxel. We observe good agreement between the model and the obtained results. This establishes the proof-of-concept for the application in cell drug therapy. PMID:25587422

  12. Targeted Delivery of Paclitaxel to EphA2-Expressing Cancer Cells

    PubMed Central

    Wang, Si; Noberini, Roberta; Stebbins, John L.; Das, Swadesh; Zhang, Ziming; Wu, Bainan; Mitra, Sayantan; Billet, Sandrine; Fernandez, Ana; Bhowmick, Neil A.; Kitada, Shinichi; Pasquale, Elena B.; Fisher, Paul B.; Pellecchia, Maurizio

    2012-01-01

    Purpose YSA is an EphA2-targeting peptide that effectively delivers anti-cancer agents to prostate cancer tumors (1). Here, we report on how we increased the drug-like properties of this delivery system. Experimental Design By introducing non-natural amino acids, we have designed two new EphA2 targeting peptides: YNH, where norleucine and homoserine replace the two methionine residues of YSA, and dYNH, where a D-tyrosine replaces the L-tyrosine at the first position of the YNH peptide. We describe the details of the synthesis of YNH and dYNH paclitaxel conjugates (YNH-PTX and dYNH-PTX) and their characterization in cells and in vivo. Results dYNH-PTX showed improved stability in mouse serum and significantly reduced tumor size in a prostate cancer xenograft model and also reduced tumor vasculature in a syngeneic orthotopic allograft mouse model of renal cancer compared to vehicle or paclitaxel treatments. Conclusion This study reveals that targeting EphA2 with dYNH drug conjugates could represent an effective way to deliver anti-cancer agents to a variety of tumor types. Translational Relevance Overexpression of the EphA2 positively correlates with tumor malignancy and poor prognosis. For this reason, EphA2 is an attractive target for cancer cell specific drug delivery. In this study, we report on the development of dYNH, an EphA2 targeting peptide that when coupled to paclitaxel (PTX) has favorable pharmacological properties and possesses powerful anti-tumor activity in vivo. dYNH-PTX may allow for an expanded therapeutic index of paclitaxel as well as precluding the need for complex formulations and long infusion times. PMID:23155185

  13. Prodigiosin down-regulates survivin to facilitate paclitaxel sensitization in human breast carcinoma cell lines

    SciTech Connect

    Ho, T.-F.; Peng, Y.-T.; Chuang, S.-M.; Lin, S.-C.; Feng, B.-L.; Lu, C.-H.; Yu, W.-J.; Chang, J.-S. Chang, C.-C.

    2009-03-01

    Prodigiosin is a bacterial metabolite with potent anticancer activity, which is attributed to its proapoptotic effect selectively active in malignant cells. Still, the molecular mechanisms whereby prodigiosin induces apoptosis remain largely unknown. In particular, the role of survivin, a vital inhibitor of apoptosis, in prodigiosin-induced apoptosis has never been addressed before and hence was the primary goal of this study. Our results showed that prodigiosin dose-dependently induced down-regulation of survivin in multiple breast carcinoma cell lines, including MCF-7, T-47D and MDA-MB-231. This down-regulation is mainly regulated at the level of transcription, as prodigiosin reduced the levels of both survivin mRNA and survivin promoter activity but failed to rescue survivin expression when proteasome-mediated degradation is abolished. Importantly, overexpression of survivin rendered cells more resistant to prodigiosin, indicating an essential role of survivin down-regulation in prodigiosin-induced apoptosis. In addition, we found that prodigiosin synergistically enhanced cell death induced by paclitaxel, a chemotherapy drug known to up-regulate survivin that in turn confers its own resistance. This paclitaxel sensitization effect of prodigiosin is ascribed to the lowering of survivin expression, because prodigiosin was shown to counteract survivin induction by paclitaxel and, notably, the sensitization effect was severely abrogated in cells that overexpress survivin. Taken together, our results argue that down-regulation of survivin is an integral component mediating prodigiosin-induced apoptosis in human breast cancer cells, and further suggest the potential of prodigiosin to sensitize anticancer drugs, including paclitaxel, in the treatment of breast cancer.

  14. Nab-paclitaxel for the management of triple-negative metastatic breast cancer: a case study.

    PubMed

    Arpino, Grazia; De Placido, Sabino; De Angelis, Carmine

    2015-01-01

    The optimal sequence of systemic chemotherapy in metastatic breast cancer (MBC) is unknown. We report the case of a woman who was successfully treated with nanoparticle albumin-bound (nab)-paclitaxel for triple negative MBC in our institution. In November 2008, a 48-year-old woman underwent surgical treatment for a triple negative invasive ductal breast cancer and subsequently received adjuvant chemotherapy with fluorouracil/epirubicin/cyclophosphamide and radiotherapy. Sixteen months after surgery, she presented with a left chest wall metastatasis. The patient received combination therapy with conventional paclitaxel (90 mg/m² weekly for 3 out of 4 weeks [QW 3/4]) and bevacizumab (10 mg/kg every 2 weeks [Q2W]) as first-line treatment for MBC (six cycles; March to September 2010) and achieved a partial response at the metastatic site. Bevacizumab monotherapy was continued until disease progression (April 2011) with the development of a single infraclavicular lymph node metastasis and an increase in the dimensions of the left chest wall lesion. From May to December 2011, the patient received nab-paclitaxel 260 mg/m² every 3 weeks (Q3W) as second-line treatment (11 cycles). After three cycles, the left chest wall lesion and the infraclavicular lymph node metastasis were undetectable and the patient was considered to have achieved a complete response. Treatment was well tolerated with no significant toxicity or need for dose reduction. Given our case, here we review the clinical evidence and discuss the potential role of nab-paclitaxel for the treatment of triple negative MBC, a subgroup typically characterized as having aggressive disease and limited treatment options. PMID:25115342

  15. Paclitaxel-Based Chemoradiotherapy in the Treatment of Patients With Operable Esophageal Cancer

    SciTech Connect

    Kelsey, Chris R. Chino, Junzo P.; Willett, Christopher G.; Clough, Robert W.; Hurwitz, Herbert I.; Morse, Michael A.; Bendell, Johanna C.; D'Amico, Thomas A.; Czito, Brian G.

    2007-11-01

    Purpose: To compare a neoadjuvant regimen of cisplatin/5-fluorouracil (5-FU) and concurrent radiation therapy (RT) with paclitaxel-based regimens and RT in the management of operable esophageal (EC)/gastroesophageal junction (GEJ) cancer. Methods and Materials: All patients receiving neoadjuvant chemotherapy (CT) and RT for EC/GEJ cancer at Duke University between January 1995 and December 2004 were included. Clinical end points were compared for patients receiving paclitaxel-based regimens (TAX) vs. alternative regimens (non-TAX). Local control (LC), disease-free survival (DFS), and overall survival (OS) were estimated using the Kaplan-Meier method. Chi-square analysis was performed to test the effect of TAX on pathologic complete response (pCR) rates and toxicity. Results: A total of 109 patients received CT-RT followed by esophagectomy (95 M; 14 F). Median RT dose was 45 Gy (range, 36-66 Gy). The TAX and non-TAX groups comprised 47% and 53% of patients, respectively. Most (83%) TAX patients received three drug regimens including platinum and a fluoropyrimidine. In the non-TAX group, 89% of the patients received cisplatin and 5-FU. The remainder received 5-FU or capecitabine alone. Grade 3-4 toxicity occurred in 41% of patients receiving TAX vs. 24% of those receiving non-TAX (p = 0.19). Overall pCR rate was 39% (39% with TAX vs. 40% with non-TAX, p = 0.9). Overall LC, DFS, and OS at 3 years were 80%, 34%, and 37%, respectively. At 3 years, there were no differences in LC (75% vs. 85%, p = 0.33) or OS (37% vs. 37%, p = 0.32) between TAX and non-TAX groups. Conclusions: In this large experience, paclitaxel-containing regimens did not improve pCR rates or clinical end points compared to non-paclitaxel-containing regimens.

  16. Paclitaxel and Its Evolving Role in the Management of Ovarian Cancer

    PubMed Central

    Kampan, Nirmala Chandralega; Madondo, Mutsa Tatenda; McNally, Orla M.; Quinn, Michael; Plebanski, Magdalena

    2015-01-01

    Paclitaxel, a class of taxane with microtubule stabilising ability, has remained with platinum based therapy, the standard care for primary ovarian cancer management. A deeper understanding of the immunological basis and other potential mechanisms of action together with new dosing schedules and/or routes of administration may potentiate its clinical benefit. Newer forms of taxanes, with better safety profiles and higher intratumoural cytotoxicity, have yet to demonstrate clinical superiority over the parent compound. PMID:26137480

  17. Involvement of the chemokine CCL3 and the purinoceptor P2X7 in the spinal cord in paclitaxel-induced mechanical allodynia

    PubMed Central

    2014-01-01

    Background Paclitaxel is an effective chemotherapeutic agent widely used for the treatment of solid tumors. The major dose-limiting toxicity of paclitaxel is peripheral neuropathy. The mechanisms underlying the development and maintenance of paclitaxel-induced peripheral neuropathy are still unclear, and there are no currently established effective treatments. Accumulating evidence in models of neuropathic pain in which peripheral nerves are lesioned has implicated spinal microglia and chemokines in pain hypersensitivity, but little is know about their roles in chemotherapy-induced peripheral neuropathy. In the present study, we investigated the role of CC-chemokine ligand 3 (CCL3) in the spinal cord in the development and maintenance of mechanical allodynia using a rat model of paclitaxel-induced neuropathy. Findings Repeated intravenous administration of paclitaxel induced a marked decrease in paw withdrawal threshold in response to mechanical stimulation (mechanical allodynia). In these rats, the number of microglia in the spinal dorsal horn (SDH) was significantly increased. Paclitaxel-treated rats showed a significant increase in the expression of mRNAs for CCL3 and its receptor CCR5 in the SDH. Intrathecal administration of a CCL3-neutralizing antibody not only attenuated the development of paclitaxel-induced mechanical allodynia but also reversed its maintenance. Paclitaxel also upregulated expression of purinoceptor P2X7 receptors (P2X7Rs), which have been implicated in the release of CCL3 from microglia, in the SDH. The selective P2X7R antagonist A438079 had preventive and reversal effects on paclitaxel-induced allodynia. Conclusions Our findings suggest a contribution of CCL3 and P2X7Rs in the SDH to paclitaxel-induced allodynia and may provide new therapeutic targets for paclitaxel-induced painful neuropathy. PMID:25127716

  18. Dose-Dense Epirubicin and Cyclophosphamide Followed by Weekly Paclitaxel in Node-Positive Breast Cancer

    PubMed Central

    Mirzaei, Hamid Reza; Mohammadi Yeganeh, Ladan; Jafari Naeini, Sepideh; Bikdeli, Pegah; Hajian, Parastoo

    2014-01-01

    Background. Adding taxanes to anthracycline-based adjuvant chemotherapy has shown significant improvement in node-positive breast cancer patients but the optimal dose schedule has still remained undetermined. Objectives. The feasibility of dose-dense epirubicin in combination with cyclophosphamide (EC) followed by weekly paclitaxel as adjuvant chemotherapy in node-positive breast cancer patients was investigated. Methods. All patients were treated with epirubicin (100?mg/m2) and cyclophosphamide (600?mg/m2) every two weeks for four cycles with daily Pegfilgrastim (G-CSF) that was administered 3–10 days after each cycle of epirubicin and cyclophosphamide infusion which followed by (80?mg/m2) paclitaxel for twelve consecutive weeks. Results. Sixty consecutive patients were analyzed, of whom 57 patients (95%) completed the regimen and no case of toxicity-related death was observed. Grade 3/4 hematologic toxicity was uncommon and the most common grade 3/4 nonhematological adverse event was neuropathy disorders. Conclusions. Dose-dense epirubicin and cyclophosphamide followed by weekly paclitaxel with G-CSF support is a well-tolerated and feasible regimen in node-positive breast cancer patients without serious complications. PMID:25276426

  19. Weekly pegylated liposomal doxorubicin and paclitaxel in patients with metastatic breast carcinoma: A phase II study

    PubMed Central

    LEONARDI, VITA; PALMISANO, VALENTINA; PEPE, ALESSIO; USSET, ANTONELLA; MANUGUERRA, GIOVANNA; SAVIO, GIUSEPPINA; DE BELLA, MANUELA TAMBURO; LAUDANI, AGATA; ALÙ, MASSIMO; CUSIMANO, MARIA PIA; SCIANNA, CATERINA; GIRESI, ARMANDO; AGOSTARA, BIAGIO

    2010-01-01

    Pegylated liposomal doxorubicin (PLD) has the advantage of delivering active anthracycline directly to the tumor site, while exposing the patient to a lesser degree of doxorubicin-associated toxicities. Recently, a regimen in which paclitaxel is infused weekly over 1 h produced substantial antitumor activity with little myelosuppression. We designed a phase II trial to study the efficacy and toxicity of 10 mg/m2 PLD on Days 1, 8 and 15, plus 70 mg/m2 paclitaxel weekly in patients with untreated metastatic breast cancer and a high risk of cardiotoxicity. The study included 35 patients, with 31 (88.5%) evaluable for efficacy and 35 (100%) for toxicity. A total of 28 patients (80%) had two or more sites of disease. Overall, 4 complete and 16 partial responses were noted with an overall response rate of 64.5%, with 6 cases of stable and 5 cases of progressive disease. Toxicity was found to be manageable in that the only grade 3–4 side effects recorded were palmar-plantar erythrodysesthesia, 8.5%; mucositis, 2.8%; leucopenia, 12.5%; anemia, 2.8% and AST/ALT, 2.8%. No cardiotoxicity was observed. In conclusion, weekly PLD plus paclitaxel appears to be a well-tolerated and effective approach for metastatic breast cancer patients with a high risk of cardiotoxicity. PMID:22966374

  20. Bevacizumab in combination with paclitaxel for HER-2 negative metastatic breast cancer: an economic evaluation.

    PubMed

    Dedes, Konstantin J; Matter-Walstra, Klazien; Schwenkglenks, Matthias; Pestalozzi, Bernhard C; Fink, Daniel; Brauchli, Peter; Szucs, Thomas D

    2009-05-01

    The addition of bevacizumab to weekly paclitaxel as primary chemotherapy for HER-2 negative metastatic breast cancer (MBC) prolongs progression-free survival without a substantial increase of toxicity. A Markov cohort simulation was used to follow the clinical course of typical patients with MBC. Information on response rates and major adverse effects was derived, and transition probabilities were estimated, based on the results of the E2100 clinical trial. Direct costs were assessed from the perspective of the Swiss health system. The addition of bevacizumab to weekly paclitaxel is estimated to cost an additional 40,369euro and to yield a gain of 0.22 quality-adjusted life years (QALYs), resulting in an incremental cost-effectiveness ratio of 189,427euro/QALY gained. Probabilistic sensitivity analysis showed that the willingness-to-pay threshold of 60,000euro was never reached. The addition of bevacizumab to paclitaxel in MBC patients is expensive given the clinical benefit in terms of QALYs gained. PMID:19147344

  1. A phase I study of dasatinib and weekly paclitaxel for metastatic breast cancer

    PubMed Central

    Fornier, M. N.; Morris, P. G.; Abbruzzi, A.; D'Andrea, G.; Gilewski, T.; Bromberg, J.; Dang, C.; Dickler, M.; Modi, S.; Seidman, A. D.; Sklarin, N.; Chang, J.; Norton, L.; Hudis, C. A.

    2011-01-01

    Background: SRC plays an important role in the pathogenesis of metastatic breast cancer (MBC). In preclinical models, paclitaxel and the oral SRC inhibitor dasatinib showed greater antitumor activity than either agent. To determine the maximum tolerated dose of this combination, we conducted a phase I study. Patients and methods: Patients with MBC; Eastern Cooperative Oncology Group performance status of zero to one; normal hepatic, renal and marrow function were eligible. Paclitaxel 80 mg/m2 was given 3 weeks of 4. The starting dasatinib dose was 70 mg and was increased, using a standard 3?+?3 dose-escalation scheme. Results: Fifteen patients enrolled (median age 54 years, range 35–74). No dose-limiting toxic effects (DLTs) occurred at dasatinib doses of 70–120 mg. One DLT (grade 3 fatigue) occurred in the dasatinib 150-mg cohort, which was expanded (six patients) with no further DLTs. However, due to cumulative toxic effects (rash, fatigue, diarrhea), the recommended phase II dose is dasatinib 120 mg. Of 13 assessable patients, a partial response was seen in 4 patients (31%), including 2 patients previously treated with taxanes; all received ?120 mg dasatinib. An additional five patients (29%) had stable disease. Conclusion: In combination with weekly paclitaxel, the recommended phase II dose of dasatinib is 120 mg daily and preliminary activity has been seen in patients with MBC. PMID:21406471

  2. [Two advanced gastric cancer cases with peritoneal metastases successfully treated by s-1/paclitaxel combination therapy].

    PubMed

    Ina, Kenji; Furuta, Ryuichi; Kataoka, Takae; Nishio, Tomoko; Nagao, Seiji; Kayukawa, Satoshi; Masaki, Ayako; Ando, Takafumi; Goto, Hidemi

    2009-06-01

    Two unresectable advanced gastric cancer cases with peritoneal metastases were successfully treated by the combination therapy of S-1 and paclitaxel. S-1 (1.25m(2): 80 mg/day, 1.25m(2)-1.50m(2)<:120 mg/day) was administered orally for 14 consecutive days followed by 14 days rest and a 2-hour infusion of paclitaxel (50 mg/m(2)) was administered on day 1 and 15 of each course. Treatment was repeated every 4 weeks unless disease progression or severe adverse effects were observed. Case 1: 65-year-old male (performance status: PS 3) with type 1 gastric cancer with malignant ascites. Case 2: 66-year-old male (PS3) with peritoneal metastases whose primary gastric lesion was surgically resected. Partial response was obtained in the former and complete response in the latter. Combination therapy of S-1 and paclitaxel can be highly recommended for patients with inoperable gastric cancer with poor PS. PMID:19542719

  3. Time-staggered inhibition of JNK effectively sensitizes chemoresistant ovarian cancer cells to cisplatin and paclitaxel.

    PubMed

    Seino, Manabu; Okada, Masashi; Sakaki, Hirotsugu; Takeda, Hiroyuki; Watarai, Hikaru; Suzuki, Shuhei; Seino, Shizuka; Kuramoto, Kenta; Ohta, Tsuyoshi; Nagase, Satoru; Kurachi, Hirohisa; Kitanaka, Chifumi

    2016-01-01

    Ovarian cancer is the most lethal gynecological malignancy, for which platinum- and taxane-based chemotherapy plays a major role. Chemoresistance of ovarian cancer poses a major obstacle to the successful management of this devastating disease; however, effective measures to overcome platinum and taxane resistance are yet to be established. In the present study, while investigating the mechanism underlying the chemoresistance of ovarian cancer, we found that JNK may have a key role in the resistance of ovarian cancer cells to cisplatin and paclitaxel. Importantly, whereas simultaneous application of a JNK inhibitor and either of the chemotherapeutic agents had contrasting effects for cisplatin (enhanced cytotoxicity) and paclitaxel (decreased cytotoxicity), JNK inhibitor treatment prior to chemotherapeutic agent application invariably enhanced the cytotoxicity of both drugs, suggesting that the basal JNK activity is commonly involved in the chemoresistance of ovarian cancer cells to cisplatin and paclitaxel in contrast to drug?induced JNK activity which may have different roles for these two drugs. Furthermore, we confirmed using non-transformed human and rodent fibroblasts that sequential application of the JNK inhibitor and the chemotherapeutic agents did not augment their toxicity. Thus, our findings highlight for the first time the possible differential roles of the basal and induced JNK activities in the chemoresistance of ovarian cancer cells and also suggest that time?staggered JNK inhibition may be a rational and promising strategy to overcome the resistance of ovarian cancer to platinum- and taxane-based chemotherapy. PMID:26534836

  4. Combination of Rotational Atherothrombectomy and Paclitaxel-Coated Angioplasty for Femoropopliteal Occlusion

    PubMed Central

    Scheer, F; Lüdtke, CW; Kamusella, P; Wiggermann, P; Vieweg, H; Schlöricke, E; Lichtenberg, M; Andresen, R; Wissgott, C

    2014-01-01

    OBJECTIVE The rotational atherothrombectomy with Straub Rotarex® is a safe and efficient treatment of acute/subactute vascular occlusions. The purpose of this study was to evaluate the benefit of paclitaxel-coated angioplasty after rotational atherothrombectomy over an observation period of six months. MATERIALS AND METHODS Overall, 29 patients were treated with the Rotarex catheter in combination with paclitaxel-coated angioplasty. All patients had acute/subacute and chronic occlusions of the superficial femoral artery (SFA) and/or popliteal arteries. The ankle-brachial index (ABI) was detected before the intervention, after the procedure, and after six months. Also clinical examination and ultrasound scans were done in the observation period. RESULTS There were no technical failures. The ABI shows a significant increase from 0.52 ± 0.17 to 0.91 ± 0.25 in the follow-up. By ultrasound examination, there were found two (6.9%) restenoses during the follow-up. There was one dissection during the intervention (3.5%). CONCLUSION The rotational atherothrombectomy in combination with paclitaxel-coated angioplasty might be an effective and safe method with a promising low rate of restenosis at six months. PMID:25983558

  5. Nanoparticle Migration and Delivery of Paclitaxel to Regional Lymph Nodes in a Large Animal Model

    PubMed Central

    Khullar, Onkar V; Griset, Aaron P; Gibbs-Strauss, Summer L; Chirieac, Lucian R; Zubris, Kimberly AV; Frangioni, John V; Grinstaff, Mark W; Colson, Yolonda L

    2012-01-01

    Background To demonstrate feasibility of migration and in situ chemotherapy delivery to regional lymph nodes (LN) in a large animal model using an expansile polymer nanoparticle (eNP) delivery system. Study Design Dual-labeled 50 nm and 100 nm eNP were prepared by encapsulating an IR-813 near-infrared (NIR) fluorescent dye within coumarin-conjugated expansile polymer nanoparticles (NIR-C-eNP). NIR imaging and fluorescent microscopy were utilized to identify intralymphatic migration of NIR-nanoparticles to draining inguinal or mesenteric LN following injection in swine hindlegs or intestine. Nanoparticle-mediated intranodal delivery of chemotherapy was subsequently assessed with Oregon Green paclitaxel-loaded NIR-eNP (NIR-OGpax-eNP). Results NIR imaging demonstrated direct lymphatic migration of 50 nm, but not 100 nm, NIR-C-eNP and NIR-OGpax-eNP to the draining regional LNs following intradermal injection in the hindleg or subserosal injection in intestine. Fluorescent microscopy demonstrated that IR-813 used for NIR real-time trafficking colocalized with both the coumarin-labeled polymer and paclitaxel chemotherapy identified within the subcapsular spaces of the draining LNs. These studies verify nodal migration of both nanoparticle and encapsulated payload, and confirm the feasibility of focusing chemotherapy delivery directly to regional nodes. Conclusions Regionally-targeted intranodal chemotherapy can be delivered to draining LNs for both skin and solid organs using 50 nm paclitaxel-loaded eNP. PMID:22225645

  6. Positive-charged solid lipid nanoparticles as paclitaxel drug delivery system in glioblastoma treatment.

    PubMed

    Chirio, Daniela; Gallarate, Marina; Peira, Elena; Battaglia, Luigi; Muntoni, Elisabetta; Riganti, Chiara; Biasibetti, Elena; Capucchio, Maria Teresa; Valazza, Alberto; Panciani, Pierpaolo; Lanotte, Michele; Annovazzi, Laura; Caldera, Valentina; Mellai, Marta; Filice, Gaetano; Corona, Silvia; Schiffer, Davide

    2014-11-01

    Paclitaxel loaded solid lipid nanoparticles (SLN) of behenic acid were prepared with the coacervation technique. Generally, spherical shaped SLN with mean diameters in the range 300–600 nm were obtained. The introduction of charged molecules, such as stearylamine and glycol chitosan into the formulation allowed to obtain positive SLN with Zeta potential in the 8-20 mV range and encapsulation efficiency in the 25–90% range.Blood–brain barrier (BBB) permeability, tested in vitro through hCMEC/D3 cells monolayer, showed a significantly increase in the permeation of Coumarin-6, used as model drug, when vehicled in SLN. Positive-charged SLN do not seem to enhance permeation although stearylamine-positive SLN resulted the best permeable formulation after 24 h.Cytotoxicity studies on NO3 glioblastoma cell line demonstrated the maintenance of cytotoxic activity of all paclitaxel-loaded SLN that was always unmodified or greater compared with free drug. No difference in cytotoxicity was noted between neutral and charged SLN.Co-culture experiments with hCMEC/D3 and different glioblastoma cells evidenced that, when delivered in SLN, paclitaxel increased its cytotoxicity towards glioblastoma cells. PMID:25445304

  7. Paclitaxel-induced lung injury and its amelioration by parecoxib sodium

    PubMed Central

    Liu, Wen-jie; Zhong, Zhong-jian; Cao, Long-hui; Li, Hui-ting; Zhang, Tian-hua; Lin, Wen-qian

    2015-01-01

    To investigate the mechanism of paclitaxel-induced lung injury and its amelioration by parecoxib sodium. In this study, rats were randomly divided into: the control group (Con); the paclitaxel chemotherapy group (Pac); the paclitaxel+ parecoxib sodium intervention group (Pac?+?Pare); and the parecoxib sodium group (Pare). We observed changes in alveolar ventilation function, alveolar-capillary membrane permeability, lung tissue pathology and measured the levels of inflammatory cytokines and cyclooxygenase-2 (Cox-2) in lung tissue, the expression of tight junction proteins (Zo-1 and Claudin-4). Compared with the Con group, the lung tissue of the Pac group showed significantly increased expression of Cox-2 protein (p?

  8. Bioresorbable copolymer of L-lactide and ?-caprolactone for controlled paclitaxel delivery.

    PubMed

    Musia?-Kulik, Monika; G?barowska, Katarzyna; Kasperczyk, Janusz; Pastusiak, Ma?gorzata; Janeczek, Henryk; Dobrzy?ski, Piotr

    2014-01-01

    Bioresorbable, aliphatic polyesters are known in medicine where serve as orthopedic devices (e.g., rods, pins and screws) or sutures and staples in wound closure. Moreover, such materials are extensively stud- ied as scaffolds--three-dimensional structures for tissue engineering but also drug delivery systems (DDS). The aim of this study was to determine the release profile of paclitaxel, one of the anti-inflammatory, antiprolifera- tive and anti-restenotic agent, from biocompatible copolymer of L-lactide and ?-caprolactone that seems to be very attractive especially for minimally invasive surgery due to its potential shape-memory property. The influ- ence of drug on copolymer hydrolytic degradation was also analyzed. Three types of matrices (3%, 5% of PTX and without drug) were prepared by solvent-casting method and degraded in vitro. The physicochemical changes of copolymer were analyzed by means of nuclear magnetic resonance spectroscopy (NMR), gel per- meation chromatography (GPC) and differential scanning calorimetry (DSC). The amount of drug released into media was monitored with the use of high-pressure liquid chromatography (HPLC). Similar drug release pro- files were obtained for matrices with paclitaxel. The drug-containing matrices degraded slightly slower than drug free matrices, regardless PTX content. Results of this work may be helpful in designing new bioresorbable paclitaxel delivery system applied in anti-cancer therapy or drug-eluting stents technology. PMID:25745774

  9. Phase II study of preoperative paclitaxel/cisplatin with radiotherapy in locally advanced esophageal cancer

    SciTech Connect

    Kim, Dong W.; Blanke, Charles D.; Wu, Huiyun; Shyr, Yu; Berlin, Jordan; Beauchamp, R. Daniel; Chakravarthy, Bapsi . E-mail: bapsi.chak@vanderbilt.edu

    2007-02-01

    Purpose: Preoperative paclitaxel-based chemoradiotherapy may improve the response rates and survival in patients with localized esophageal cancer. We evaluated paclitaxel-based induction chemoradiotherapy in patients with localized esophageal cancer to determine its feasibility, clinical response, pathologic response, and overall survival. Methods and Materials: Between 1995 and 1998, 50 patients were enrolled in this study. At study entry, patients were categorized as either resectable or unresectable according to evaluation by an experienced thoracic surgeon. All patients were treated with paclitaxel 175 mg/m{sup 2} and cisplatin 75 mg/m{sup 2} on Day 1, 29 with radiotherapy to 3,000 cGy in 15 fractions. Resectable patients underwent esophagectomy 4 weeks later. Postoperatively, patients received two cycles of paclitaxel 175 mg/m{sup 2} on Day 1 and 5-fluorouracil 350 mg/m{sup 2} and leucovorin 300 mg on Days 1-3, given every 28 days. Patients who were deemed unsuitable for resection from the outset continued radiotherapy to a total dose of 6,000 cGy. Results: Of the 50 patients, all began neoadjuvant chemoradiotherapy, 40 patients underwent surgery, and 25 patients completed postoperative chemotherapy. A pathologic complete response was seen in 7 patients (17.5%). Patients with a pathologic response had a median survival of 32.4 months vs. 14.4 months for nonresponders (p <0.001). Patients with a clinical response had a median survival of 25.2 months compared with 15.6 months for nonresponders (p = 0.002). At a median follow up of 19.8 months (range 2.4-100.8), the median survival was 20.4 months and the 3-year overall survival rate was 23.2%. Conclusion: Although preoperative cisplatin/paclitaxel with 3,000 cGy was tolerable, this multimodality regimen did not appear to be superior to standard cisplatin/5-fluorouracil-containing regimens and its use is not recommended.

  10. Molecular evidences for the chemosensitizing efficacy of liposomal curcumin in paclitaxel chemotherapy in mouse models of cervical cancer.

    PubMed

    Sreekanth, C N; Bava, S V; Sreekumar, E; Anto, R J

    2011-07-14

    The microtubule-targeting antineoplastic agent, paclitaxel, is highly efficacious against a wide spectrum of human cancers. However, dose-limiting toxicity and development of drug resistance limit its clinical application. Development of novel strategies that overcome chemoresistance and sensitize cancer cells to paclitaxel can enhance the therapeutic effect of this drug. We have previously shown that curcumin, a natural polyphenol, enhances paclitaxel-induced cytotoxicity in vitro through downregulation of nuclear factor (NF)-?B and Akt pathways. This study was undertaken to determine whether this synergism exists in vivo and to elucidate the underlying molecular mechanisms. Mouse cervical multistage squamous cell carcinoma model using 3-methylcholanthrene (3-MC) and a xenograft model of human cervical cancer in nonobese diabetic severe combined immunodeficient (NOD-SCID) mice using HeLa cells were used to evaluate the synergism. We observed that the combined treatment of curcumin and paclitaxel induced a synergestic reduction in the tumor incidence as well as tumor volume of animals compared with the individual treatments of paclitaxel or curcumin, although curcumin alone could not induce any significant effect at the concentration used. The results suggest that a suboptimal concentration of curcumin augments the antitumor action of paclitaxel by downregulating the activation and downstream signaling of antiapoptotic factors and survival signals such as NF-?B, Akt and mitogen-activated protein kinases that have significant roles in proliferation, survival, angiogenesis and metastasis. This study revealed for the first time that 3-MC-induced tumorigenesis in mice is associated with a strong constitutive activation of NF-?B activity. Furthermore, we also observed that pre-exposure of carcinoma cells isolated from 3-MC-induced tumors to curcumin potentiates paclitaxel-induced apoptosis. Overall, the findings of this preclinical study provide a strong rationale for the validation of this combination through clinical trials. As curcumin could effectively downregulate all these survival signals induced by paclitaxel, we suggest it as a potent chemosensitizer to improve the therapeutic index of paclitaxel. PMID:21317920

  11. Autophagy inhibition re-sensitizes pulse stimulation-selected paclitaxel-resistant triple negative breast cancer cells to chemotherapy-induced apoptosis.

    PubMed

    Wen, Jian; Yeo, Syn; Wang, Chenran; Chen, Song; Sun, Shaogang; Haas, Michael A; Tu, Wei; Jin, Feng; Guan, Jun-Lin

    2015-02-01

    Chemotherapy is the mainstay of systemic treatment for triple negative breast cancer (TNBC); however, the development of drug resistance limits its effectiveness. Therefore, we investigated the underlying mechanism for drug resistance and potential approaches to overcome it for a more effective treatment for TNBCs. Using a pulse-stimulated selection strategy to mimic chemotherapy administration in the clinic, we developed a new paclitaxel-resistant MDA-MB-231 cell line and analyzed these cells for changes in autophagy activity, and the role and mechanisms of the increased autophagy in promoting drug resistance were determined. We found that the pulse-stimulated selection strategy with paclitaxel resulted in MDA-MB-231 variant cells with enhanced resistance to paclitaxel. These resistant cells were found to have enhanced basal autophagy activity, which confers a cytoprotective function under paclitaxel treatment stress. Inhibition of autophagy enhanced paclitaxel-induced cell death in these paclitaxel-resistant cells. We further revealed that up-regulated autophagy in resistant cells enhanced the clearance of damaged mitochondria. Last, we showed that the paclitaxel-resistant cancer cells acquired cross resistance to epirubicin and cisplatin. Together, these results suggest that combining autophagy inhibition with chemotherapy may be an effective strategy to improve treatment outcome in paclitaxel-resistant TNBC patients. PMID:25638397

  12. A novel paclitaxel-loaded poly(epsilon-caprolactone)/Poloxamer 188 blend nanoparticle overcoming multidrug resistance for cancer treatment.

    PubMed

    Zhang, Yangqing; Tang, Lina; Sun, Leilei; Bao, Junbo; Song, Cunxian; Huang, Laiqiang; Liu, Kexin; Tian, Yan; Tian, Ge; Li, Zhen; Sun, Hongfan; Mei, Lin

    2010-06-01

    Multidrug resistance (MDR) of tumor cells is a major obstacle to the success of cancer chemotherapy. Poloxamers have been used in cancer therapy to overcome MDR. The objective of this research is to test the feasibility of paclitaxel-loaded poly(epsilon-caprolactone)/Poloxamer 188 (PCL/Poloxamer 188) nanoparticles to overcome MDR in a paclitaxel-resistant human breast cancer cell line. Paclitaxel-loaded nanoparticles were prepared by a water-acetone solvent displacement method using commercial PCL and self-synthesized PCL/Poloxamer 188 compound, respectively. PCL/Poloxamer 188 nanoparticles were found to be of spherical shape and tended to have a rough and porous surface. The nanoparticles had an average size of around 220nm, with a narrow size distribution. The in vitro drug release profile of both nanoparticle formulations showed a clear biphasic release pattern. There was an increased level of uptake of PCL/Poloxamer 188 nanoparticles (PPNP) in the paclitaxel-resistant human breast cancer cell line MCF-7/TAX, in comparison with PCL nanoparticles. The cytotoxicity of PCL nanoparticles was higher than commercial Taxol in the MCF-7/TAX cell culture, but the differences were not significant. However, the PCL/Poloxamer 188 nanoparticles achieved a significantly higher level of cytotoxicity than both of PCL nanoparticle formulation and Taxol(R), indicating that paclitaxel-loaded PCL/Poloxamer 188 nanoparticles could overcome MDR in human breast cancer cells and therefore could have considerable therapeutic potential for breast cancer. PMID:19969111

  13. Natural History of Paclitaxel-Associated Acute Pain Syndrome: Prospective Cohort Study NCCTG N08C1

    PubMed Central

    Loprinzi, Charles L.; Reeves, Brandi N.; Dakhil, Shaker R.; Sloan, Jeff A.; Wolf, Sherry L.; Burger, Kelli N.; Kamal, Arif; Le-Lindqwister, Nguyet A.; Soori, Gamini S.; Jaslowski, Anthony J.; Novotny, Paul J.; Lachance, Daniel H.

    2011-01-01

    Purpose The characteristics and natural history of the paclitaxel–acute pain syndrome (P-APS) and paclitaxel's more chronic neuropathy have not been well delineated. Methods Patients receiving weekly paclitaxel (70 to 90 mg/m2) completed daily questionnaires and weekly European Organisation for Research and Treatment of Cancer (EORTC) Chemotherapy-Induced Peripheral Neuropathy (CIPN) –20 instruments during the entire course of therapy. Results P-APS symptoms peaked 3 days after chemotherapy. Twenty percent of patients had pain scores of 5 to 10 of 10 with the first dose of paclitaxel. Sensory neuropathy symptoms were more prominent than were motor or autonomic neuropathy symptoms. Of the sensory neuropathy symptoms, numbness and tingling were more prominent than was shooting or burning pain. Patients with higher P-APS pain scores with the first dose of paclitaxel appeared to have more chronic neuropathy. Conclusion These data support that the P-APS is related to nerve pathology as opposed to being arthralgias and/or myalgias. Numbness and tingling are more prominent chronic neuropathic symptoms than is shooting or burning pain. PMID:21383290

  14. Paclitaxel-loaded microparticles for intratumoral administration via the TMT technique: preparation, characterization, and preliminary antitumoral evaluation.

    PubMed

    Hamoudeh, Misara; Diab, Roudayna; Fessi, Hatem; Dumontet, Charles; Cuchet, Delphine

    2008-07-01

    In our pursuit to develop suitable therapeutic particulate systems for intratumoral delivery by the targeted multi-therapy (TMT) technique, we describe the preparation of paclitaxel-loaded poly(D,L-lactic-co-glycolic) acid (PLGA) microparticles (MPs) (drug loading 35-38%, wt/wt; size 0.7-5 microm). Magnetite (15%, wt/wt) was also incorporated in some preparations for a future magnetic resonance imaging (MRI)-guided delivery. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) experiments showed that paclitaxel was not encapsulated in its initial crystalline form. The paclitaxel in vitro release pattern showed a biphasic tendency with a burst effect followed by a sustained release (28% released amount after 1 month), which was accompanied with MP erosion and degradation signs as confirmed by scanning electronic microscopy (SEM) micrographs. The paclitaxel-loaded MPs demonstrated a dose-dependent antitumor effect on human uterine cancer cells, with an IC(50) value relatively close to that of commercial Taxol. This paclitaxel delivery system represents a potent antiprofilerative and radiosensitizer agent for intratumoral administration via the TMT technique. PMID:18612910

  15. Overexpression of stathmin is resistant to paclitaxel treatment in patients with non-small cell lung cancer.

    PubMed

    Sun, Ruifang; Liu, Zhigang; Wang, Lumin; Lv, Weidong; Liu, Jia; Ding, Caixia; Yuan, Yong; Lei, Guangyan; Xu, Changfu

    2015-08-01

    Paclitaxel can exert therapeutic effects by interacting with microtubules. Stathmin and ?-III-tubulin, which have impact on microtubule activity, are believed to be involved in the chemotherapy. The purpose of the present study was to evaluate the associations between stathmin and ?-III-tubulin expression and treatment response and survivals in patients with non-small cell lung cancer (NSCLC). Two hundred thirty-eight patients who were treated by platinum-based chemotherapy were enrolled in this study, among them, 111 patients also received paclitaxel treatment. Formalin-fixed and paraffin-embedded tumor tissues were collected for messenger RNA (mRNA) and protein detection. We assessed the associations of the two molecules with treatment response and survival outcome. High level of stathmin exhibited poor response to chemotherapy (for mRNA, P?=?0.041; for protein, P?=?0.017). Overexpression of stathmin was associated with shorter overall survival (for mRNA, P?=?0.012; for protein, P?=?0.014) and progression-free survival (for mRNA, P?=?0.039; for protein, P?=?0.022). Of note, this association was only observed in patients who were treated by both platinum and paclitaxel. Similar effects were not observed for ?-III-tubulin. The findings demonstrated that paclitaxel effect may be interfered with stathmin; overexpression of stathmin is a predictive marker for a worse prognosis in patients with NSCLC who were treated by both platinum and paclitaxel chemotherapy. PMID:25894372

  16. Apoptotic effect of cordycepin combined with cisplatin and/or paclitaxel on MA-10 mouse Leydig tumor cells

    PubMed Central

    Kang, Fu-Chi; Chen, Pei-Jung; Pan, Bo-Syong; Lai, Meng-Shao; Chen, Yung-Chia; Huang, Bu-Miin

    2015-01-01

    Background Chemotherapy is not limited to a single treatment, and the evidence demonstrates that different drug combinations can have positive results in patients. In this study, we sought to determine whether cordycepin combined with cisplatin and/or paclitaxel would have an additive effective on inducing apoptosis in mouse Leydig tumor cells, and the mechanisms were also briefly examined. Methods The additive effects of cordycepin combined with cisplatin and/or paclitaxel on apoptosis in MA-10 cells were investigated by monitoring changes in morphological characteristics and examining cell viability, flow cytometry assays, and Western blot analyses. Results Combination of cordycepin plus cisplatin and/or paclitaxel for 12 and 24 hours induced apoptotic features in MA-10 cells. The MTT assay showed that the combination treatment reduced the viability of MA-10 cells in a dose-dependent manner, with additive effects. Cell cycle analysis showed that combination treatment significantly increased subG1 phase cell numbers in MA-10 cells, indicating apoptosis. Moreover, cordycepin plus cisplatin and/or paclitaxel significantly induced cleavage of caspase-8, caspase-9, caspase-3, and poly ADP-ribose polymerase, and phosphorylation of c-Jun NH2-terminal kinase, extracellular signal-regulated kinase, p38, and p53 proteins in MA-10 cells. Conclusion Cordycepin plus cisplatin and/or paclitaxel can have an additive effect on apoptosis in MA-10 cells, with activation of caspase, mitogen-activated protein kinase, and p53 signal pathways. PMID:26366090

  17. Etodolac, a cyclooxygenase-2 inhibitor, attenuates paclitaxel-induced peripheral neuropathy in a mouse model of mechanical allodynia.

    PubMed

    Ito, Sunao; Tajima, Koyuki; Nogawa, Masaki; Inoue, Naoki; Kyoi, Takashi; Takahashi, Yosuke; Sasagawa, Takahiro; Nakamura, Akio; Kotera, Takashi; Ueda, Makoto; Yamashita, Yasuhiro; Banno, Kouji

    2012-07-01

    The effect of the cyclooxygenase-2 (COX-2) inhibitor etodolac on the mechanical allodynia induced by paclitaxel was investigated in mice and compared with the effects of the nonselective COX inhibitors indomethacin and diclofenac, the selective COX-2 inhibitor celecoxib, the calcium channel ?(2)? subunit inhibitor pregabalin, the sodium channel blocker mexiletine, and the serotonin-norepinephrine reuptake inhibitor duloxetine. The decrease in the paw-withdrawal threshold induced by paclitaxel was reversed by oral administration of etodolac at 10 mg/kg but was not affected by indomethacin, diclofenac, or celecoxib. The antiallodynic effect of etodolac gradually increased during repeated administration, and after 2 weeks the paw-withdrawal threshold at the preadministration point was significantly increased. Pregabalin, duloxetine, and mexiletine also showed an antiallodynic effect in this model. Whereas pregabalin had a preadministration effect similar to that of etodolac during repeated administration, mexiletine or duloxetine had no such effect. There was almost no difference in the distribution of etodolac and diclofenac in nervous tissue, indicating that COX inhibition is unlikely to be involved in the antiallodynic effect of etodolac. Etodolac did not show a neuroprotective effect against morphological transformations such as the axonal degeneration induced by paclitaxel. Instead, etodolac probably acts at the level of functional changes accompanying paclitaxel treatment, such as alterations in the activation state of components of the pain transmission pathway. Our findings suggest that etodolac attenuates paclitaxel-induced peripheral neuropathy by a COX-independent pathway and that it might be useful for the treatment of paclitaxel-induced peripheral neuropathy. PMID:22460833

  18. Effect of sun ginseng potentiation on epirubicin and paclitaxel-induced apoptosis in human cervical cancer cells

    PubMed Central

    Lin, Yingjia; Jiang, Dan; Li, Yang; Han, Xinye; Yu, Di; Park, Jeong Hill; Jin, Ying-Hua

    2014-01-01

    Background Sun ginseng (SG), a specific formulation of quality-controlled red ginseng, contains approximately equal amounts of three major ginsenosides (RK1, Rg3, and Rg5), which reportedly has antitumor-promoting activities in animal models. Methods MTT assay was used to assess whether SG can potentiate the anticancer activity of epirubicin or paclitaxel in human cervical adenocarcinoma HeLa cells, human colon cancer SW111C cells, and SW480 cells; apoptosis status was analyzed by annexin V-FITC and PI and analyzed by flow cytometry; and apoptosis pathway was studied by analysis of caspase-3, -8, and -9 activation, mitochondrial accumulation of Bax and Bak, and cytochrome c release. Results SG remarkably enhances cancer cell death induced by epirubicin or paclitaxel in human cervical adenocarcinoma HeLa cells, human colon cancer SW111C cells, and SW480 cells. Results of the mechanism study highlighted the cooperation between SG and epirubicin or paclitaxel in activating caspase-3 and -9 but not caspase-8. Moreover, SG significantly increased the mitochondrial accumulation of both Bax and Bak triggered by epirubicin or paclitaxel as well as the subsequent release of cytochrome c in the targeted cells. Conclusion SG significantly potentiated the anticancer activities of epirubicin and paclitaxel in a synergistic manner. These effects were associated with the increased mitochondrial accumulation of both Bax and Bak that led to an enhanced cytochrome c release, caspase-9/-3 activation, and apoptosis. Treating cancer cells by combining epirubicin and paclitaxel with SG may prove to be a novel strategy for enhancing the efficacy of the two drug types. PMID:25535473

  19. NAC-1, a potential stem cell pluripotency factor, contributes to paclitaxel resistance in ovarian cancer through inactivating Gadd45 pathway.

    PubMed

    Jinawath, N; Vasoontara, C; Yap, K-L; Thiaville, M M; Nakayama, K; Wang, T-L; Shih, I-M

    2009-05-01

    Nucleus accumbens-1 (Nac1 or NAC-1) belongs to the BTB/POZ (Pox virus and Zinc finger/Bric-a-brac Tramtrack Broad complex) transcription factor family and is a novel protein that potentially participates in self-renewal and pluripotency in embryonic stem cells. In human cancer, NAC-1 is upregulated in several types of neoplasms, but particularly in recurrent chemoresistant ovarian carcinomas, suggesting a biological role for NAC-1 in the development of drug resistance in ovarian cancer. We have assessed this possibility and shown a correlation between NAC-1 expression and ex vivo paclitaxel resistance in ovarian serous carcinoma tissues and cell lines. We found that expression of Gadd45-gamma-interacting protein 1 (Gadd45gip1), a downstream target negatively regulated by NAC-1, was reduced in paclitaxel-resistant cells. Ectopic expression of NAC-1 or knockdown of Gadd45gip1 conferred paclitaxel resistance, whereas NAC-1 knockdown or ectopic expression of Gadd45gip1 increased paclitaxel sensitivity. Furthermore, silencing NAC-1 expression or disrupting NAC-1 homodimerization by a dominant negative NAC-1 protein that contained only the BTB/POZ domain induced the expression of Gadd45gamma, which interacted with Gadd45gip1. Reducing Gadd45gamma expression by small hairpin RNAs partially enhanced paclitaxel resistance. Thus, this study provides new evidence that NAC-1 upregulation and homodimerization contribute to tumor recurrence by equipping ovarian cancer cells with the paclitaxel-resistant phenotype through negative regulation of the Gadd45 pathway. PMID:19305429

  20. Mechanisms of tissue uptake and retention of paclitaxel-coated balloons: impact on neointimal proliferation and healing

    PubMed Central

    Granada, Juan F; Stenoien, Mark; Buszman, Piotr P; Tellez, Armando; Langanki, Dan; Kaluza, Greg L; Leon, Martin B; Gray, William; Jaff, Michael R; Schwartz, Robert S

    2014-01-01

    Background The efficacy of paclitaxel-coated balloons (PCB) for restenosis prevention has been demonstrated in humans. However, the mechanism of action for sustained drug retention and biological efficacy following single-time drug delivery is still unknown. Methods and results The pharmacokinetic profile and differences in drug concentration (vessel surface vs arterial wall) of two different paclitaxel coating formulations (3?µg/mm2) displaying opposite solubility characteristics (CC=crystalline vs AC=amorphous) were tested in vivo and compared with paclitaxel-eluting stents (PES). Also, the biological effect of both PCB formulations on vascular healing was tested in the porcine coronary injury model. One hour following balloon inflation, both formulations achieved similar arterial paclitaxel levels (CC=310 vs AC=245?ng/mg; p=NS). At 24?h, the CC maintained similar tissue concentrations, whereas the AC tissue levels declined by 99% (p<0.01). At this time point, arterial levels were 20-fold (CC) and 5-fold (AC) times higher compared to the PES group (p<0.05). At 28?days, arterial levels retained were 9.2% (CC) and 0.04% (AC, p<0.01) of the baseline levels. Paclitaxel concentration on the vessel surface was higher in the CC at 1 (CC=36.7% vs AC=13.1%, p<0.05) and 7?days (CC=38.4% vs AC=11%, p<0.05). In addition, the CC induced higher levels of neointimal inhibition, fibrin deposition and delayed healing compared with the AC group. Conclusions The presence of paclitaxel deposits on the vessel surface driving diffusion into the arterial tissue in a time-dependent fashion supports the mechanism of action of PCB. This specific pharmacokinetic behaviour influences the patterns of neointimal formation and healing. PMID:25332821

  1. Chemotherapy-related amenorrhea after adjuvant paclitaxel-trastuzumab (APT trial).

    PubMed

    Ruddy, Kathryn J; Guo, Hao; Barry, William; Dang, Chau T; Yardley, Denise A; Moy, Beverly; Marcom, P Kelly; Albain, Kathy S; Rugo, Hope S; Ellis, Matthew J; Shapira, Iuliana; Wolff, Antonio C; Carey, Lisa A; Overmoyer, Beth A; Hudis, Clifford; Krop, Ian E; Burstein, Harold J; Winer, Eric P; Partridge, Ann H; Tolaney, Sara M

    2015-06-01

    Chemotherapy-related amenorrhea (CRA) is associated with infertility and menopausal symptoms. Learning how frequently paclitaxel and trastuzumab cause amenorrhea is important. Most other adjuvant breast cancer therapies induce CRA in approximately 50 % of all premenopausal recipients [1]. 410 patients enrolled on the APT Trial, a single-arm phase 2 adjuvant study of 12 weeks of paclitaxel and trastuzumab followed by nine months of trastuzumab monotherapy. Eligible patients had ?3 cm node-negative HER2 + breast cancers. Premenopausal enrollees were asked to complete menstrual surveys every 3-12 months for 72 months. Women who responded to at least one survey at least 15 months after chemotherapy initiation (and who did not undergo hysterectomy and/or bilateral oophorectomy or receive ovarian suppressing medications prior to 15 months) were included in this analysis. A participant was defined as having amenorrhea in follow-up if her self-reported last menstrual period at last follow-up was greater than 12 months prior to the survey. Among the 64 women in the evaluable population (median age at study entry 44 years, range 27-52 years), the median time between chemotherapy initiation and last menstrual survey was 51 months (range 16-79). 18 of 64 women (28 %, 95 % CI 18-41 %) were amenorrheic at that time point. Amenorrhea rates among premenopausal women treated with adjuvant paclitaxel and trastuzumab for early stage breast cancer appear lower than those seen historically with standard alkylator-based breast cancer regimens. Future studies are needed to understand the impact of this regimen on related issues of fertility and menopausal symptoms. PMID:25981899

  2. Expression of Drug Targets in Patients Treated with Sorafenib, Carboplatin and Paclitaxel

    PubMed Central

    Jilaveanu, Lucia B.; Zhao, Fengmin; Zito, Christopher R.; Kirkwood, John M.; Nathanson, Katherine L.; D'Andrea, Kurt; Wilson, Melissa; Rimm, David L.; Flaherty, Keith T.; Lee, Sandra J.; Kluger, Harriet M.

    2013-01-01

    Introduction Sorafenib, a multitarget kinase inhibitor, targets members of the mitogen-activated protein kinase (MAPK) pathway and VEGFR kinases. Here we assessed the association between expression of sorafenib targets and biomarkers of taxane sensitivity and response to therapy in pre-treatment tumors from patients enrolled in ECOG 2603, a phase III comparing sorafenib, carboplatin and paclitaxel (SCP) to carboplatin, paclitaxel and placebo (CP). Methods Using a method of automated quantitative analysis (AQUA) of in situ protein expression, we quantified expression of VEGF-R2, VEGF-R1, VEGF-R3, FGF-R1, PDGF-R?, c-Kit, B-Raf, C-Raf, MEK1, ERK1/2, STMN1, MAP2, EB1 and Bcl-2 in pretreatment specimens from 263 patients. Results An association was found between high FGF-R1 and VEGF-R1 and increased progression-free survival (PFS) and overall survival (OS) in our combined cohort (SCP and CP arms). Expression of FGF-R1 and VEGF-R1 was higher in patients who responded to therapy ((CR+PR) vs. (SD+PD+ un-evaluable)). Conclusions In light of the absence of treatment effect associated with sorafenib, the association found between FGF-R1 and VEGF-R1 expression and OS, PFS and response might reflect a predictive biomarker signature for carboplatin/paclitaxel-based therapy. Seeing that carboplatin and pacitaxel are now widely used for this disease, corroboration in another cohort might enable us to improve the therapeutic ratio of this regimen. PMID:23936348

  3. [A case of Paclitaxel-induced peripheral neuropathy successfully treated with duloxetine].

    PubMed

    Nagashima, Satoshi; Kiba, Takayoshi; Ogawa, Yoshikazu; Mura, Takuya; Kajiume, Sayoko; Okada, Yuuko; Morii, Nao; Takahashi, Hirotoshi; Ichiba, Yasunori; Yamashiro, Hiroyasu

    2015-05-01

    Here, we report about a 60-year-old woman with metastatic breast cancer who was successfully treated for paclitaxelinduced peripheral neuropathy with duloxetine. She was administered trastuzumab plus paclitaxel(PTX)combination therapy that was ultimately discontinued because of grade 3 peripheral neuropathy detected on day 15, according to the CTCAE (v4.0). She was administered duloxetine on day 90 after the end of the previous therapy because of the peripheral neuropathy. Thereafter, the peripheral neuropathy decreased to grade 1, which enabled PTX administration on her request. Further trials are required to confirm the efficacy of duloxetine. PMID:25981658

  4. Forkhead box K2 modulates epirubicin and paclitaxel sensitivity through FOXO3a in breast cancer.

    PubMed

    Nestal de Moraes, G; Khongkow, P; Gong, C; Yao, S; Gomes, A R; Ji, Z; Kandola, N; Delbue, D; Man, E P S; Khoo, U S; Sharrocks, A D; Lam, E W-F

    2015-01-01

    The forkhead transcription factor FOXK2 has recently been implicated in cancer cell proliferation and survival, but a role in cancer chemotherapeutic drug resistance has hitherto not been explored. Here we demonstrate that FOXK2 has a central role in mediating the cytotoxic drug response in breast cancer. Clonogenic and cell viability assays showed that enhanced FOXK2 expression sensitizes MCF-7 breast cancer cells to paclitaxel or epirubicin treatment, whereas FOXK2 depletion by small interfering RNAs (siRNAs) confers drug resistance. Our data also showed that the activation of the tumour suppressor FOXO3a by paclitaxel and epirubicin is mediated through the induction of FOXK2, as depletion of FOXK2 by siRNA limits the induction of FOXO3a by these drugs in MCF-7 cells. Chromatin immunoprecipitation (ChIP) analysis showed that in response to drug treatment, FOXK2 accumulates and binds to the proximal FOXO3a promoter region in MCF-7 cells. Furthermore, we also uncovered that FOXK2 is deregulated and, therefore, can express at high levels in the nucleus of both the paclitaxel and epirubicin drug-resistant MCF-7 cells. Our results showed that ectopically overexpressed FOXK2 accumulates in the nuclei of drug-resistant MCF-7 cells but failed to be recruited to target genes, including FOXO3a. Crucially, we found that FOXO3a is required for the anti-proliferative and epirubicin-induced cytotoxic function of FOXK2 in MCF-7 cells by sulphorhodamine and clonogenic assays. The physiological importance of the regulation of FOXO3a by FOXK2 is further confirmed by the significant correlations between FOXO3a and FOXK2 expression in breast carcinoma patient samples. Further survival analysis also reveals that high nuclear FOXK2 expression significantly associates with poorer clinical outcome, particularly in patients who have received conventional chemotherapy, consistent with our finding that FOXK2 is deregulated in drug-resistant cells. In summary, our results suggest that paclitaxel and epirubicin target the FOXK2 to modulate their cytotoxicity and deregulated FOXK2 confers drug resistance. PMID:26344694

  5. Vasculitis resulting from a superficial femoral artery angioplasty with a paclitaxel-eluting balloon.

    PubMed

    Thomas, Shannon D; McDonald, Robert R A; Varcoe, Ramon L

    2014-02-01

    Drug-eluting balloons (DEBs) coated with the antiproliferative agent paclitaxel may improve primary patency by reducing recurrent luminal stenosis. A proportion of the active drug and excipient coating are known to embolize distally, but until now, there have been no reports of adverse events resulting from their use. We report an unusual case of a painful nodular, biopsy specimen-proven vasculitic rash that afflicted the ipsilateral lower limb of a patient after superficial femoral artery treatment with a DEB. This adverse event may have implications for the use of DEB in this and other vascular territories. PMID:23642919

  6. Integrating Image-Based High-Content Screening with Mouse Models Identifies 5-Hydroxydecanoate as a Neuroprotective Drug for Paclitaxel-Induced Neuropathy.

    PubMed

    Chen, Li-Hsien; Sun, Yuan-Ting; Chen, Yih-Fung; Lee, Mei-Yi; Chang, Lian-Yun; Chang, Jang-Yang; Shen, Meng-Ru

    2015-10-01

    Chemotherapy-induced neurotoxicity is a common adverse effect of cancer treatment. No medication has been shown to be effective in the prevention or treatment of chemotherapy-induced neurotoxicity. This study aimed to discover potential neuroprotective drugs for paclitaxel-induced neurotoxicity. An image-based high-content platform was first developed to screen for potential neuroprotective drugs. The screening system comprised of automated image acquisition and multiparameter analysis, including neuronal viability, neurite outgrowth, and synaptogenesis. By this platform, we obtained a candidate list from compound libraries. In the drug screening from compound libraries of ion channel ligands, REDOX and GABAergic ligands, 5-hydroxydecanoate (5-HD) exhibited the most significant neuroprotective effects against paclitaxel-induced neurotoxicity in both cortical and dorsal root ganglion (DRG) neurons. In mouse behavioral tests, 5-HD restored the thermal sensitivity and alleviated mechanical allodynia induced by paclitaxel. Electron micrographs of sciatic nerve revealed that 5-HD reduced the damages caused by paclitaxel in the nonmyelinated and smaller myelinated fibers. The mechanistic study on DRG neurons suggested that 5-HD rescued the dysregulation of intracellular calcium homeostasis provoked by paclitaxel. Importantly, 5-HD did not jeopardize the antitumor effect of paclitaxel in tumor xenograft models. In conclusion, we established an imaged-based high-content screening platform and a protocol for verifying the neuroprotective effect in vivo, by which 5-HD was identified and validated as a potential neuroprotective drug for paclitaxel-induced neuropathy. Mol Cancer Ther; 14(10); 2206-14. ©2015 AACR. PMID:26294744

  7. Prospective evaluation of concurrent paclitaxel and radiation therapy after adjuvant doxorubicin and cyclophosphamide chemotherapy for Stage II or III breast cancer

    SciTech Connect

    Burstein, Harold J. . E-mail: hburstein@partners.org; Bellon, Jennifer R.; Galper, Sharon; Lu, H.-M.; Kuter, Irene; Wong, Julia; Gelman, Rebecca; Bunnell, Craig A.; Parker, Leroy M.; Garber, Judy E.; Winer, Eric P.; Harris, Jay R.; Powell, Simon N.

    2006-02-01

    Purpose: To evaluate the safety and feasibility of concurrent radiation therapy and paclitaxel-based adjuvant chemotherapy, given either weekly or every 3 weeks, after adjuvant doxorubicin and cyclophosphamide (AC). Methods and Materials: After definitive breast surgery and AC chemotherapy, 40 patients with operable Stage II or III breast cancer received protocol-based treatment with concurrent paclitaxel and radiation therapy. Paclitaxel was evaluated on 2 schedules, with treatment given either weekly x 12 weeks (60 mg/m{sup 2}), or every 3 weeks x 4 cycles (135-175 mg/m{sup 2}). Radiation fields and schedules were determined by the patient's surgery and pathology. The tolerability of concurrent therapy was evaluated in cohorts of 8 patients as a phase I study. Results: Weekly paclitaxel treatment at 60 mg/m{sup 2} per week with concurrent radiation led to dose-limiting toxicity in 4 of 16 patients (25%), including 3 who developed pneumonitis (either Grade 2 [1 patient] or Grade 3 [2 patients]) requiring steroids. Efforts to eliminate this toxicity in combination with weekly paclitaxel through treatment scheduling and CT-based radiotherapy simulation were not successful. By contrast, dose-limiting toxicity was not encountered among patients receiving concurrent radiation with paclitaxel given every 3 weeks at 135-175 mg/m{sup 2}. However, Grade 2 radiation pneumonitis not requiring steroid therapy was seen in 2 of 24 patients (8%) treated in such a fashion. Excessive radiation dermatitis was not observed with either paclitaxel schedule. Conclusions: Concurrent treatment with weekly paclitaxel and radiation therapy is not feasible after adjuvant AC chemotherapy for early-stage breast cancer. Concurrent treatment using a less frequent paclitaxel dosing schedule may be possible, but caution is warranted in light of the apparent possibility of pulmonary injury.

  8. A Randomized Trial Investigating the Efficacy and Safety of Water Soluble Micellar Paclitaxel (Paccal Vet) for Treatment of Nonresectable Grade 2 or 3 Mast Cell Tumors in Dogs

    PubMed Central

    Vail, D.M.; von Euler, H.; Rusk, A.W.; Barber, L.; Clifford, C.; Elmslie, R.; Fulton, L.; Hirschberger, J.; Klein, M.; London, C.; Martano, M.; McNiel, E.A.; Morris, J.S.; Northrup, N.; Phillips, B.; Polton, G.; Post, G.; Rosenberg, M.; Ruslander, D.; Sahora, A.; Siegel, S.; Thamm, D.; Westberg, S.; Winter, J.; Khanna, C.

    2013-01-01

    Background Effective treatments for dogs with advanced stage mast cell tumors (MCT) remain a pressing need. A micellar formulation of paclitaxel (paclitaxel [micellar]) has shown promise in early-phase studies. Hypothesis/Objectives The objective was to demonstrate greater activity for paclitaxel (micellar) compared with lomustine. The null hypothesis was ?p = ?L (ie, proportion of responders for the paclitaxel [micellar] and lomustine groups, respectively). Animals Two hundred and fifty-two dogs with advanced stage nonresectable grade 2 or 3 MCT. Methods Prospective multicenter randomized double-blind positive-controlled clinical trial. The primary endpoint was confirmed overall response rate (CORR) at 14 weeks. A secondary endpoint, biologic observed response rate (BORR), also was calculated. Safety was assessed by the characterization and grading of adverse events (AE). Results Overall CORR (7% versus 1%; P = .048) and BORR (23% versus 10%; P = .012) were greater for paclitaxel (micellar) compared with lomustine. Paclitaxel (micellar)-treated dogs were 6.5 times more likely to have a confirmed response and 3.1 times more likely to experience a biologic observed response. The majority of AE with paclitaxel (micellar) were transient and clinically manageable. Twenty-seven dogs (33%) receiving lomustine were discontinued because of hepatopathy compared with 3 dogs (2%) receiving paclitaxel (micellar) (P < .0001; odds ratio 26.7). Conclusions and Clinical Importance Paclitaxel (micellar)’s activity and safety profile are superior to lomustine. The addition of an active and novel taxane to the veterinary armamentarium could fill a substantial need and, as its mechanism of action and AE profile do not overlap with currently available TKI, its availability could lead to effective combination protocols. PMID:22390318

  9. Recurrent peritoneal serous carcinoma that was unmanageable with paclitaxel–carboplatin therapy responded to autologous formalin-fixed tumor vaccine

    PubMed Central

    Chen, Jui-Tung; Ohno, Tadao

    2015-01-01

    Key Clinical Message Paclitaxel–carboplatin therapy (TC) usually controls primary peritoneal serous carcinoma (PPSC) but not recurrent disease. In this case, PPSC recurred after three courses of TC, responded dramatically to additional autologous formalin-fixed tumor vaccine (AFTV), and resulted in prolonged, progression-free survival without visible lesions detected by positron emission tomography–computed tomography. PMID:26509016

  10. Coadministration of indomethacin and minocycline attenuates established paclitaxel-induced neuropathic thermal hyperalgesia: Involvement of cannabinoid CB1 receptors

    PubMed Central

    Parvathy, Subramanian S.; Masocha, Willias

    2015-01-01

    Taxanes such as paclitaxel, which are chemotherapeutic drugs, cause dose-dependent painful neuropathy in some patients. We investigated whether coadministration of minocycline and indomethacin produces antinociceptive effects in mice with paclitaxel-induced neuropathic thermal hyperalgesia and if the cannabinoid system is involved. Previously, we reported that coadministration of these two drugs results in antinociception against inflammatory pain at doses where either drug alone lack significant activity. In the current study, we observed that treatment of female mice with indomethacin or minocycline alone did not affect established paclitaxel-induced thermal hyperalgesia, whereas coadministration of the two drugs attenuated it. In male mice indomethacin had some antihyperalgesic activity, whilst minocycline did not. Coadministration of the two drugs had supraadditive antihyperalgesic activity in male mice. Administration of a cannabinoid CB1 receptor antagonist AM 251 blocked the antihyperalgesic effects of the combination of minocycline and indomethacin in both male and female mice. In conclusion our results indicate that coadministration of minocycline and indomethacin abrogates established paclitaxel-induced neuropathic thermal hyperalgesia in mice, and the potentiation of the antinociceptive effects of this combination involves the cannabinoid system. PMID:26085115

  11. Paclitaxel-loaded nanoparticles of star-shaped cholic acid-core PLA-TPGS copolymer for breast cancer treatment

    NASA Astrophysics Data System (ADS)

    Tang, Xiaolong; Cai, Shuyu; Zhang, Rongbo; Liu, Peng; Chen, Hongbo; Zheng, Yi; Sun, Leilei

    2013-10-01

    A system of novel nanoparticles of star-shaped cholic acid-core polylactide- d-?-tocopheryl polyethylene glycol 1000 succinate (CA-PLA-TPGS) block copolymer was developed for paclitaxel delivery for breast cancer treatment, which demonstrated superior in vitro and in vivo performance in comparison with paclitaxel-loaded poly( d, l-lactide- co-glycolide) (PLGA) nanoparticles and linear PLA-TPGS nanoparticles. The paclitaxel- or couramin 6-loaded nanoparticles were fabricated by a modified nanoprecipitation method and then characterized in terms of size, surface charge, surface morphology, drug encapsulation efficiency, and in vitro drug release. The CA-PLA-TPGS nanoparticles were found to be spherical in shape with an average size of around 120 nm. The nanoparticles were found to be stable, showing no change in the particle size and surface charge during 90-day storage of the aqueous solution. The release profiles of the paclitaxel-loaded nanoparticles exhibited typically biphasic release patterns. The results also showed that the CA-PLA-TPGS nanoparticles have higher antitumor efficacy than the PLA-TPGS nanoparticles and PLGA nanoparticles in vitro and in vivo. In conclusion, such nanoparticles of star-shaped cholic acid-core PLA-TPGS block copolymer could be considered as a potentially promising and effective strategy for breast cancer treatment.

  12. Stability of parenteral nanoemulsions loaded with paclitaxel: the influence of lipid phase composition, drug concentration and storage temperature.

    PubMed

    Kadam, Alisha N; Najlah, Mohammad; Wan, Ka-Wai; Ahmed, Waqar; Crean, St John; Phoenix, David A; Taylor, Kevin M G; Elhissi, Abdelbary M A

    2014-12-01

    Paclitaxel was loaded into licensed parenteral nutrition nanoemulsions (Clinoleic® and Intralipid®) using bath sonication, and the stability of the formulations was investigated following storage for two weeks at room temperature or at 4?°C. In general, Clinoleic droplets were smaller than Intralipid droplets, being around 255 and 285?nm, respectively, for blank and freshly loaded emulsions. Regardless of storage temperature, the Clinoleic exhibited a very slight or no increase in droplet size upon storage, whilst the droplet size of the Intralipid emulsion increased significantly. The droplet size of both emulsions was minimally affected by paclitaxel concentration within the range of 0, 1, 3 and 6?mg/ml. The pH of both emulsions markedly decreased upon storage at room temperature, which was possibly attributed to the production of fatty acids resulting from phospholipid hydrolysis. However, at 4?°C, the pH of Clinoleic emulsion was unaffected by storage or paclitaxel concentration while the Intralipid emulsion demonstrated a trend for pH reduction. Both nanoemulsions had a negative zeta potential, with the Clinoleic formulations having the highest charge, possibly explaining the better size stability of this emulsion. Overall, this study has shown that paclitaxel was successfully loaded into clinically licensed parenteral emulsions and that Clinoleic showed greater stability than the Intralipid. PMID:24093888

  13. A Dicarboxylic Fatty Acid Derivative of Paclitaxel for Albumin Assisted Drug Delivery

    PubMed Central

    Hackett, Michael J.; Joolakanti, Shyamsunder; Hartranft, Megan E.; Guley, Patrick C.; Cho, Moo J.

    2013-01-01

    Paclitaxel is a potent chemotherapy for many cancers but it suffers from very poor solubility. Consequently the TAXOL formulation uses copious amounts of the surfactant Cremophor EL to solubilize the drug for injection resulting in severe hypersensitivity and neutropenia. In contrast to Cremophor EL, presented is a way to solubilize paclitaxel (PTX) by conjugation of a dicarboxylic fatty acid for specific binding to the ubiquitous protein, serum albumin. The conjugation chemistry was simplified to a single step using the activated anhydride form of 3-pentadecylglutaric (PDG) acid which is reactive to a variety of nucleophiles. The PDG derivative is less cytotoxic than the parent compound and was found to slowly hydrolyze to PTX (~5% over 72 h) in serum, tumor cytosol, and tumor tissue homogenate. When injected intravenously to tumor bearing mice, [3H]-PTX in the TAXOL formulation was cleared rapidly with a half-life of 7 hours. In the case of the PDG derivative of PTX, the drug is quickly distributed and approximately 20% of the injected dose remained in the vasculature experiencing a 23-h half-life. These improvements from modifying PTX with the PDG fatty acid present the opportunity for PDG to become a generic modification for the improvement of many therapeutics. PMID:22674061

  14. Paclitaxel in cancer treatment: perspectives and prospects of its delivery challenges.

    PubMed

    Singh, Somnath; Dash, Alekha K

    2009-01-01

    Paclitaxel (PTX) is a potent anticancer agent whose clinical usefulness is marred by a delivery problem that is caused by its unfavorable pharmacokinetic and physical properties. Paclitaxel is currently formulated in a mixture of Cremophor EL and ethanol, which is diluted 5-20 times with normal saline or 5% dextrose prior to administration via slow infusion to avoid precipitation in plasma. Many adverse reactions to the PTX formulation have been reported because of the presence of Cremophor EL, including hypersensitivity reactions, nephrotoxicity, and neurotoxicity. Cremophor EL also causes vasodilation, labored breathing, lethargy, hypotension, and leaching of plasticizers, such as diethylhexylpthalate, from the polyvinylchloride infusion bags/sets. Significant research efforts have been conducted to develop an alternative formulation approach to increase the aqueous solubility of PTX without using Cremophor, thereby decreasing its toxicity. This article reviews the various investigated formulation approaches including pastes; liposomes; conjugates with antibodies, peptides, and fatty acids; nanospheres and microspheres; cyclodextrin complexes; emulsions; mucoadhesive gel; prodrugs; and nanoparticulate systems. The pros and cons of each approach are also discussed. Finally, this review concludes with a discussion of nanoparticulate delivery, which is the most promising PTX delivery system of the future because it incorporates the benefits of other approaches such as conjugation, complexation, and prodrugs. PMID:20001890

  15. Optimization of drug loading to improve physical stability of paclitaxel-loaded long-circulating liposomes.

    PubMed

    Kannan, Vinayagam; Balabathula, Pavan; Divi, Murali K; Thoma, Laura A; Wood, George C

    2015-12-01

    The effect of formulation and process parameters on drug loading and physical stability of paclitaxel-loaded long-circulating liposomes was evaluated. The liposomes were prepared by hydration-extrusion method. The formulation parameters such as total lipid content, cholesterol content, saturated-unsaturated lipid ratio, drug-lipid ratio and process parameters such as extrusion pressure and number of extrusion cycles were studied and their impact on drug loading and physical stability was evaluated. A proportionate increase in drug loading was observed with increase in the total phospholipid content. Cholesterol content and saturated lipid content in the bilayer showed a negative influence on drug loading. The short-term stability evaluation of liposomes prepared with different drug-lipid ratios demonstrated that 1:60 as the optimum drug-lipid ratio to achieve a loading of 1-1.3?mg/mL without the risk of physical instability. The vesicle size decreased with an increase in the extrusion pressure and number of extrusion cycles, but no significant trends were observed for drug loading with changes in process pressure or number of cycles. The optimization of formulation and process parameters led to a physically stable formulation of paclitaxel-loaded long-circulating liposomes that maintain size, charge and integrity during storage. PMID:25541107

  16. Endocytosis of fluorescent cyclodextrins by intestinal Caco-2 cells and its role in paclitaxel drug delivery.

    PubMed

    Réti-Nagy, Katalin; Malanga, Milo; Fenyvesi, Éva; Szente, Lajos; Vámosi, György; Váradi, Judit; Bácskay, Ildikó; Fehér, Pálma; Ujhelyi, Zoltán; Róka, Eszter; Vecsernyés, Miklós; Balogh, György; Vasvári, Gábor; Fenyvesi, Ferenc

    2015-12-30

    Cyclodextrins are widely used excipients in pharmaceutical formulations. They are mainly utilized as solubilizers and absorption enhancers, but recent results revealed their effects on cell membranes and pharmacological barriers. In addition to the growing knowledge on their interaction with plasma membranes, it was confirmed that cyclodextrins are able to enter cells by endocytosis. The number of the tested cyclodextrins was limited, and the role of this mechanism in drug absorption and delivery is not known. Our aim was to examine the endocytosis of fluorescently labeled hydroxypropyl-?-cyclodextrin, random methyl-?-cyclodextrin and soluble ?-cyclodextrin polymer, and the cellular uptake of the fluorescent paclitaxel derivative-random methyl-?-cyclodextrin complex. The studied cyclodextrin derivatives were able to enter Caco-2 intestinal cells and localized in vesicles in the cytoplasm, while their permeability was very limited through Caco-2 monolayers. We demonstrated for the first time that the fluorescent paclitaxel derivative and rhodamine-labeled random methyl-?-cyclodextrin were detected in the same intracellular vesicles after treating cells with their inclusion complex. These results indicate that the endocytosis of cyclodextrin complexes can contribute to drug absorption processes. PMID:26498369

  17. De Novo Characterization of a Cephalotaxus hainanensis Transcriptome and Genes Related to Paclitaxel Biosynthesis

    PubMed Central

    Cong, Hanqing; Wang, Rongxiang; Yin, Junmei; Qian, Dan; Wang, Zhunian; Nick, Peter

    2014-01-01

    Cephalotaxus hainanensis, an endangered plant, is known to contain several metabolites with anti-cancer activity. Despite its clinical impact, the alkaloid metabolism of this species has remained largely uncharacterized. The potential of Cephalotaxus for metabolic engineering of medically interesting compounds has, so far, not been exploited, due to the almost complete lack of molecular information. We have therefore performed a high throughput RNA-seq analysis and assembled the transcriptome de novo. Raw reads comprising 4.3 Gbp were assembled de novo into 39,416 unique sequences (unigenes) with a mean length of 1,089.8 bp and a total assembly size of 45.8 Mbp, which equals to more than 50 times the number of Cephalotaxaceae sequences currently deposited in the GenBank (as of August 2013). As proof of principle for medically interesting pathways, gene fragments related to paclitaxel biosynthesis were searched and detected. To verify their functionality, the metabolic product paclitaxel, and its precursor baccatin III, were identified in the leaves of C. hainanensis by HPLC, and shown to be induced by MeJA. This finding demonstrates exemplarily the potential of the annotated transcriptome as information resource for the biotechnological exploitation of plant secondary metabolism. PMID:25203398

  18. Fentanyl Enhances Hepatotoxicity of Paclitaxel via Inhibition of CYP3A4 and ABCB1 Transport Activity in Mice

    PubMed Central

    Pan, Jia-Hao; Bi, Bing-Tian; Feng, Kun-Yao; Huang, Wan; Zeng, Wei-An

    2015-01-01

    Fentanyl, a potent opioid analgesic that is used to treat cancer pain, is commonly administered with paclitaxel in advanced tumors. However, the effect of fentanyl on the hepatotoxicity of paclitaxel and its potential mechanism of action is not well studied. The purpose of this study was to investigate the effect of fentanyl on the hepatotoxicity of paclitaxel and its potential mechanisms of action. Pharmacokinetic parameters of paclitaxel were tested using reversed phase high-performance liquid chromatography (RP-HPLC). Aspartate transaminase (AST), alanine aminotransferase (ALT), and mouse liver histopathology were examined. Moreover, the cytotoxicity of anti-carcinogens was examined using 1-(4, 5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), and the intracellular accumulation of doxorubicin and rhodamine 123 was detected by flow cytometry. Furthermore, the expression of ABCB1 and the activity of ABCB1 ATPase and CYP3A4 were also examined. In this study, the co-administration of fentanyl and paclitaxel prolonged the half-life (t1/2) of paclitaxel from 1.455 hours to 2.344 hours and decreased the clearance (CL) from 10.997 ml/h to 7.014 ml/h in mice. Fentanyl significantly increased the levels of ALT in mice to 88.2 U/L, which is more than 2-fold higher than the level detected in the control group, and it increased the histological damage in mouse livers. Furthermore, fentanyl enhanced the cytotoxicity of anti-carcinogens that are ABCB1 substrates and increased the accumulation of doxorubicin and rhodamine 123. Additionally, fentanyl stimulated ABCB1 ATPase activity and inhibited CYP3A4 activity in the liver microsomes of mice. Our study indicates that the obvious hepatotoxicity during this co-administration was due to the inhibition of CYP3A4 activity and ABCB1 transport activity. These findings suggested that the accumulation-induced hepatotoxicity of paclitaxel when it is combined with fentanyl should be avoided. PMID:26633878

  19. Weekly paclitaxel plus trastuzumab in metastatic breast cancer pretreated with anthracyclines-a phase II multipractice study

    PubMed Central

    2012-01-01

    Background The 3-weekly combination of trastuzumab and paclitaxel has been approved for the treatment of advanced breast cancer based on a large pivotal study. However, mono and combination chemotherapy trials suggest that weekly paclitaxel has a better therapeutic index, especially in the palliative setting. The present trial examined the efficacy and safety of weekly paclitaxel over a limited duration combined with continued trastuzumab in HER2+ patients. Methods Patients with histologically confirmed metastatic breast cancer overexpressing HER2 were eligible if pretreated with anthracycline in either the adjuvant or palliative setting. Treatment consisted of weekly trastuzumab (2 mg/kg/week for up to one year after a loading dose of 4 mg/kg in week 1) and paclitaxel (90 mg/m², administered in weeks 1–6 and 8–13). Results Twenty-seven German centers enrolled 121 patients. The median number of metastatic sites was two (range 1–5); 38% of patients had received chemotherapy for advanced disease. After a median 42 weeks of trastuzumab treatment, limited by disease progression in roughly half the patients, a best objective response rate (complete response?+?partial response) of 76% was achieved, including complete remissions in 29%. 74% of patients lived without tumor progression at six months. Median progression-free and overall survival were 9.4 (95% confidence interval [CI]: 8.1–11.3) and 22 months (95% CI: 17–46). After alopecia, Common Toxicity Criteria grade ?2 toxicity was predominantly hematological (leukopenia [31%] and anemia [41%]); however, thrombocytopenia occurred in only 5%. Neurotoxicity was remarkably low. Two cardiac events (grades 2 and 3) were presumed treatment-related. Conclusions Weekly paclitaxel plus trastuzumab allows an increased dose density and offers an attractive and effective alternative to the conventional schedule. Limiting the duration of cytotoxic therapy to 3 months seems to be an option to reduce neurotoxicity without impairing long-term outcome. PMID:22559145

  20. A Phase I study of capecitabine, carboplatin, and paclitaxel with external beam radiation therapy for esophageal carcinoma

    SciTech Connect

    Czito, Brian G. . E-mail: czito@radonc.duke.edu; Kelsey, Chris R.; Hurwitz, Herbert I.; Willett, Chris G.; Morse, Michael A.; Blobe, Gerard C.; Fernando, Nishan H.; D'Amico, Thomas A.; Harpole, David H.; Honeycutt, Wanda R.N.; Yu Daohai; Bendell, Johanna C.

    2007-03-15

    Purpose: Concurrent chemotherapy and radiation therapy (RT) are used to treat patients with esophageal cancer. The optimal combination of chemotherapeutic agents with RT is undefined. We evaluated a combination of capecitabine, carboplatin, and paclitaxel with RT in a phase I study. Methods and Materials: Patients with squamous cell carcinoma or adenocarcinoma of the esophagus initially received capecitabine, carboplatin, and paclitaxel with RT (1.8 Gy daily to 50.4 Gy). After completion, patients were restaged and evaluated for surgery. Primary endpoints included determination of dose-limiting toxicities (DLT) and a recommended phase II dose, non-DLT, and preliminary radiographic and pathologic response rates. Results: Thirteen patients were enrolled (10 men, 3 women). All were evaluable for toxicity and efficacy. Two of 3 patients at dose level 1 (capecitabine 825 mg/m{sup 2} twice daily on RT days, carboplatin area under the curve (AUC) 2 weekly, paclitaxel 60 mg/m{sup 2} weekly) had DLT (both Grade 4 esophagitis). Of these 3, 2 underwent esophagectomy and had pathologic complete response (pCR). Ten patients were then enrolled at dose level -1 (capecitabine 600 mg/m{sup 2} twice daily, carboplatin AUC 1.5, paclitaxel 45 mg/m{sup 2}). Overall, 3 of 10 patients at dose level -1 developed DLT (2 Grade 3 esophagitis, 1 Grade 3 hypotension). Esophagectomy was performed in 6 of 10 patients. All patients had pathologic downstaging and 2 of 6 had pCR. Conclusions: The maximally tolerated/recommended phase II doses were capecitabine 600 mg/m{sup 2} twice daily, carboplatin AUC 1.5 weekly, and paclitaxel 45 mg/m{sup 2} weekly with RT to 50.4 Gy. In our small study, this regimen appears active but is accompanied by significant toxicities, primarily esophagitis.

  1. Synergistic antitumor effect of a combination of paclitaxel and carboplatin with nobiletin from Citrus depressa on non-small-cell lung cancer cell lines.

    PubMed

    Uesato, Shinichi; Yamashita, Hirofumi; Maeda, Ryu; Hirata, Yoshiyuki; Yamamoto, Maho; Matsue, Saki; Nagaoka, Yasuo; Shibano, Makio; Taniguchi, Masahiko; Baba, Kimiye; Ju-ichi, Motoharu

    2014-04-01

    Non-small-cell lung carcinomas do not sufficiently respond to cancer chemotherapeutic drugs. Combination effects of cancer chemotherapy drugs (paclitaxel and carboplatin) with nobiletin or powdered Shiikuwasha extract from Citrus depressa were examined by isobologram and combination index analyses. It was demonstrated that the combination generated a synergistic inhibitory effect against the proliferation of the human non-small-cell lung carcinoma cell lines A549 and H460 and that of the two chemotherapy drugs, paclitaxel was responsible for this synergistic effect. Furthermore, the percentage of apoptotic cells was decreased with increasing rates of nobiletin to paclitaxel and carboplatin. These findings were considered to be attributed to the ability of nobiletin to regulate cells in the G1 phase, which escaped cell death initiated by paclitaxel and carboplatin. An antitumor activity assay showed that this combination significantly suppressed the growth of subcutaneous A549 tumor xenografts in nude mice. PMID:24687742

  2. Nonvascular drug-eluting stent coated with sodium caprate-incorporated polyurethane for the efficient penetration of paclitaxel into tumor tissue.

    PubMed

    Jeong, Dooyong; Lee, Don Haeng; Lee, Dong Ki; Na, Kun

    2015-03-01

    To increase the therapeutic potency of nonvascular drug-eluting stents, sodium caprate was employed as a drug-penetration enhancer. A polytetrafluoroethylene-covered drug-eluting stent was coated with a mixture containing sodium caprate, paclitaxel, and polyurethane via the rolling coating technique. The coated stent has a smooth membrane surface with a 40-µm membrane thickness. Paclitaxel was released from the coated stent for two months. In the multilayered cell sheet model, sodium caprate in the polyurethane membrane (PUSC10) showed the possibility of enhancing the paclitaxel tissue penetration. The amount of penetrated paclitaxel for the sodium caprate-containing polyurethane membrane (PUSC10) was two times higher than that of sodium caprate-free polyurethane membrane. Additionally, the potential of sodium caprate was confirmed by a tumor-bearing small animal model. PUSC10 incorporated with Nile red (as a model fluorescence dye for visualization of drug penetration; PUSC10-Nile red) or PUSC10 incorporated with paclitaxel (PUSC10-paclitaxel) membrane was implanted at tumor sites in Balb/c mice. In the case of PUSC10-Nile red, the tissue penetration depth of Nile red was significantly increased from 30?µm (without sodium caprate) to 1060?µm (with sodium caprate). After seven days, an almost four times higher therapeutic area of PUSC10-paclitaxel was observed compared to that of polyurethane-paclitaxel (without sodium caprate) by a terminal deoxynucleotidyl transferase dUTP nick end labeling assay. The results indicate that sodium caprate improves the penetration and therapeutic efficiencies of drugs in drug-eluting stents, and thus, it has potential for local stent therapy. PMID:25252589

  3. Bulleyaconitine A depresses neuropathic pain and potentiation at C-fiber synapses in spinal dorsal horn induced by paclitaxel in rats.

    PubMed

    Zhu, He-Quan; Xu, Jing; Shen, Kai-Feng; Pang, Rui-Ping; Wei, Xu-Hong; Liu, Xian-Guo

    2015-11-01

    Paclitaxel, a widely used chemotherapeutic agent, often induces painful peripheral neuropathy and at present no effective drug is available for treatment of the serious side effect. Here, we tested if intragastrical application of bulleyaconitine A (BLA), which has been approved for clinical treatment of chronic pain in China since 1985, could relieve the paclitaxel-induced neuropathic pain. A single dose of BLA attenuated the mechanical allodynia, thermal hyperalgesia induced by paclitaxel dose-dependently. Repetitive administration of the drug (0.4 and 0.8mg/kg, t.i.d. for 7 d) during or after paclitaxel treatment produced a long-lasting inhibitory effect on thermal hyperalgesia, but not on mechanical allodynia. In consistency with the behavioral results, in vivo electrophysiological experiments revealed that spinal synaptic transmission mediated by C-fiber but not A fiber was potentiated, and the magnitude of long-term potentiation (LTP) at C-fiber synapses induced by the same high frequency stimulation was ~50% higher in paclitaxel-treated rats, compared to the naïve rats. Spinal or intravenous application of BLA depressed the spinal LTP, dose-dependently. Furthermore, patch clamp recordings in spinal cord slices revealed that the frequency but not amplitude of both spontaneous excitatory postsynaptic current (sEPSCs) and miniature excitatory postsynaptic currents (mEPSCs) in lamina II neurons was increased in paclitaxel-treated rats, and the superfusion of BLA reduced the frequency of sEPSCs and mEPSCs in paclitaxel-treated rats but not in naïve ones. Taken together, we provide novel evidence that BLA attenuates paclitaxel-induced neuropathic pain and that depression of spinal LTP at C-fiber synapses via inhibiting presynaptic transmitter release may contribute to the effect. PMID:26376216

  4. Colchitaxel, a coupled compound made from microtubule inhibitors colchicine and paclitaxel

    PubMed Central

    Bombuwala, Karunananda; Kinstle, Thomas; Popik, Vladimir; Uppal, Sonal O; Olesen, James B; Viña, Jose; Heckman, Carol A

    2006-01-01

    Background Tumor promoters enhance tumor yield in experimental animals without directly affecting the DNA of the cell. Promoters may play a role in the development of cancer, as humans are exposed to them in the environment. In work based on computer-assisted microscopy and sophisticated classification methods, we showed that cells could be classified by reference to a database of known normal and cancerous cell phenotypes. Promoters caused loss of properties specific to normal cells and gain of properties of cancer cells. Other compounds, including colchicine, had a similar effect. Colchicine given together with paclitaxel, however, caused cells to adopt properties of normal cells. This provided a rationale for tests of microtubule inhibitor combinations in cancer patients. The combination of a depolymerizing and a stabilizing agent is a superior anti-tumor treatment. The biological basis of the effect is not understood. Results A single compound containing both colchicine and paclitaxel structures was synthesized. Colchicine is an alkaloid with a trimethoxyphenyl ring (ring A), a ring with an acetamide linkage (ring B), and a tropolone ring (ring C). Although rings A and C are important for tubulin-binding activity, the acetamide linkage on ring B could be replaced by an amide containing a glutamate linker. Alteration of the C-7 site on paclitaxel similarly had little or no inhibitory effect on its biological activity. The linker was attached to this position. The coupled compound, colchitaxel (1), had some of the same effects on microtubules as the combination of starting compounds. It also caused shortening and fragmentation of the + end protein cap. Conclusion Since microtubule inhibitor combinations give results unlike those obtained with either inhibitor alone, it is important to determine how such combinations affect cell shape and growth. Colchitaxel shows a subset of the effects of the inhibitor combination. Thus, it may be able to bind the relevant cellular target of the combination. It will be useful to determine the basis of the shape reversal effect and possibly, the reasons for therapeutic efficacy of microtubule inhibitor combinations. PMID:16813651

  5. Molecular mechanism of local drug delivery with Paclitaxel-eluting membranes in biliary and pancreatic cancer: new application for an old drug.

    PubMed

    Bang, Sookhee; Jang, Sung Ill; Lee, Su Yeon; Baek, Yi-Yong; Yun, Jieun; Oh, Soo Jin; Lee, Chang Woo; Jo, Eun Ae; Na, Kun; Yang, Sugeun; Lee, Don Haeng; Lee, Dong Ki

    2015-01-01

    Implantation of self-expanding metal stents (SEMS) is palliation for patients suffering from inoperable malignant obstructions associated with biliary and pancreatic cancers. Chemotherapeutic agent-eluting stents have been developed because SEMS are susceptible to occlusion by tumor in-growth. We reported recently that paclitaxel-eluting SEMS provide enhanced local drug delivery in an animal model. However, little is known about the molecular mechanisms by which paclitaxel-eluting stents attenuate tumor growth. We investigated the signal transduction pathways underlying the antiproliferative effects of a paclitaxel-eluting membrane (PEM) implanted in pancreatic/cholangiocarcinoma tumor bearing nude mice. Molecular and cellular alterations were analyzed in the PEM-implanted pancreatic/cholangiocarcinoma xenograft tumors by Western blot, immunoprecipitation, and immunofluorescence. The quantities of paclitaxel released into the tumor and plasma were determined by liquid chromatography-tandem mass spectroscopy. Paclitaxel from the PEM and its diffusion into the tumor inhibited angiogenesis, which involved suppression of mammalian target of rapamycin (mTOR) through regulation of hypoxia inducible factor (HIF-1) and increased apoptosis. Moreover, implantation of the PEM inhibited tumor-stromal interaction-related expression of proteins such as CD44, SPARC, matrix metalloproteinase-2, and vimentin. Local delivery of paclitaxel from a PEM inhibited growth of pancreatic/cholangiocarcinoma tumors in nude mice by suppressing angiogenesis via the mTOR and inducing apoptosis signal pathway. PMID:25983747

  6. Farnesyltransferase inhibitor R115777 (Zarnestra, Tipifarnib) synergizes with paclitaxel to induce apoptosis and mitotic arrest and to inhibit tumor growth of multiple myeloma cells

    PubMed Central

    Zhu, Kuichun; Gerbino, Elvira; Beaupre, Darrin M.; Mackley, Paul A.; Muro-Cacho, Carlos; Beam, Craig; Hamilton, Andrew D.; Lichtenheld, Mathias G.; Kerr, William G.; Dalton, William; Alsina, Melissa; Sebti, Saïd M.

    2005-01-01

    Despite major advances, multiple myeloma (MM) remains an incurable malignancy. Recently we have found that disease stabilization was achieved in 64% of patients with advanced MM treated with the farnesyltransferase inhibitor R115777 (Zarnestra) in a phase 2 clinical trial. In order to enhance R115777 antitumor activity in MM, we examined the combination of this novel agent with other anticancer drugs in MM cell lines. In this study, R115777 was found to synergize with paclitaxel and docetaxel, but not with other chemotherapy agents, including doxorubicin, 5-fluorouracil, cisplastin, melphalan, mitoxantrone, and dexamethasone. R115777 synergized with paclitaxel to inhibit MM cell proliferation and to induce apoptosis. Synergism in the induction of apoptosis was accompanied by increase in cytochrome c release and caspase-3 activation. Furthermore, flow cytometry analysis also showed that paclitaxel and R115777 synergized to induce G2/M cell-cycle arrest. Importantly, synergism was observed in taxane- and R115777-resistant MM cells. In the human severe combined immunodeficient (SCID-hu) bone model of myeloma growth, the ability of paclitaxel to inhibit tumor growth in vivo was enhanced by R115777. Combination of paclitaxel or docetaxel with R115777 in the treatment of MM cells from patients with multiple myeloma was more beneficial than treatment with single agents. Our results provide the basis for combination therapy clinical trials with paclitaxel or docetaxel with R115777 in MM patients. (Blood. 2005;105:4759-4766) PMID:15728126

  7. Enhanced antitumor efficacy of vitamin E TPGS-emulsified PLGA nanoparticles for delivery of paclitaxel.

    PubMed

    Sun, Yanbin; Yu, Bo; Wang, Guoying; Wu, Yongsheng; Zhang, Xiaomin; Chen, Yanmin; Tang, Suoqing; Yuan, Yuan; Lee, Robert J; Teng, Lesheng; Xu, Shun

    2014-11-01

    Nanoparticles are efficient delivery vehicles for cancer therapy such as paclitaxel (PTX). In this study, we formulated PTX into PLGA polymeric nanoparticles. Vitamin E TPGS was used as an emulsifier to stabilize the nanoparticle formulation. PTX was encapsulated in TPGS-emulsified polymeric nanoparticles (TENPs) by a nanoprecipitation method in ethanol-water system. The resultant PTX-TENPs showed a very uniform particle size (?100 nm) and high drug encapsulation (>80%). The cytotoxicity of PTX-TENPs was examined in A549 lung cancer cell line. Preferential tumor accumulation of TENPs was observed in the A549 lung cancer xenograft model. Tumor growth was significantly inhibited by intravenous injection of PTX-TENPs. Our results suggested that the modified nanoprecipitation method holds great potential for the fabrication of the PTX loaded polymeric nanoparticles. TPGS can be used in the manufacture of polymeric nanoparticles for the controlled release of PTX and other anti-cancer drugs. PMID:25456995

  8. Silicate Esters of Paclitaxel and Docetaxel: Synthesis, Hydrophobicity, Hydrolytic Stability, Cytotoxicity, and Prodrug Potential

    PubMed Central

    2015-01-01

    We report here the synthesis and selected properties of various silicate ester derivatives (tetraalkoxysilanes) of the taxanes paclitaxel (PTX) and docetaxel (DTX) [i.e., PTX-OSi(OR)3 and DTX-OSi(OR)3]. Both the hydrophobicity and hydrolytic lability of these silicates can be (independently) controlled by choice of the alkyl group (R). The synthesis, structural characterization, hydrolytic reactivity, and in vitro cytotoxicity against the MDA-MB-231 breast cancer cell line of most of these derivatives are described. We envision that the greater hydrophobicity of these silicates (vis-à-vis PTX or DTX itself) should be advantageous from the perspective of preparation of stable aqueous dispersions of amphiphilic block-copolymer-based nanoparticle formulations. PMID:24564494

  9. [A case of gastric cancer with peritoneal dissemination successfully treated by S-1/paclitaxel combination chemotherapy].

    PubMed

    Shoji, Teruaki

    2011-02-01

    A 62-year-old woman visited our hospital with diarrhea, bloating, vomiting, and black stool. Borrmann-type 3 gastric cancer with hemorrhaging was revealed by stomach endoscopy. The biopsy showed a poorly-differentiated adenocarcinoma. Moreover, peritoneal dissemination was found by computed tomography and we combined S-1 80 mg/m²(4 weeks administration and week rest)with paclitaxel(PTX)50 mg/ m² (day 1, 8, 15, 3 weeks rest). After 2 courses, endoscopy showed tumor shrinkage. Therefore, we conducted total gastrectomy with resection of gall bladder and spleen. The final findings were Stage II .We conducted S-1/PTX combination chemotherapy(4 courses)followed by monotherapy as adjuvant chemotherapy. Recently, the woman had been living without relapse four years after operation. PMID:21368499

  10. Enhanced combination therapy effect on paclitaxel-resistant carcinoma by chloroquine co-delivery via liposomes

    PubMed Central

    Gao, Menghua; Xu, Yuzhen; Qiu, Liyan

    2015-01-01

    A novel composite liposomal system co-encapsulating paclitaxel (PTX) with chloroquine phosphate (CQ) was designed for treating PTX-resistant carcinoma. It was confirmed that liposomal CQ can sensitize PTX by means of autophagy inhibition and competitively binding with multidrug-resistance transporters. Furthermore, according to the in vitro cytotoxicity and apoptosis assay, real-time observation of cellular uptake, and in vivo tissue distribution study, co-encapsulation of PTX and CQ in liposomes was validated as superior to the mixture of PTX liposome plus CQ liposome due to the simultaneous delivery and synergetic effect of the two drugs. Consequently, this composite liposome achieved significantly stronger anticancer efficacy in vivo than the PTX liposome plus CQ liposome mixture. This study helps to guide and enlighten ongoing and future clinical trials about the optimal administration modes for drug combination therapy. PMID:26543365

  11. Acute and subchronic toxicity analysis of surface modified paclitaxel attached hydroxyapatite and titanium dioxide nanoparticles

    PubMed Central

    Venkatasubbu, Gopinath Devanand; Ramasamy, S; Gaddam, Pramod Reddy; Kumar, J

    2015-01-01

    Nanoparticles are widely used for targeted drug delivery applications. Surface modification with appropriate polymer and ligands is carried out to target the drug to the affected area. Toxicity analysis is carried out to evaluate the safety of the surface modified nanoparticles. In this study, paclitaxel attached, folic acid functionalized, polyethylene glycol modified hydroxyapatite and titanium dioxide nanoparticles were used for targeted drug delivery system. The toxicological behavior of the system was studied in vivo in rats and mice. Acute and subchronic studies were carried out. Biochemical, hematological, and histopathological analysis was also done. There were no significant alterations in the biochemical parameters at a low dosage. There was a small change in alkaline phosphatase (ALP) level at a high dosage. The results indicate a safe toxicological profile. PMID:26491315

  12. Piperlongumine Induces Apoptosis and Synergizes with Cisplatin or Paclitaxel in Human Ovarian Cancer Cells

    PubMed Central

    Chen, Xiu-Xiu; Wang, Huan; Jiang, Qi-Wei; Pan, Shi-Shi; Qiu, Jian-Ge; Mei, Xiao-Long; Xue, You-Qiu; Qin, Wu-Ming; Zheng, Fei-Yun; Yan, Xiao-Jian

    2014-01-01

    Piperlongumine (PL), a natural alkaloid from Piper longum L., possesses the highly selective and effective anticancer property. However, the effect of PL on ovarian cancer cells is still unknown. In this study, we firstly demonstrate that PL selectively inhibited cell growth of human ovarian cancer cells. Furthermore, PL notably induced cell apoptosis, G2/M phase arrest, and accumulation of the intracellular reactive oxidative species (ROS) in a dose- and time-dependent manner. Pretreatment with antioxidant N-acety-L-cysteine could totally reverse the PL-induced ROS accumulation and cell apoptosis. In addition, low dose of PL/cisplatin or paclitaxel combination therapies had a synergistic antigrowth effect on human ovarian cancer cells. Collectively, our study provides new therapeutic potential of PL on human ovarian cancer. PMID:24895529

  13. Programmed co-delivery of paclitaxel and doxorubicin boosted by camouflaging with erythrocyte membrane

    NASA Astrophysics Data System (ADS)

    Fu, Qiang; Lv, Piping; Chen, Zhongke; Ni, Dezhi; Zhang, Lijun; Yue, Hua; Yue, Zhanguo; Wei, Wei; Ma, Guanghui

    2015-02-01

    Combination chemotherapy has been proven promising for cancer treatment, but unsatisfactory therapeutic data and increased side effects slow down the development in the clinic. In this study, we develop an effective approach to co-encapsulate a hydrophilic-hydrophobic chemotherapeutic drug pair (paclitaxel and doxorubicin) into magnetic O-carboxymethyl-chitosan nanoparticles. To endow them with the ability of programmed delivery, these carriers are further camouflaged with an Arg-Gly-Asp anchored erythrocyte membrane. Compared with the traditional polyethylene glycol coating method, this biomimetic decoration strategy is demonstrated to be superior in prolonging circulation time, improving tumor accumulation, facilitating tumor uptake, and tuning intracellular fate. These outstanding properties enable the as-designed nanodevice to exhibit greater tumor growth inhibition ability and much lower side effects than the combined use of commercial formulations.Combination chemotherapy has been proven promising for cancer treatment, but unsatisfactory therapeutic data and increased side effects slow down the development in the clinic. In this study, we develop an effective approach to co-encapsulate a hydrophilic-hydrophobic chemotherapeutic drug pair (paclitaxel and doxorubicin) into magnetic O-carboxymethyl-chitosan nanoparticles. To endow them with the ability of programmed delivery, these carriers are further camouflaged with an Arg-Gly-Asp anchored erythrocyte membrane. Compared with the traditional polyethylene glycol coating method, this biomimetic decoration strategy is demonstrated to be superior in prolonging circulation time, improving tumor accumulation, facilitating tumor uptake, and tuning intracellular fate. These outstanding properties enable the as-designed nanodevice to exhibit greater tumor growth inhibition ability and much lower side effects than the combined use of commercial formulations. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr07027e

  14. Phase I trial of intraperitoneal pemetrexed, cisplatin, and paclitaxel in optimally debulked ovarian cancer

    PubMed Central

    Chambers, Setsuko K.; Chow, H-H. Sherry; Janicek, Mike F.; Cragun, Janiel M.; Hatch, Kenneth D.; Cui, Haiyan; Laughren, Cynthia; Clouser, Mary C.; Cohen, Janice L.; Wright, Heather M.; Abu Shahin, Nisreen; Alberts, David S.

    2012-01-01

    Purpose This phase I trial evaluated intraperitoneal (IP) pemetrexed, cisplatin, and paclitaxel in optimally debulked ovarian cancer. Experimental Design Dose escalation of d1 IP pemetrexed accrued 3 patients to each of 5 dose levels (60mg/m2 to 1000mg/m2), along with d2 IP cisplatin (75mg/m2), and d8 IP paclitaxel (60mg/m2). The goals were to determine maximum tolerated dose (MTD), 18-month progression-free survival (PFS), and pharmacokinetics (PK) of IP pemetrexed. Results Cycles, given every 21d, had an 80% 6-cycle completion rate. There was minimal grade 3 toxicity in the first 4 dose levels and remarkably an almost complete absence of peripheral neuropathy and alopecia. At the highest dose level, 2 of 3 patients experienced ?grade 3 and dose-limiting toxicity (DLT) (hematologic, infection, gastrointestinal). There was a PK advantage for IP pemetrexed with a IP:plasma area under the concentration-time-curve ratio of 13-fold. Neither analysis of PK nor homocysteine levels explains the unexpected severity of toxicity in those 2 patients. Based on plasma C24 h levels, the 42 cycles at ?500mg/m2 IP pemetrexed without DLT, the MTD appears to be 500 mg/m2. Median PFS is 30.1 months; 18-month PFS is 78.6% (median follow-up 22.4 months). Conclusions This IP only regimen in front-line ovarian cancer is feasible with PFS in line with recent literature. We suggest phase II trials of this regimen in this population with IP pemetrexed at 500mg/m2. The favorable toxicity profile at doses <1000mg/m2, which needs to be confirmed, appears to compare well with standard combination intravenous/IP platinum/taxane chemotherapy in this disease. PMID:22421191

  15. Adjuvant paclitaxel and carboplatin chemotherapy with involved field radiation in advanced endometrial cancer: A sequential approach

    SciTech Connect

    Lupe, Krystine; Kwon, Janice . E-mail: Janice.kwon@lhsc.on.ca; D'Souza, David; Gawlik, Christine; Stitt, Larry; Whiston, Frances; Nascu, Patricia; Wong, Eugene; Carey, Mark S.

    2007-01-01

    Purpose: To determine the feasibility of adjuvant paclitaxel and carboplatin chemotherapy interposed with involved field radiotherapy for women with advanced endometrial cancer. Methods and Materials: This was a prospective cohort study of women with Stage III and IV endometrial cancer. Adjuvant therapy consisted of 4 cycles of paclitaxel (175 mg/m{sup 2}) and carboplatin (350 mg/m{sup 2}) every 3 weeks, followed sequentially by external beam radiotherapy (RT) to the pelvis (45 Gy), followed by an additional two cycles of chemotherapy. Para-aortic RT and/or HDR vault brachytherapy (BT) were added at the discretion of the treating physician. Results: Thirty-three patients (median age, 63 years) received treatment between April 2002 and June 2005. Median follow-up was 21 months. Stage distribution was as follows: IIIA (21%), IIIC (70%), IVB (9%). Combination chemotherapy was successfully administered to 30 patients (91%) and 25 patients (76%), before and after RT respectively. Nine patients (27%) experienced acute Grade 3 or 4 chemotherapy toxicities. All patients completed pelvic RT; 19 (58%) received standard 4-field RT and 14 (42%) received intensity-modulated radiotherapy. Ten (30%) received extended field radiation. Four patients (12%) experienced acute Grade 3 or 4 RT toxicities. Six (18%) patients developed chronic RT toxicity. There were no treatment-related deaths. Two-year disease-free and overall survival rates were both 55%. There was only one pelvic relapse (3%). Conclusions: Adjuvant treatment with combination chemotherapy interposed with involved field radiation in advanced endometrial cancer was well tolerated. This protocol may be suitable for further evaluation in a clinical trial.

  16. Complete Regression of Xenograft Tumors upon Targeted Delivery of Paclitaxel via ?-? Stacking Stabilized Polymeric Micelles

    PubMed Central

    Shi, Yang; van der Meel, Roy; Theek, Benjamin; Blenke, Erik Oude; Pieters, Ebel H.E.; Fens, Marcel H.A.M.; Ehling, Josef; Schiffelers, Raymond M.; Storm, Gert; van Nostrum, Cornelus F.; Lammers, Twan; Hennink, Wim E.

    2015-01-01

    Treatment of cancer patients with taxane-based chemotherapeutics, such as paclitaxel (PTX), is complicated by their narrow therapeutic index. Polymeric micelles are attractive nanocarriers for tumor-targeted delivery of PTX, as they can be tailored to encapsulate large amounts of hydrophobic drugs and achieve prolonged circulation kinetics. As a result, PTX deposition in tumors is increased while drug exposure to healthy tissues is reduced. However, many PTX-loaded micelle formulations suffer from low stability and fast drug release in the circulation, limiting their suitability for systemic drug targeting. To overcome these limitations, we have developed paclitaxel (PTX)-loaded micelles which are stable without chemical crosslinking and covalent drug attachment. These micelles are characterized by excellent loading capacity and strong drug retention, attributed to ?-? stacking interaction between PTX and the aromatic groups of the polymer chains in the micellar core. The micelles are based on methoxy poly(ethylene glycol)-b-(N-(2-benzoyloxypropyl) methacrylamide) (mPEG-b-p(HPMAm-Bz)) block copolymers, which improved the pharmacokinetics and the biodistribution of PTX, and substantially increased PTX tumor accumulation (by more than 2000%; as compared to Taxol® or control micellar formulations). Improved biodistribution and tumor accumulation were confirmed by hybrid ?CT-FMT imaging using near-infrared labeled micelles and payload. The PTX-loaded micelles were well tolerated at different doses while they induced complete tumor regression in two different xenograft models (i.e. A431 and MDA-MB-468). Our findings consequently indicate that ?-? stacking-stabilized polymeric micelles are promising carriers to improve the delivery of highly hydrophobic drugs to tumors and to increase their therapeutic index. PMID:25831471

  17. Weekly cisplatin, epirubicin, and paclitaxel with granulocyte colony-stimulating factor support vs triweekly epirubicin and paclitaxel in locally advanced breast cancer: final analysis of a sicog phase III study.

    PubMed

    Frasci, G; D'Aiuto, G; Comella, P; Thomas, R; Botti, G; Di Bonito, M; De Rosa, V; Iodice, G; Rubulotta, M R; Comella, G

    2006-10-23

    The present study aimed at evaluating whether a weekly cisplatin, epirubicin, and paclitaxel (PET) regimen could increase the pathological complete response (pCR) rate in comparison with a tri-weekly epirubicin and paclitaxel administration in locally advanced breast cancer (LABC) patients. Patients with stage IIIB disease were randomised to receive either 12 weekly cycles of cisplatin 30 mg m(-2), epirubicin 50 mg m(-2), and paclitaxel 120 mg m(-2) (PET) plus granulocyte-colony stimulating factor support, or four cycles of epirubicin 90 mg m(-2)+paclitaxel 175 mg m(-2) (ET) every 3 weeks. Overall, 200 patients (PET/ET=100/100) were included in this study. A pCR in both breast and axilla occurred in 16 (16%) PET patients and in six (6%) ET patients (P=0.02). The higher activity of PET was evident only in ER negative (27.5 vs 5.4%; P=0.026), and in HER/neu positive (31 vs 5%; P=0.037) tumours. The two arms yielded similar pCR rate in ER positive (PET/ET=7.5/7.1%) and HER/neu negative (PET/ET=10/6%) patients. At a 39 months median follow-up, 70 patients showed a progression or relapses (PET, 32 vs ET, 38). Anaemia, mucositis, peripheral neuropathy, and gastrointestinal toxicity were substantially more frequent in the PET arm. The PET weekly regimen is superior to ET in terms of pCR rate in LABC patients with ER negative and/or HER2 positive tumours Mature data in terms of disease-free and overall survival are needed to ascertain whether this approach could improve the prognosis of these subsets of LABC patients. PMID:17047649

  18. Fhit Delocalizes Annexin A4 from Plasma Membrane to Cytosol and Sensitizes Lung Cancer Cells to Paclitaxel

    PubMed Central

    Gaudio, Eugenio; Paduano, Francesco; Spizzo, Riccardo; Ngankeu, Apollinaire; Zanesi, Nicola; Gaspari, Marco; Ortuso, Francesco; Lovat, Francesca; Rock, Jonathan; Hill, Grace A.; Kaou, Mohamed; Cuda, Giovanni; Aqeilan, Rami I.; Alcaro, Stefano; Croce, Carlo M.; Trapasso, Francesco

    2013-01-01

    Fhit protein is lost or reduced in a large fraction of human tumors, and its restoration triggers apoptosis and suppresses tumor formation or progression in preclinical models. Here, we describe the identification of candidate Fhit-interacting proteins with cytosolic and plasma membrane localization. Among these, Annexin 4 (ANXA4) was validated by co-immunoprecipitation and confocal microscopy as a partner of this novel Fhit protein complex. Here we report that overexpression of Fhit prevents Annexin A4 translocation from cytosol to plasma membrane in A549 lung cancer cells treated with paclitaxel. Moreover, paclitaxel administration in combination with AdFHIT acts synergistically to increase the apoptotic rate of tumor cells both in vitro and in vivo experiments. PMID:24223161

  19. Effective Drug Delivery, in vitro and in vivo, By Carbon-Based Nanovectors Non-Covalently Loaded With Unmodified Paclitaxel

    PubMed Central

    Berlin, Jacob M.; Leonard, Ashley D.; Pham, Tam T.; Sano, Daisuke; Marcano, Daniela C.; Yan, Shayou; Fiorentino, Stefania; Milas, Zvonimir L.; Kosynkin, Dmitry V.; Katherine Price, B.; Lucente-Schultz, Rebecca M.; Wen, XiaoXia; Gabriela Raso, M.; Craig, Suzanne L.; Tran, Hai T.; Myers, Jeffrey N.; Tour, James M.

    2010-01-01

    Many new drugs have low aqueous solubility and high therapeutic efficacy. Paclitaxel (PTX) is a classic example of this type of compound. Here we show that extremely small (<40 nm) hydrophilic carbon clusters (HCCs) that are PEGylated (PEG-HCCs) are effective drug delivery vehicles when simply mixed with paclitaxel. This formulation of PTX sequestered in PEG-HCCs (PTX/PEG-HCCs) is stable for at least twenty weeks. The PTX/PEG-HCCs formulation was as effective as PTX in a clinical formulation in reducing tumor volumes in an orthotopic murine model of oral squamous cell carcinoma. Preliminary toxicity and biodistribution studies suggest that the PEG-HCCs are not acutely toxic and, like many other nanomaterials, are primarily accumulated in the liver and spleen. This work demonstrates that carbon nanomaterials are effective drug delivery vehicles in vivo when non-covalently loaded with an unmodified drug. PMID:20681596

  20. Resistant metastatic penile carcinoma and response to biochemotherapy with paclitaxel and epidermal growth factor receptor monoclonal antibody, nimotuzumab

    PubMed Central

    Pandey, Avinash; Noronha, Vanita; Joshi, Amit; Tongaonkar, Hemant; Bakshi, Ganesh; Prabhash, Kumar

    2013-01-01

    Carcinoma penis is one of the common malignancies in developing world especially among rural population. Multimodality treatment with surgery, radiation and chemotherapy for advanced penile carcinoma with groin nodal metastasis is crucial to optimise the outcome. Cisplatin, fluorouracil, methotrexate, vinorelbine, bleomycin and paclitaxel are the common chemotherapeutic agents used along with local therapy. Paucity of data to show superiority of one chemotherapeutic regime over another and only modest response to any combination chemotherapy. Progression of disease after surgery, radiation and chemotherapy is associated with poor outcome and quality of life. Nimotuzumab, Anti EGFR monoclonal antibody, along with paclitaxel in our case of resistant metastatic penile carcinoma has shown good symptomatic palliation and clinical response. PMID:23878483

  1. Phase II trial of metformin and paclitaxel for patients with gemcitabine-refractory advanced adenocarcinoma of the pancreas

    PubMed Central

    Braghiroli, Maria Ignez; de Celis Ferrari, Anezka C R; Pfiffer, Tulio Eduardo; Alex, Alexandra Kichfy; Nebuloni, Daniela; Carneiro, Allyne S; Caparelli, Fernanda; Senna, Luiz; Lobo, Juliana; Hoff, Paulo Marcelo; Riechelmann, Rachel P

    2015-01-01

    Background In patients with adenocarcinoma of the pancreas, there are no standard second-line regimens. Many pre-clinical studies have shown that metformin alone or when combined with paclitaxel has antitumour effects on this tumour. We have tested here the combination of paclitaxel and metformin for patients with gemcitabine-refractory pancreatic cancer. Methods An uncontrolled phase II trial was carried out based on a two–stage Simon’s design, with metformin and paclitaxel for patients with locally advanced or metastatic pancreatic cancer whose disease had progressed during first line treatment with a gemcitabine-based regimen. The primary endpoint was the disease control rate at eight weeks as per response evaluation criteria in solid tumours (RECIST) 1.1. Patients received paclitaxel 80 mg/m2 weekly for three weeks every 28 days and metformin 850 mg p.o. t.i.d. continuously until progression or intolerance state was reached. Results Twenty patients were enrolled from July 2011 to January 2014: N = 6 (31.6%) achieved the primary endpoint, with all presenting stable disease. Median overall survival (OS) was 128 days (range 17–697) and the median progression free survival (PFS) was 44 days (range 14–210). Eight patients (40%) presented treatment-related G3-4 toxicities with the most common one being diarrhoea. Conclusions Despite the encouraging pre-clinical evidence of the antitumour activity of metformin in adenocarcinoma of the pancreas, the primary endpoint of the disease control rate was not met. Besides, the treatment combination was poorly tolerated and could not be studied further. This study highlights the importance of performing clinical trials to reassure preclinical or observational data. PMID:26316884

  2. Astrocyte activation in the anterior cingulate cortex and altered glutamatergic gene expression during paclitaxel-induced neuropathic pain in mice

    PubMed Central

    2015-01-01

    Spinal astrocyte activation contributes to the pathogenesis of paclitaxel-induced neuropathic pain (PINP) in animal models. We examined glial fibrillary acidic protein (GFAP; an astrocyte marker) immunoreactivity and gene expression of GFAP, glutamate transporters and receptor subunits by real time PCR in the anterior cingulate cortex (ACC) at 7 days post first administration of paclitaxel, a time point when mice had developed thermal hyperalgesia. The ACC, an area in the brain involved in pain perception and modulation, was chosen because changes in this area might contribute to the pathophysiology of PINP. GFAP transcripts levels were elevated by more than fivefold and GFAP immunoreactivity increased in the ACC of paclitaxel-treated mice. The 6 glutamate transporters (GLAST, GLT-1 EAAC1, EAAT4, VGLUT-1 and VGLUT-2) quantified were not significantly altered by paclitaxel treatment. Of the 12 ionotropic glutamate receptor subunits transcripts analysed 6 (GLuA1, GLuA3, GLuK2, GLuK3, GLuK5 and GLuN1) were significantly up-regulated, whereas GLuA2, GLuK1, GLuK4, GLuN2A and GLuN2B were not significantly altered and GLuA4 was lowly expressed. Amongst the 8 metabotropic receptor subunits analysed only mGLuR8 was significantly elevated. In conclusion, during PINP there is astrocyte activation, with no change in glutamate transporter expression and differential up-regulation of glutamate receptor subunits in the ACC. Thus, targeting astrocyte activation and the glutamatergic system might be another therapeutic avenue for management of PINP. PMID:26528412

  3. Neoadjuvant concurrent chemoradiation with weekly paclitaxel and carboplatin for patients with oesophageal cancer: a phase II study

    PubMed Central

    van Meerten, E; Muller, K; Tilanus, H W; Siersema, P D; Eijkenboom, W M H; van Dekken, H; Tran, T C K; van der Gaast, A

    2006-01-01

    This study was performed to assess the efficacy and safety of preoperative chemoradiation consisting of carboplatin and paclitaxel and concurrent radiotherapy for patients with resectable (T2-3N0-1M0) oesophageal cancer. Treatment consisted of paclitaxel 50?mg?m?2 and carboplatin AUC=2 on days 1, 8, 15, 22 and 29 and concurrent radiotherapy (41.4?Gy in 23 fractions, 5 days per week), followed by oesophagectomy. All 54 entered patients completed the chemoradiation without delay or dose-reduction. Grade 3–4 toxicities were: neutropaenia 15%, thrombocytopaenia 2%, and oesophagitis 7.5%. After completion of the chemoradiotherapy 63% had a major endoscopical response. Fifty-two patients (96%) underwent a resection. The postoperative mortality rate was 7.7%. All patients had an R0-resection. The pathological complete response rate was 25%, and an additional 36.5% had less than 10% vital residual tumour cells. At a median follow-up of 23.2 months, the median survival time has not yet been reached. The probability of disease-free survival after 30 months was 60%. In conclusion, weekly neoadjuvant paclitaxel and carboplatin with concurrent radiotherapy is a very tolerable regimen and can be given on an outpatient basis. It achieves considerable down staging and a subsequent 100% radical resection rate in this series. A phase III trial with this regimen is now ongoing. PMID:16670722

  4. Dose-dense epirubicin and paclitaxel with G-CSF: a study of decreasing intervals in metastatic breast cancer

    PubMed Central

    Lalisang, R I; Voest, E E; Wils, J A; Nortier, J W; Erdkamp, F L; Hillen, H F; Wals, J; Schouten, H C; Blijham, G H

    2000-01-01

    Anthracyclines and taxanes are very effective drugs in the treatment of advanced breast cancer. With G-CSF support, the dose-intensity of this combination can be increased by reducing the interval between chemotherapy cycles, the so-called ‘shortening of cycle time’. We treated 36 patients with advanced breast cancer in a multicentre phase I/II study. The treatment regimen consisted of epirubicin 75 mg m?2followed by paclitaxel 135 mg m?2(3 h) in combination with G-CSF. At least six patients were treated in each cohort and were evaluated over the first three cycles. Starting at an interval of 14 days, in subsequent cohorts of patients the interval could be shortened to 10 days. An 8-day interval was not feasible due mainly to incomplete neutrophil recovery at the day of the next scheduled cycle. In the 10-day interval cohort it was feasible to increase the paclitaxel dose to 175 mg m?2. The haematological and non-haematological toxicity was relatively mild. No cumulative myelosuppression was observed over at least three consecutive cycles. In combination with G-CSF, epirubicin 75 mg m?2and paclitaxel 175 mg m?2could be safely administered every 10 days over at least three cycles, enabling a dose intensity of 52 and 122 mg m?2per week, respectively. © 2000 Cancer Research Campaign PMID:10864197

  5. Development and characterization of a novel Cremophor EL free liposome-based paclitaxel (LEP-ETU) formulation.

    PubMed

    Zhang, J Allen; Anyarambhatla, Gopal; Ma, Lan; Ugwu, Sydney; Xuan, Tong; Sardone, Tommaso; Ahmad, Imran

    2005-01-01

    Taxol is a marketed product for the treatment of ovarian, breast, non-small cell lung cancer and AIDS-related Kaposi's Sarcoma. It is thus far one of the most effective anticancer drugs available on the market. However, paclitaxel is only sparingly soluble in water and therefore, intravenous administration depends on the use of the non-ionic surfactant Cremophor EL (polyethoxylated castor oil) to achieve a clinically relevant concentrated solution. Unfortunately, Cremophor EL increases toxicity and leads to hypersensitivity reactions in certain individuals. We have developed a well characterized novel lyophilized liposome-based paclitaxel (LEP-ETU) formulation that is sterile, stable and easy-to-use. The mean particle size of the liposomes is about 150 nm before and after lyophilization, and the drug entrapment efficiency is greater than 90%. Stability data indicated that the lyophilized LEP-ETU was physically and chemically stable for at least 12 months at 2-8 and 25 degrees C. Moreover, the formulation can be diluted to about 0.25mg/ml without drug precipitation or change in particle size. In vitro drug release study in phosphate-buffered saline (PBS, pH 7.4) showed that less than 6% of the entrapped paclitaxel was released after 120 h, indicating that the drug is highly stable in an entrapped form at physiologic temperature. PMID:15567316

  6. Stable phosphatidylcholine-bile salt mixed micelles enhance oral absorption of paclitaxel: preparation and mechanism in rats.

    PubMed

    Zhao, Yanli; Cui, Yanan; Li, Yimu; Li, Lingbing

    2014-12-01

    The aim of this study is to prepare a stable phosphatidylcholine/bile salt micelles with Pluronic F127-polyethylenimine conjugates (F127-PEI), d-?-tocopheryl polyethylene glycol 1000 succinate (TPGS), soybean phosphatidylcholine (SPC) and sodium cholate (NaC) and to elucidate the effects and possible mechanism of micelle components on the intestinal absorption of paclitaxel (PTX) in rats. The results of intestinal absorption revealed that the PTX in SPC/NaC micelles displayed superior permeability across intestinal barrier than free drug and PTX in TPGS/SPC/NaC and F127-PEI/TPGS/SPC/NaC mixed micelles exhibited the strongest permeability across intestinal barrier. These results were also proved by the studies on cell uptake tests. The mechanism was demonstrated in connection with inhibition of the efflux mediated by intestinal P-gp and enhancement of the drug transportation across the unstirred water layer to the endothelial lining, thereby promoting the permeation across the intestinal wall. Pharmacokinetic study demonstrated that the area under the plasma concentration-time curve (AUC0??) of paclitaxel in F127-PEI/TPGS/SPC/NaC micelles was much greater than that in TPGS/SPC/NaC micelles. This phenomenon deviated from the results of uptake studies by cells and permeability experiments through rat intestine and revealed that the micelle stability had a great effect on intestinal absorption of paclitaxel. PMID:25077358

  7. Efficient Drug Delivery of Paclitaxel Glycoside: A Novel Solubility Gradient Encapsulation into Liposomes Coupled with Immunoliposomes Preparation

    PubMed Central

    Murakami, Masaharu; Sekhar, Sreeja C.; Tominaga, Yuki; Okada, Masashi; Kudoh, Takayuki; Mizutani, Akifumi; Murakami, Hiroshi; Salomon, David S.; Mikuni, Katsuhiko; Mandai, Tadakatsu; Hamada, Hiroki; Seno, Masaharu

    2014-01-01

    Although the encapsulation of paclitaxel into liposomes has been extensively studied, its significant hydrophobic and uncharged character has generated substantial difficulties concerning its efficient encapsulation into the inner water core of liposomes. We found that a more hydrophilic paclitaxel molecule, 7-glucosyloxyacetylpaclitaxel, retained tubulin polymerization stabilization activity. The hydrophilic nature of 7-glucosyloxyacetylpaclitaxel allowed its efficient encapsulation into the inner water core of liposomes, which was successfully accomplished using a remote loading method with a solubility gradient between 40% ethylene glycol and Cremophor EL/ethanol in PBS. Trastuzumab was then conjugated onto the surface of liposomes as immunoliposomes to selectively target human epidermal growth factor receptor-2 (HER2)-overexpressing cancer cells. In vitro cytotoxicity assays revealed that the immunoliposomes enhanced the toxicity of 7-glucosyloxyacetylpaclitaxel in HER2-overexpressing cancer cells and showed more rapid suppression of cell growth. The immunoliposomes strongly inhibited the tumor growth of HT-29 cells xenografted in nude mice. Notably, mice survived when treated with the immunoliposomes formulation, even when administered at a lethal dose of 7-glucosyloxyacetylpaclitaxel in vivo. This data successfully demonstrates immunoliposomes as a promising candidate for the efficient delivery of paclitaxel glycoside. PMID:25264848

  8. Biodegradable paclitaxel-loaded microparticles prepared from novel block copolymers: influence of polymer composition on drug encapsulation and release.

    PubMed

    Sartori, Susanna; Caporale, Andrea; Rechichi, Alfonsina; Cufari, Domenico; Cristallini, Caterina; Barbani, Niccoletta; Giusti, Paolo; Ciardelli, Gianluca

    2013-04-01

    This study covers the preparation of microspheres for the controlled and targeted release of paclitaxel, using novel degradable polymers as carrier materials. Paclitaxel-loaded microspheres were prepared by oil-in-water single-emulsion solvent extraction/evaporation technique by using a series of polyurethanes and a block copolymer; the physicochemical properties of these polymers were modulated by changing nature and composition of their structural units. The obtained microparticles showed a regular morphology and properties (diameter: 1-100 µm; resuspension index: 18.8-100%; encapsulation efficiency: 26.6-97.2%) depending on polymer hydrophilicity and emulsifier used. In vitro release curves showed in all cases almost zero-order kinetics after an initial low burst effect (from 1 to 8.4%), which is required to minimize the drug side effects. This work also proposes a novel strategy to combine a controlled and a targeted release through the functionalization of the polymer matrix with peptide sequences. An RGD-functionalized polyurethane was used to successfully prepare paclitaxel-loaded microparticles. Studies on the preparation of polymer microspheres are reported. PMID:23495215

  9. Urinary N telopeptide levels in predicting the anti-nociceptive responses of zoledronic acid and paclitaxel in a rat model of bone metastases

    PubMed Central

    GUI, QI; XU, CHENGCHENG; LI, DAPENG; ZHUANG, LIANG; XIA, SHU; YU, SHIYING

    2015-01-01

    The present study investigated the hypothesis that urinary levels of N telopeptide (NTx) can be used to predict the anti-nociceptive responses of zoledronic acid and paclitaxel on bone metastases in a rat model. Rats were implanted with intra-femur Walker 256 carcinoma cells or control solution, and were treated with either normal saline, zoledronic acid or paclitaxel on the 10th day following surgery. Mechanical allodynia was recorded and the urine collagen-crosslinked NTx values were measured prior to, and 7, 14 and 21 days following the injections. Bone sections and osteoclasts were stained on the 14th day (4 days post-injection). Furthermore, the mRNA and protein expression levels of c-fos in the spinal cord and acid-sensing ion channel 3 (ASIC3) in the dorsal root ganglion (DRG) were analyzed. The mechanical allodynia of rats was attenuated from day 14 in the zoledronic acid group and from day 21 in the paclitaxel group. A positive correlation was observed between the anti-nociceptive responses of zoledronic acid and paclitaxel, and the urinary levels of NTx (r=0.619; P<0.001). The mRNA levels of c-fos in the spinal cord and ASIC3 in the DRG in the zoledronic acid group were reduced 14 and 21 days after inoculation, and this reduction was observed in the paclitaxel group 21 days after inoculation. Low dose paclitaxel was observed to have a weaker anti-nociceptive effect on bone cancer pain, with a later-onset, compared with zoledronic acid. The results suggested that urinary levels of NTx may predict the anti-nociceptive responses of zoledronic acid and paclitaxel in a rat model of bone metastases. PMID:26081451

  10. Identification of the First Inhibitor of the GBP1:PIM1 Interaction. Implications for the Development of a New Class of Anticancer Agents against Paclitaxel Resistant Cancer Cells

    PubMed Central

    2015-01-01

    Class III ?-tubulin plays a prominent role in the development of drug resistance to paclitaxel by allowing the incorporation of the GBP1 GTPase into microtubules. Once in the cytoskeleton, GBP1 binds to prosurvival kinases such as PIM1 and initiates a signaling pathway that induces resistance to paclitaxel. Therefore, the inhibition of the GBP1:PIM1 interaction could potentially revert resistance to paclitaxel. A panel of 44 4-azapodophyllotoxin derivatives was screened in the NCI-60 cell panel. The result is that 31 are active and the comparative analysis demonstrated specific activity in paclitaxel-resistant cells. Using surface plasmon resonance, we were able to prove that NSC756093 is a potent in vitro inhibitor of the GBP1:PIM1 interaction and that this property is maintained in vivo in ovarian cancer cells resistant to paclitaxel. Through bioinformatics, molecular modeling, and mutagenesis studies, we identified the putative NSC756093 binding site at the interface between the helical and the LG domain of GBP1. According to our results by binding to this site, the NSC756093 compound is able to stabilize a conformation of GBP1 not suitable for binding to PIM1. PMID:25211704

  11. Sub-Tenon Injections of Triamcinolone Acetonide Had Limited Effect on Cystoid Macular Edema Secondary to Nanoparticle Albumin-Bound-Paclitaxel (Abraxane)

    PubMed Central

    Matsuoka, Naoki; Hasebe, Hiruma; Mayama, Tetsuji; Fukuchi, Takeo

    2015-01-01

    Purpose. To report the first case of cystoid macular edema (CME) induced by nanoparticle albumin-bound- (nab-) paclitaxel treated with sub-Tenon injections of triamcinolone acetonide (STTA) with detailed long-term follow-up. Case. A 39-year-old Japanese woman with breast cancer presents with decreased vision in both eyes while receiving nab-paclitaxel. Two STTA treatments were administered for persistent CME in her right eye. Central retinal thickness (CRT) of the treated eye decreased after the first STTA, but there was no change after the second STTA. CRT of the other eye and bilateral visual acuity (VA) showed no change after each treatment. However, this patient experienced gradual recovery of visual function after nab-paclitaxel treatment was completed, 3 months after the second STTA. Improvements in VA and CRT did not overlap in time. Moreover, there was a big improvement time lag in VA between the eyes. Conclusion. Cessation of nab-paclitaxel could lead to resolution of CME more than STTA, although STTA had some effect. Since nab-paclitaxel has been recently approved for treating more types of malignancies, the number of the patients with this CME is expected to increase in the near future. Patients and physicians should understand this side effect and prepare for other treatment options. PMID:26366312

  12. Enhanced oral bioavailability of paclitaxel formulated in vitamin E-TPGS emulsified nanoparticles of biodegradable polymers: in vitro and in vivo studies.

    PubMed

    Zhao, Lingyun; Feng, Si-Shen

    2010-08-01

    This work evaluates the effects of paclitaxel loaded polymeric nanoparticles (NPs) composed of poly(D,L-lactic-co-glycolic acid) (PLGA) with vitamin E TPGS as emulsifier for oral chemotherapy. NPs prepared by a modified solvent extraction/evaporation technique were observed in spherical shape of 200-300 nm diameter with a high drug encapsulation efficiency (EE) of 80.9%. The TPGS-emulsified PLGA NPs formulation of paclitaxel was found of great advantages over that of Taxol. The in vitro viability experiment showed that the NP formulation could be 1.28, 1.38, 1.12 times more effective than Taxol(R) after 24, 48, 72 h incubation with MCF-7 human breast cancer cell line at 2.5 microg/mL paclitaxel concentration. In vivo evaluation confirmed the advantages of the TPGS-emulsified PLGA NP formulation versus Taxol in promoting oral bioavailability of paclitaxel. Such a NP formulation achieved more than 10 times higher oral bioavailability than Taxol, which resulted 9.74-fold higher therapeutic effect and 12.56-fold longer sustainable therapeutic time than Taxol. The present proof-of-concept experimental data proved that the formulation of vitamin E TPGS emulsified PLGA NPs is a promising approach for paclitaxel oral administration. Oral chemotherapy by NPs formulation is feasible. PMID:20564384

  13. Paclitaxel-sensitization enhanced by curcumin involves down-regulation of nuclear factor-?B and Lin28 in Hep3B cells.

    PubMed

    Zhou, Mingjie; Li, Zhaohui; Han, Ziwu; Tian, Nan

    2015-12-01

    Although paclitaxel is an effective chemotherapeutic drug used in the treatment of many tumors, hepatoma cells, in particular, are known to be highly resistant to it. Previously, we discovered that Lin28 was closely associated with resistance to paclitaxel in Hep3B cells. The nuclear factor-kappa B (NF-?B) transcription factor, which plays an important role in tumor survival, directly activates Lin28 expression through a binding site on the first intron. Curcumin, a non-toxic anti-inflammatory agent, inhibits NF-?B activity in vitro. In this study, we reported that a combination of curcumin and paclitaxel exhibited synergistic anti-proliferative and pro-apoptosis effects on Hep3B cells, and curcumin down-regulated paclitaxel-induced enhanced expression of Lin28 and NF-?B activation. Furthermore, our results revealed that curcumin reduced Lin28 levels via mechanisms directly mediated by inhibition of NF-?B activity. These mechanism-based observations evidence that curcumin enhances the sensitivity of hepatoma cells to paclitaxe, and strongly support the notion that paclitaxel in combination with curcumin may provide a superior therapeutic index for HCC chemotherapy. PMID:26108226

  14. Effect of Antioxidants and Carbohydrates in Callus Cultures of Taxus brevifolia: Evaluation of Browning, Callus Growth, Total Phenolics and Paclitaxel Production

    PubMed Central

    Yari Khosroushahi, Ahmad; Naderi-Manesh, Hossein; Toft Simonsen, Henrik

    2011-01-01

    Introduction To control the tissue browning phenomenon, callus growth, total phenolics and paclitaxel production, in the current investigation, we evaluated the effects of citric acid and ascorbic acid (as antioxidants) and glucose, fructose and sucrose in callus cultures of Taxus brevifolia. Methods To obtain healthy callus/cell lines of Taxus brevifolia, the effects of two antioxidants ascorbic acid (100-1000 mg/L) and citric acid (50-500 mg/L), and three carbohydrates (glucose, fructose and sucrose (5-10 g/L)) were studied evaluating activities of polyphenol oxidase (PPO) and peroxidase (PO) enzymes, callus growth/browning, total phenolics and paclitaxel production. Results These antioxidants (ascorbic acid and citric acid) failed to show significant effects on callus growth, browning intensity or paclitaxel production. However, the carbohydrates imposed significant effects on the parameters studied. High concentrations of both glucose and sucrose increased the browning intensity, thus decreased callus growth. Glucose increased paclitaxel production, but sucrose decreased it. Conclusion These results revealed that the browning phenomenon can be controlled through supplementation of the growth media with glucose, sucrose (5 g/L) and fructose (10 g/L), while increased paclitaxel production can be obtain by the optimized media supplemented with glucose (10 g/L), sucrose and fructose (5 g/L). PMID:23678406

  15. Dendritic polyglycerol sulfate as a novel platform for paclitaxel delivery: pitfalls of ester linkage

    NASA Astrophysics Data System (ADS)

    Sousa-Herves, Ana; Würfel, Patrick; Wegner, Nicole; Khandare, Jayant; Licha, Kai; Haag, Rainer; Welker, Pia; Calderón, Marcelo

    2015-02-01

    In this study, dendritic polyglycerol sulfate (dPGS) is evaluated as a delivery platform for the anticancer, tubulin-binding drug paclitaxel (PTX). The conjugation of PTX to dPGS is conducted via a labile ester linkage. A non-sulfated dendritic polyglycerol (dPG) is used as a control, and the labeling with an indocarbocyanine dye (ICC) renders multifunctional conjugates that can be monitored by fluorescence microscopy. The conjugates are characterized by 1H NMR, UV-vis measurements, and RP-HPLC. In vitro cytotoxicity of PTX and dendritic conjugates is evaluated using A549 and A431 cell lines, showing a reduced cytotoxic efficacy of the conjugates compared to PTX. The study of uptake kinetics reveals a linear, non saturable uptake in tumor cells for dPGS-PTX-ICC, while dPG-PTX-ICC is hardly taken up. Despite the marginal uptake of dPG-PTX-ICC, it prompts tubulin polymerization to a comparable extent as PTX. These observations suggest a fast ester hydrolysis and premature drug release, as confirmed by HPLC measurements in the presence of plasma enzymes.In this study, dendritic polyglycerol sulfate (dPGS) is evaluated as a delivery platform for the anticancer, tubulin-binding drug paclitaxel (PTX). The conjugation of PTX to dPGS is conducted via a labile ester linkage. A non-sulfated dendritic polyglycerol (dPG) is used as a control, and the labeling with an indocarbocyanine dye (ICC) renders multifunctional conjugates that can be monitored by fluorescence microscopy. The conjugates are characterized by 1H NMR, UV-vis measurements, and RP-HPLC. In vitro cytotoxicity of PTX and dendritic conjugates is evaluated using A549 and A431 cell lines, showing a reduced cytotoxic efficacy of the conjugates compared to PTX. The study of uptake kinetics reveals a linear, non saturable uptake in tumor cells for dPGS-PTX-ICC, while dPG-PTX-ICC is hardly taken up. Despite the marginal uptake of dPG-PTX-ICC, it prompts tubulin polymerization to a comparable extent as PTX. These observations suggest a fast ester hydrolysis and premature drug release, as confirmed by HPLC measurements in the presence of plasma enzymes. Electronic supplementary information (ESI) available: 1H NMR spectra of the conjugates, HPLC chromatograms, internalization images of dPGS-PTX-ICC (5), elimination kinetics of dPGS-PTX-ICC (5) and dPGS-ICC (7), comparison of IC50 values of PTX and dPGS-PTX (3) in A431 and A549 cell lines and cell viability of dPGS amine (1). See DOI: 10.1039/c4nr04428b

  16. The Quest for a Simple Bioactive Analog of Paclitaxel as a Potential Anticancer Agent

    PubMed Central

    2015-01-01

    Conspectus Paclitaxel (PTX), introduced into the clinic in 1991, has revealed itself as an effective antimicrotubule drug for treatment of a range of otherwise intractable cancers. Along with docetaxel (DTX) and in combination with other agents such as cisplatin, it has proven to be a first-line therapy. Unfortunately, PTX and DTX carry severe liabilities such as debilitating side effects, rapid onset of resistance, and rather complex molecular structures offering substantial challenges to ease of synthetic manipulation. Consequently, the past 15 years has witnessed many efforts to synthesize and test highly modified analogs based on intuitive structural similarity relationships with the PTX molecular skeleton, as well as efforts to mimic the conformational profile of the ligand observed in the macromolecular tubulin–PTX complex. Highly successful improvements in potency, up to 50-fold increases in IC50, have been achieved by constructing bridges between distal centers in PTX that imitate the conformer of the electron crystallographic binding pose. Much less successful have been numerous attempts to truncate PTX by replacing the baccatin core with simpler moieties to achieve PTX-like potencies and applying a wide range of flexible synthesis-based chemistries. Reported efforts, characterized by a fascinating array of baccatin substitutes, have failed to surpass the bioactivities of PTX in both microtubule disassembly assays and cytotoxicity measurements against a range of cell types. Most of the structures retain the main elements of the PTX C13 side chain, while seeking a smaller rigid bicycle as a baccatin replacement adorned with substituents to mimic the C2 benzoyl moiety and the oxetane ring. We surmise that past studies have been handicapped by solubility and membrane permeability issues, but primarily by the existence of an expansive taxane binding pocket and the discrepancy in molecular size between PTX and the pruned analogs. A number of these molecules offer molecular volumes 50–60% that of PTX, fewer contacts with the tubulin protein, severe mismatches with the PTX pharmacophore, lessened capacity to dispel binding site waters contributing to ?Gbind, and unanticipated binding poses. The latter is a critical drawback if molecular designs of simpler PTX structures are based on a perceived or known PTX binding conformation. We conclude that design and synthesis of a highly cytotoxic tubulin-assembly agent based on the paclitaxel pharmacophore remains an unsolved challenge, but one that can be overcome by focus on the architecture of the taxane binding site independent of the effective, but not unique, hand-in-glove match represented by the PTX–tubulin complex. PMID:25052294

  17. Akt is upstream and MAPKs are downstream of NF-?B in paclitaxel-induced survival signaling events, which are down-regulated by curcumin contributing to their synergism.

    PubMed

    Bava, Smitha V; Sreekanth, Chanickal N; Thulasidasan, Arun Kumar T; Anto, Nikhil P; Cheriyan, Vino T; Puliyappadamba, Vineshkumar T; Menon, Sajna G; Ravichandran, Santhosh D; Anto, Ruby John

    2011-03-01

    Paclitaxel is the most promising chemotherapeutic agent of plant origin despite its high cost and dose-limiting toxicity. Our earlier report has shown that cervical cancer cells can be sensitized by curcumin to paclitaxel-induced apoptosis through down-regulation of NF-?B and Akt. In the present study we have attempted to decipher the signaling pathways regulating the synergism of paclitaxel and curcumin. The study has clearly proved that Akt and NF-?B function successively in the sequence of paclitaxel induced signaling events where Akt is upstream of NF-?B. While inhibition of NF-?B led to complete inhibition of the synergism of paclitaxel and curcumin, inhibition of Akt brought about only partial reduction of the same, suggesting that, apart from Akt, there are other pathways induced by paclitaxel leading to NF-?B activation, which are also down-regulated by curcumin. Inactivation of NF-?B did not affect the activation of Akt and survivin, while that of Akt significantly inhibited NF-?B and completely inhibited up-regulation of survivin. Up-regulation of Cyclin-D1, Cox-2, XIAP and cIAP1 and phosphorylation of MAPKs, were completely inhibited on inactivation of NF-?B assigning a key regulatory role to NF-?B in the synergistic effect of paclitaxel and curcumin. While up-regulation of survivin by paclitaxel is regulated by Akt, independent of NF-?B, inactivation of neither Akt nor NF-?B produced any change in Bcl-2 level suggesting a distinct pathway for its action. As curcumin could effectively down-regulate all these survival signals induced by paclitaxel, we suggest it as a potent chemosensitizer to improve the therapeutic index of paclitaxel. PMID:20883815

  18. Preparation and characterization of amphiphilic calixarene nanoparticles as delivery carriers for paclitaxel.

    PubMed

    Zhao, Zi-Ming; Wang, Yu; Han, Jin; Zhu, Hui-Dong; An, Lin

    2015-01-01

    Two types of amphoteric calix[n]arene carboxylic acid (CnCA) derivative, i.e., calix[6]arene hexa-carboxylic acid (C6HCA) and calix[8]arene octo-carboxylic acid (C8OCA), were synthesized by introducing acetoxyls into the hydroxyls of calix[n]arene (n=6, 8). C6HCA and C8OCA nanoparticles (NPs) were prepared successfully using the dialysis method. CnCA NPs had regular spherical shapes with an average diameter of 180-220?nm and possessed negative charges of greater than -30?mV. C6HCA and C8OCA NPs were stable in 4.5% bovine serum albumin solutions and buffers (pH 5-9), with a low critical aggregation concentration value of 5.7?mg·L(-1) and 4.0?mg·L(-1), respectively. C6HCA and C8OCA NPs exhibited good paclitaxel (PTX) loading capacity, with drug loading contents of 7.5% and 8.3%, respectively. The overall in vitro release behavior of PTX from the CnCA NPs was sustained, and C8OCA NPs had a slower release rate compared with C6HCA NPs. These favorable properties of CnCA NPs make them promising nanocarriers for tumor-targeted drug delivery. PMID:25757488

  19. Construction of polymer-paclitaxel conjugate linked via a disulfide bond.

    PubMed

    Yan, Qunfang; Yang, Yuchi; Chen, Wulian; Hu, Jianhua; Yang, Dong

    2016-01-01

    Covalently linked amphiphilic polymer-paclitaxel (PTX) could self-assemble into micelles to overcome many drawbacks of existing delivery systems of PTX by virtue of tunable compositions, variable sizes, high drug loading content and zero burst release. Moreover, a reduction-responsive system based on glutathione (GSH) can be established by introducing disulfide bonds into the polymeric carriers to improve the selectivity for cancer cells. Herein, we reported a disulfide bond linked polymer-PTX, P(PEGMEA)-co-P(PDPHEMA)-g-PTX with a high PTX loading content of 43.7wt.%. In vitro cell assay showed that the polymer carrier has almost no cytotoxicity. The half maximal inhibitory concentration (IC50) values of the polymer-PTX conjugate against HEK-293 cells was about 10 times higher than that of HeLa cells after incubation for 72h. Such a dramatic selectivity for cancer and normal cells provides a promising strategy to improve the therapeutic efficacy and decrease the side effects of PTX in chemotherapy. PMID:26478347

  20. Effects of PEGylated paclitaxel nanocrystals on breast cancer and its lung metastasis

    NASA Astrophysics Data System (ADS)

    Zhang, Hua; Hu, Hongxiang; Zhang, Haoran; Dai, Wenbing; Wang, Xinglin; Wang, Xueqing; Zhang, Qiang

    2015-06-01

    As an attractive strategy developed rapidly in recent years, nanocrystals are used to deliver insoluble drugs. PEGylation may further prolong the circulation time of nanoparticles and improve the therapeutic outcome of drugs. In this study, paclitaxel (PTX) nanocrystals (PTX-NCs) and PEGylated PTX nanocrystals (PEG-PTX-NCs) were prepared using antisolvent precipitation augmented by probe sonication. The characteristics and antitumor efficacy of nanocrystals were investigated. The results indicated that the nanocrystals showed rod-like morphology, and the average particle size was 240 nm and 330 nm for PTX-NCs and PEG-PTX-NCs, respectively. The PEG molecules covered the surface of nanocrystals with an 11.54 nm fixed aqueous layer thickness (FALT), much higher than that of PTX-NCs (0.2 nm). PEG-PTX-NCs showed higher stability than PTX-NCs under both storage and physiological conditions. In breast cancer xenografted mice, PEG-PTX-NCs showed significantly better tumor inhibition compared to saline (p < 0.001) and PTX-NC groups (p < 0.05) after intravenous administration. In a model of lung tumor metastasis quantified by the luciferase activity, the PEG-PTX-NCs group showed higher anticancer efficacy not only than saline and PTX-NCs groups, but also than Taxol®, achieving an 82% reduction at the end of the experiment. These studies suggested the potential advantages of PEGylated PTX nanocrystals as alternative drug delivery systems for anticancer therapy.

  1. [A case of paclitaxel-resistant recurrent gastric cancer responsive to S-1 plus docetaxel].

    PubMed

    Nishikawa, Kazuhiro; Iwase, Kazuhiro; Aono, Toyokazu; Yoshida, Hiroshi; Nomura, Masaya; Tamagawa, Hiroshi; Matsuda, Chu; Deguchi, Takashi; Kawada, Junji; Higashi, Shigeyoshi; Deguchi, Koichi; Noguchi, Yuki; Okumura, Yuichiro; Nomura, Masatoshi; Fushimi, Hiroaki; Takagi, Mari; Fukui, Akiko; Fujitani, Kazumasa; Endo, Shunji; Tanaka, Yasuhiro

    2013-11-01

    We report the case of a patient with paclitaxel (PTX) -resistant recurrent gastric cancer who was effectively treated with S-1 plus docetaxel( DOC). A 62-year-old woman underwent total gastrectomy for Stage IV advanced gastric cancer (type 4, por 2>sig, pT4a (SE), pN3a, pP1, CY1) in 2009. Although S-1 was administered as first-line chemotherapy, recurrent peritoneal metastasis was diagnosed 22 months after surgery. S-1 plus irinotecan (CPT-11) was administered as second-line chemotherapy, and this was followed by weekly PTX (80 mg/m2) as third-line chemotherapy. However, computed tomography (CT) showed increased ascites and peritoneal wall thickening in the pelvis. As the tumor proved resistant to PTX, making the treatment ineffective, S-1( 80 mg/m2, day 1-14, q3w) plus DOC( 40 mg/m2, day 1, q3w) was initiated. Two months later, the ascites and peritoneal wall thickening in the pelvis disappeared. Twelve months after initiation of S-1 plus DOC chemotherapy, no sign of recurrence has been noted. PMID:24394078

  2. A7RC peptide modified paclitaxel liposomes dually target breast cancer.

    PubMed

    Cao, Jingyan; Wang, Ran; Gao, Ning; Li, Minghui; Tian, Xuyu; Yang, Weili; Ruan, Ying; Zhou, Chunlan; Wang, Guangtian; Liu, Xiaoying; Tang, Shukun; Yu, Yan; Liu, Ying; Sun, Guangyu; Peng, Haisheng; Wang, Qun

    2015-12-10

    A7R peptide (ATWLPPR), a ligand of the NRP-1 receptor, regulates the intracellular signal transduction related to tumor vascularization and tumor growth. Here, we designed A7R-cysteine peptide (A7RC) surface modified paclitaxel liposomes (A7RC-LIPs) to achieve targeting delivery and inhibition of tumor growth and angiogenesis simultaneously. The cytotoxicity, inhibiting angiogenesis, and internalization of various liposomes by cells were assessed in vitro to confirm the influence of the peptide modification. The accumulations of A7RC-LIPs in various xenografts in mice were tracked to further identify the function of the peptide on the liposomes' surface. The results confirmed that A7RC peptides could enhance the uptake of vesicles by MDA-MB-231 cells, leading to stronger cytotoxicity in vitro and higher accumulation of vesicles in MDA-MB-231 xenografts in vivo. In addition, A7RC peptides enhanced the inhibitory effects of LIPs on the HUVEC tubular formation on Matrigel. The A7RC-LIPs may be promising drug carriers for anticancer therapy. PMID:26291480

  3. Solid-nanoemulsion preconcentrate for oral delivery of paclitaxel: formulation design, biodistribution, and ? scintigraphy imaging.

    PubMed

    Ahmad, Javed; Mir, Showkat R; Kohli, Kanchan; Chuttani, Krishna; Mishra, Anil K; Panda, A K; Amin, Saima

    2014-01-01

    Aim of present study was to develop a solid nanoemulsion preconcentrate of paclitaxel (PAC) using oil [propylene glycol monocaprylate/glycerol monooleate, 4:1?w/w], surfactant [polyoxyethylene 20 sorbitan monooleate/polyoxyl 15 hydroxystearate, 1:1?w/w], and cosurfactant [diethylene glycol monoethyl ether/polyethylene glycol 300, 1:1?w/w] to form stable nanocarrier. The prepared formulation was characterized for droplet size, polydispersity index, and zeta potential. Transmission electron microscopy (TEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR) were used to assess surface morphology and drug encapsulation and its integrity. Cumulative drug release of prepared formulation through dialysis bag and permeability coefficient through everted gut sac were found to be remarkably higher than the pure drug suspension and commercial intravenous product (Intaxel), respectively. Solid nanoemulsion preconcentrate of PAC exhibited strong inhibitory effect on proliferation of MCF-7 cells in MTT assay. In vivo systemic exposure of prepared formulation through oral administration was comparable to that of Intaxel in ? scintigraphy imaging. Our findings suggest that the prepared solid nanoemulsion preconcentrate can be used as an effective oral solid dosage form to improve dissolution and bioavailability of PAC. PMID:25114933

  4. Paclitaxel targeting to lungs by way of liposomes prepared by the effervescent dispersion technique.

    PubMed

    Wei, Yumeng; Xue, Zhengkai; Ye, Yun; Huang, Yu; Zhao, Ling

    2014-06-01

    In order to develop a novel lung targeting drug delivery system (LTDDS) with large-sized liposomes containing paclitaxel (PTX), the liposomes composed of PTX, phosopholipon 90H and tween-80 were prepared by the effervescent dispersion technique with optimal formulation composition. The liposomes were found to be relatively uniform in particle size (8.166 ± 0.459 ?m) with a negative zeta-potential (-12.45 ± 1.34 mv), and high entrapment efficiency (92.20 ± 2.56 %). They kept stable for at least 3 months and exhibited a slow release behavior without any hemolysis reaction. Via intravenous administration in rabbits, the PTX liposomes presented a longer mean residence time and elimination half-life, and a much larger area under the plasma drug concentration-time curve compared with its injection; meanwhile, the liposomes altered its biodistribution and exhibited a significant lung targeting characteristic. For example, the relative intake rate (Re) and the ratio of peak concentration (Ce) of lung were 14.87 and 26.44, respectively. Compared with heart, liver, spleen and kidney, the ratios of targeting efficacy (Te)liposomes to (Te)injection of lung were increased by a factor of 20.08, 11.10, 6.97 and 14.41, respectively. To sum up, the liposome could be a promising drug carrier for PTX as LTDDS for lung cancer treatment. PMID:23775475

  5. A paclitaxel-loaded recombinant polypeptide nanoparticle outperforms Abraxane in multiple murine cancer models

    NASA Astrophysics Data System (ADS)

    Bhattacharyya, Jayanta; Bellucci, Joseph J.; Weitzhandler, Isaac; McDaniel, Jonathan R.; Spasojevic, Ivan; Li, Xinghai; Lin, Chao-Chieh; Chi, Jen-Tsan Ashley; Chilkoti, Ashutosh

    2015-08-01

    Packaging clinically relevant hydrophobic drugs into a self-assembled nanoparticle can improve their aqueous solubility, plasma half-life, tumour-specific uptake and therapeutic potential. To this end, here we conjugated paclitaxel (PTX) to recombinant chimeric polypeptides (CPs) that spontaneously self-assemble into ~60 nm near-monodisperse nanoparticles that increased the systemic exposure of PTX by sevenfold compared with free drug and twofold compared with the Food and Drug Administration-approved taxane nanoformulation (Abraxane). The tumour uptake of the CP-PTX nanoparticle was fivefold greater than free drug and twofold greater than Abraxane. In a murine cancer model of human triple-negative breast cancer and prostate cancer, CP-PTX induced near-complete tumour regression after a single dose in both tumour models, whereas at the same dose, no mice treated with Abraxane survived for >80 days (breast) and 60 days (prostate), respectively. These results show that a molecularly engineered nanoparticle with precisely engineered design features outperforms Abraxane, the current gold standard for PTX delivery.

  6. Inhalable, large porous PLGA microparticles loaded with paclitaxel: preparation, in vitro and in vivo characterization.

    PubMed

    Alipour, Shohreh; Montaseri, Hashem; Tafaghodi, Mohsen

    2015-11-01

    Large porous particles (LPPs) could be used as a useful carrier for non-invasive delivery to the deep lung. Pulmonary delivery of paclitaxel-loaded LPPs (PTX-LPPs) can help to eliminate the highly complicated and harmful solvent used in PTX parenteral formulations. PTX-LPPs with mass median aerodynamic diameter (MMAD) of 5.74?±?0.09??m, high encapsulation efficiency and good aerosolisation properties were produced using ammonium bicarbonate as porogen. Cytotoxicity of PTX-LPPs on A549 and Calu-6 cell lines was comparable with Free-PTX. Endotracheal administration of PTX-LPPs in rats exhibited PTX plasma concentration in the therapeutic range which lasted 4-fold longer than i.v. injection. The bioavailability was measured as 51?±?7.1%. The lung targeting efficiency (Te) of PTX-LPPs was 11.9-fold higher than i.v. administration. PTX-LPPs could deliver a higher PTX to lung with a non-toxic plasma level in a longer duration which shows their pulmonary delivery suitability. PMID:26415914

  7. Nanocomposite hydrogel incorporating gold nanorods and paclitaxel-loaded chitosan micelles for combination photothermal-chemotherapy.

    PubMed

    Zhang, Nan; Xu, Xuefan; Zhang, Xue; Qu, Ding; Xue, Lingjing; Mo, Ran; Zhang, Can

    2016-01-30

    Development of combination photothermal-chemotherapy platform is of great interest for enhancing antitumor efficacy and inhibiting tumor recurrence, which supports selective and dose-controlled delivery of heat and anticancer drugs to tumor. Here, an injectable nanocomposite hydrogel incorporating PEGylated gold nanorods (GNRs) and paclitaxel-loaded chitosan polymeric micelles (PTX-M) is developed in pursuit of improved local tumor control. After intratumoral injection, both GNRs and PTX-M can be simultaneously delivered and immobilized in the tumor tissue by the thermo-sensitive hydrogel matrix. Exposure to the laser irradiation induces the GNR-mediated photothermal damage confined to the tumor with sparing the surrounding normal tissue. Synergistically, the co-delivered PTX-M shows prolonged tumor retention with the sustained release of anticancer drug to efficiently kill the residual tumor cells that evade the photothermal ablation due to the heterogeneous heating in the tumor region. This combination photothermal-chemotherapy presents superior effects on suppressing the tumor recurrence and prolonging the survival in the Heps-bearing mice, compared to the photothermal therapy alone. PMID:26608619

  8. Paclitaxel-eluting balloon dilation of biliary anastomotic stricture after liver transplantation

    PubMed Central

    Hüsing, Anna; Reinecke, Holger; Cicinnati, Vito R; Beckebaum, Susanne; Wilms, Christian; Schmidt, Hartmut H; Kabar, Iyad

    2015-01-01

    AIM: To investigate the safety and effectiveness of endoscopic therapy with a paclitaxel-eluting balloon (PEB) for biliary anastomotic stricture (AS) after liver transplantation (LT). METHODS: This prospective pilot study enrolled 13 consecutive eligible patients treated for symptomatic AS after LT at the University Hospital of Münster between January 2011 and March 2014. The patients were treated by endoscopic therapy with a PEB and followed up every 8 wk by endoscopic retrograde cholangiopancreatography (ERCP). In cases of re-stenosis, further balloon dilation with a PEB was performed. Follow-up was continued until 24 mo after the last intervention. RESULTS: Initial technical feasibility, defined as successful balloon dilation with a PEB during the initial ERCP procedure, was achieved in 100% of cases. Long-term clinical success (LTCS), defined as no need for further endoscopic intervention for at least 24 mo, was achieved in 12 of the 13 patients (92.3%). The mean number of endoscopic interventions required to achieve LTCS was only 1.7 ± 1.1. Treatment failure, defined as the need for definitive alternative treatment, occurred in only one patient, who developed recurrent stenosis with increasing bile duct dilatation that required stent placement. CONCLUSION: Endoscopic therapy with a PEB is very effective for the treatment of AS after LT, and seems to significantly shorten the overall duration of endoscopic treatment by reducing the number of interventions needed to achieve LTCS. PMID:25624733

  9. Concurrent cisplatin, 5-FU, paclitaxel, and radiation therapy in patients with locally advanced esophageal cancer

    SciTech Connect

    Roof, Kevin S. . E-mail: kroof@sero.net; Coen, John; Lynch, Thomas J.; Wright, Cameron; Fidias, Panos; Willett, Christopher G.; Choi, Noah C.

    2006-07-15

    Purpose: Phase I-II data regarding neoadjuvant cisplatin, 5-fluorouracil (5-FU), paclitaxel, and radiation (PFT-R) from our institution demonstrated encouraging pathologic complete response (pCR) rates. This article updates our experience with PFT-R, and compares these results to our experience with cisplatin, 5-FU, and radiation therapy (PF-R) in locally advanced esophageal cancer. Patients and Methods: We searched the Massachusetts General Hospital cancer registry for esophageal cancer patients treated with radiation therapy and chemotherapy between 1994-2002. Records of patients treated with curative, neoadjuvant therapy were examined for chemotherapeutic regimen. Outcomes of patients treated with PF-R or PFT-R were assessed for response to therapy, toxicity, and survival. Results: A total of 177 patients were treated with neoadjuvant therapy with curative intent; 164 (93%) received PF-R (n = 81) or PFT-R (n = 83). Median overall survival was 24 months. After a median follow-up of 54 months for surviving patients, 3-year overall survival was 40% with no significant difference between PF-R (39%) and PFT-R (42%). Conclusions: Our findings failed to demonstrate an improvement in pCR or survival with PFT-R vs. PF-R. These results do not support this regimen of concurrent neoadjuvant PFT-R in esophageal cancer, and suggest that further investigations into alternative regimens and novel agents are warranted.

  10. Weekly Paclitaxel plus Capecitabine versus Docetaxel Every 3 Weeks plus Capecitabine in Metastatic Breast Cancer.

    PubMed

    Wist, E A; Mjaaland, I; Løkkevik, E; Sommer, H H

    2012-01-01

    Background. We performed a randomized phase II study comparing efficacy and toxicity of weekly paclitaxel 80?mg/m(2) (Weetax) with three weekly docetaxel 75?mg/m(2) (Threetax), both in combination with oral capecitabine 1000?mg/m(2) twice daily for 2 weeks followed by a 1-week break. Patients. Thirty-seven women with confirmed metastatic breast cancer were randomized. Results. Median TTF was 174 (Weetax) versus 147 days (Threetax) (P=0.472). Median OS was 933 (Weetax) versus 464 days (Threetax) (P=0.191). Reasons for TTF were PD 8/18 (Weetax), 9/19 (Threetax); and toxicity: 8/18 (Weetax), 8/19 (Threetax). ORR was 72% (Weetax) versus 26% (Threetax) (P = 0.01). The Threetax-combination resulted in a higher incidence of leuco-/neutropenia compared to Weetax. Grade II anemia was more pronounced in the Weetax group. No difference was found in quality of life. Conclusion. Taxanes in combination with capecitabine resulted in a high level of toxicity. Taxanes and capecitabine should be considered given sequentially and not in combination. PMID:22291703

  11. Codelivery of Doxorubicin and Paclitaxel by Cross-Linked Multilamellar Liposome Enables Synergistic Antitumor Activity

    PubMed Central

    2015-01-01

    Combining chemotherapeutics is a promising method of improving cancer treatment; however, the clinical success of combination therapy is limited by the distinct pharmacokinetics of combined drugs, which leads to nonuniform distribution. In this study, we report a new robust approach to load two drugs with different hydrophilicities into a single cross-linked multilamellar liposomal vesicle (cMLV) to precisely control the drug ratio that reaches the tumor in vivo. The stability of cMLVs improves the loading efficiency and sustained release of doxorubicin (Dox) and paclitaxel (PTX), maximizing the combined therapeutic effect and minimizing the systemic toxicity. Furthermore, we show that the cMLV formulation maintains specific drug ratios in vivo for over 24 h, enabling the ratio-dependent combination synergy seen in vitro to translate to in vivo antitumor activity and giving us control over another parameter important to combination therapy. This combinatorial delivery system may provide a new strategy for synergistic delivery of multiple chemotherapeutics with a ratiometric control over encapsulated drugs to treat cancer and other diseases. PMID:24673622

  12. Nanoparticles Containing High Loads of Paclitaxel-Silicate Prodrugs: Formulation, Drug Release, and Anticancer Efficacy.

    PubMed

    Han, Jing; Michel, Andrew R; Lee, Han Seung; Kalscheuer, Stephen; Wohl, Adam; Hoye, Thomas R; McCormick, Alon V; Panyam, Jayanth; Macosko, Christopher W

    2015-12-01

    We have investigated particle size, interior structure, drug release kinetics, and anticancer efficacy of PEG-b-PLGA-based nanoparticles loaded with a series of paclitaxel (PTX)-silicate prodrugs [PTX-Si(OR)3]. Silicate derivatization enabled us to adjust the hydrophobicity and hydrolytic lability of the prodrugs by the choice of the alkyl group (R) in the silicate derivatives. The greater hydrophobicity of these prodrugs allows for the preparation of nanoparticles that are stable in aqueous dispersion even when loaded with up to ca. 75 wt % of the prodrug. The hydrolytic lability of silicates allows for facile conversion of prodrugs back to the parent drug, PTX. A suite of eight PTX-silicate prodrugs was investigated; nanoparticles were made by flash nanoprecipitation (FNP) using a confined impingement jet mixer with a dilution step (CIJ-D). The resulting nanoparticles were 80-150 nm in size with a loading level of 47-74 wt % (wt %) of a PTX-silicate, which corresponds to 36-59 effective wt % of free PTX. Cryogenic transmission electron microscopy images show that particles are typically spherical with a core-shell structure. Prodrug/drug release profiles were measured. Release tended to be slower for prodrugs having greater hydrophobicity and slower hydrolysis rate. Nanoparticles loaded with PTX-silicate prodrugs that hydrolyze most rapidly showed in vitro cytotoxicity similar to that of the parent PTX. Nanoparticles loaded with more labile silicates also tended to show greater in vivo efficacy. PMID:26505116

  13. Erlotinib versus carboplatin and paclitaxel in advanced lepidic adenocarcinoma: IFCT-0504.

    PubMed

    Cadranel, Jacques; Gervais, Radj; Merle, Patrick; Moro-Sibilot, Denis; Westeel, Virginie; Bigay-Game, Laurence; Quoix, Elisabeth; Friard, Sylvie; Barlesi, Fabrice; Lethrosne, Claire; Moreau, Lionel; Monnet, Isabelle; Salaun, Mathieu; Oliviero, Gérard; Souquet, Pierre-Jean; Antoine, Martine; Langlais, Alexandra; Morin, Franck; Wislez, Marie; Zalcman, Gérard

    2015-11-01

    The IFCT-0504 phase II trial evaluated the efficacy of erlotinib versus carboplatin-paclitaxel (CP) as first-line treatment in 130 cases of advanced lepidic-predominant adenocarcinoma (ADC).The primary objective of the study was treatment efficacy, evaluated based on an end-point of disease control at 16?weeks.The primary objective was met, with a disease control in 35 (53%) out of 66 patients treated with CP and in 25 (39.1%) out of 64 patients treated with erlotinib. Median progression-free survival (PFS) for the total population was 3.6?months. The disease control rate did not differ between either the therapeutic arms or pathological subtypes, whereas there was a strong interaction between treatment arms and tumour pathological subtypes for PFS (p=0.009). Mucinous tumour patients treated with erlotinib exhibited an increased progression risk (hazard ratio 3.4, 95% CI 1.7-6.5; p?0.001). The PFS for nonmucinous tumour patients was similar in both arms. Median overall survival was 20.1?months and did not differ between therapeutic arms. These findings were not further elucidated by molecular analyses and the toxicity profiles were as expected.Our study demonstrated the dominant role of CP alongside erlotinib in the management of advanced lepidic ADC. Based on these findings, erlotinib should not be administered in first-line therapy to patients with lepidic ADC in the absence of an epidermal growth factor receptor mutation. PMID:26381515

  14. Multifunctional mesoporous silica nanoparticles mediated co-delivery of paclitaxel and tetrandrine for overcoming multidrug resistance.

    PubMed

    Jia, Lejiao; Li, Zhenyu; Shen, Jingyi; Zheng, Dandan; Tian, Xiaona; Guo, Hejian; Chang, Ping

    2015-07-15

    The objective of the study is to fabricate multifunctional mesoporous silica nanoparticles for achieving co-delivery of conventional antitumor drug paclitaxel (PTX) and the multidrug resistance reversal agent tetrandrine (TET) expecting to overcome multidrug resistance of MCF-7/ADR cells. The nanoparticles were facile to prepare by self-assemble in situ drug loading approach. Namely, PTX and TET were solubilized in the cetyltrimethylammonium bromide (CTAB) micelles and simultaneously silica resources hydrolyze and condense to form nanoparticles. The obtained nanoparticles, denoted as PTX/TET-CTAB@MSN, exhibited pH-responsive release property with more easily released in the weak acidic environment. Studies on cellular uptake of nanoparticles demonstrated TET could markedly increase intracellular accumulation of nanoparticles. Furthermore, the PTX/TET-CTAB@MSN suppressed tumor cells growth more efficiently than only delivery of PTX (PTX-CTAB@MSN) or the free PTX. Moreover, the nanoparticle loading drugs with a PTX/TET molar ratio of 4.4:1 completely reversed the resistance of MCF-7/ADR cells to PTX and the resistance reversion index was 72.3. Mechanism research showed that both TET and CTAB could arrest MCF-7/ADR cells at G1 phase; and besides PTX arrested cells at G2 phase. This nanocarrier might have important potential in clinical implications for co-delivery of multiple drugs to overcome MDR. PMID:25956050

  15. Ultrasonication assisted Layer-by-Layer technology for the preparation of multi-functional anticancer drugs paclitaxel and lapatinib

    NASA Astrophysics Data System (ADS)

    Zhang, Xingcai

    In this dissertation, ultrasonication assisted Layer-by-Layer (LbL) technology for the preparation of multifunctional poorly water-soluble anticancer drug nanoparticles, paclitaxel and lapatinib, has been developed. Many FDA approved drugs are very low soluble in water; therefore, it is very difficult to load and control their release and targeting efficiently, which greatly confines their application. The development of this method will pave the way for the development and application of those low soluble anticancer drugs. In the first part of this dissertation, the first approach for powerful ultrasonication, the top-down approach (sonicating bulk drug crystals in polyelectrolyte solution), was successfully applied for the preparation of the nanoparticles of paclitaxel. For this approach, a 200 nm diameter was a kind of "magic" barrier for colloidal particles prepared. This diameter barrier may be related to the nucleation size of the solvent vapor microbubbles. Consequently, agents enhancing bubbling formation (such as NH4HCO3) were applied to decrease paclitaxel colloid particles to 100-120 nm. Those paclitaxel nanoparticles were Layer-by-Layer coated with a 10-20 nm polycation/polyanion shell to provide aqueous colloidal stability and slower particle dissolution. However, a large obstacle of these powerful ultrasonication methods was a necessity of long ca 45 minutes high power ultrasonication which resulted in TiO2 contamination from titanium electrode. The small amount of TiO2 contamination from ultrasonication did negatively affect the in vivo testing of this system in mice, and had to be removed before low toxicity of the Layer-by-Layer coated paclitaxel nanoparticles were observed. In the second part of the dissertation, the second approach for sonication, the bottom-up approach (sonicating drug in a water-miscible organic solvent followed by slow water add-in) was successfully applied for the preparation of the nanoparticles of lapatinib and paclitaxel with less powerful sonication. By using polymeric excipients combined with non-ionic and anionic surfactants along with regular sonication, the prepared particle sizes was uniform at around 140-150 nm. Less sonication time (ca 15 minutes) and lower sonication power avoided TiO2 contamination. The amphiphiles attached to the hydrophobic nanoparticles and served as anchors for LbL shell. The inner LbL layers and surfactants minimized the surface free energy, thereby preventing crystal form changes and nanoparticles coalescence, while the outermost layers enhanced colloidal stability. In the third part of the dissertation, LbL shells with PEGylation (using a block copolymer of poly-L-lysine (PLL) and PEG) for lapatinib were developed for enhanced colloidal stability in high molarity PBS buffer. In the above proposed paclitaxel and lapatinib formulation, we obtained 150-200 nm with high drug content of 80-90% due to very thin capsule walls (ca 10 nm). The drug release time from the LbL capsules was found to be between 10 and 20 hours depending on the shell thickness. Washless Layer-by-Layer assembly was used: 1) addition of polycation in the amount that is enough to reverse surface charge of the dispersion to a high positive (+30 mV) value; 2) addition of polyanion in the amount that is enough to reverse surface charge of the dispersion to a high negative (-30 mV) value. No intermediate washing of nanoparticles was done until the shell was complete. The washless method had the advantage of time and energy saving, preservation of the sample structure and no losses of sample. In the last part of the dissertation, we elaborated nanoformulation of two drugs in one nanocapsule locating paclitaxel in the core and lapatinib on the shell periphery. With this formulation, combining in one nanoparticle dual drugs, we reached the drugs' efficiency synergy. In a multidrug-resistant (MDR) ovarian cancer cell line, OVCAR-3, LbL lapatinib/paclitaxel nanocolloids mediated an enhanced cell growth inhibition in comparison with the LbL paclitaxel-only and LbL lapatinib-only

  16. Polyethylene Glycol–Phosphatidylethanolamine (PEG–PE)/Vitamin E Micelles for Co-Delivery of Paclitaxel and Curcumin to Overcome Multi-Drug Resistance in Ovarian Cancer

    PubMed Central

    Abouzeid, Abraham H.; Patel, Niravkumar R.

    2014-01-01

    The therapeutic potential of mixed micelles, made of PEG-PE and vitamin E co-loaded with curcumin and paclitaxel, was investigated against SK-OV-3 human ovarian adenocarcinoma along with its multi-drug resistant version SK-OV-3-paclitaxel-resistant (TR) cells in vitro and in vivo. The addition of curcumin at various concentrations did not significantly enhance the cytotoxicity of paclitaxel against SK-OV-3 in vitro. However, a clear synergistic effect was observed with the combination treatment against SK-OV-3TR in vitro. In vivo, this combination treatment produced a three-fold tumor inhibition with each of these cell lines. Our results indicate that such co-loaded mixed micelles could have significant clinical advantages for the treatment of resistant ovarian cancer. PMID:24440402

  17. The Effect of Short-term Intra-arterial Delivery of Paclitaxel on Neointimal Hyperplasia and the Local Thrombotic Environment after Angioplasty

    SciTech Connect

    Yajun, E; He Nengshu Fan Hailun

    2013-08-01

    PurposeTo evaluate the effects of short-term intra-arterial delivery of paclitaxel on neointimal hyperplasia and the local thrombotic environment after angioplasty.MethodsAn experimental common carotid artery injury model was established in 60 rats, which were divided into experimental groups (40 rats) and controls (20 rats). Local intra-arterial administration of paclitaxel was applied at 2 doses (90 and 180 {mu}g/30 {mu}l), and the effects of short-term delivery of paclitaxel on neointimal hyperplasia and the expression of tissue factor (TF), plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (t-PA) were evaluated at days 15 and 30 by hematoxylin and eosin staining and immunohistochemistry.ResultsAt 15 and 30 days after injury, neointimal thickness and area, the ratio of intimal area to medial area and the stenotic rate were all significantly decreased in the group provided the high concentrations (180 {mu}g/30 {mu}l) of paclitaxel for 2 min or 10 min and in the group provided the low concentration (90 {mu}g/30 {mu}l) of paclitaxel for 10 min (p < 0.05). At 30 days after injury, there were no significant changes in TF expression among all experimental groups. PAI-1 expression increased in the neointima of the high concentration 10 min group (p < 0.05), while t-PA expression decreased in the neointima of the high concentration 2 min group (p < 0.05).ConclusionIn the rat common carotid artery injury model, the short-term delivery of paclitaxel could effectively inhibit neointimal hyperplasia in the long term, with very little influence on the local expression of TF and PAI-1.

  18. Durable complete response induced by paclitaxel-nimotuzumab-methotrexate chemotherapy in a patient with metastatic head and neck squamous cell carcinoma.

    PubMed

    Verduzco-Rodríguez, L; Aguirre-González, E H; Verduzco-Aguirre, H C

    2011-01-01

    A 61-year-old male patient with metastatic poorly differentiated squamous cell carcinoma of the larynx to lymph nodes and lung was treated with a third-line chemotherapy regimen of paclitaxel, nimotuzumab and low-dose methotrexate, receiving a total of 30 cycles. The response was complete and maintained at 16 months. Nimotuzumab is a humanized monoclonal antibody used to treat squamous cell carcinomas of the head and neck. This third-line chemotherapy combination with paclitaxel-nimotuzumab-methotrexate seems to be an active combination and needs further evaluation in clinical trials to validate its use in heavily treated patients. PMID:22198189

  19. Preoperative concurrent paclitaxel-radiation in locally advanced breast cancer: pathologic response correlates with five-year overall survival

    PubMed Central

    Adams, Sylvia; Chakravarthy, A. Bapsi; Donach, Martin; Spicer, Darcy; Lymberis, Stella; Singh, Baljit; Bauer, Joshua A.; Hochman, Tsivia; Goldberg, Judith D.; Muggia, Franco; Schneider, Robert J.; Pietenpol, Jennifer A.

    2013-01-01

    We have previously demonstrated high pathologic response rates after neoadjuvant concurrent chemoradiation in patients with locally advanced breast cancer (LABC). We now report disease-free survival (DFS) and overall survival (OS) in the context of pathologic response. 105 LABC patients (White 46%, Non-White 54%) were treated with paclitaxel (30 mg/m2 intravenously twice a week) for 10–12 weeks. Daily radiotherapy was delivered to breast, axillary, and supraclavicular lymph nodes during weeks 2–7 of paclitaxel treatment, at 1.8 Gy per fraction to a total dose of 45 Gy with a tumor boost of 14 Gy at 2 Gy/fraction. Pathological complete response (pCR) was defined as the absence of invasive cancer in breast and lymph nodes and pathological partial response (pPR) as the persistence of <10 microscopic foci of invasive carcinoma in breast or lymph nodes. Pathologic response (pCR and pPR) after neoadjuvant chemoradiation was achieved in 36/105 patients (34%) and was associated with significantly better DFS and OS. Pathological responders had a lower risk of recurrence or death (HR = 0.35, P = 0.01) and a longer OS (HR = 4.27, P = 0.01) compared with non-responders. Median DFS and OS were 57 and 84 months for non-responders, respectively, and have not yet been reached for responders. Importantly, pathologic response was achieved in 54% of patients with HR negative tumors (26/48). In conclusion, pathologic response to concurrent paclitaxel-radiation translated into superior DFS and OS. Half of the patients with HR negative tumors achieved a pathologic response. PMID:20878462

  20. Phase 1b dose-finding study of motesanib with docetaxel or paclitaxel in patients with metastatic breast cancer.

    PubMed

    De Boer, Richard H; Kotasek, Dusan; White, Shane; Koczwara, Bogda; Mainwaring, Paul; Chan, Arlene; Melara, Rebeca; Ye, Yining; Adewoye, Adeboye H; Sikorski, Robert; Kaufman, Peter A

    2012-08-01

    The purpose of this study was to investigate the safety, tolerability, and pharmacokinetics of motesanib when combined with docetaxel or paclitaxel in patients with metastatic breast cancer. In this open-label, dose-finding, phase 1b study, patients received motesanib 50 or 125-mg orally once daily (QD), beginning day 3 of cycle 1 of chemotherapy, continuously in combination with either paclitaxel 90 mg/m(2) on days 1, 8, and 15 every 28-day cycle (Arm A) or docetaxel 100 mg/m(2) on day 1 every 21-day cycle (Arm B). Dose escalation to motesanib 125 mg QD occurred if the incidence of dose-limiting toxicities (DLTs, primary endpoint) was ? 33 %. If the maximum tolerated dose (MTD) of motesanib was established in Arm B, additional patients could receive motesanib at the MTD plus docetaxel 75 mg/m(2). Forty-six patients were enrolled and 45 received ? 1 dose of motesanib. The incidence of DLTs was <33 % in all cohorts; thus, motesanib 125 mg QD was established as the MTD. Seven patients (16 %) had grade 3 motesanib-related adverse events including cholecystitis (2 patients) and hypertension (2 patients). Pharmacokinetic parameters of motesanib were similar to those reported in previous studies. The objective response rate was 56 % among patients with measurable disease at baseline who received motesanib in combination with taxane-based chemotherapy. The addition of motesanib to either paclitaxel or docetaxel was generally tolerable up to the 125-mg QD dose of motesanib. The objective response rate of 56 % suggests a potential benefit of motesanib in combination with taxane-based chemotherapy. PMID:22872523

  1. Long-Term Outcomes and Toxicity of Concurrent Paclitaxel and Radiotherapy for Locally Advanced Head-and-Neck Cancer

    SciTech Connect

    Citrin, Deborah Mansueti, John; Likhacheva, Anna; Sciuto, Linda; Albert, Paul S.; Rudy, Susan F.; Cooley-Zgela, Theresa; Cotrim, Ana; Solomon, Beth; Colevas, A. Dimitrios; Russo, Angelo; Morris, John C.; Herscher, Laurie; Smith, Sharon

    2009-07-15

    Purpose: To report the long-term outcomes and toxicity of a regimen of infusion paclitaxel delivered concurrently with radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck. Patients and Methods: Between 1995 and 1999, 35 patients with nonmetastatic, Stage III or IV squamous cell carcinoma of the head and neck were treated with three cycles of paclitaxel as a 120-h continuous infusion beginning on Days 1, 21, and 42, concurrent with radiotherapy. The initial 16 patients received 105 mg/m{sup 2}/cycle, and the subsequent 19 patients received 120 mg/m{sup 2}/cycle. External beam radiotherapy was delivered to a dose of 70.2-72 Gy at five fractions weekly. Patients were followed to evaluate the disease outcomes and late toxicity of this regimen. Results: The median follow-up for all patients was 56.5 months. The median survival was 56.5 months, and the median time to local recurrence was not reached. Of the 35 patients, 15 (43%) developed hypothyroidism. Of the 33 patients who underwent percutaneous endoscopic gastrostomy tube placement, 11 were percutaneous endoscopic gastrostomy tube dependent until death or their last follow-up visit. Also, 5 patients (14%) required a tracheostomy until death, and 3 (9%) developed a severe esophageal stricture. All evaluated long-term survivors exhibited salivary hypofunction. Fibrosis in the radiation field occurred in 24 patients (69%). Conclusion: The results of our study have shown that concurrent chemoradiotherapy with a 120-h infusion of paclitaxel provides long-term local control and survival in patients with squamous cell carcinoma of the head and neck. Xerostomia, hypothyroidism, esophageal and pharyngeal complications, and subcutaneous fibrosis were common long-term toxicities; however, the vast majority of toxicities were grade 1 or 2.

  2. Clinical and cost effectiveness of paclitaxel, docetaxel, gemcitabine, and vinorelbine in non-small cell lung cancer: a systematic review

    PubMed Central

    Clegg, A; Scott, D; Hewitson, P; Sidhu, M; Waugh, N

    2002-01-01

    Background: Lung cancer remains a devastating disease with few effective treatment options. Recent developments in chemotherapy have led to cautious optimism. This paper reviews the evidence on the clinical and cost effectiveness of four of the new generation drugs for patients with lung cancer. Methods: A systematic review of randomised controlled trials (RCTs) identified from 11 electronic databases (including Medline, Cochrane library and Embase), reference lists and contact with experts and industry was performed to assess clinical effectiveness of paclitaxel, docetaxel, gemcitabine and vinorelbine. Clinical effectiveness was assessed using the outcomes of patient survival, quality of life, and adverse effects. Cost effectiveness was assessed by development of a costing model and presented as incremental cost per life year saved (LYS) compared with best supportive care (BSC). Results: Of the 33 RCTs included, five were judged to be of good quality, 10 of adequate quality, and 18 of poor quality. Gemcitabine, paclitaxel, and vinorelbine as first line treatment and docetaxel as second line treatment appear to be more beneficial for non-small cell lung cancer than BSC and older chemotherapy agents, increasing patient survival by 2–4 months against BSC and some comparator regimes. These gains in survival do not appear to be at the expense of quality of life. Survival gains were delivered at reasonable levels of incremental cost effectiveness for vinorelbine, vinorelbine with cisplatin, gemcitabine, gemcitabine with cisplatin, and paclitaxel with cisplatin regimens compared with BSC. Conclusion: Although the clinical benefits of the new drugs appear relatively small, their benefit to patients with lung cancer appears to be worthwhile and cost effective. PMID:11809985

  3. Phase II study of bi-weekly administration of paclitaxel and cisplatin in patients with advanced oesophageal cancer

    PubMed Central

    Polee, M B; Eskens, F A L M; van der Burg, M E L; Splinter, T A W; Siersema, P D; Tilanus, H W; Verweij, J; Stoter, G; van der Gaast, A

    2002-01-01

    In a phase I study we demonstrated the feasibility of a bi-weekly combination of paclitaxel 180?mg?m?2 with cisplatin 60?mg?m?2. In this study we further assessed toxicity and efficacy of this schedule in the treatment of advanced cancer of the oesophagus or the gastro-oesophageal junction. Patients received paclitaxel 180?mg?m?2 administered over 3?h followed by a 3-h infusion of cisplatin 60?mg?m?2. Patients were retreated every 2 weeks unless granulocytes were <0.75×109 or platelets <75×109. Patients were evaluated after three and six cycles and responding patients received a maximum of eight cycles. Fifty-one patients were enrolled into the study. The median age was 56 years (range 32–78). WHO performance status were: 0 (19 patients); 1 (29 patients); 2 (three patients). All patients received at least three cycles of chemotherapy and all were evaluable for toxicity and response. Haematological toxicity consisted of uncomplicated neutropenia grade 3 in 39% and grade 4 in 31% of patients. Five patients (10%) were hospitalised, three patients because of treatment related complications and two patients because of infections without neutropenia. Sensory neurotoxicity was the predominant non-haematological toxicity; grade 1 and 2 neurotoxicity was observed in 43 and 20% of patients, respectively. Response evaluation in 51 patients with measurable disease: complete response 4%, partial response 39%, stable disease 43% and progressive disease in 14% of the patients. The median duration of response was 8 months. The median survival for all patients was 9 (range 2–29+) months and the one-year survival rate was 43%. Four patients who received additional local treatment (two patients surgery and two patients radiotherapy) are still disease free after a follow-up of 20–29 months. This bi-weekly treatment of paclitaxel and cisplatin is well tolerated by patients with advanced oesophageal cancer. The toxicity profile of this regimen compares favourable to that of previously used cisplatin- and paclitaxel-based regimens. Trials are underway evaluating this bi-weekly regimen in a neo-adjuvant setting. British Journal of Cancer (2002) 86, 669–673. DOI: 10.1038/sj/bjc/6600166 www.bjcancer.com © 2002 Cancer Research UK PMID:11875723

  4. Jasmonate-responsive expression of paclitaxel biosynthesis genes in Taxus cuspidata cultured cells is negatively regulated by the bHLH transcription factors TcJAMYC1, TcJAMYC2, and TcJAMYC4

    PubMed Central

    Lenka, Sangram K.; Nims, N. Ezekiel; Vongpaseuth, Kham; Boshar, Rosemary A.; Roberts, Susan C.; Walker, Elsbeth L.

    2015-01-01

    Taxus cell suspension culture is a sustainable technology for the industrial production of paclitaxel (Taxol®), a highly modified diterpene anti-cancer agent. The methyl jasmonate (MJ)-mediated paclitaxel biosynthetic pathway is not fully characterized, making metabolic engineering efforts difficult. Here, promoters of seven genes (TASY, T5?H, DBAT, DBBT, PAM, BAPT, and DBTNBT), encoding enzymes of the paclitaxel biosynthetic pathway were isolated and used to drive MJ-inducible expression of a GUS reporter construct in transiently transformed Taxus cells, showing that elicitation of paclitaxel production by MJ is regulated at least in part at the level of transcription. The paclitaxel biosynthetic pathway promoters contained a large number of E-box sites (CANNTG), similar to the binding sites for the key MJ-inducible transcription factor AtMYC2 from Arabidopsis thaliana. Three MJ-inducible MYC transcription factors similar to AtMYC2 (TcJAMYC1, TcJAMYC2, and TcJAMYC4) were identified in Taxus. Transcriptional regulation of paclitaxel biosynthetic pathway promoters by transient over expression of TcJAMYC transcription factors indicated a negative rather than positive regulatory role of TcJAMYCs on paclitaxel biosynthetic gene expression. PMID:25767476

  5. Transient stimulation of the c-Jun-NH2-terminal kinase/activator protein 1 pathway and inhibition of extracellular signal-regulated kinase are early effects in paclitaxel-mediated apoptosis in human B lymphoblasts.

    PubMed

    Amato, S F; Swart, J M; Berg, M; Wanebo, H J; Mehta, S R; Chiles, T C

    1998-01-15

    We demonstrate here that paclitaxel exposure to RPMI-1788 B lymphoblasts caused a dose- and time-dependent increase in nuclear factor activator protein 1 (AP-1) DNA binding activity. The basal DNA binding activities of nuclear factors NF-kappaB and Ets were not affected by paclitaxel. Consistent with these biochemical events, paclitaxel stimulated AP-1-dependent chloramphenicol acetyltransferase (CAT) reporter gene transcription in vivo, as directed from a tetradecanoyl phorbol acetate-inducible promoter. AP-1 binding activity of nuclear extracts isolated from paclitaxel treated cells was reduced following immunodepletion with antibodies directed against individual Jun family proteins, whereas anti-cFos, anti-Fra1, and anti-FosB antibodies were not inhibitory. Paclitaxel caused a rapid and transient increase in c-Jun NH2-terminal kinase (JNK) activity, a proposed mediator of stress activation pathways. By contrast, exposure to paclitaxel produced a transient reduction in the extracellular signal-regulated mitogen-activated protein kinase 2 (ERK2) activity, a proposed mediator of growth factor-stimulated proliferation pathways. Transient activation of the c-Jun-NH2-terminal kinase/AP-1 pathway, together with down-regulation of ERK2 activity, may be a key event in the early response of RPMI-1788 B lymphoblasts to paclitaxel exposure. PMID:9443400

  6. Lactoferrin-appended solid lipid nanoparticles of paclitaxel for effective management of bronchogenic carcinoma.

    PubMed

    Pandey, Vikas; Gajbhiye, Kavita Rai; Soni, Vandana

    2015-02-01

    Lung cancer is a dreadful disease which claims to be more life threatening as compared to total sum up of colon, prostate and breast cancers. Thus, there is an urgent need to develop an effective delivery approach for its management. Paclitaxel (PTX) is one of the well-known choice as antineoplasitic agent used for the treatment of different types of human cancers such as non-small-cell lung, head and neck cancers, leukemia, breast, ovarian and melanoma. Lactoferrin (Lf), a "multifunctional protein" is crucial for natural immunity which is secreted by exocrine glands. Lf receptors are expressed on the apical surface on bronchial epithelial cells. These over-expressed LF receptors can be utilized for the transportation of Lf-conjugated drug or nanocarrier devices. The present study was aimed to develop PTX-loaded Lf-coupled solid lipid nanoparticles (SLNs) for the treatment of lung cancer. PTX-loaded SLNs were prepared, characterized and then coupled with Lf using carbodiimide chemistry. The formulations were characterized by transmission electron microscopy, particle size, polydispersity index and zeta potential, whereas Lf conjugation was confirmed by FT-IR and ¹H NMR and efficiency of prepared system was evaluated by in vitro, ex vivo and in vivo evaluations. The ex vivo cytotoxicity studies on human bronchial epithelial cell lines, BEAS-2B, revealed superior anticancer activity of Lf-coupled SLNs than plain SLNs and free PTX. In vivo biodistribution studies showed higher concentrations of PTX accumulated in lungs via Lf-coupled SLNs than plain SLNs and free PTX. These studies suggested that Lf-coupled PTX-loaded SLNs could be used as potential targeting carrier for delivering anticancer drug to the lungs with the minimal side effects. PMID:24467582

  7. Integrin-assisted drug delivery of nano-scaled polymer therapeutics bearing paclitaxel

    PubMed Central

    Eldar-Boock, Anat; Miller, Keren; Sanchis, Joaquin; Lupu, Ruth; Vicent, María J.; Satchi-Fainaro, Ronit

    2011-01-01

    Angiogenesis plays a prominent role in cancer progression. Anti-angiogenic therapy therefore, either alone or in combination with conventional cytotoxic therapy, offers a promising therapeutic approach. Paclitaxel (PTX) is a widely-used potent cytotoxic drug that also exhibits anti-angiogenic effects at low doses. However, its use, at its full potential, is limited by severe side effects. Here we designed and synthesized a targeted conjugate of PTX, a polymer and an integrin-targeted moiety resulting in a polyglutamic acid (PGA)-PTX-E-[c(RGDfK)2] nano-scaled conjugate. Polymer conjugation converted PTX to a macromolecule, which passively targets the tumor tissue exploiting the enhanced permeability and retention effect, while extravasating via the leaky tumor neovasculature. The cyclic RGD peptidomimetic enhanced the effects previously seen for PGA-PTX alone, utilizing the additional active targeting to the ?v?3 integrin overexpressed on tumor endothelial and epithelial cells. This strategy is particularly valuable when tumors are well-vascularized, but they present poor vascular permeability. We show that PGA is enzymatically-degradable leading to PTX release under lysosomal acidic pH. PGA-PTX-E-[c(RGDfK)2] inhibited the growth of proliferating ?v?3-expressing endothelial cells and several cancer cells. We also showed that PGA-PTX-E-[c(RGDfK)2] blocked endothelial cells migration towards vascular endothelial growth factor; blocked capillary-like tube formation; and inhibited endothelial cells attachment to fibrinogen. Orthotopic studies in mice demonstrated preferential tumor accumulation of the RGD-bearing conjugate, leading to enhanced antitumor efficacy and a marked decrease in toxicity as compared with free PTX-treated mice. PMID:21376390

  8. Improved anti-glioblastoma efficacy by IL-13R?2 mediated copolymer nanoparticles loaded with paclitaxel

    PubMed Central

    Wang, Baoyan; Lv, Lingyan; Wang, Zhi; Jiang, Yan; Lv, Wei; Liu, Xin; Wang, Zhongyuan; Zhao, Yue; Xin, Hongliang; Xu, Qunwei

    2015-01-01

    Glioma presents one of the most malignant brain tumors, and the therapeutic effect is often limited due to the existence of brain tumor barrier. Based on interleukin-13 receptor ?2 (IL-13R?2) over-expression on glioma cell, it was demonstrated to be a potential receptor for glioma targeting. In this study, Pep-1-conjugated PEGylated nanoparticles loaded with paclitaxel (Pep-NP-PTX) were developed as a targeting drug delivery system for glioma treatment. The Pep-NP-PTX presented satisfactory size of 95.78?nm with narrow size distribution. Compared with NP-PTX, Pep-NP-PTX exhibited significantly enhanced cellular uptake in C6 cells (p?

  9. Targeting mitotic exit with hyperthermia or APC/C inhibition to increase paclitaxel efficacy

    PubMed Central

    Giovinazzi, Serena; Bellapu, Dhruv; Morozov, Viacheslav M; Ishov, Alexander M

    2013-01-01

    Microtubule-poisoning drugs, such as Paclitaxel (or Taxol, PTX), are powerful and commonly used anti-neoplastic agents for the treatment of several malignancies. PTX triggers cell death, mainly through a mitotic arrest following the activation of the spindle assembly checkpoint (SAC). Cells treated with PTX slowly slip from this mitotic block and die by mitotic catastrophe. However, cancer cells can acquire or are intrinsically resistant to this drug, posing one of the main obstacles for PTX clinical effectiveness. In order to override PTX resistance and increase its efficacy, we investigated both the enhancement of mitotic slippage and the block of mitotic exit. To test these opposing strategies, we used physiological hyperthermia (HT) to force exit from PTX-induced mitotic block and the anaphase-promoting complex/cyclosome (APC/C) inhibitor, proTAME, to block mitotic exit. We observed that application of HT on PTX-treated cells forced mitotic slippage, as shown by the rapid decline of cyclin B levels and by microscopy analysis. Similarly, HT induced mitotic exit in cells blocked in mitosis by other antimitotic drugs, such as Nocodazole and the Aurora A inhibitor MLN8054, indicating a common effect of HT on mitotic cells. On the other hand, proTAME prevented mitotic exit of PTX and MLN8054 arrested cells, prolonged mitosis, and induced apoptosis. In addition, we showed that proTAME prevented HT-mediated mitotic exit, indicating that stress-induced APC/C activation is necessary for HT-induced mitotic slippage. Finally, HT significantly increased PTX cytotoxicity, regardless of cancer cells’ sensitivity to PTX, and this activity was superior to the combination of PTX with pro-TAME. Our data suggested that forced mitotic exit of cells arrested in mitosis by anti-mitotic drugs, such as PTX, can be a more successful anticancer strategy than blocking mitotic exit by inactivation of the APC/C. PMID:23907120

  10. Paclitaxel therapy promotes breast cancer metastasis in a TLR4-dependent manner

    PubMed Central

    Volk-Draper, Lisa; Hall, Kelly; Griggs, Caitlin; Rajput, Sandeep; Kohio, Pascaline; DeNardo, David; Ran, Sophia

    2014-01-01

    Emerging evidence suggests that cytotoxic therapy may actually promote drug resistance and metastasis while inhibiting the growth of primary tumors. Work in preclinical models of breast cancer have shown that acquired chemoresistance to the widely used drug paclitaxel (PXL) can be mediated by activation of the Toll-like receptor TLR4 in cancer cells. In this study, we determined the pro-metastatic effects of tumor-expressed TLR4 and PXL therapy and we investigated the mechanisms mediating these effects. While PXL treatment was largely efficacious in inhibiting TLR4-negative tumors, it significantly increased the incidence and burden of pulmonary and lymphatic metastasis by TLR4-positive tumors. TLR4 activation by PXL strongly increased the expression of inflammatory mediators, not only locally in the primary tumor microenvironment but also systemically in the blood, lymph nodes, spleen, bone marrow and lungs. These pro-inflammatory changes promoted the outgrowth of Ly6C+ and Ly6G+ myeloid progenitor cells and their mobilization to tumors, where they increased blood vessel formation but not invasion of these vessels. In contrast, PXL-mediated activation of TLR4-positive tumors induced de novo generation of deep intratumoral lymphatic vessels that were highly permissive to invasion by malignant cells. These results suggest that PXL therapy of patients with TLR4-expressing tumors may activate systemic inflammatory circuits that promote angiogenesis, lymphangiogenesis and metastasis, both at local sites and premetastatic niches where invasion occurs in distal organs. Taken together, our findings suggest that efforts to target TLR4 on tumor cells may simultaneously quell local and systemic inflammatory pathways that promote malignant progression, with implications for how to prevent tumor recurrence and the establishment of metastatic lesions, either during chemotherapy or after it is completed. PMID:25274031

  11. Improved anti-glioblastoma efficacy by IL-13R?2 mediated copolymer nanoparticles loaded with paclitaxel.

    PubMed

    Wang, Baoyan; Lv, Lingyan; Wang, Zhi; Jiang, Yan; Lv, Wei; Liu, Xin; Wang, Zhongyuan; Zhao, Yue; Xin, Hongliang; Xu, Qunwei

    2015-01-01

    Glioma presents one of the most malignant brain tumors, and the therapeutic effect is often limited due to the existence of brain tumor barrier. Based on interleukin-13 receptor ?2 (IL-13R?2) over-expression on glioma cell, it was demonstrated to be a potential receptor for glioma targeting. In this study, Pep-1-conjugated PEGylated nanoparticles loaded with paclitaxel (Pep-NP-PTX) were developed as a targeting drug delivery system for glioma treatment. The Pep-NP-PTX presented satisfactory size of 95.78?nm with narrow size distribution. Compared with NP-PTX, Pep-NP-PTX exhibited significantly enhanced cellular uptake in C6 cells (p?

  12. Paclitaxel-Releasing Thin Biodegradable Film for Prevention of Bleb Avascularity Without Compromising Filtration in Rabbits

    PubMed Central

    Okuda, Tetsuhiko; Higashide, Tomomi; Sakurai, Mayumi; Fukuhira, Yukako; Kaneko, Hiroaki; Shimomura, Masatsugu; Sugiyama, Kazuhisa

    2015-01-01

    Purpose: A honeycomb-patterned film (HPF) prevents bleb scarring and mitomycin C (MMC)-related bleb avascularity in a rabbit model of filtration surgery. In this study, we examined whether a HPF-releasing paclitaxel (PTX) can prevent bleb avascularity without compromising filtration. Methods: Filtration surgery was performed in one eye of rabbits. A 14-?m thick HPF made from poly(L-lactide-co-?-caprolactone) was placed subconjunctivally over the filtration site with the honeycomb surface turned toward the subconjunctival Tenon tissue. The rabbits were divided into four groups (n = 5 each): 1, HPF with no drug; 2, HPF + PTX 50 ?g; 3, HPF + 5 ?g; 4, HPF + 0.5 ?g. Intraocular pressure (IOP) measurements and bleb evaluations using ultrasound biomicroscopy were performed periodically for 4 weeks followed by histological examination. A longer follow-up study (12 weeks) was performed for group 4 (experiment 2; n = 8). Results: Among all groups at the 4-week follow up, two blebs failed in group 1. The postoperative IOP decrease was significantly greater in PTX-treated eyes than in group 1. The bleb avascular area persisted for 4 weeks in groups 2 and 3. However, no avascular area was observed in groups 1 and 4 at 4 weeks postoperatively. Histology showed minimal fibrosis at the filtration site in all the PTX groups. In experiment 2, some blebs became flatter starting at 10 weeks after surgery. Conclusions: PTX released from HPF promoted bleb survival and IOP decrease. The lowest dose of PTX (0.5 ?g) was effective at preventing bleb avascularity without compromising filtration. PMID:26101723

  13. Folate-modified lipid–polymer hybrid nanoparticles for targeted paclitaxel delivery

    PubMed Central

    Zhang, Linhua; Zhu, Dunwan; Dong, Xia; Sun, Hongfan; Song, Cunxian; Wang, Chun; Kong, Deling

    2015-01-01

    The purpose of this study was to develop a novel lipid–polymer hybrid drug carrier comprised of folate (FA) modified lipid-shell and polymer-core nanoparticles (FLPNPs) for sustained, controlled, and targeted delivery of paclitaxel (PTX). The core-shell NPs consist of 1) a poly(?-caprolactone) hydrophobic core based on self-assembly of poly(?-caprolactone)–poly(ethylene glycol)–poly(?-caprolactone) (PCL-PEG-PCL) amphiphilic copolymers, 2) a lipid monolayer formed with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)-2000] (DSPE-PEG2000), 3) a targeting ligand (FA) on the surface, and were prepared using a thin-film hydration and ultrasonic dispersion method. Transmission electron microscopy and dynamic light scattering analysis confirmed the coating of the lipid monolayer on the hydrophobic polymer core. Physicochemical characterizations of PTX-loaded FLPNPs, such as particle size and size distribution, zeta potential, morphology, drug loading content, encapsulation efficiency, and in vitro drug release, were also evaluated. Fluorescent microscopy proved the internalization efficiency and targeting ability of the folate conjugated on the lipid monolayer for the EMT6 cancer cells which overexpress folate receptor. In vitro cytotoxicity assay demonstrated that the cytotoxic effect of PTX-loaded FLPNPs was lower than that of Taxol®, but higher than that of PTX-loaded LPNPs (without folate conjugation). In EMT6 breast tumor model, intratumoral administration of PTX-loaded FLPNPs showed similar antitumor efficacy but low toxicity compared to Taxol®. More importantly, PTX-loaded FLPNPs showed greater tumor growth inhibition (65.78%) than the nontargeted PTX-loaded LPNPs (48.38%) (P<0.05). These findings indicated that the PTX loaded-FLPNPs with mixed lipid monolayer shell and biodegradable polymer core would be a promising nanosized drug formulation for tumor-targeted therapy. PMID:25844039

  14. MicroRNA-7 sensitizes non-small cell lung cancer cells to paclitaxel

    PubMed Central

    LIU, RONGHUA; LIU, XIAOMING; ZHENG, YIJIE; GU, JIE; XIONG, SHUDAO; JIANG, PEI; JIANG, XUECHAO; HUANG, ENYU; YANG, YIXIAN; GE, DI; CHU, YIWEI

    2014-01-01

    Paclitaxel (PTX) is the front-line chemotherapeutic agent against human non-small cell lung cancer (NSCLC). However, its therapeutic efficacy is restricted by the increasing frequency of chemotherapeutic resistance in NSCLC. Accumulating evidence has shown the potential role of microRNAs (miRNAs) in the chemotherapeutic sensitivity of cancer cells. Previously it was reported that microRNA-7 (miR-7) acts as an important tumor suppressor in NSCLC. Therefore, the present study was conducted to determine the regulatory role of miR-7 in PTX chemotherapy for NSCLC. Four NSCLC cell lines were used to analyze the correlation of the PTX-sensitivity and endogenoaus miR-7 expression. miR-7 expression was up- and downregulated using miR-7 mimics and inhibitors respectively, and the role of miR-7 in sensitizing NSCLC cells to PTX was assessed by cell viability and apoptosis assays. The molecular mechanism of PTX sensitivity was determined by quantitative polymerase chain reaction and western blotting. It was found that the sensitivity of NSCLC cells to PTX was dependent on endogenous miR-7. Upregulation of miR-7 enhanced the PTX-sensitivity of NSCLC cells by suppressing cell proliferation and promoting cell apoptosis, while the inhibition of miR-7 abrogated the antiproliferative proapoptotic effects of PTX. Pretreatment of miR-7 mimics enhanced the PTX-mediated downregulation of epidermal growth factor receptor (EGFR) in NSCLC cells. These results have identified miR-7 as a potential EGFR-targeting sensitizer in PTX therapy. These data may facilitate the development of novel chemotherapeutic approaches for NSCLC. PMID:25289099

  15. Concurrent chemoradiotherapy using paclitaxel plus cisplatin in the treatment of elderly patients with esophageal cancer

    PubMed Central

    Song, Tao; Zhang, Xuebang; Fang, Min; Wu, Shixiu

    2015-01-01

    Objective This study aimed at assessing the efficiency and safety of concurrent chemoradiotherapy (CCRT) using paclitaxel (PTX) plus cisplatin (CDDP) in elderly (age ?70 years) esophageal cancer patients. Patients and methods Between July 2008 and June 2011, 82 esophageal cancer patients aged ?70 years were retrospectively analyzed. Chemotherapy consisted of CDDP for 3 days plus PTX given for 3 hours. The preplanned total dose of concurrent irradiation with 60 Gy/30 Fx was given at the 1st day of chemotherapy. Results The average age for the enrolled patients was 76.41 years (range: 70–87 years), and the clinical stages were stage I (two patients), stage II (23 patients), stage III (49 patients), and stage IV (eight patients). A total of 66 patients finished CCRT on schedule, including 55 (67.1%) patients in whom treatment regimen was not changed, and the clinical complete response was achieved in 29 patients. With a median follow-up time of 20.4 months, the median overall survival (OS) time and progression-free survival (PFS) time were 26.9 months and 18.2 months, respectively. The 2-year OS and PFS rates for stage I–II and III–IV were 76.0%, 64.0% and 38.6%, 21.2%, respectively. Grade ?3 leukopenia was observed in 25 patients, and the most common nonhematologic toxicity was esophagitis including five and two patients with grade 3 and 4, respectively. Multivariate analysis revealed that clinical stage was a strong factor for OS and PFS. Conclusion CCRT using PTX plus CDDP for selected elderly esophageal cancer patients resulted in encouraging survival outcomes and tolerable toxicities. Future prospective studies in large cohorts are highly warranted to confirm the findings in our report. PMID:26543377

  16. In vitro evaluation of paclitaxel coatings for delivery via drug-coated balloons.

    PubMed

    Kempin, Wiebke; Kaule, Sebastian; Reske, Thomas; Grabow, Niels; Petersen, Svea; Nagel, Stefan; Schmitz, Klaus-Peter; Weitschies, Werner; Seidlitz, Anne

    2015-10-01

    Lately, drug-coated balloons have been introduced in interventional cardiology as an approach to treat occluded blood vessel. They were developed for the rapid transfer of antiproliferative drugs during the angioplasty procedure in stenosed vessels with the intent to reduce the risk of restenosis. In this study five different paclitaxel (PTX) balloon coatings were tested in vitro in order to examine how solvents and additives influence coating stability and drug transfer rates. PTX-coated balloons were advanced through a guiding catheter and a simulated coronary artery pathway under perfusion and were then inflated in a hydrogel acceptor compartment. The fractions transferred to the gel, remaining on the balloon and the PTX lost in the simulated coronary pathway were then analysed. The results obtained suggest that the solvent used for the coating process strongly influences the surface structure and the stability of the coating. Ethanol/water and acetone based PTX coatings showed the lowest drug transfer rates to the simulated vessel wall (both <1%) due to their high drug losses during the prior passage through the coronary artery model (more than 95%). Balloons coated with PTX from ethyl acetate-solutions showed smaller drug loss (83%±9%), but most of the remaining PTX was not transferred (mean balloon residue approximately 15%). Beside the solvent, the use of additives seemed to have a great impact on transfer properties. The balloon pre-treatment with a crosslinked polyvinylpyrrolidone (PVP) film was able to increase the PTX transfer rate from less than 1% (without PVP) to approximately 6%. The best results in this study were obtained for balloon coatings with commercially available SeQuent© Please balloons containing the contrast agent iopromide. For this formulation drug transfer rates of approximately 17% were determined. Fluorescence microscopic imaging could visualize the particulate transfer of labelled PTX from the balloon surface during dilatation. The findings of this study underline the importance of drug adhesion and coating stability for the efficiency of PTX transfer. PMID:26318979

  17. Transferrin-conjugated magnetic silica PLGA nanoparticles loaded with doxorubicin and paclitaxel for brain glioma treatment.

    PubMed

    Cui, Yanna; Xu, Qingxing; Chow, Pierce Kah-Hoe; Wang, Deping; Wang, Chi-Hwa

    2013-11-01

    The effective treatment of malignant brain glioma is hindered by the poor transport across the blood-brain barrier (BBB) and the low penetration across the blood-tumor barrier (BTB). In this study, transferrin-conjugated magnetic silica PLGA nanoparticles (MNP-MSN-PLGA-Tf NPs) were formulated to overcome these barriers. These NPs were loaded with doxorubicin (DOX) and paclitaxel (PTX), and their anti-proliferative effect was evaluated in vitro and in vivo. The in vitro cytotoxicity of drug-loaded NPs was evaluated in U-87 cells. The delivery and the subsequent cellular uptake of drug-loaded NPs could be enhanced by the presence of magnetic field and the usage of Tf as targeting ligand, respectively. In particular, cells treated with DOX-PTX-NPs-Tf with magnetic field showed the highest cytotoxicity as compared to those treated with DOX-PTX-NPs-Tf, DOX-PTX-NPs, DOX-PTX-NPs-Tf with free Tf. The in vivo therapeutic efficacy of drug-loaded NPs was evaluated in intracranial U-87 MG-luc2 xenograft of BALB/c nude mice. In particular, the DOX-PTX-NPs-Tf treatment exhibited the strongest anti-glioma activity as compared to the PTX-NPs-Tf, DOX-NPs-Tf or DOX-PTX-NPs treatment. Mice did not show acute toxicity after administrating with blank MNP-MSN-PLGA-Tf NPs. Overall, MNP-MSN-PLGA-Tf NPs are promising carriers for the delivery of dual drugs for effective treatment of brain glioma. PMID:23932498

  18. Anticancer efficacy and toxicokinetics of a novel paclitaxel-clofazimine nanoparticulate co-formulation.

    PubMed

    Koot, Dwayne; Cromarty, Duncan

    2015-06-01

    Contemporary chemotherapy is limited by disseminated, resistant cancer. Targeting nanoparticulate drug delivery systems that encapsulate synergistic drug combinations are a rational means to increase the therapeutic index of chemotherapeutics. A lipopolymeric micelle co-encapsulating an in vitro optimized, synergistic fixed-ratio combination of paclitaxel (PTX) and clofazimine (B663) has been developed and called Riminocelles™. The present pre-clinical study investigated the acute toxicity, systemic exposure, repeat dose toxicity and efficacy of Riminocelles in parallel to Taxol® at an equivalent PTX dose of 10 mg/kg. Daily and weekly dosing schedules were evaluated against Pgp-expressing human colon adenocarcinoma (HCT-15) xenografts implanted subcutaneously in athymic mice. Riminocelles produced statistically significant (p

  19. Correlation of somatic mutations and clinical outcome in melanoma patients treated with carboplatin, paclitaxel, and sorafenib

    PubMed Central

    Wilson, Melissa A.; Zhao, Fengmin; Letrero, Richard; D’Andrea, Kurt; Rimm, David L.; Kirkwood, John M.; Kluger, Harriet M.; Lee, Sandra J.; Schuchter, Lynn M.; Flaherty, Keith T.; Nathanson, Katherine L.

    2014-01-01

    Purpose Sorafenib is an inhibitor of VEGFR, PDGFR, and RAF kinases, amongst others. We assessed the association of somatic mutations with clinicopathologic features and clinical outcomes in patients with metastatic melanoma treated on E2603, comparing treatment with carboplatin, paclitaxel +/? sorafenib (CP vs. CPS). Experimental Design Pre-treatment tumor samples from 179 unique individuals enrolled on E2603 were analyzed. Genotyping was performed using a custom iPlex panel interrogating 74 mutations in 13 genes. Statistical analysis was performed using Fisher’s exact test, logistic regression, and Cox’s proportional-hazards models. Progression free survival and overall survival were estimated using Kaplan-Meier methods. Results BRAF and NRAS mutations were found at frequencies consistent with other metastatic melanoma cohorts. BRAF-mutant melanoma was associated with worse performance status, increased number of disease sites, and younger age at diagnosis; NRAS-mutant melanoma was associated with better performance status, fewer sites of disease, and female gender. BRAF and NRAS mutations were not significantly predictive of response or survival when treated with CPS vs. CP. However, patients with NRAS-mutant melanoma trended towards a worse response and PFS on CP than those with BRAF-mutant or WT/WT melanoma, an association that was reversed for this group on the CPS arm. Conclusions This study of somatic mutations in melanoma is the last prospectively collected phase III clinical trial population prior to the era of BRAF targeted therapy. A trend towards improved clinical response in patients with NRAS-mutant melanoma treated with CPS was observed, possibly due to sorafenib’s effect on CRAF. PMID:24714776

  20. Synergistic Apoptotic Effect of Crocin and Paclitaxel or Crocin and Radiation on MCF-7 Cells, a Type of Breast Cancer Cell Line

    PubMed Central

    Vali, Faeze; Changizi, Vahid; Safa, Majid

    2015-01-01

    Background. Chemotherapy, radiotherapy, and surgery are routine treatments of breast cancer. However, these methods could only improve the living survival. Nowadays the combined therapy including herbals such as crocin is to study for improving breast cancer treatment. The purpose of this study was to evaluate the effects of crocin, paclitaxel, and radiation on MCF-7 cell. Methods. To evaluate the effect of crocin, paclitaxel, and radiation on survival rate of MCF-7 cells MTT assay was done. To investigate the apoptotic effect of experimental groups PI-flow cytometry was used and expression of apoptotic proteins (caspase-7, caspase-9, PARP, and p53) was studied by western blot. Results. This study revealed that the combined therapy of 0.01µmol/mL paclitaxel and 2.5 mg/mL crocin after 48?h could cause IC50 for MCF-7 cell line. This study showed that the combined therapy of 2?Gy gamma radiation with crocin could rise apoptosis in MCF-7 cell line from 21% (related to using 2?Gy gamma radiation alone) to 46.6%. Conclusion. Crocin and paclitaxel and crocin and gamma radiation had synergistic effect on MCF-7 cell line to get more significant apoptosis. PMID:26693354

  1. Polylactide-based Paclitaxel-loaded Nanoparticles Fabricated by Dispersion Polymerization: Characterization, Evaluation in Cancer Cell Lines, and Preliminary Biodistribution Studies

    PubMed Central

    Adesina, Simeon K.; Holly, Alesia; Kramer-Marek, Gabriela; Capala, Jacek; Akala, Emmanuel O.

    2015-01-01

    The macromonomer method was used to prepare crosslinked, paclitaxel-loaded polylactide-polyethylene glycol (stealth) nanoparticles using free-radical dispersion polymerization. The method can facilitate the attachment of other molecules to the nanoparticle surface to make it multifunctional. Proton NMR and FT-IR spectra confirm the synthesis of polylactide macromonomer and crosslinking agent. Formation of stealth nanoparticles was confirmed by scanning and transmission electron microscopy. The drug release isotherm of paclitaxel-loaded nanoparticles shows that the encapsulated drug is released over 7 days. In vitro cytotoxicity assay in selected breast and ovarian cancer cell lines reveal that the blank nanoparticle is biocompatible compared to medium-only treated controls. In addition, the paclitaxel-loaded nanoparticles exhibit similar cytotoxicity compared to paclitaxel in solution. Confocal microscopy reveals that the nanoparticles are internalized by MCF-7 breast cancer cells within one hour. Preliminary biodistribution studies also show nanoparticle accumulation in tumour xenograft model. The nanoparticles are suitable for the controlled delivery of bioactive agents. PMID:24961596

  2. Cyclin-dependent kinase 1 inhibitor RO3306 promotes mitotic slippage in paclitaxel-treated HepG2 cells.

    PubMed

    Xiao, J; Qiu, P; Lai, X; He, P; Wu, Y; Du, B; Tan, Y

    2013-09-20

    Hepatocellular carcinoma (HCC) is the most common primary liver neoplasm and current systemic chemotherapy are mostly ineffective. Paclitaxel (PTX) has a?clinically significant effect on many malignant tumors. Cells treated with PTX undergo reversible mitotic arrest and although high doses can cause side effects it may also induce apoptosis. We investigated the effect of a?sequential combination of PTX and RO3306, a?cyclin-dependent kinase 1 inhibitor, on the hepatocellular carcinoma HepG2 cell line. The sequential drug treatment protocol involved the addition of PTX (0.2 µmol/L) for 18 h?followed by RO3306 (2 µmol/L) for a?further 6 h. Cell viability and proliferation were measured using tetrazolium dye (MTT) and colony formation assay. Cell cycle profiles were established by flow cytometry. The expression level of protein was examined by immunoblotting. We observed a?synergistic effect of PTX and RO3306 treatment on cell growth and proliferation as well as an increased proportion of cells in sub-G1 phase. Expression levels of cyclin B, cyclin E?and phosphorylated Histone H3 demonstrated that RO3306 enhanced apoptosis in PTX treated cells by mitotic slippage. Our data suggested that the combination of PTX and RO3306 may be an effective therapeutic combination for the treatment of liver cancer. Keywords: paclitaxel; RO3306; apoptosis; mitotic slippage; HepG2 cells. PMID:24050548

  3. Gold nanoparticles surface-functionalized with paclitaxel drug and biotin receptor as theranostic agents for cancer therapy.

    PubMed

    Heo, Dong Nyoung; Yang, Dae Hyeok; Moon, Ho-Jin; Lee, Jung Bok; Bae, Min Soo; Lee, Sang Cheon; Lee, Won Jun; Sun, In-Cheol; Kwon, Il Keun

    2012-01-01

    We describe in this study whether the gold nanoparticle (AuNP) surface-functionalized with PEG, biotin, paclitaxel (PTX) and rhodamine B linked beta-cyclodextrin (?-CD) (AuNP-5') can be useful as a theranostic agent for cancer therapy without the cytotoxic effect on normal cells. Prior to surface-functionalizing AuNPs, the cytotoxicity of the nanoparticles was evaluated, followed by their cytocompatibility. PTX, an anti-cancer agent, formed inclusion complexations with ?-CD conjugated AuNPs, and effectively released from the AuNP-2' surface-functionalized with PEG, beta-cyclodextrin (?-CD) and paclitaxel (PTX) using the intracellular glutathione (GSH) level (10 mm). Two types of AuNP-4 surface-functionalized with PEG and rhodamine B linked ?-CD and AuNP-5 surface-functionalized PEG, biotin and rhodamine B linked ?-CD were used for evaluating their specific interaction on cancer cells such as HeLa, A549 and MG63. These were also tested against normal NIH3T3 cell, determining that the AuNP-5 was more effectively involved with the cancer cells. Confocal laser scanning microscopy (CLSM), fluorescence-activated cell-sorting (FACS) and cell viability analyses showed that the AuNP-5' plays a significant role in the diagnosis and therapy of the cancer cells, and may be used in theranostic agents. PMID:22036101

  4. Integrated Analysis of Gene Expression Profiles Associated with Response of Platinum/Paclitaxel-Based Treatment in Epithelial Ovarian Cancer

    PubMed Central

    Xiao, Zhen; Zhang, Wei; Cao, Yanfei; Qu, Like; Shou, Chengchao

    2012-01-01

    Purpose This study aims to explore gene expression signatures and serum biomarkers to predict intrinsic chemoresistance in epithelial ovarian cancer (EOC). Patients and Methods Gene expression profiling data of 322 high-grade EOC cases between 2009 and 2010 in The Cancer Genome Atlas project (TCGA) were used to develop and validate gene expression signatures that could discriminate different responses to first-line platinum/paclitaxel-based treatments. A gene regulation network was then built to further identify hub genes responsible for differential gene expression between the complete response (CR) group and the progressive disease (PD) group. Further, to find more robust serum biomarkers for clinical application, we integrated our gene signatures and gene signatures reported previously to identify secretory protein-encoding genes by searching the DAVID database. In the end, gene-drug interaction network was constructed by searching Comparative Toxicogenomics Database (CTD) and literature. Results A 349-gene predictive model and an 18-gene model independent of key clinical features with high accuracy were developed for prediction of chemoresistance in EOC. Among them, ten important hub genes and six critical signaling pathways were identified to have important implications in chemotherapeutic response. Further, ten potential serum biomarkers were identified for predicting chemoresistance in EOC. Finally, we suggested some drugs for individualized treatment. Conclusion We have developed the predictive models and serum biomarkers for platinum/paclitaxel response and established the new approach to discover potential serum biomarkers from gene expression profiles. The potential drugs that target hub genes are also suggested. PMID:23300757

  5. Caveolin-1 regulates cell apoptosis and invasion ability in paclitaxel-induced multidrug-resistant A549 lung cancer cells

    PubMed Central

    Han, Fei; Zhang, Long; Zhou, Yongxin; Yi, Xianghua

    2015-01-01

    The aim of the study was to investigate the effect and potential mechanism of caveolin-1 (Cav1) knockdown in paclitaxel-resistant lung cancer A549/Taxol cells. The human paclitaxel-resistant lung cancer cell line A549/Taxol was transfected with a Cav1 shRNA lentiviral vector. Interference efficiency for Cav1 was detected by real-time PCR and Western blotting. A MTT assay was used to determine cell proliferation, and flow cytometry was used to detect the cell cycle stage and apoptosis. Cell migration and invasion capability were detected by a transwell assay. Protein levels of related signaling molecules were detected by Western blotting. We successfully constructed a stable A549/Taxol cell line expressing low levels of Cav1. Cav1 knockdown significantly inhibited cell proliferation and induced G0/G1 arrest and cell apoptosis in vitro and in vivo. In addition, these effects correlated significantly with a reduction in cyclin D1 expression and activation of the Bcl-2/Bax-mediated mitochondrial apoptosis pathway. Furthermore, knockdown of Cav1 inhibited cell migration and invasion, and this may be related to the inhibition of AKT and the subsequent decreased protein expression of MMP2, MMP7 and MMP9. PMID:26464635

  6. Paclitaxel/tetrandrine coloaded nanoparticles effectively promote the apoptosis of gastric cancer cells based on "oxidation therapy".

    PubMed

    Li, Xiaolin; Lu, Xiaowei; Xu, Huae; Zhu, Zhenshu; Yin, Haitao; Qian, Xiaoping; Li, Rutian; Jiang, Xiqun; Liu, Baorui

    2012-02-01

    Paclitaxel (Ptx) has demonstrated encouraging activity in the treatment of gastric cancer. Development of drug-containing biodegradable polymeric nanoparticles (np) becomes one of the solutions to relieve side effects of Ptx. However, Ptx-loaded nanoparticles prepared by the nanoprecipitation method are unstable in the aqueous phase. Here we report that tetrandrine (Tet) effectively increases the stability of Ptx-loaded nanoparticles when Tet is coencapsulated with Ptx into mPEG-PCL nanoparticles. The current study demonstrates the synergistic antitumor effect of Tet and Ptx against gastric cancer cells, which provides the basis of coadministration of Tet and Ptx by nanoparticles. It is reported that the cellular chemoresistance to Ptx correlates with intracellular antioxidant capacity and the depletion of cellular antioxidant capacity could enhance the cytotoxicity of Ptx. Tet effectively induces intracellular ROS production. Therefore, the present study provides a promising novel therapeutic strategy basing on "oxidation therapy" that it could amplify the antitumor effect of paclitaxel by employing Tet as a pro-oxidant. More intracellular Tet accumulation by endocytosis of Ptx/Tet-np than equivalent doses of free drug leads to more intracellular ROS induction, which could efficiently enhance the cytotoxicity of Ptx by sequential inhibition of ROS-dependent Akt pathway and activation of apoptotic pathways, all of which would mediate the superior cytotoxicity of Ptx/Tet-np over free drug. The present results suggest that the codelivery of Ptx and Tet by nanoparticles provides a novel therapeutic strategy basing on "oxidation therapy" against gastric cancer. PMID:22171565

  7. pH-sensitive polymeric micelles formed by doxorubicin conjugated prodrugs for co-delivery of doxorubicin and paclitaxel.

    PubMed

    Ma, Yakun; Fan, Xiaohui; Li, Lingbing

    2016-02-10

    A doxorubicin conjugated prodrug incorporated acid-sensitive linkage between drug and Pluronic F127-chitosan (F127-CS) polymer was successfully synthesized. Subsequently a pH-sensitive polymeric micelle system was designed based on the conjugated prodrugs (F127-CS-DOX) to co-deliver doxorubicin and paclitaxel. Paclitaxel (PTX) was physically entrapped in the hydrophobic inner core of the micelles simultaneously. The structures of conjugates were analyzed by means of (1)H NMR and UV-vis spectrum. Size distribution and morphology of the micelles were observed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The results indicated that obtained micelles had good dispersity and the diameter was between 56.3 and 403.4nm. The loading of PTX into the micelle increased with higher DOX content. DOX and PTX release from polymeric micelles followed an acid-triggered manner. Furthermore, in vivo pharmacokinetic study also showed that the area under the plasma concentration time curve (AUC0-?) values of PTX and DOX for PTX-loaded F127-CS-DOX micelles in rats were 3.97 and 4.38-fold higher than those for PTX plus DOX solution. These results suggested the PTX-loaded F127-CS-DOX micelles would be a promising carrier for co-delivering DOX and PTX. PMID:26686101

  8. Prospective study on nanoparticle albumin-bound paclitaxel in advanced breast cancer: clinical results and biological observations in taxane-pretreated patients

    PubMed Central

    Fabi, Alessandra; Giannarelli, Diana; Malaguti, Paola; Ferretti, Gianluigi; Vari, Sabrina; Papaldo, Paola; Nisticò, Cecilia; Caterino, Mauro; De Vita, Roy; Mottolese, Marcella; Iacorossi, Laura; Cognetti, Francesco

    2015-01-01

    Background There is a deep need to improve the care of metastatic breast cancer (MBC) patients, since even today it remains an incurable disease. Taxanes are considered the most effective cytotoxic drugs for the treatment of MBC, both in monotherapy and in combined schedules, but the need for synthetic solvents contributes to the severe toxicities and may have a negative impact on the efficacy. Nanoparticle albumin-bound paclitaxel (Nab-paclitaxel) is a colloidal suspension of paclitaxel and human serum albumin initially developed to avoid the toxicities associated with conventional taxanes. Patients and methods The aim of this prospective, single-center open-label, noncomparative study was to evaluate the efficacy and safety of nab-paclitaxel in MBC patients pretreated with taxanes. The patients were treated with nab-paclitaxel as a single agent, 260 mg/m2 on day 1 of each 3-week cycle or 125 mg/m2 weekly. The primary endpoint was the overall response rate (ORR). Secondary objectives were duration of response, clinical benefit rate, progression-free survival (PFS), overall survival, and safety. Results A total of 42 patients (median age 48 years, median Eastern Cooperative Oncology Group performance status 0, triple-negative MBC 19%, all pretreated with a taxane-based therapy, mainly in advanced disease) were enrolled in the study. The ORR was 23.8%, including one complete response (2.4%) and nine partial responses (21.4%); the disease control rate was 50%. The median duration of response was 7.2 months. After a median follow-up of 9 months, the median PFS was 4.6 months. ORR and PFS were similar irrespective of the previous chemotherapy lines, metastatic sites, and biomolecular expression. Nab-paclitaxel was well tolerated, and the most frequent treatment-related toxicities were mild to moderate (grades 1–2). Conclusion This real-life study shows that nab-paclitaxel has a significant antitumor activity and a manageable safety profile in patients pretreated with taxanes and experiencing a treatment failure after at least one line of chemotherapy. PMID:26640370

  9. Antiangiogenic gene therapy with soluble VEGF-receptors -1, -2 and -3 together with paclitaxel prolongs survival of mice with human ovarian carcinoma.

    PubMed

    Sopo, Minna; Anttila, Maarit; Sallinen, Hanna; Tuppurainen, Laura; Laurema, Anniina; Laidinen, Svetlana; Hamalainen, Kirsi; Tuunanen, Pasi; Koponen, Jonna K; Kosma, Veli-Matti; Heinonen, Seppo; Alitalo, Kari; Yla-Herttuala, Seppo

    2012-11-15

    We compared effects of antiangiogenic gene therapy with a combination of soluble sVEGFR-1, sVEGFR-2 and sVEGFR-3 to chemotherapy with carboplatin and paclitaxel and to antiangiogenic monoclonal anti-VEGF-antibody bevacizumab in an intraperitoneal ovarian cancer xenograft model in mice (n = 80). Gene therapy was also combined with chemotherapy. Therapy was initiated when sizable tumors were confirmed in magnetic resonance imaging (MRI). Adenovirus-mediated gene transfer was performed intravenously (2 × 109 pfu), while chemotherapy and monoclonal anti-VEGF-antibody were dosed intraperitoneally. The study groups were as follows: AdLacZ control (n = 21); combination of AdsVEGFR-1, -2 and -3 (n = 21); combination of AdsVEGFR-1, -2, -3 and paclitaxel (n = 9); bevacizumab (n = 14); paclitaxel (n = 9) and carboplatin (n = 5). Effectiveness was assessed by survival time and surrogate measures such as sequential MRI, immunohistochemistry, microvessel density and tumor growth. Antiangiogenic gene therapy combined with paclitaxel significantly prolonged the mean survival of mice (25 days) compared to the controls (15 days) and all other treatment groups (p = 0.001). Bevacizumab treatment did not have any significant effect on the survival. Tumors of the mice treated by gene therapy were significantly smaller than in the control group (p = 0.021). The mean vascular density and total vascular area were also significantly smaller in the tumors of the gene therapy group (p = 0.01). These results show potential of the antiangiogenic gene therapy to improve efficacy of chemotherapy with paclitaxel and support testing of this approach in a phase I clinical trial for the treatment of ovarian cancer. PMID:22336998

  10. Further Data Supporting that the Paclitaxel-Associated Acute Pain Syndrome is Associated with the Development of Peripheral Neuropathy: NCCTG Trial N08C11

    PubMed Central

    Reeves, Brandi N.; Dakhil, Shaker R.; Sloan, Jeff A.; Wolf, Sherry L.; Burger, Kelli N.; Kamal, Arif; Le-Lindqwister, Nguyet A.; Soori, Gamini S.; Jaslowski, Anthony J.; Kelaghan, Joseph; Novotny, Paul J.; Lachance, Daniel H.; Loprinzi, Charles L.

    2012-01-01

    Background Paclitaxel causes an acute pain syndrome (P-APS), occurring within days after each dose and usually abating within days. Paclitaxel also causes a more classic peripheral neuropathy, which steadily increases in severity with increasing paclitaxel total doses. Little detail is available regarding the natural history of these two syndromes, or any relationship between them, although a recent publication does provide natural history data about weekly paclitaxel, supporting an association between the severity of P-APS and eventual peripheral neuropathy symptoms. Methods Patients entering this study were about to receive paclitaxel and carboplatin every 3 weeks. Daily questionnaires were completed for the first week after every chemotherapy dose and EORTC QLQ-CIPN 20 instruments were completed weekly. Results The P-APS severity peaked on day 4 after the initial chemotherapy dose, with 12%, 29%, 23%, and 36% of patients having maximal pain scores of 0, 1–4, 5–6, or 7–10 during the first week after the first dose of therapy, respectively. Patients with P-APS scores of 0–4 with the first dose of chemotherapy had less eventual sensory neuropathy than did patients with P-APS scores of 5–10 (p=0.001). With regard to the more peripheral neuropathy, sensory neuropathy was more problematic than was either motor or autonomic neuropathy. Numbness and tingling were more common components of the sensory neuropathy, than was pain. Conclusions Patients with worse P-APS severities appear to have more eventual chemotherapy induced peripheral neuropathy. This provides support for the concept that the P-APS is a form of nerve pathology. PMID:22415454

  11. A phase I trial of radiotherapy and simultaneous 24-hour paclitaxel in patients with locally advanced head and neck squamous cell carcinoma.

    PubMed

    Steinberg, L; Hassan, M; Olmsted, L; Sharan, V; Stepnick, D; Hoppel, C; Mugharbil, A; Subramanyan, S; McGloin, B; Mackay, W; Strauss, M

    1997-12-01

    Preclinical studies have demonstrated that tumor cells exposed to paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) for protracted periods (ie, 24 hours) and then irradiated undergo enhanced radiation-induced cell kill. Importantly, paclitaxel-induced tumor cell mitotic arrest at the time of radiation was associated with the enhanced cell kill. At the Case Western Reserve Cancer Center, we have conducted a phase I trial in 24 patients with either locally advanced or recurrent/metastatic head and neck squamous cell carcinoma to evaluate the clinical and pharmacologic effects of a 24-hour paclitaxel infusion combined with radiotherapy. The maximum tolerated dose was < or =75 mg/m2. Dose-limiting toxicity was febrile granulocytopenia. Mucositis was significant and necessitated the use of enteral feeding tubes in the majority of patients. All patients with locally advanced disease demonstrated either a complete response or major partial response. At a median follow-up of 13.4 months, disease has relapsed in only two of 22 patients with locally advanced disease. Pharmacokinetic studies revealed that a dose of > or =75 mg/m2 achieved near steady-state mean paclitaxel plasma concentrations greatly exceeding the threshold concentrations shown to alter microtubule function and induce tumor cell mitotic arrest in vitro. Pharmacodynamic studies performed at 21 to 26 hours after initiation of infusion demonstrated that a dose of > or =75 mg/m2 uniformly induced tumor cell mitotic arrest and oral epithelial mitotic arrest. The pharmacologic data and outcome results provide a strong rationale for the continued use of a 24-hour paclitaxel infusion and concurrent radiation for the treatment of newly diagnosed, locally advanced head and neck squamous cell carcinoma in an experimental setting. PMID:9427267

  12. Dendritic poly(ethylene glycol) bearing paclitaxel and alendronate for targeting bone neoplasms.

    PubMed

    Clementi, Chiara; Miller, Keren; Mero, Anna; Satchi-Fainaro, Ronit; Pasut, Gianfranco

    2011-08-01

    Poly(ethylene glycol) (PEG) is the most popular polymer for protein conjugation, but its potential as carrier of low molecular weight drugs has been limited by the intrinsic low loading, owing to its chemical structure. In fact, only the two end chain groups of PEG can be modified and exploited for drug coupling. We have demonstrated that by synthesizing a dendrimer structure at the polymer end chains, it is possible to increase the drug payload and overcome this limitation. Furthermore, this approach can be improved by using heterobifunctional PEG. These polymers allow the precise linking of two different drugs, or a drug and a targeting agent, on the same polymeric chain. Heterobifunctional PEG-dendrimers have been obtained with defined chemical structures leading to their attractive use as drug delivery systems. In fact, they offer a double benefit; first, the possibility to choose the best drug/targeting agent ratio, and second, the separation of the two functions, activity and targeting, which are coupled at the opposite polymer end chains. In this study, we investigated the role of a PEG-dendrimer, H(2)N-PEG-dendrimer-(COOH)(4), as carrier for a combination of paclitaxel (PTX) and alendronate (ALN). PTX is a potent anticancer drug that is affected by severe side effects originating from both the drug itself and its solubilizing formulation, Cremophor EL. ALN is an aminobiphosphonate used for the treatment of osteoporosis and bone metastases as well as a bone-targeting moiety. The PTX-PEG-ALN conjugate was designed to exploit active targeting by the ALN molecule and passive targeting through the enhanced permeability and retention (EPR) effect. Our conjugate demonstrated a great binding affinity to the bone mineral hydroxyapatite in vitro and an IC(50) comparable to that of the free drugs combination in human adenocarcinoma of the prostate (PC3) cells. The PTX-PEG-ALN conjugate exhibited an improved pharmacokinetic profile compared with the free drugs owed to the marked increase in their half-life. In addition, PTX-PEG-ALN could be solubilized directly in physiological solutions without the need for Cremophor EL. The data presented in this manuscript encourage further investigations on the potential of PTX-PEG-ALN as treatment for cancer bone metastases. PMID:21608527

  13. CDK5 Regulates Paclitaxel Sensitivity in Ovarian Cancer Cells by Modulating AKT Activation, p21Cip1- and p27Kip1-Mediated G1 Cell Cycle Arrest and Apoptosis

    PubMed Central

    Mao, Weiqun; Ahmed, Ahmed A.; Yang, Hailing; Zhou, Jinhua; Jennings, Nicholas; Rodriguez-Aguayo, Cristian; Lopez-Berestein, Gabriel; Miranda, Roberto; Qiao, Wei; Baladandayuthapani, Veera; Li, Zongfang; Sood, Anil K.; Liu, Jinsong; Le, Xiao-Feng; Bast, Robert C.

    2015-01-01

    Cyclin-dependent kinase 5 (CDK5) is a cytoplasmic serine/ threonine kinase. Knockdown of CDK5 enhances paclitaxel sensitivity in human ovarian cancer cells. This study explores the mechanisms by which CDK5 regulates paclitaxel sensitivity in human ovarian cancers. Multiple ovarian cancer cell lines and xenografts were treated with CDK5 small interfering RNA (siRNA) with or without paclitaxel to examine the effect on cancer cell viability, cell cycle arrest and tumor growth. CDK5 protein was measured by immunohistochemical staining of an ovarian cancer tissue microarray to correlate CDK5 expression with overall patient survival. Knockdown of CDK5 with siRNAs inhibits activation of AKT which significantly correlates with decreased cell growth and enhanced paclitaxel sensitivity in ovarian cancer cell lines. In addition, CDK5 knockdown alone and in combination with paclitaxel induced G1 cell cycle arrest and caspase 3 dependent apoptotic cell death associated with post-translational upregulation and nuclear translocation of TP53 and p27Kip1 as well as TP53-dependent transcriptional induction of p21Cip1 in wild type TP53 cancer cells. Treatment of HEYA8 and A2780 wild type TP53 xenografts in nu/nu mice with CDK5 siRNA and paclitaxel produced significantly greater growth inhibition than either treatment alone. Increased expression of CDK5 in human ovarian cancers correlates inversely with overall survival. CDK5 modulates paclitaxel sensitivity by regulating AKT activation, the cell cycle and caspase-dependent apoptosis. CDK5 inhibition can potentiate paclitaxel activity in human ovarian cancer cells. PMID:26146988

  14. Biotinylated Cubosomes: A Versatile Tool for Active Targeting and Codelivery of Paclitaxel and a Fluorescein-Based Lipid Dye.

    PubMed

    Aleandri, Simone; Bandera, Davide; Mezzenga, Raffaele; Landau, Ehud M

    2015-11-24

    The functionalization of cubosomes with biotin is reported here as an alternative method for the preparation of drug delivery systems capable of active targeting specific receptors that are (over)expressed by cancer cells. We describe the design, synthesis, assembly, and characterization of these novel cubosome nanoparticles by small-angle X-ray scattering (SAXS) and dynamic laser light scattering (DLS) and show their application to human adenocarcinoma cell line HeLa. These cubosomes are stabilized and functionalized with a novel, designed biotin-based block copolymer and are able to simultaneously transport paclitaxel, a potent anticancer drug, and a hydrophobic fluorescent dye in the active targeting of cancer cells. Such biotinylated cubosomes are potentially applicable in diagnosis, drug delivery, and monitoring of the therapeutic response for active targeting versus cancer cells. PMID:26513646

  15. Anti-HER2/neu peptide-conjugated iron oxide nanoparticles for targeted delivery of paclitaxel to breast cancer cells.

    PubMed

    Mu, Qingxin; Kievit, Forrest M; Kant, Rajeev J; Lin, Guanyou; Jeon, Mike; Zhang, Miqin

    2015-10-29

    Nanoparticles (NPs) for targeted therapy are required to have appropriate size, stability, drug loading and release profiles, and efficient targeting ligands. However, many of the existing NPs such as albumin, liposomes, polymers, gold NPs, etc. encounter size limit, toxicity and stability issues when loaded with drugs, fluorophores, and targeting ligands. Furthermore, antibodies are bulky and this can greatly affect the physicochemical properties of the NPs, whereas many small molecule-based targeting ligands lack specificity. Here, we report the utilization of biocompatible, biodegradable, small (?30 nm) and stable iron oxide NPs (IONPs) for targeted delivery of paclitaxel (PTX) to HER2/neu positive breast cancer cells using an anti-HER2/neu peptide (AHNP) targeting ligand. We demonstrate the uniform size and high stability of these NPs in biological medium, their effective tumour targeting in live mice, as well as their efficient cellular targeting and selective killing in human HER2/neu-positive breast cancer cells. PMID:26469772

  16. Molecular Inclusion Complexes of ?-Cyclodextrin Derivatives Enhance Aqueous Solubility and Cellular Internalization of Paclitaxel: Preformulation and In vitro Assessments

    PubMed Central

    Shah, Milin; Shah, Vatsal; Ghosh, Anasuya; Zhang, Zheng; Minko, Tamara

    2015-01-01

    Drugs with low aqueous solubility and permeability possess substantial challenges in designing effective and safe formulations. Synergistic solubility and permeability enhancement in a simple formulation can increase bioavailability and efficacy of such drugs. To overcome limitations of the clinical formulation of Taxol®, Paclitaxel (PTX) was reformulated with various ?-cyclodextrin (CD) derivatives suitable for parenteral administration. Results indicated that ?-CDs can efficiently form complexes with PTX at lower molar ratios, enhance aqueous solubility up to 500 times and improved cellular internalization of PTX. All ?-CD derivatives were found to be safe as excipient since none showed detectable signs of cyto-genotoxicity. As a result, the CD-PTX complexes significantly increased the cytotoxicity of the drug. The study concluded that CD-PTX formulations could substitute the current intravenous infusion of PTX obviating the use of non-inert excipient Cremophor EL. PMID:25950011

  17. Ultrasound-mediated destruction of oxygen and paclitaxel loaded lipid microbubbles for combination therapy in hypoxic ovarian cancer cells.

    PubMed

    Sun, Jiangchuan; Yin, Mingyue; Zhu, Shenyin; Liu, Li; Zhu, Yi; Wang, Zhigang; Xu, Ronald X; Chang, Shufang

    2016-01-01

    We synthesized oxygen and paclitaxel (PTX) loaded lipid microbubbles (OPLMBs) for ultrasound mediated combination therapy in hypoxic ovarian cancer cells. Our experiments successfully demonstrated that ultrasound induced OPLMBs destruction significantly enhanced the local oxygen release. We also demonstrated that OPLMBs in combination with ultrasound (300kHz, 0.5W/cm(2), 15s) yielded anti-proliferative activities of 52.8±2.75% and cell apoptosis ratio of 35.25±0.17% in hypoxic cells at 24h after the treatment, superior to other treatment groups such as PTX only and PTX-loaded MBs (PLMBs) with or without ultrasound mediation. RT-PCR and Western blot tests further confirmed the reduced expression of HIF-1? and MDR-1/P-gp after ultrasound mediation of OPLMBs. Our experiment suggests that ultrasound mediation of oxygen and drug-loaded MBs may be a useful method to overcome chemoresistance in the hypoxic ovarian cancer cells. PMID:26384914

  18. A Pharmacodynamic Study of the P-glycoprotein Antagonist CBT-1® in Combination With Paclitaxel in Solid Tumors

    PubMed Central

    Kelly, Ronan J.; Robey, Robert W.; Chen, Clara C.; Draper, Deborah; Luchenko, Victoria; Barnett, Daryl; Oldham, Robert K.; Caluag, Zinnah; Frye, A. Robin; Steinberg, Seth M.; Fojo, Tito

    2012-01-01

    Background: This pharmacodynamic trial evaluated the effect of CBT-1® on efflux by the ATP binding cassette (ABC) multidrug transporter P-glycoprotein (Pgp/MDR1/ABCB1) in normal human cells and tissues. CBT-1® is an orally administered bisbenzylisoquinoline Pgp inhibitor being evaluated clinically. Laboratory studies showed potent and durable inhibition of Pgp, and in phase I studies CBT-1® did not alter the pharmacokinetics of paclitaxel or doxorubicin. Methods: CBT-1® was dosed at 500 mg/m2 for 7 days; a 3-hour infusion of paclitaxel at 135 mg/m2 was administered on day 6. Peripheral blood mononuclear cells (PBMCs) were obtained prior to CBT-1® administration and on day 6 prior to the paclitaxel infusion. 99mTc-sestamibi imaging was performed on the same schedule. The area under the concentration–time curve from 0–3 hours (AUC0–3) was determined for 99mTc-sestamibi. Results: Twelve patients were planned and enrolled. Toxicities were minimal and related to paclitaxel (grade 3 or 4 neutropenia in 18% of cycles). Rhodamine efflux from CD56+ PBMCs was a statistically significant 51%–100% lower (p < .0001) with CBT-1®. Among 10 patients who completed imaging, the 99mTc-sestamibi AUC0–3 for liver (normalized to the AUC0–3 of the heart) increased from 34.7% to 100.8% (median, 71.9%; p < .0001) after CBT-1® administration. Lung uptake was not changed. Conclusion: CBT-1® is able to inhibit Pgp-mediated efflux from PBMCs and normal liver to a degree observed with Pgp inhibitors studied in earlier clinical trials. Combined with its ease of administration and lack of toxicity, the data showing inhibition of normal tissue Pgp support further studies with CBT-1® to evaluate its ability to modulate drug uptake in tumor tissue. Discussion: Although overexpression of ABCB1 and other ABC transporters has been linked with poor outcome following chemotherapy efforts to negate that through pharmacologic inhibition have generally failed. This is thought to be a result of several factors, including (a) failure to select patients with tumors in which ABCB1 is a dominant resistance mechanism; (b) inhibitors that were not potent, or that impaired drug clearance; and (c) the existence of other mechanisms of drug resistance, including other ABC transporters. Although an animal model for Pgp has been lacking, recent studies have exploited a Brca1?/?; p53?/? mouse model of hereditary breast cancer that develops sporadic tumors similar to cancers in women harboring BRCA1 mutations. Treatment with doxorubicin, docetaxel, or the poly(ADP-ribose) polymerase inhibitor olaparib brings about shrinkage, but resistance eventually emerges. Overexpression of the Abcb1a gene, the mouse ortholog of human ABCB1, has been shown to be a mechanism of resistance in a subset of these tumors. Treating mice with resistant tumors with olaparib plus the Pgp inhibitor tariquidar resensitized the tumors to olaparib. Although results in this animal model support a new look at Pgp as a target, in this era of “targeted therapies,” trial designs that directly assess modulation of drug uptake, including quantitative nuclear imaging, should be pursued before clinical efficacy assessments are undertaken. Such assessment should be performed with compounds that inhibit tissue Pgp without altering the pharmacokinetics of chemotherapeutic agents. This pharmacodynamic study demonstrated that CBT-1®, inhibits Pgp-mediated efflux from PBMCs and normal liver. PMID:22416063

  19. Poly-?,?-Polyasparthydrazide-Based Nanogels for Potential Oral Delivery of Paclitaxel: In Vitro and In Vivo Properties.

    PubMed

    Guo, Jingwen; Ma, Mingxin; Chang, Di; Zhang, Qiang; Zhang, Chen; Yue, Yang; Liu, Jia; Wang, Siling; Jiang, Tongying

    2015-12-01

    A family of nanogel drug carriers has been designed to enhance the oral absorption of paclitaxel (PTX). The PAHy-based nanogels were prepared by the interpenetration of poly-?,?-polyasparthydrazide (PAHy) chains and dicarboxyl-poly (ethylene glycol) (CPEG), forming a smart chain network. The PAHy-based nanogels were characterized by Fourier Transform Infrared Spectroscopy (FT-IR), dynamic light scattering (DLS), X-ray diffraction (XRD) and high performance liquid chromatography (HPLC). The adhesion and retention properties of fluorescein isothiocyanate (FITC)-nanogels in vivo were investigated using an in vivo imaging system and confocal laser scanning microscopy (CLSM). The smart nanogels had a particle size of -200 nm, increased the degree and rate of release, and spent over 12 h in the gastrointestinal tract. They also produced excellent adhesion, permeability and retention (APR) effects and increased oral absorption, confirming their use as potential sustained-release carriers for the oral delivery of the hydrophobic anticancer agent PTX. PMID:26510316

  20. Ultrafine PEG-PLA fibers loaded with both paclitaxel and doxorubicin hydrochloride and their in vitro cytotoxicity.

    PubMed

    Xu, Xiuling; Chen, Xuesi; Wang, Zhanfeng; Jing, Xiabin

    2009-05-01

    By means of "emulsion-electrospinning", both hydrophobic and hydrophilic drugs, paclitaxel (PTX) and doxorubicin hydrochloride (DOX), were successfully loaded into PEG-PLA nanofiber mats to realize multi-drug delivery. The release behaviors of both the drugs from the same fiber mats were ascribed to their solubility properties and distribution status in the fibers. Due to its high hydrophilicity, DOX was easy to diffuse out from the fibers, and its release rate was always faster than that of hydrophobic PTX. Moreover, the release rate of PTX was accelerated by DOX's release from the same drug-loaded fibers. In vitro cytotoxicity against rat Glioma C6 cells indicated that the dual drug combination showed a higher inhibition and apoptosis against C6 cells than a single drug-loaded system, which suggests the promise for multi-drug delivery on combination therapy. PMID:19027067

  1. Influence of MiR-451 on Drug Resistances of Paclitaxel-Resistant Breast Cancer Cell Line

    PubMed Central

    Gu, Xi; Li, Jian-Yi; Guo, Jiao; Li, Pi-Song; Zhang, Wen-Hai

    2015-01-01

    Background This study aimed to investigate the potential influence of microRNA-451 (miR-451) in drug resistances of the Paclitaxel-resistant breast cancer cell line by transfecting miR-451 mimics and miR-451 inhibitors to MCE-7, MCF-7/EPI, and MCF-7/DOC. Material/Methods Real-time quantitative PCR (qRT-PCR) was performed for detecting whether transfected miR-451 mimics and miR-451 inhibitors could regulate the expression of miR-451 effectively. The apoptosis of the 3 cell lines was measured by applying Annexin V-APC/PI staining. Western blot was used for the detection of the protein expression of Bcl-2 and Caspase 3 after the transfection of miR-451 mimics /inhibitors. Bioinformatics analysis demonstrated that Bcl-2 protein is a potential target gene for miR-451. Results In comparison to the control group, after transfection with miR-451 mimics, there was a significant increase in miR-451 expression in MCF-7, MCF-7/EPI, and MCF-7/DOC. Cells in the three cell lines had increased apoptosis, Bcl-2 protein expression decreased significantly, and Caspase protein expression increased obviously. After the transfection with miR-451 inhibitors, miR-451 expression was significantly decreased and apoptosis in the 3 cell lines had no significant decrease compared with the control group. Conclusions Increased miR-451 expression may negatively regulate Bcl-2 mRNA and protein expression, followed by affecting the protein expression of caspase 3, and accelerate the apoptosis in breast cancer, indicating that miR-451 might influence the drug resistances of the Paclitaxel-resistant breast cancer cell line. PMID:26516138

  2. Anti-HER2/neu peptide-conjugated iron oxide nanoparticles for targeted delivery of paclitaxel to breast cancer cells

    NASA Astrophysics Data System (ADS)

    Mu, Qingxin; Kievit, Forrest M.; Kant, Rajeev J.; Lin, Guanyou; Jeon, Mike; Zhang, Miqin

    2015-10-01

    Nanoparticles (NPs) for targeted therapy are required to have appropriate size, stability, drug loading and release profiles, and efficient targeting ligands. However, many of the existing NPs such as albumin, liposomes, polymers, gold NPs, etc. encounter size limit, toxicity and stability issues when loaded with drugs, fluorophores, and targeting ligands. Furthermore, antibodies are bulky and this can greatly affect the physicochemical properties of the NPs, whereas many small molecule-based targeting ligands lack specificity. Here, we report the utilization of biocompatible, biodegradable, small (~30 nm) and stable iron oxide NPs (IONPs) for targeted delivery of paclitaxel (PTX) to HER2/neu positive breast cancer cells using an anti-HER2/neu peptide (AHNP) targeting ligand. We demonstrate the uniform size and high stability of these NPs in biological medium, their effective tumour targeting in live mice, as well as their efficient cellular targeting and selective killing in human HER2/neu-positive breast cancer cells.Nanoparticles (NPs) for targeted therapy are required to have appropriate size, stability, drug loading and release profiles, and efficient targeting ligands. However, many of the existing NPs such as albumin, liposomes, polymers, gold NPs, etc. encounter size limit, toxicity and stability issues when loaded with drugs, fluorophores, and targeting ligands. Furthermore, antibodies are bulky and this can greatly affect the physicochemical properties of the NPs, whereas many small molecule-based targeting ligands lack specificity. Here, we report the utilization of biocompatible, biodegradable, small (~30 nm) and stable iron oxide NPs (IONPs) for targeted delivery of paclitaxel (PTX) to HER2/neu positive breast cancer cells using an anti-HER2/neu peptide (AHNP) targeting ligand. We demonstrate the uniform size and high stability of these NPs in biological medium, their effective tumour targeting in live mice, as well as their efficient cellular targeting and selective killing in human HER2/neu-positive breast cancer cells. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr04867b

  3. Analysis of pathological complete response rates with paclitaxel-based regimens in trimodality therapy for esophageal cancer.

    PubMed

    Boggs, D H; Tarabolous, C; Morris, C G; Hanna, A; Burrows, W; Horiba, N; Suntharalingam, M

    2015-10-01

    The study aimed to examine whether omission of 5-fluorouracil (5-FU)-containing chemotherapy alters pathological complete response rates in patients receiving trimodality therapy for locally advanced esophageal cancer. A total of 159 patients were identified. One hundred twenty-nine patients received platinum/5-FU concurrently with radiotherapy, and 30 received taxane/platinum-containing chemoradiotherapy prior to esophagectomy. Patients were staged using the 2002 American Joint Committee on Cancer staging system. Patients were matched between chemotherapeutic groups, with no significant demographic or clinical differences other than T stage (14% T2 in the 5-FU group; no T2 in the platinum/taxane group) and radiotherapy technique (8.5% received intensity-modulated radiotherapy in the 5-FU group; 60% in the platinum/taxane group). Pathological complete response rates for 5-FU and platinum/taxane-based groups were not significantly different (45% and 30%, respectively; P = 0.1548). Five-year overall survival and progression-free survival were not statistically different between the two groups. Significant predictors of pathological complete response included N stage (56% N0 and 33% N1; P = 0.0083), histology (37% adenocarcinoma and 59% squamous cell; P = 0.0123), tumor location (39% distal and 59% proximal/mid; P = 0.048), gastroesophageal junction involvement (33% involved and 55% uninvolved; P = 0.005), and radiotherapy end-to-surgery interval (50% < 55 days and 34% ? 55 days; P = 0.04). Grades 3-4 hematological toxicity was higher in the 5-FU group (36%) than in the paclitaxel-containing therapy group (17%; P = 0.0484). Use of paclitaxel-containing chemoradiotherapy did not result in inferior pathological complete response, overall survival, or progression-free survival rates, and resulted in less hematological toxicity than 5-FU treatment. PMID:24863682

  4. Prophylactic cannabinoid administration blocks the development of paclitaxel-induced neuropathic nociception during analgesic treatment and following cessation of drug delivery

    PubMed Central

    2014-01-01

    Background Chemotherapeutic treatment results in chronic pain in an estimated 30-40 percent of patients. Limited and often ineffective treatments make the need for new therapeutics an urgent one. We compared the effects of prophylactic cannabinoids as a preventative strategy for suppressing development of paclitaxel-induced nociception. The mixed CB1/CB2 agonist WIN55,212-2 was compared with the cannabilactone CB2-selective agonist AM1710, administered subcutaneously (s.c.), via osmotic mini pumps before, during, and after paclitaxel treatment. Pharmacological specificity was assessed using CB1 (AM251) and CB2 (AM630) antagonists. The impact of chronic drug infusion on transcriptional regulation of mRNA markers of astrocytes (GFAP), microglia (CD11b) and cannabinoid receptors (CB1, CB2) was assessed in lumbar spinal cords of paclitaxel and vehicle-treated rats. Results Both WIN55,212-2 and AM1710 blocked the development of paclitaxel-induced mechanical and cold allodynia; anti-allodynic efficacy persisted for approximately two to three weeks following cessation of drug delivery. WIN55,212-2 (0.1 and 0.5 mg/kg/day s.c.) suppressed the development of both paclitaxel-induced mechanical and cold allodynia. WIN55,212-2-mediated suppression of mechanical hypersensitivity was dominated by CB1 activation whereas suppression of cold allodynia was relatively insensitive to blockade by either CB1 (AM251; 3 mg/kg/day s.c.) or CB2 (AM630; 3 mg/kg/day s.c.) antagonists. AM1710 (0.032 and 3.2 mg/kg /day) suppressed development of mechanical allodynia whereas only the highest dose (3.2 mg/kg/day s.c.) suppressed cold allodynia. Anti-allodynic effects of AM1710 (3.2 mg/kg/day s.c.) were mediated by CB2. Anti-allodynic efficacy of AM1710 outlasted that produced by chronic WIN55,212-2 infusion. mRNA expression levels of the astrocytic marker GFAP was marginally increased by paclitaxel treatment whereas expression of the microglial marker CD11b was unchanged. Both WIN55,212-2 (0.5 mg/kg/day s.c.) and AM1710 (3.2 mg/kg/day s.c.) increased CB1 and CB2 mRNA expression in lumbar spinal cord of paclitaxel-treated rats in a manner blocked by AM630. Conclusions and implications Cannabinoids block development of paclitaxel-induced neuropathy and protect against neuropathic allodynia following cessation of drug delivery. Chronic treatment with both mixed CB1/CB2 and CB2 selective cannabinoids increased mRNA expression of cannabinoid receptors (CB1, CB2) in a CB2-dependent fashion. Our results support the therapeutic potential of cannabinoids for suppressing chemotherapy-induced neuropathy in humans. PMID:24742127

  5. Impaired wound healing and expansion of a large ulcer after bevacizumab with paclitaxel for skin metastases from breast cancer: report of a case.

    PubMed

    Kijima, Yuko; Yoshinaka, Heiji; Hirata, Munetsugu; Nakajo, Akihiro; Arima, Hideo; Shinden, Yoshiaki; Ijichi, Tetsuya; Eguchi, Yuka; Okumura, Hiroshi; Uenosono, Yoshikazu; Kurahara, Hiroshi; Ishigami, Sumiya; Natsugoe, Shoji

    2015-04-01

    A 48-year-old Japanese woman was found to have local recurrence of breast cancer in the chest wall following neoadjuvant chemotherapy, total mastectomy with axillary lymphadenectomy, postoperative radiation therapy to the chest wall, and adjuvant systemic therapy using trastuzumab. As a third line of treatment after recurrence, bevacizumab with paclitaxel was initiated for several metastatic lesions on the skin of the chest wall, left internal costal lymph nodes, and right axillary lymph nodes. The wound on the chest wall continued to expand in diameter and depth after the third course of bevacizumab with paclitaxel until the rib was exposed. After stopping the bevacizumab, granulation tissue expanded and by 3 months, had covered the bottom of the ulcer. The patient died soon thereafter, despite systemic chemotherapy with eribulin; however, there was no further bleeding from the ulcer on the chest wall or the exposed ribs. PMID:24831658

  6. Serial optical coherence tomography assessments at 2- and 4-month follow-up after paclitaxel-eluting stenting of the superficial femoral artery.

    PubMed

    Aihara, Hideaki; Soga, Yoshimitsu; Kuramitsu, Shoichi

    2015-04-01

    A 71-year-old man underwent endovascular therapy (EVT) with a paclitaxel-eluting stent in superficial femoral artery (SFA). Optical coherence tomography (OCT) of SFA at 2 months after EVT revealed that several struts were not covered with neointima. Moreover, some mural thrombi were detected within the stent. Although OCT revealed that the frequency of stent strut coverage was improved at the 4-month follow-up, uncovered stent strut still remained and some mural thrombi were observed within the stent even at 4 months after EVT. This is the first report to demonstrate the vascular response after paclitaxel-eluting stent placement for the lesion using serial OCT examinations. PMID:24718979

  7. Phase I-II study of vorinostat plus paclitaxel and bevacizumab in metastatic breast cancer: evidence for vorinostat-induced tubulin acetylation and Hsp90 inhibition in vivo.

    PubMed

    Ramaswamy, B; Fiskus, W; Cohen, B; Pellegrino, C; Hershman, D L; Chuang, E; Luu, Thehang; Somlo, G; Goetz, M; Swaby, R; Shapiro, C L; Stearns, V; Christos, P; Espinoza-Delgado, I; Bhalla, K; Sparano, J A

    2012-04-01

    In preclinical models, the histone deacetylase inhibitor vorinostat sensitizes breast cancer cells to tubulin-polymerizing agents and to anti-vascular endothelial growth factor-directed therapies. We sought to determine the safety and efficacy of vorinostat plus paclitaxel and bevacizumab as first-line therapy in metastatic breast cancer (MBC), and the biological effects of vorinostat in vivo. For this purpose of this study, 54 patients with measurable disease and no prior chemotherapy for MBC received vorinostat (200 or 300 mg PO BID) on days 1-3, 8-10, and 15-17, plus paclitaxel (90 mg/m(2)) on days 2, 9, 16, and bevacizumab (10 mg/kg) on days 2 and 16 every 28 days. The primary objective of the phase I study was to determine the recommended phase II dose (RPTD) of vorinostat, and for the phase II to detect an improvement of response rate from 40 to 60% (alpha = 0.10, beta = 0.10). No dose limiting toxicities were observed, and the RPTD of vorinostat was 300 mg BID. For the primary efficacy analysis in 44 patients at the RPTD, we observed 24 objective responses (55%, 95% confidence intervals (C.I) 39%, 70%). The adverse event profile was consistent with paclitaxel-bevacizumab, with the exception of increased diarrhea with the addition of vorinostat. Analysis of serial tumor biopsies in seven patients showed increased acetylation of Hsp90 and ?-tubulin following vorinostat. Vorinostat induces histone and alpha tubulin acetylation and functional inhibition of Hsp90 in breast cancer in vivo and can be safely combined with paclitaxel and bevacizumab. PMID:22200869

  8. Phase I–II study of vorinostat plus paclitaxel and bevacizumab in metastatic breast cancer: evidence for vorinostat-induced tubulin acetylation and Hsp90 inhibition in vivo

    PubMed Central

    Ramaswamy, B; Fiskus, W.; Cohen, B; Pellegrino, C; Hershman, DL; Chuang, E; Luu, Thehang; Somlo, G; Goetz, M; Swaby, R; Shapiro, CL; Stearns, V; Christos, P; Espinoza-Delgado, I; Bhalla, K; Sparano, JA

    2012-01-01

    Purpose In preclinical models, the histone deacetylase inhibitor vorinostat sensitizes breast cancer cells to tubulin polymerizing agents and to anti-vascular endothelial growth factor (VEGF) directed therapies. We sought to determine the safety and efficacy of vorinostat plus paclitaxel and bevacizumab as first-line therapy in metastatic breast cancer (MBC), and the biological effects of vorinostat in vivo. Patients and Methods Fifty-four patients with measurable disease and no prior chemotherapy for MBC received vorinostat (200 or 300 mg PO BID) on days 1–3, 8–10, and 15–17, plus paclitaxel (90mg/m2) on days 2, 9, 16 and bevacizumab (10mg/kg) on days 2 and 16 every 28 days. The primary objective of the phase I study was to determine the recommended phase II dose (RPTD) of vorinostat, and for the phase II to detect an improvement of response rate from 40% to 60% (alpha =0.10, beta=0.10). Results No dose limiting toxicities were observed, and the RPTD of vorinostat was 300 mg BID. For the primary efficacy analysis in 44 patients at the RPTD, we observed 24 objective responses (55%, 95% confidence intervals [C.I.] 39%, 70%). The adverse event profile was consistent with paclitaxel-bevacizumab, with the exception of increased diarrhea with the addition of vorinostat. Analysis of serial tumor biopsies in 7 patients showed increased acetylation of Hsp 90 and -tubulin following vorinostat. Conclusions Vorinostat induces histone and alpha tubulin acetylation and functional inhibition of Hsp90 in breast cancer in vivo and can be safely combined with paclitaxel and bevacizumab. PMID:22200869

  9. Overexpression of Forkhead Box Protein M1 (FOXM1) in Ovarian Cancer Correlates with Poor Patient Survival and Contributes to Paclitaxel Resistance

    PubMed Central

    Zhao, Fung; Siu, Michelle K. Y.; Jiang, LiLi; Tam, Kar Fai; Ngan, Hextan Y. S.; Le, Xiao Feng; Wong, Oscar G. W.; Wong, Esther S. Y.; Gomes, Ana R.; Bella, Laura; Khongkow, Pasarat; Lam, Eric W-F; Cheung, Annie N. Y.

    2014-01-01

    Aim Deregulation of FOXM1 has been documented in various cancers. The aim of this study was to evaluate the role of FOXM1 in ovarian cancer tumorigenesis and paclitaxel resistance. Experimental Design Expression of FOXM1 was examined in 119 clinical samples by immunohistochemistry and correlated with clinicopathological parameters. Effects of FOXM1 knockdown on ovarian cancer cell migration, invasion and mitotic catastrophe were also studied. qPCR and ChIP-qPCR were used to establish KIF2C as a novel FOXM1 target gene implicated in chemoresistance. Results High nuclear FOXM1 expression in ovarian cancer patient samples was significantly associated with advanced stages (P?=?0.035), shorter overall (P?=?0.019) and disease-free (P?=?0.014) survival. Multivariate analysis confirmed FOXM1 expression as an independent prognostic factor for ovarian cancer. FOXM1 knockdown significantly inhibited migration and invasion of ovarian cancer cells and enhanced paclitaxel-mediated cell death and mitotic catastrophe in a p53-independent manner. Bioinformatics analysis suggested a number of potential transcription targets of FOXM1. One of the potential targets, KIF2C, exhibited similar expression pattern to FOXM1 in chemosensitive and chemoresistant cells in response to paclitaxel treatment. FOXM1 could be detected at the promoter of KIF2C and FOXM1 silencing significantly down-regulated KIF2C. Conclusion Our findings suggest that FOXM1 is associated with poor patient outcome and contributes to paclitaxel resistance by blocking mitotic catastrophe. KIF2C is identified as a novel FOXM1 transcriptional target that may be implicated in the acquisition of chemoresistance. FOXM1 should be further investigated as a potential prognostic marker and therapeutic target for ovarian cancer. PMID:25411964

  10. Digitoxin and its synthetic analog MonoD have potent antiproliferative effects on lung cancer cells and potentiate the effects of hydroxyurea and paclitaxel.

    PubMed

    Yakisich, Juan Sebastian; Azad, Neelam; Venkatadri, Rajkumar; Kulkarni, Yogesh; Wright, Clayton; Kaushik, Vivek; O'Doherty, George A; Iyer, Anand Krishnan V

    2016-02-01

    Despite significant advances in the understanding of lung cancer biology, the prognosis of cancer patients remains poor. Part of the failure of anticancer therapy is due to intratumoral heterogeneity in these patients that limits the efficacy of single agents. Therefore, there is an urgent need for new anticancer drugs or drug combination regimens that possess increased activity against all cellular subtypes found within the tumor. In this study, we evaluated the in vitro antiproliferative activity of the cardiac glycosides (CGs) digitoxin and its synthetic analog MonoD on H460 lung cancer cells grown under different culture conditions. The CGs were tested alone in H460 cells under routine culture as well as in cells growing under short (24-72 h) and prolonged serum starvation (7 days) in order to evaluate the activity of drugs on cancer cells under varied degrees of proliferation. Our results showed that both CGs, and MonoD in particular, have potent antiproliferative activity at clinically relevant concentrations against cells in all the tested culture conditions. In contrast, paclitaxel, hydroxyurea and colchicine were only active in cells growing in routine culture conditions, and relatively inactive in serum-starved conditions. Importantly, both CGs were able to potentiate the effect of clinically relevant concentrations of hydroxyurea or paclitaxel in serum-starved conditions. When paclitaxel was used in combination with CGs, the highest antiproliferative effect was obtained when paclitaxel was administered first, followed by either digitoxin or MonoD. Our results indicate that CGs have potential clinical applications in translational oncology especially in combination with other drugs, and warrants further investigation of CGs in more advanced preclinical models of lung cancer. PMID:26573786

  11. The thrombospondin-1 mimetic ABT-510 increases the uptake and effectiveness of cisplatin and paclitaxel in a mouse model of epithelial ovarian cancer.

    PubMed

    Campbell, Nicole E; Greenaway, James; Henkin, Jack; Moorehead, Roger A; Petrik, Jim

    2010-03-01

    Epithelial ovarian cancer (EOC) comprises approximately 90% of ovarian cancers and arises from the surface epithelium. Typical treatment of EOC involves cytoreductive surgery combined with chemotherapy. More recent therapies have targeted the tumor vasculature using antiangiogenic compounds such as thrombospondin-1 (TSP-1). TSP-1 mimetic peptides such as ABT-510 have been created and have been in various clinical trials. We have previously shown that ABT-510 reduces abnormal vasculature associated with tumor tissue and increases the presence of mature blood vessels. It has been hypothesized that treatment with antiangiogenic compounds would allow increased delivery of cytotoxic agents and enhance treatment. In this study, we evaluated the potential role of ABT-510 and various chemotherapeutics (cisplatin and paclitaxel) on tumor progression, angiogenesis, and the benefits of combinational treatments on tissue uptake and perfusion using an orthotopic syngeneic mouse model of EOC. Animals were treated with ABT-510 (100 mg/kg per day) alone or in combination with cisplatin (2 mg/kg per 3 days) or paclitaxel (10 mg/kg per 2 days) at 60 days after tumor induction. Radiolabeled and fluorescently labeled paclitaxel demonstrated a significant increase in tumor uptake after ABT-510 treatment. Combined treatment with ABT-510 and cisplatin or paclitaxel resulted in a significant increase in tumor cell and tumor endothelial cell apoptosis and a resultant decrease in ovarian tumor size. Combined treatment also regressed secondary lesions and eliminated the presence of abdominal ascites. The results from this study show that through vessel normalization, ABT-510 increases uptake of chemotherapy drugs and can induce regression of advanced ovarian cancer. PMID:20234821

  12. Chemoradiation With Paclitaxel and Carboplatin in High-Risk Cervical Cancer Patients After Radical Hysterectomy: A Korean Gynecologic Oncology Group Study

    SciTech Connect

    Lee, Taek Sang; Kang, Soon Beom; Kim, Young Tak; Park, Byung Joo; Kim, Yong Man; Lee, Jong Min; Kim, Seok Mo; Kim, Young Tae; Kim, Jae Hoon; Kim, Kyung Tai

    2013-06-01

    Purpose: To evaluate the efficacy and toxicity of concurrent chemoradiation with paclitaxel and carboplatin in patients with high-risk cervical cancer. Methods and Materials: Patients after radical hysterectomy for cervical cancer, with at least 1 high-risk characteristic, were administered paclitaxel 135 mg/m{sup 2}, carboplatin area under the curve = 5 every 3 weeks for 3 cycles concomitant with radiation therapy as adjuvant treatment. Results: This prospective study enrolled 71 consecutive patients. Sixty-six patients (93%) completed the planned treatment. The majority of grade 3/4 neutropenia or nonhematologic toxicities were usually self-limited. Diarrhea grades 3/4 were observed in 4 patients (5.6%). One patient developed anaphylactic shock after infusion of paclitaxel. With a median follow-up of 57 months, recurrences occurred in 16 patients. Multivariable analysis indicated that common iliac lymph node involvement is an independent risk factor for disease recurrence (odds ratio 13.48; 95% confidence interval 2.93-62.03). In the intent-to-treat population (n=71), the estimated 5-year disease-free survival and overall survival rates were 77.3% and 80.3% respectively. In the per-protocol population (n=62), disease-free survival was 78.9% and overall survival was 83.9%. Conclusions: Concurrent chemoradiation with paclitaxel/carboplatin is well tolerated and seems to be effective for patients who undergo radical hysterectomy. Therefore, a prospective, randomized controlled study should be designed to evaluate efficacy of this approach for patients with high-risk cervical cancer.

  13. Randomized trial of single agent paclitaxel given weekly versus every three weeks and with peroral versus intravenous steroid premedication to patients with ovarian cancer previously treated with platinum.

    PubMed

    Rosenberg, Per; Andersson, Håkan; Boman, Karin; Ridderheim, Mona; Sorbe, Bengt; Puistola, Ulla; Parö, Gunnar

    2002-01-01

    The aim of this study was to evaluate the efficacy and toxicity of paclitaxel given at the same dose intensity and administered weekly (arm A) or every 3 weeks (arm B). and to assess the safety of intravenous steroids versus standard peroral premedication. Two hundred and eight patients with advanced ovarian cancer previously treated with no more than one platinum-containing regimen were randomized to receive either a weekly infusion of paclitaxel or an infusion every 3 weeks. The median delivered dose intensity was 77.6 mg/m2/week in the weekly arm, and 72.7 mg/m2/week in the every 3 weeks arm. WHO grade 3-4 hematological and non-hematological toxicity occurred more frequently in arm B. No difference in number of severe events of hypersensitivity, response rate, time to progression or survival between arms was observed. Weekly paclitaxel at a dose of 67 mg/m2/week was found to have a better safety profile and seemed to be as effective as the equivalently dosed schedule every 3 weeks. Intravenous steroids are a safe alternative to oral steroids. PMID:12442916

  14. Novel ZnO hollow-nanocarriers containing paclitaxel targeting folate-receptors in a malignant pH-microenvironment for effective monitoring and promoting breast tumor regression

    NASA Astrophysics Data System (ADS)

    Puvvada, Nagaprasad; Rajput, Shashi; Kumar, B. N. Prashanth; Sarkar, Siddik; Konar, Suraj; Brunt, Keith R.; Rao, Raj R.; Mazumdar, Abhijit; Das, Swadesh K.; Basu, Ranadhir; Fisher, Paul B.; Mandal, Mahitosh; Pathak, Amita

    2015-07-01

    Low pH in the tumor micromilieu is a recognized pathological feature of cancer. This attribute of cancerous cells has been targeted herein for the controlled release of chemotherapeutics at the tumour site, while sparing healthy tissues. To this end, pH-sensitive, hollow ZnO-nanocarriers loaded with paclitaxel were synthesized and their efficacy studied in breast cancer in vitro and in vivo. The nanocarriers were surface functionalized with folate using click-chemistry to improve targeted uptake by the malignant cells that over-express folate-receptors. The nanocarriers released ~75% of the paclitaxel payload within six hours in acidic pH, which was accompanied by switching of fluorescence from blue to green and a 10-fold increase in the fluorescence intensity. The fluorescence-switching phenomenon is due to structural collapse of the nanocarriers in the endolysosome. Energy dispersion X-ray mapping and whole animal fluorescent imaging studies were carried out to show that combined pH and folate-receptor targeting reduces off-target accumulation of the nanocarriers. Further, a dual cell-specific and pH-sensitive nanocarrier greatly improved the efficacy of paclitaxel to regress subcutaneous tumors in vivo. These nanocarriers could improve chemotherapy tolerance and increase anti-tumor efficacy, while also providing a novel diagnostic read-out through fluorescent switching that is proportional to drug release in malignant tissues.

  15. Novel ZnO hollow-nanocarriers containing paclitaxel targeting folate-receptors in a malignant pH-microenvironment for effective monitoring and promoting breast tumor regression

    PubMed Central

    Puvvada, Nagaprasad; Rajput, Shashi; Kumar, B.N. Prashanth; Sarkar, Siddik; Konar, Suraj; Brunt, Keith R.; Rao, Raj R.; Mazumdar, Abhijit; Das, Swadesh K.; Basu, Ranadhir; Fisher, Paul B.; Mandal, Mahitosh; Pathak, Amita

    2015-01-01

    Low pH in the tumor micromilieu is a recognized pathological feature of cancer. This attribute of cancerous cells has been targeted herein for the controlled release of chemotherapeutics at the tumour site, while sparing healthy tissues. To this end, pH-sensitive, hollow ZnO-nanocarriers loaded with paclitaxel were synthesized and their efficacy studied in breast cancer in vitro and in vivo. The nanocarriers were surface functionalized with folate using click-chemistry to improve targeted uptake by the malignant cells that over-express folate-receptors. The nanocarriers released ~75% of the paclitaxel payload within six hours in acidic pH, which was accompanied by switching of fluorescence from blue to green and a 10-fold increase in the fluorescence intensity. The fluorescence-switching phenomenon is due to structural collapse of the nanocarriers in the endolysosome. Energy dispersion X-ray mapping and whole animal fluorescent imaging studies were carried out to show that combined pH and folate-receptor targeting reduces off-target accumulation of the nanocarriers. Further, a dual cell-specific and pH-sensitive nanocarrier greatly improved the efficacy of paclitaxel to regress subcutaneous tumors in vivo. These nanocarriers could improve chemotherapy tolerance and increase anti-tumor efficacy, while also providing a novel diagnostic read-out through fluorescent switching that is proportional to drug release in malignant tissues. PMID:26145450

  16. A phase I pharmacokinetic study of matuzumab in combination with paclitaxel in patients with EGFR-expressing advanced non-small cell lung cancer.

    PubMed

    Hartmann, J T; Kollmannsberger, C; Cascorbi, I; Mayer, F; Schittenhelm, M M; Heeger, S; Bokemeyer, C

    2013-06-01

    Matuzumab is a humanized IgG1 EGFR monoclonal antibody. This phase I study investigated the tolerability, safety and pharmacokinetics (PK) of matuzumab in combination with paclitaxel in patients with EGFR-expressing advanced non-small cell lung cancer (NSCLC). Six dose levels/schedules of matuzumab were explored in combination with paclitaxel. Dose was escalated from 100 mg to 1,600 mg on a modified Fibonacci scheme according to the incidence of dose-limiting toxicity (DLT) over the first two cycles. DLT was assessed in patients who completed the first two treatment cycles or who stopped treatment because of a DLT during those cycles. Patients with non-progressive disease could then continue to receive study treatment for up to 6 months. The safety population comprised 44 patients, with DLT evaluable in 33. The maximum tolerated dose was not reached, with only one DLT reported at the 1,600 mg 3-weekly dose level. The most frequent grade 3/4 adverse events across all cycles were dyspnea (23 %) and neutropenia (11 %). Matuzumab exhibited non-linear PK, with accumulation after escalation and repeated dosing. Tumor growth control was seen in 15/44 (34 %) patients, including 5/9 (56 %) at the 800 mg weekly dose level. Matuzumab combined with paclitaxel was generally well tolerated in patients with advanced NSCLC. There was some evidence of anticancer activity in relation to the matuzumab 800 mg weekly dose. PMID:22832803

  17. A Phase 2 Trial of Radiation Therapy With Concurrent Paclitaxel Chemotherapy After Surgery in Patients With High-Risk Endometrial Cancer: A Korean Gynecologic Oncologic Group Study

    SciTech Connect

    Cho, Hanbyoul; Nam, Byung-Ho; Kim, Seok Mo; Cho, Chi-Heum; Kim, Byoung Gie; Ryu, Hee-Sug; Kang, Soon Beom; Kim, Jae-Hoon

    2014-09-01

    Purpose: A phase 2 study was completed by the Korean Gynecologic Oncologic Group to evaluate the efficacy and toxicity of concurrent chemoradiation with weekly paclitaxel in patients with high-risk endometrial cancer. Methods and Materials: Pathologic requirements included endometrial endometrioid adenocarcinoma stages III and IV. Radiation therapy consisted of a total dose of 4500 to 5040 cGy in 5 fractions per week for 6 weeks. Paclitaxel 60 mg/m{sup 2} was administered once weekly for 5 weeks during radiation therapy. Results: Fifty-seven patients were enrolled between January 2006 and March 2008. The median follow-up time was 60.0 months (95% confidence interval [CI], 51.0-58.2). All grade 3/4 toxicities were hematologic and usually self-limited. There was no life-threatening toxicity. The cumulative incidence of intrapelvic recurrence sites was 1.9% (1/52), and the cumulative incidence of extrapelvic recurrence sites was 34.6% (18/52). The estimated 5-year disease-free and overall survival rates were 63.5% (95% CI, 50.4-76.5) and 82.7% (95% CI, 72.4-92.9), respectively. Conclusions: Concurrent chemoradiation with weekly paclitaxel is well tolerated and seems to be effective for high-risk endometrioid endometrial cancers. This approach appears reasonable to be tested for efficacy in a prospective, randomized controlled study.

  18. MicroRNA-101 inhibits cell progression and increases paclitaxel sensitivity by suppressing MCL-1 expression in human triple-negative breast cancer

    PubMed Central

    Chen, Jianping; Song, Cailu; Yang, Lu; Liu, Peng; Wang, Neng; Xie, Xinhua; Lin, Xiaoti; Xie, Xiaoming

    2015-01-01

    Triple-negative breast cancer is the most aggressive breast cancer subtype. The aim of our study was to investigate the functional role of both miR-101 and MCL-1 in the sensitivity of human triple-negative breast cancer (TNBC) to paclitaxel. We found that the expression of miR-101 was strongly decreased in triple-negative breast cancer tissues and cell lines. The expression of miR-101 was not associated with clinical stage or lymph node infiltration in TNBC. Ectopic overexpression of miR-101 inhibit growth and induced apoptosis in vitro and suppressed tumorigenicity in vivo. MCL-1 was significantly overexpressed in most of the TNBC tissues and cell lines. Luciferase assay results confirmed MCL-1 as a direct target gene of miR-101. MiR-101 inhibited MCL-1 expression in TNBC cells and transplanted tumors. There was a negative correlation between the level of expression of miR-101 and MCL-1 in TNBC tissues. Suppression of MCL-1 enhanced the sensitivity of MDA-MB-435 cells to paclitaxel. Furthermore, miR-101 increased paclitaxel sensitivity by inhibiting MCL-1 expression. Our findings provide significant insight into the molecular mechanisms of TNBC carcinogenesis and may have clinical relevance for the development of novel, targeted therapies for TNBC. PMID:26036638

  19. A Near-Complete Response to Treatment with Gemcitabine plus nab®-Paclitaxel in a Patient with Metastatic Pancreatic Cancer and Poor Performance Status: A Case Report

    PubMed Central

    Shakir, Abdur R.

    2014-01-01

    Patients with metastatic pancreatic adenocarcinoma and poor performance status (PS) are typically excluded from clinical trials of new systemic treatments. Due to concerns that such patients cannot tolerate the greater toxicity sometimes associated with combination chemotherapy regimens, the recommended treatment for pancreatic cancer patients with poor PS is gemcitabine monotherapy. We report the case of a 79-year-old female with pancreatic adenocarcinoma metastatic to the lungs, with multiple comorbidities and an Eastern Cooperative Oncology Group PS of 3, who achieved a rapid and prolonged objective response to gemcitabine plus nab®-paclitaxel. The patient received a total of 11 cycles of treatment. Although her disease was well controlled with gemcitabine plus nab-paclitaxel, she died just over 11 months after diagnosis as a result of her comorbid conditions compounded by treatment-related hematologic toxicity. This case suggests that patients with metastatic pancreatic adenocarcinoma and poor PS may benefit from first-line combination therapy with gemcitabine plus nab-paclitaxel. Further study of this regimen in such patients is warranted. PMID:25493084

  20. The efficacy and toxicities of combined lobaplatin with paclitaxel as a first-line chemotherapy for advanced esophageal squamous cell carcinoma

    PubMed Central

    Chen, Ming-Qiu; Chen, Cheng; Lu, Hai-Jie

    2015-01-01

    Background To assess the efficacy and toxicities of combined lobaplatin with paclitaxel (LP) as a first line chemotherapy in esophageal cancer. Methods The clinical data of 45 patients with esophageal squamous cell carcinoma treated initially with lobaplatin-paclitaxel chemotherapy were collected and reviewed retrospectively. The overall response, treatment toxicities and dysphagia relief were analyzed with SPSS software. Results The overall response rate was 42.2%, with 1 patient (2.2%) showing complete remission, 18 patients (40.0%) with partial remission, 19 (42.2%) with stable disease (SD), and 7 (15.6%) with progressive disease, respectively. The most common hematological toxicity was leucopenia with grade 0, I, II, III and IV in 16 (35.6%), 10 (22.2%), 11 (24.4%), 7 (15.6%), and 1 patient (2.2%), respectively. Thirty-seven patients (82.2%) experienced grade I-II nausea/vomiting without grade III-IV instances occurring. Four patients (8.9%) experienced grade I hepatotoxicity. No nephrotoxicity was observed. Five in thirteen patients treated with concurrent chemoradiotherapy (CRT) suffered severe radiation pneumonitis. The dysphagia resolved or improved in 32 patients (71%). Conclusions Lobaplatin-paclitaxel showed a significant antitumor effect to squamous esophageal cancer with manageable toxicities. Limitation of the surveillance time and the retrospective nature, the effect that based on these data formal prospective trials appear warranted and are needed prior to routine first line use of this regimen.

  1. Biological Assessment of Triazine Dendrimers as Candidate Platforms for Nanomedicine: Toxicological Profiles, Solution Behavior, Biodistribution, and Drug Release and Efficacy in a PEGylated, Paclitaxel Construct

    PubMed Central

    Lo, Su-Tang; Stern, Stephan; Clogston, Jeffrey D.; Zheng, Jiwen; Adiseshaiah, Pavan P.; Dobrovolskaia, Marina; Lim, Jongdoo; Patri, Anil; Sun, Xiankai; Simanek, Eric E.

    2010-01-01

    The physicochemical characteristics, in vitro properties, and in vivo toxicity and efficacy of a third generation triazine dendrimer bearing approximately nine 2 kDa polyethylene glycol chains and twelve ester linked paclitaxel groups are reported. The hydrodynamic diameter of the neutral construct varies slightly with aqueous solvent ranging from 15.6–19.4 nm. Mass spectrometry and light scattering suggest radically different molecular weights with the former ~40 kDa mass consistent with expectation, and the latter 400 kDa mass consistent with a decameric structure and the observed hydrodynamic radii. HPLC can be used to assess purity as well as paclitaxel release, which is insignificant in organic solvents or aqueous solutions at neutral and low pH. Paclitaxel release occurs in vitro in human, rat, and mouse plasma and is non-linear, ranging from 7–20% cumulative release over a 48 hour incubation period. The construct is 2–3 orders of magnitude less toxic than Taxol® by weight in human hepatocarcinoma (Hep G2), porcine renal proximal tubule (LLC-PK1), and human colon carcinoma (LS174T) cells, but shows similar cytotoxicity to Abraxane® in LS174T cells. Both Taxol® and the construct appear to induce caspase 3-dependent apoptosis. The construct shows a low level of endotoxin, is not hemolytic and does not induce platelet aggregation in vitro, but does appear to reduce collagen-induced platelet aggregation in vitro. Furthermore, the dendrimer formulation slightly activates the complement system in vitro due most likely to the presence of trace amounts (<1%) of free paclitaxel. An animal study provided insight into the maximum tolerated dose (MTD) wherein 10, 25, 50 and 100 mg paclitaxel/kg of construct or Abraxane were administered once per week for three consecutive weeks to non-tumor bearing athymic nude mice. The construct showed in vivo toxicity comparable to Abraxane. Both formulations were found to be non-toxic at the administered doses, and the dendrimer had an acute MTD greater than the highest dose administered. In a prostate tumor model (PC-3-luc), efficacy was observed over 70 days with an arrest of tumor growth and lack of luciferase activity observed in the twice treated cohort. PMID:20481608

  2. A Phase I Study of UFT/Leucovorin, Carboplatin, and Paclitaxel in Combination With External Beam Radiation Therapy for Advanced Esophageal Carcinoma

    SciTech Connect

    Czito, Brian G. Cohen, Darrel P.; Kelsey, Chris R.; Lockhart, A. Craig; Bendell, Johanna C.; Willett, Christopher G.; Petros, William P.; D'Amico, Thomas A.; Truax, Roxanne R.N.; Hurwitz, Herbert I.

    2008-03-15

    Purpose: Concurrent chemotherapy and radiation therapy (RT) are used to treat patients with esophageal cancer. The optimal combination of chemotherapeutic agents with RT is not well established. We evaluated the safety and preliminary efficacy of a combination of UFT/leucovorin, carboplatin, and paclitaxel with RT in a Phase I study of patients with advanced esophageal cancer. Methods and Materials: Patients with squamous cell carcinoma or adenocarcinoma of the esophagus initially received UFT/leucovorin, carboplatin, and paclitaxel with RT (1.8 Gy daily to 45 Gy). After completion, the disease was restaged and patients were evaluated for surgery. Primary end points included determination of dose-limiting toxicities (DLTs) and a recommended Phase II dose. Secondary objectives included determination of non-DLTs, as well as preliminary radiographic and pathologic response rates. Results: Twelve patients were enrolled (11 men, 1 woman). All were assessable for toxicity and efficacy. One of 6 patients at Dose Level 1 (UFT/leucovorin, 200/30 mg twice daily on RT days; carboplatin, area under the curve [AUC] 5, Weeks 1 and 4; paclitaxel, 175 mg/m{sup 2} Weeks 1 and 4) had a DLT (febrile neutropenia). Of these 6 patients, 4 underwent esophagectomy and none achieved a pathologic complete response. Six patients were then enrolled at Dose Level 2 (UFT/leucovorin, 300/30 mg in the morning and 200/30 mg in the evening on RT days; carboplatin, AUC 5, Weeks 1 and 4; paclitaxel, 175 mg/m{sup 2} Weeks 1 and 4). Two of 6 patients at Dose Level 2 developed DLTs (febrile neutropenia in both). Esophagectomy was performed in 3 patients, with 2 achieving a pathologic complete response. Conclusions: Maximum tolerated doses in this study were UFT/leucovorin, 200/30 mg twice daily on RT days; carboplatin, AUC 5, Weeks 1 and 4; and paclitaxel, 175 mg/m{sup 2} Weeks 1 and 4 when delivered with external RT. In this small study, this regimen appears active, but toxic.

  3. Azithromycin enhances the favorable results of paclitaxel and cisplatin in patients with advanced non-small cell lung cancer.

    PubMed

    Chu, D J; Yao, D E; Zhuang, Y F; Hong, Y; Zhu, X C; Fang, Z R; Yu, J; Yu, Z Y

    2014-01-01

    Although new chemotherapeutic drugs have been applied constantly, their efficacy for non-small cell lung cancer (NSCLC) is still not satisfactory. In recent years, epidemiological investigations have shown that lung cancer may be induced by chronic Chlamydia pneumoniae (Cpn) infection, since stable high titers of Cpn antibodies, especially IgA, are a hallmark of chronic infections. Azithromycin is commonly used for the treatment of Cpn infections; however, there are only few reports regarding the application of azithromycin (A) combined with paclitaxel and cisplatin (TP) for advanced NSCLC. Considering that patients with NSCLC have a higher rate of Cpn infection, we proposed to employ azithromycin for Cpn infection in chemotherapy for advanced NSCLC. The aim of this study was to explore the effects of azithromycin on chemotherapy for NSCLC. A total of 86 patients with stage III-IV NSCLC were randomly divided into TP and ATP groups; the characteristics of patients in the two groups showed no significant differences. The TP group was treated with paclitaxel and cisplatin, and the ATP group was treated with azithromycin combined with TP for at least 4 weeks, followed by evaluation and comparison of efficacy, side effects and patients' quality of life before and after chemotherapy between the two groups. Testing for Cpn infection revealed a significant difference in the case number before and after therapy in the ATP group (P < 0.01) compared with the TP group (P > 0.05), and a statistical difference was observed (P < 0.01) between the ATP and TP groups after treatment. The changes in quality of life of patients after two different chemotherapy regimens were statistically significant (P < 0.05), but there was a significant difference in only cognitive function after treatment. The changes in symptom scores of patients after the two different chemotherapy regimens were statistically significant (P < 0.05), but there was a significant difference in only shortness of breath and cough after treatment. Kaplan-Meier estimate was utilized to describe the survival function of patients in the two groups. The median survival time was 12.0 months for the TP group and 13.0 months for the ATP group. One-year survival rates of the TP and ATP groups were 45.0 and 75.0%, respectively, which were significantly different (P < 0.05). Our study of azithromycin+paclitaxe l+cisplatin on stage III-IV NSCLC patients achieved favorable results in terms of side effects and overall survival. PMID:24782093

  4. Synthesis and Self-Assembly of a Mikto-Arm Star Dual Drug Amphiphile Containing both Paclitaxel and Camptothecin

    PubMed Central

    Cheetham, A.G.; Zhang, P.; Lin, Y.-A.; Lin, R.; Cui, H.

    2014-01-01

    Self-assembly of anticancer therapeutics into discrete nanostructures provides an innovative way to develop a self-delivering nanomedicine with a high, quantitative drug loading. We report here the synthesis and assembly of a mikto-arm star dual drug amphiphile (DA) containing both a bulky paclitaxel (PTX) and a planar camptothecin (CPT). The two anti-cancer drugs of interest were stochastically conjugated to a ?-sheet forming peptide (Sup35) and under physiologically-relevant conditions the dual DA could spontaneously associate into supramolecular filaments with a fixed 41% total drug loading (29% PTX and 12% CPT). Transmission electron microscopy imaging and circular dichroism spectroscopy studies reveal that the bulkiness of the PTX, as well as the ?-? interaction preference between the CPT units, has a significant impact on the assembly kinetics, molecular level packing, and nanostructure morphology and stability. We found that the DA containing two PTX units assembled into non-filamentous micelle-like structures, in contrast to the filamentous structures formed by the hetero dual DA and the DA containing two CPTs. The hetero dual DA was found to effectively release the two anticancer agents, exhibiting superior cytotoxicity against PTX-resistant cervical cancer cells. The presented work offers a potential method to generate well-defined entwined filamentous nanostructures and provides the basis for a future combination therapy platform. PMID:25667746

  5. Improved antitumor effect of paclitaxel administered in vivo as pH and glutathione-sensitive nanohydrogels.

    PubMed

    Pérez, Elena; Martínez, Ana; Teijón, César; Olmo, Rosa; Teijón, José María; Blanco, María Dolores

    2015-08-15

    Most antitumor drugs usually affect not only rapidly dividing cells, such as those in tumors, but also highly proliferative cells in normal tissues. This nonspecific drawback could be successfully solved by using nanocarriers as controlled drug delivery systems. In this work, pH and redox-responsive nanohydrogels (NG) based on N-isopropylacrilamide (NIPA), N-hydroxyethyl acrylamide (HEEA) 2-acrylamidoethyl carbamate (2AAECM) and N,N'-cystaminebisacrylamide (CBA) as crosslinker were evaluated as bioreducible paclitaxel (PTX) nanocarriers for improving the accumulation of the drug within the tumor tissue and avoiding its conventional side effects. A single dose of PTX solution, unloaded-NHA 80/15/5CBA NG and PTX-loaded NHA 80/15/5-CBA NG (30 mg/kg PTX equivalent) were subcutaneously injected in female athymic nude mice bearing HeLa human tumor xenografts. PTX-loaded nanohydrogels showed higher antitumor activity than free PTX, as tumor evolution and Ki67 detection demonstrated. Histological tumor images revealed a higher content of defective mitotic figures and apoptotic bodies in PTX- treated tumors than in control or unloaded NG treated tumor samples. Nanohydrogels injection did not change any biochemical blood parameters, which means no liver or kidney damage after NG injection. However, differences in antioxidant defenses in MPS systems (liver, kidney and spleen) were observed among treatments, which may indicate an oxidative stress response after PTX injection. PMID:26160666

  6. Zerumbone inhibits growth of hormone refractory prostate cancer cells by inhibiting JAK2/STAT3 pathway and increases paclitaxel sensitivity.

    PubMed

    Jorvig, Jessica E; Chakraborty, Arup

    2015-02-01

    Zerumbone, a phytochemical isolated from Zingiber zerumbet has been shown previously to exhibit antineoplastic activity. But, the effect of zerumbone in prostate cancer has not been evaluated. Prostate cancer is frequently associated with elevated levels of interleukin-6 (IL-6), which exerts its oncogenic effects through activation of Janus kinase 2 (JAK2) followed by activation of the transcription factor STAT3 (signal transducer and activator of transcription 3). Here, we investigated whether the anticancer effects of zerumbone are mediated through inhibition of the JAK2/STAT3 signaling pathway and whether zerumbone can increase the paclitaxel (PTX) sensitivity of prostate cancer cells. Zerumbone exerted significant cytotoxicity of DU145 versus PC3 prostate cancer cells through cell cycle arrest at G0/G1 phase followed by apoptosis. Zerumbone selectively inhibited JAK2 in both DU145 and PC3 cells. However, the biological axis of IL-6/JAK2/STAT3 was inhibited only in DU145 cells as no STAT3 phosphorylation was detected in PC3 cells even after IL-6 stimulation. Other signaling pathways in DU145 cells remained unaffected. The expression of prostate cancer-associated genes, including cyclin D1, IL-6, COX2, and ETV1, was blocked. Zerumbone also synergistically increased the sensitivity to PTX. Further preclinical study might reveal the potential use of zerumbone as a chemotherapeutic agent for hormone refractory prostate cancer where IL-6/JAK2/STAT3 signaling is aberrantly active and may be combined with PTX. PMID:25243457

  7. Cyclin-dependent kinase 1 inhibitor RO3306 promotes mitotic slippage in paclitaxel-treated HepG2 cells.

    PubMed

    Xiao, J; Qiu, P; Lai, X; He, P; Wu, Y; Du, B; Tan, Y

    2014-01-01

    Hepatocellular carcinoma (HCC) is the most common primary liver neoplasm and current systemic chemotherapy are mostly ineffective. Paclitaxel (PTX) has a clinically significant effect on many malignant tumors. Cells treated with PTX undergo reversible mitotic arrest and although high doses can cause side effects it may also induce apoptosis. We investigated the effect of a sequential combination of PTX and RO3306, a cyclin-dependent kinase 1 inhibitor, on the hepatocellular carcinoma HepG2 cell line. The sequential drug treatment protocol involved the addition of PTX (0.2 µmol/L) for 18 h followed by RO3306 (2 µmol/L) for a further 6 h. Cell viability and proliferation were measured using tetrazolium dye (MTT) and colony formation assay. Cell cycle profiles were established by flow cytometry. The expression level of protein was examined by immunoblotting. We observed a synergistic effect of PTX and RO3306 treatment on cell growth and proliferation as well as an increased proportion of cells in sub-G1 phase. Expression levels of cyclin B, cyclin E and phosphorylated Histone H3 demonstrated that RO3306 enhanced apoptosis in PTX treated cells by mitotic slippage. Our data suggested that the combination of PTX and RO3306 may be an effective therapeutic combination for the treatment of liver cancer. PMID:24195507

  8. Percutaneous coronary intervention in heavily calcified lesions using rotational atherectomy and paclitaxel-eluting stents: outcomes at one year.

    PubMed

    García de Lara, Juan; Pinar, Eduardo; Ramón Gimeno, Juan; Hurtado, José Antonio; Lacunza, Javier; Valdesuso, Raúl; Valdés Chávarri, Mariano

    2010-01-01

    Heavily calcified lesions present a challenge for percutaneous coronary intervention. With rotational atherectomy, it is possible to treat these lesions and paclitaxel-eluting stents (PESs) reduce the risk of restenosis over the long term. This retrospective study investigated clinical outcomes with rotational atherectomy and PESs in 50 consecutive patients with heavily calcified lesions. Mortality and target lesion revascularization at 1 year (median, 14 months; interquartile range, 8.75-25.5 months) were recorded. Some 52% of patients were aged over 70 years, 68% were male, 52% had acute coronary syndrome, 80% had multivessel disease and 44% were receiving abciximab. Two patients died in hospital, three died during follow-up (one cardiac death) and 3 (6%) underwent target lesion revascularization. At 1 year, the survival rate free of cardiac death was 94% and the survival rate free of target lesion revascularization was 94%. These findings demonstrate that the combination of rotational atherectomy and PESs gives excellent results in heavily calcified lesions. PMID:20089233

  9. Ultrasound-Mediated Destruction of LHRHa Targeted and Paclitaxel Loaded Lipid Microbubbles for the Treatment of Intraperitoneal Ovarian Cancer Xenografts

    PubMed Central

    Chang, Shufang; Liu, Hongxia; Zhu, Yi; Wang, Zhigang; Xu, Ronald X.

    2014-01-01

    Ultrasound-targeted microbubble destruction (UTMD) is a promising technique to facilitate the delivery of chemotherapy in cancer treatment. However, the process typically uses non-specific microbubbles, leading to low tumor-to-normal tissue uptake ratio and adverse side effects. In this study, we synthesized the LHRH receptor targeted and paclitaxel (PTX) loaded lipid microbubbles (TPLMBs) for tumor-specific binding and enhanced therapeutic effect at the tumor site. An ovarian cancer xenograft model was established by injecting A2780/DDP cells intraperitoneally in BALB/c nude mice. Microscopic imaging of tumor sections after intraperitoneal injection of TPLMBs showed effective binding of the microbubbles with cancer cells. Ultrasound mediated destruction of the intraperitoneally injected TPLMBs yielded a superior therapeutic outcome in comparison with other treatment options. Immunohistochemical analyses of the dissected tumor tissue further confirmed the increased tumor apoptosis and reduced angiogenesis. Our experiment suggests that ultrasound mediated intraperitoneal administration of the targeted drug-loaded microbubbles may be a useful method for the treatment of ovarian cancer. PMID:24237050

  10. Telodendrimer nanocarrier for co-delivery of paclitaxel and cisplatin: A synergistic combination nanotherapy for ovarian cancer treatment.

    PubMed

    Cai, Liqiong; Xu, Gaofei; Shi, Changying; Guo, Dandan; Wang, Xu; Luo, Juntao

    2015-01-01

    Cisplatin (CDDP) and paclitaxel (PTX) are two established chemotherapeutic drugs used in combination for the treatment of many cancers, including ovarian cancer. We have recently developed a three-layered linear-dendritic telodendrimer micelles (TM) by introducing carboxylic acid groups in the adjacent layer via "thio-ene" click chemistry for CDDP complexation and conjugating cholic acids via peptide chemistry in the interior layer of telodendrimer for PTX encapsulation. We hypothesize that the co-delivery of low dosage PTX with CDDP could act synergistically to increase the treatment efficacy and reduce their toxic side effects. This design allowed us to co-deliver PTX and CDDP at various drug ratios to ovarian cancer cells. The in vitro cellular assays revealed strongest synergism in anti-tumor effects when delivered at a 1:2 PTX/CDDP loading ratio. Using the SKOV-3 ovarian cancer xenograft mouse model, we demonstrate that our co-encapsulation approach resulted in an efficient tumor-targeted drug delivery, decreased cytotoxic effects and stronger anti-tumor effect, when compared with free drug combination or the single loading TM formulations. PMID:25453973

  11. Structural Characterization of Anticancer Drug Paclitaxel and Its Metabolites Using Ion Mobility Mass Spectrometry and Tandem Mass Spectrometry

    NASA Astrophysics Data System (ADS)

    Lee, Hong Hee; Hong, Areum; Cho, Yunju; Kim, Sunghwan; Kim, Won Jong; Kim, Hugh I.

    2015-10-01

    Paclitaxel (PTX) is a popular anticancer drug used in the treatment of various types of cancers. PTX is metabolized in the human liver by cytochrome P450 to two structural isomers, 3'-p-hydroxypaclitaxel (3p-OHP) and 6?-hydroxypaclitaxel (6?-OHP). Analyzing PTX and its two metabolites, 3p-OHP and 6?-OHP, is crucial for understanding general pharmacokinetics, drug activity, and drug resistance. In this study, electrospray ionization ion mobility mass spectrometry (ESI-IM-MS) and collision induced dissociation (CID) are utilized for the identification and characterization of PTX and its metabolites. Ion mobility distributions of 3p-OHP and 6?-OHP indicate that hydroxylation of PTX at different sites yields distinct gas phase structures. Addition of monovalent alkali metal and silver metal cations enhances the distinct dissociation patterns of these structural isomers. The differences observed in the CID patterns of metalated PTX and its two metabolites are investigated further by evaluating their gas-phase structures. Density functional theory calculations suggest that the observed structural changes and dissociation pathways are the result of the interactions between the metal cation and the hydroxyl substituents in PTX metabolites.

  12. Paclitaxel induces calcium oscillations via an inositol 1,4,5-trisphosphate receptor and neuronal calcium sensor 1-dependent mechanism

    PubMed Central

    Boehmerle, Wolfgang; Splittgerber, Ute; Lazarus, Michael B.; McKenzie, Kathleen M.; Johnston, David G.; Austin, David J.; Ehrlich, Barbara E.

    2006-01-01

    Taxol (Paclitaxel) is an important natural product for the treatment of solid tumors. Despite a well documented tubulin-stabilizing effect, many side effects of taxol therapy cannot be explained by cytoskeletal mechanisms. In the present study submicromolar concentrations of taxol, mimicking concentrations found in patients, induced cytosolic calcium (Ca2+) oscillations in a human neuronal cell line. These oscillations were independent of extracellular and mitochondrial Ca2+ but dependent on intact signaling via the phosphoinositide signaling pathway. We identified a taxol binding protein, neuronal Ca2+ sensor 1 (NCS-1), a Ca2+ binding protein that interacts with the inositol 1,4,5-trisphosphate receptor from a human brain cDNA phage display library. Taxol increased binding of NCS-1 to the inositol 1,4,5-trisphosphate receptor. Short hairpin RNA-mediated knockdown of NCS-1 in the same cell line abrogated the response to taxol but not to other agonists stimulating the phosphoinositide signaling pathway. These findings are important for studies involving taxol as a research tool in cell biology and may help to devise new strategies for the management of side effects induced by taxol therapy. PMID:17114292

  13. Poly(ethylene glycol)-paclitaxel-alendronate self-assembled micelles for the targeted treatment of breast cancer bone metastases.

    PubMed

    Miller, Keren; Clementi, Chiara; Polyak, Dina; Eldar-Boock, Anat; Benayoun, Liat; Barshack, Iris; Shaked, Yuval; Pasut, Gianfranco; Satchi-Fainaro, Ronit

    2013-05-01

    Paclitaxel (PTX) and alendronate (ALN) are effective drugs used for the treatment of breast cancer bone metastases. Growing evidence suggests that low-dose taxanes and bisphosphonates possess anti-angiogenic properties. However, PTX is water-insoluble and toxic, even if administered at anti-angiogenic dosing schedule. Polymer conjugation of PTX will increase water-solubility and improve its pharmacokinetic profile directing it to the tumor site. We further propose to combine it with ALN for active bone targeting. We conjugated ALN and PTX with poly(ethylene glycol) (PEG) forming self-assembled micelles where PTX molecules are located at the inner core and the water-soluble ALN molecules at the outer shell. PTX-PEG-ALN micelles exhibited similar in vitro cytotoxic and anti-angiogenic activity as the free drugs. Biodistribution analysis demonstrated preferential tumor accumulation of FITC-labeled PTX-PEG-ALN micelles. Pharmacokinetic studies revealed longer t1/2 of the conjugate than free PTX. PTX-PEG-ALN micelles achieved improved efficacy and safety profiles over free PTX in syngeneic and xenogeneic mouse models of mCherry-infected mammary adenocarcinoma in the tibia, as monitored intravitally non-invasively by a fluorescence imaging system. The described data warrants the potential use of PTX-PEG-ALN as bone-targeted anticancer and anti-angiogenic therapy for breast cancer bone metastases. PMID:23434349

  14. Antiangiogenic antitumor activity of HPMA copolymer-paclitaxel-alendronate conjugate on breast cancer bone metastasis mouse model.

    PubMed

    Miller, Keren; Eldar-Boock, Anat; Polyak, Dina; Segal, Ehud; Benayoun, Liat; Shaked, Yuval; Satchi-Fainaro, Ronit

    2011-08-01

    Polymer therapeutics have shown promise as tumor-targeted drug delivery systems in mice. The multivalency of polymers allows the attachment of different functional agents to a polymeric backbone, including chemotherapeutic and antiangiogenic drugs, as well as targeting moieties, such as the bone-targeting agent alendronate (ALN). We previously reported the conjugation of ALN and the chemotherapeutic drug paclitaxel (PTX) with N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer. The in vitro physicochemical properties, cancer cytotoxicity and antiangiogenic activity of HPMA copolymer-PTX-ALN conjugate were extensively characterized. The reported results warranted in vivo evaluations of the conjugate. In this manuscript, we evaluated the in vivo anticancer and antiangiogenic activity of HPMA copolymer-PTX-ALN conjugate. The conjugate exhibited an antiangiogenic effect by decreasing microvessel density (MVD), and inducing apoptotic circulating endothelial cells (CEC) following treatment of the mice. Using intravital imaging system and mCherry-labeled breast cancer cell lines, we were able to monitor noninvasively the progression of orthotopic metastatic tumors injected into the tibia of the mice. HPMA copolymer-PTX-ALN conjugate showed the greatest antitumor efficacy on mCherry-labeled 4T1 mammary adenocarcinoma inoculated into the tibia, as compared with PTX alone or in combination with ALN. Treatment with the bone-targeted polymeric conjugate demonstrated improved efficacy, was better tolerated, and was more easily administered intravenously than the clinically used PTX formulated in Cremophor/ethanol. PMID:21545170

  15. Controlled release and reversal of multidrug resistance by co-encapsulation of paclitaxel and verapamil in solid lipid nanoparticles.

    PubMed

    Baek, Jong-Suep; Cho, Cheong-Weon

    2015-01-30

    Paclitaxel (PTX) has been used in the treatment of wide range of cancers but its entry into cancer cell is restricted by p-glycoprotein (p-gp). Also, it was reported that verapamil (VP) could inhibit p-gp efflux. Hence, three kinds of solid lipid nanoparticles (SLN) such as PVS (PTX and VP co-loaded SLN), PSV (PTX loaded SLN, later added VP) and PVSV (PTX and VP co-loaded SLN, later added VP) were prepared to overcome MDR by combination of PTX and VP. PVS was the SLN loaded with both PTX and VP at the same time. PSV was the SLN loaded with PTX and then modified with VP - complexed hydroxypropyl-?-cylcodextrin (HPCD). Finally, PVSV was the SLN loaded with PTX and half of VP at the same time subsequently, modified with half of VP - complexed HPCD. The physicochemical characterizations of PVS, PSV or PVSV such as particle size, zeta potential, encapsulation efficiency or in vitro PTX release were examined. PVSV showed that release of VP was higher than PTX solution in first 15h and sustained release of both VP and PTX. PVSV showed significantly higher cytotoxicity and cellular uptake than that of the PTX solution in MCF-7/ADR resistant cells. Furthermore, PVSV significantly down regulated the expression of p-gp than the PTX solution in MCF-7/ADR resistant cells. Based on these findings, this study indicated that the PVSV exhibited great potential for breast cancer therapy. PMID:25510604

  16. Low molecular weight chitosan-coated polymeric nanoparticles for sustained and pH-sensitive delivery of paclitaxel

    PubMed Central

    Abouelmagd, Sara A.; Ku, Youn Jin; Yeo, Yoon

    2015-01-01

    Low molecular weight chitosan (LMWC) is a promising polymer for surface modification of nanoparticles (NPs), which can impart both stealth effect and electrostatic interaction with cells at mildly acidic pH of tumors. We previously produced LMWC-coated NPs via covalent conjugation to poly(lactic-co-glycolic) acid (PLGA-LMWC NPs). However, this method had several weaknesses including inefficiency and complexity of the production as well as increased hydrophilicity of the polymer matrix, which led to poor drug release control. Here, we used the dopamine polymerization method to produce LMWC-coated NPs (PLGA-pD-LMWC NPs), where the core NPs were prepared with PLGA that served best to load and retain drugs and then functionalized with LMWC via polydopamine layer. The PLGA-pD-LMWC NPs overcame the limitations of PLGA-LMWC NPs while maintaining their advantages. First of all, PLGA-pD-LMWC NPs attenuated the release of paclitaxel to a greater extent than PLGA-LMWC NPs. Moreover, PLGA-pD-LMWC NPs had a pH-dependent surface charge profile and cellular interactions similar to PLGA-LMWC NPs, enabling acid-specific NP-cell interaction and enhanced drug delivery to cells in weakly acidic environment. Although the LMWC layer did not completely prevent protein binding in serum solution, PLGA-pD-LMWC NPs showed less phagocytic uptake than bare PLGA NPs. PMID:26453168

  17. Preparation and characterization of paclitaxel-loaded DSPE-PEG-liquid crystalline nanoparticles (LCNPs) for improved bioavailability.

    PubMed

    Zeng, Ni; Hu, Quanyin; Liu, Zhongyang; Gao, Xiaoling; Hu, Rongkuan; Song, Qingxiang; Gu, Guangzhi; Xia, Huimin; Yao, Lei; Pang, Zhiqing; Jiang, Xinguo; Chen, Jun; Fang, Liang

    2012-03-15

    Lipid-based liquid crystalline nanoparticles (LCNPs) have attracted growing interest as a new drug nanocarrier system for improving bioavailability for both hydrophilic and hydrophobic drugs. In this study, self-assembled LCNPs based on soy phosphatidyl choline and glycerol dioleate, which was known possessing low toxicity and negligible hemolysis, were prepared using poly(ethylene glycol)-grafted 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine (DSPE-PEG) as the dispersing agent. Paclitaxel (PTX) was used as a model hydrophobic drug. The particle size of the optimized DSPE-PEG-LCNPs and PTX-loaded DSPE-PEG-LCNPs were around 70nm. Crossed polarized light microscopy was used to characterize the phase behavior of liquid crystalline (LC) matrices, which showed a fan-like birefringent texture in dark background indicating the coexistence of reversed cubic and hexagonal phase in the optimized LC matrix. Transmission electron microscopy and cryo-field emission scanning electron microscopy revealed its internal water channel and "twig-like" surface morphology. PTX-loaded DSPE-PEG-LCNPs exhibited a biphasic drug sustained release pattern with a relatively fast release at the initial stage and a sustained release afterwards. PTX-loaded DSPE-PEG-LCNPs presented higher AUC (410.942±72.522?g/Lh) when compared with commercial product Taxol (212.670±41.396?g/Lh). These results indicated that DSPE-PEG-LCNPs might serve as a potential sustained release system for poorly water-soluble agents. PMID:22240390

  18. Abraxane, the Nanoparticle Formulation of Paclitaxel Can Induce Drug Resistance by Up-Regulation of P-gp

    PubMed Central

    Bu, Xiangli; Ma, Huailei; Gong, He; Liu, Juan; Fang, Xiangdong; Hu, Zhiyuan; Fang, Qiaojun

    2015-01-01

    P-glycoprotein (P-gp) can actively pump paclitaxel (PTX) out of cells and induces drug resistance. Abraxane, a nanoparticle (NP) formulation of PTX, has multiple clinical advantages over the single molecule form. However, it is still unclear whether Abraxane overcomes the common small molecule drug resistance problem mediated by P-gp. Here we were able to establish an Abraxane-resistant cell line from the lung adenocarcinoma cell line A549. We compared the transcriptome of A549/Abr resistant cell line to that of its parental cell line using RNA-Seq technology. Several pathways were found to be up or down regulated. Specifically, the most significantly up-regulated gene was ABCB1, which translates into P-glycoprotein. We verified the overexpression of P-glycoprotein and confirmed its function by reversing the drug resistance with P-gp inhibitor Verapamil. The results suggest that efflux pathway plays an important role in the Abraxane-resistant cell line we established. However, the relevance of this P-gp mediated Abraxane resistance in tumors of lung cancer patients remains unknown. PMID:26182353

  19. Porous quaternized chitosan nanoparticles containing paclitaxel nanocrystals improved therapeutic efficacy in non-small-cell lung cancer after oral administration.

    PubMed

    Lv, Pi-Ping; Wei, Wei; Yue, Hua; Yang, Ting-Yuan; Wang, Lian-Yan; Ma, Guang-Hui

    2011-12-12

    Clinical application of paclitaxel (PTX) is limited because of its poor solubility in aqueous media. To overcome this hurdle, we devised an oral delivery system by encapsulating PTX into N-((2-hydroxy-3-trimethylammonium) propyl) chitosan chloride (HTCC) nanoparticles. These nanoparticles were small (~130 nm), had a narrow size distribution, and displayed high loading efficiency owing to the homogeneous distribution of PTX nanocrystals. The matrix hydrophilicity and porous structure of the obtained nanoparticles accelerated their degradation and improved drug release. In vitro and in vivo transport experiments had proved that the presence of positive charges enhanced the intestinal permeability of these nanoparticles. Further in vitro experiment of cytotoxicity showed that the PTX-loaded HTCC nanoparticle (HTCC-NP:PTX) was more effective than native PTX owing to enhanced cellular uptake. Drug distribution in tissues and in vivo imaging studies confirmed the preferred accumulation of HTCC-NP:PTX in subcutaneous tumor tissue. Subsequent tumor xenograft assays demonstrated the promising therapeutic effect of HTCC-NP:PTX on inhibition of tumor growth and induction of apoptosis in tumor cells. Additional investigation into side effects revealed that HTCC-NP:PTX caused lower Cremophor EL-associated toxicities compared with Taxol. These results strongly supported the notion that HTCC nanoparticle (HTCC-NP) is a promising candidate as an oral carrier of PTX for cancer therapy. PMID:22044456

  20. Codelivery of mTERT siRNA and paclitaxel by chitosan-based nanoparticles promoted synergistic tumor suppression.

    PubMed

    Wei, Wei; Lv, Pi-Ping; Chen, Xiao-Ming; Yue, Zhan-Guo; Fu, Qiang; Liu, Shi-Ying; Yue, Hua; Ma, Guang-Hui

    2013-05-01

    Clinical applications of siRNA are being hindered by poor intracellular uptake and enzymatic degradation. To address these problems, we devised an oral delivery system for telomerase reverse transcriptase siRNA using N-((2-hydroxy-3-trimethylammonium) propyl) chitosan chloride (HTCC) nanoparticles (HNP). Both the porous structure and the positive charge of HNP facilitated siRNA encapsulation. The outer coating of HTCC not only protected siRNA from enzymatic degradation, but also improved siRNA permeability in intestine tract. In vivo and in vitro experiments proved that HNP could effectively deliver siRNA to lesion site and further into tumor cells. On the basis of confirming the antitumor activity of HNP:siRNA, we continued to encapsulate a hydrophobic chemotherapeutic drug-paclitaxel (PTX) into HNP to form a "two-in-one" nano-complex (HNP:siRNA/PTX). We demonstrated that HNP:siRNA/PTX could simultaneously ferry siRNA and PTX into tumor cells and increase drug concentration, which, in particular, was much more effective in tumor suppression than that of traditional cocktail therapy. These results suggested that the HNP, as a powerful delivery system for both siRNA and chemotherapeutic drug, would have a far-reaching application in human cancer therapy. PMID:23453062

  1. Optimization of Paclitaxel Containing pH-Sensitive Liposomes By 3 Factor, 3 Level Box-Behnken Design

    PubMed Central

    Rane, Smita; Prabhakar, Bala

    2013-01-01

    The aim of this study was to investigate the combined influence of 3 independent variables in the preparation of paclitaxel containing pH-sensitive liposomes. A 3 factor, 3 levels Box-Behnken design was used to derive a second order polynomial equation and construct contour plots to predict responses. The independent variables selected were molar ratio phosphatidylcholine:diolylphosphatidylethanolamine (X1), molar concentration of cholesterylhemisuccinate (X2), and amount of drug (X3). Fifteen batches were prepared by thin film hydration method and evaluated for percent drug entrapment, vesicle size, and pH sensitivity. The transformed values of the independent variables and the percent drug entrapment were subjected to multiple regression to establish full model second order polynomial equation. F was calculated to confirm the omission of insignificant terms from the full model equation to derive a reduced model polynomial equation to predict the dependent variables. Contour plots were constructed to show the effects of X1, X2, and X3 on the percent drug entrapment. A model was validated for accurate prediction of the percent drug entrapment by performing checkpoint analysis. The computer optimization process and contour plots predicted the levels of independent variables X1, X2, and X3 (0.99, –0.06, 0, respectively), for maximized response of percent drug entrapment with constraints on vesicle size and pH sensitivity. PMID:24302796

  2. Encapsulated paclitaxel nanoparticles exhibit enhanced anti-tumor efficacy in A549 non-small lung cancer cells.

    PubMed

    Huang, Guojin; Zang, Bao; Wang, Xiaowei; Liu, Gang; Zhao, Jianqiang

    2015-12-01

    In the present study, paclitaxel (PTX) were encapsulated with polyethylene glycol (PEG)-polylactide (PLA)/D-? tocopheryl polyethylene glycol 1000 succinate (TPGS) (PEG-PLA/TPGS) and the enhanced anti-tumor activity of this PTX mixed micelles (PTX-MM) was evaluated in lung cancer cells. The PTX-MM prepared by a solvent evaporation method was demonstrated to have high drug-loading efficiency (23.2%), high encapsulation efficiency (76.4%), and small size (59 nm). In vitro release assay showed the slow release behavior of PTX-MM, suggesting the good stability of the PTX-MM essential for long circulation time. In vitro kinetics assay demonstrated that PTX-MM could promote absorption and increase relative bioavailability. The anti-cancer efficiency of PTX-MM was also examined by both in vitro and in vivo studies. PTX-MM exhibits obvious cytotoxicity against lung cancer cells with much lower IC50 value when compared with commercial formulated PTX or PTX + TPGS. The xenograft tumor model studies on nude mice indicated that PTX-MM inhibits tumor growth more effectively than other formulations. It was also found that most of mixed micelles were integral in tumor site to exhibit anti-cancer activity. Our results suggested that the use of PTX-MM as an anti-cancer drug may be an effective approach to treat lung cancer. PMID:26525950

  3. Two-year Outcome of Turkish Patients Treated with Zotarolimus Versus Paclitaxel Eluting Stents in an Unselected Population with Coronary Artery Disease in the Real World: A Prospective Non-randomized Registry in Southern Turkey

    PubMed Central

    Çiçek, Davran; Pekdemir, Hasan; Haberal, Cevahir; Kalay, Nihat; Binici, Süleyman; Altay, Hakan; Müderriso?lu, Haldun

    2011-01-01

    Background: Our purpose was to investigate the clinical outcomes of Zotarolimus- and Paclitaxel-eluting stents in Turkish patients with coronary artery disease (CAD). In general, the outcome of drug-eluting stent (DES) placement has a proven efficacy in randomized trials. However, the difference in efficacy between the Zotarolimus and Paclitaxel-eluting stents in unselected Turkish patients is controversial. Therefore, we investigated the clinical outcomes of these two drug-eluting stents in the real-world. Methods: We created a registry and prospectively analyzed data on a consecutive series of all patients who presented to our institution with symptomatic coronary artery disease between February 2005 and March 2007 and who were treated with the zotarolimus- or the paclitaxel-eluting stent. The follow-up period was approximately two years. The primary end-point was major cardiac events, and the secondary end-point was definite stent thrombosis. Informed consent was obtained from all subjects, and the study protocol was approved by the local ethical committee. Results: In total, 217 patients were treated with either the zotarolimus-eluting stent (n = 116) or the paclitaxel-eluting stent (n = 101). The lesions in the 2 arms of the study were treated similarly by conventional technique. At 24-month follow-up the paclitaxel-eluting stent group showed significantly higher non-Q wave myocardial infarction (2.6% vs 5.9%, p: 0.02), Q wave myocardial infarction (1.7% vs 5.9%, p: 0.049), coronary artery binding graft surgery (2.6% vs 6.9%, p: 0.002), and late stent thrombosis (1.7% vs 3.9%, p: 0.046). Conclusions: Zotarolimus-eluting stents demonstrated better clinical outcomes than Paclitaxel-eluting stents in a daily routine practice of coronary intervention in an unselected Turkish population. PMID:21234271

  4. A Phase II Study of Radiotherapy and Concurrent Paclitaxel Chemotherapy in Breast-Conserving Treatment for Node-Positive Breast Cancer

    SciTech Connect

    Chen, William C.; Kim, Janice; Kim, Edward; Silverman, Paula; Overmoyer, Beth; Cooper, Brenda W.; Anthony, Sue; Shenk, Robert; Leeming, Rosemary; Hanks, Shelli H.; Lyons, Janice A.

    2012-01-01

    Purpose: Administering adjuvant chemotherapy before breast radiotherapy decreases the risk of systemic recurrence, but delays in radiotherapy could yield higher local failure. We assessed the feasibility and efficacy of placing radiotherapy earlier in the breast-conserving treatment course for lymph node-positive breast cancer. Methods and Materials: Between June 2000 and December 2004, 44 women with node-positive Stage II and III breast cancer were entered into this trial. Breast-conserving surgery and 4 cycles of doxorubicin (60 mg/m{sup 2})/cyclophosphamide (600 mg/m{sup 2}) were followed by 4 cycles of paclitaxel (175 mg/m{sup 2}) delivered every 3 weeks. Radiotherapy was concurrent with the first 2 cycles of paclitaxel. The breast received 39.6 Gy in 22 fractions with a tumor bed boost of 14 Gy in 7 fractions. Regional lymphatics were included when indicated. Functional lung volume was assessed by use of the diffusing capacity for carbon monoxide as a proxy. Breast cosmesis was evaluated with the Harvard criteria. Results: The 5-year actuarial rate of disease-free survival is 88%, and overall survival is 93%. There have been no local failures. Median follow-up is 75 months. No cases of radiation pneumonitis developed. There was no significant change in the diffusing capacity for carbon monoxide either immediately after radiotherapy (p = 0.51) or with extended follow-up (p = 0.63). Volume of irradiated breast tissue correlated with acute cosmesis, and acute Grade 3 skin toxicity developed in 2 patients. Late cosmesis was not adversely affected. Conclusions: Concurrent paclitaxel chemotherapy and radiotherapy after breast-conserving surgery shortened total treatment time, provided excellent local control, and was well tolerated.

  5. Concurrent Chemoradiotherapy With Paclitaxel and Nedaplatin Followed by Consolidation Chemotherapy in Locally Advanced Squamous Cell Carcinoma of the Uterine Cervix: Preliminary Results of a Phase II Study

    SciTech Connect

    Zhang Meiqin; Liu Suping; Wang, Xiang-E.

    2010-11-01

    Purpose: To evaluate the efficacy and toxicities of concurrent chemoradiotherapy (CCRT) and consolidation chemotherapy in patients with locally advanced squamous cell cervical carcinoma. Methods and Materials: Patients with LASCC (FIGO Stage IIB-IIIB) were treated with pelvic external beam radiotherapy (45 Gy for Stage IIB and 50 Gy for Stage III) and high-dose-rate intracavitary brachytherapy (50 Gy for Stage IIB and 35 Gy for Stage III). The cumulative dose at point A was 50 Gy for Stage IIB and 65 Gy for Stage III. Concurrent chemotherapy with paclitaxel (35 mg/m{sup 2}) and nedaplatin (20 mg/m{sup 2}) was given every week for 6 weeks. Consolidation chemotherapy with paclitaxel (135 mg/m{sup 2}) and nedaplatin (60 mg/m{sup 2}) was administered every 3 weeks for 4 cycles. Results: All patients completed CCRT, and 28 of 34 patients completed consolidation chemotherapy. The complete response rate was 88% (95% CI, 73-96%). The most common Grade 3 or higher toxicities were leukopenia/neutropenia (10.9% of the cycles). During a median follow up of 23 months (range, 14-30 months), 5 patients had locoregional failure and 1 patient had distant metastasis. The estimated 2-year progression-free survival and overall survival were 82% (95% CI, 68-95%) and 93% (95% CI, 83-100%), respectively. Grade 3 late complications occurred in 3 patients (9%). Conclusions: CCRT with paclitaxel and nedaplatin followed by consolidation chemotherapy is well tolerated and effective in patients with locally advanced squamous cell cervical carcinoma. Further randomized trials of comparing this regimen with the standard treatment are worth while.

  6. Epirubicin and paclitaxel with G-CSF support in first line metastatic breast cancer: a randomized phase II study of dose-dense and dose-escalated chemotherapy.

    PubMed

    Lalisang, R I; Erdkamp, F L G; Rodenburg, C J; Knibbeler-van Rossum, C T A M; Nortier, J W R; van Bochove, A; Slee, P H Th J; Voest, E E; Wils, J A; Wals, J; Loosveld, O J L; Smals, A E M; Blijham, G H; Tjan-Heijnen, V C G; Schouten, H C

    2011-07-01

    An increased dose-intensity can be achieved by either higher dose of chemotherapy per cycle (dose-escalation) or by shortening the interval between cycles (dose-dense). This multicenter randomized phase II study assessed the efficacy and safety of two different approaches: epirubicin 110 mg/m(2) combined with paclitaxel 200 mg/m(2) every 21 days and epirubicin 75 mg/m(2) combined with paclitaxel 175 mg/m(2) every 10 days, both supported with G-CSF. Patients with advanced breast cancer and without prior palliative chemotherapy were scheduled for 6 cycles. Evaluable for response were 101 patients and for toxicity 106 patients. Grade ? 3 toxicities occurred in 39% of patients in the dose-escalated arm and in 29% of the dose-dense arm, mainly febrile neutropenia, thrombocytopenia, neurotoxicity and (asymptomatic) cardiotoxicity. The median delivered cumulative doses for epirubicin/paclitaxel were 656/1194 and 448/1045 mg/m(2), treatment durations were 126 and 61 days, and delivered dose intensities were 36/67 and 51/120 mg/m(2)/week for the dose-escalated and dose-dense arm, respectively. Response rates were 75 and 70%, the progression-free survival 6 and 7 months, respectively. Dose-dense chemotherapy with a lower cumulative dose, a halved treatment time, but a higher dose-intensity may be as effective and safe as dose-escalated chemotherapy. The value of dose-densification over standard scheduled chemotherapy regimes yet needs to be determined. PMID:21584666

  7. Comparative study analyzing survival and safety of bevacizumab/carboplatin/paclitaxel versus carboplatin/docetaxel in initial treatment of metastatic Her-2-negative breast cancer

    PubMed Central

    Kader, Yasser Abdel; Spielmann, Marc; El-Nahas, Tamer; Sakr, Amr; Metwally, Hassan

    2013-01-01

    Purpose In view of the previous reports demonstrating the positive outcome of bevacizumab in metastatic breast cancer, we aimed at comparing the role of bevacizumab-based metronomic combination with taxane (paclitaxel) versus a different taxane (docetaxel)-based regimen in addition to carboplatin as initial treatment for metastatic Her-2-negative breast cancer. Patients and methods This is a randomized Phase III study comparing the progression-free survival (PFS) and safety in Her-2-negative female patients with initial diagnosis of metastatic breast cancer with World Health Organization performance status of 0–II. Forty-one patients were randomized from September 2008 to July 2009 to receive either; (1) bevacizumab 5 mg/kg day 1 and day 15, carboplatin area under the curve (AUC)-2 day 1, day 8, and day 15, and paclitaxel 60 mg/m2 day 1, day 8, and day 15 (arm-I); or (2) carboplatin AUC-5 day 1, docetaxel 75 mg/m2 day 1 (arm-II). The Kaplan–Meier method was used for estimating survival; log-rank test for comparing survival curves. The primary end point was PFS, and secondary end points were overall survival (OS) and safety. Results PFS was 10 months in arm I versus 10.2 months in arm II (P = 0.9). The OS rate was similar in both arms: 37.6 months for arm I versus 37.4 months for arm II (P = 0.92). The toxicity revealed higher incidence of hypertension and proteinuria in arm I; however, with higher incidence of grade III–IV neutropenia and neutropenic fever in arm II. No treatment-related mortality was recorded. Conclusion Bevacizumab/carboplatin/paclitaxel and carboplatin/docetaxel show comparable PFS and OS with different toxicity profiles. PMID:24648756

  8. Phase II trial of paclitaxel, 13-cis retinoic acid and interferon alfa-2b in the treatment of advanced stage or recurrent cervical cancer

    PubMed Central

    Song, Mihae; DiPaola, Robert S.; Cracchiolo, Bernadette M.; Gibbon, Darlene G.; Hellmann, Mira; Nieves-Neira, Wilberto; Vaidya, Ami; Wagreich, Allison R.; Shih, Weichung J.; Rodriguez-Rodriguez, Lorna

    2014-01-01

    Objective Overexpression of bcl-2 is a mechanism of drug resistance in cervical cancer. Agents that downregulate bcl-2 may decrease tumor cell threshold and sensitize tumor cells to chemotherapy. The objective of this multi-institutional phase II trial was to evaluate the efficacy and toxicity of paclitaxel and bcl-2 modulators (13-cis retinoic acid and interferon alfa-2b) in patients with advanced-stage or recurrent cervical cancer. Methods/materials Patients had biopsy-proven metastatic, first relapse, or persistent cervical cancer with no prior chemotherapy except for chemosensitizing agents. The treatment consisted of oral 13-cis retinoic acid 1 mg/kg and subcutaneous interferon alfa-2b 6 mU/m2, days 1-4, and intravenous paclitaxel 175 mg/m2, day 4 until disease progression or adverse events prohibited treatment. The primary endpoint was overall response rate. Results Thirty-three patients were enrolled between March 2001 and June 2009. Thirty-one patients were eligible for evaluation of treatment response. Twenty-seven patients (82%) received prior concurrent chemoradiation or radiotherapy alone before study enrollment. The overall response rate was 30% (six complete responses, four partial responses). Furthermore, seven patients (21%) had stable disease. Grade 3 or 4 adverse events included neutropenia (n=16, 48%), febrile neutropenia (n=1, 3%), and anemia (n=1, 3%). There were no treatment-related deaths. The median progression-free survival was 3.4 months (95% CI, 2.0-7.4 months), and overall survival was 11.2 months (95% CI, 7.5-26.2 months). Of six patients with complete responses, five survived more than two years. Conclusions Combination therapy with paclitaxel, 13-cis retinoic acid, and interferon alfa-2b is feasible and safe in treating patients with advanced and recurrent cervical cancer. PMID:25304678

  9. Preclinical Evaluation of Genexol-PM, a Nanoparticle Formulation of Paclitaxel, as a Novel Radiosensitizer for the Treatment of Non-Small Cell Lung Cancer

    SciTech Connect

    Werner, Michael E.; Cummings, Natalie D.; Sethi, Manish; Wang, Edina C.; Sukumar, Rohit; Carolina Center for Cancer Nanotechnology Excellence, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina ; Moore, Dominic T.; Wang, Andrew Z.

    2013-07-01

    Purpose: A key research objective in radiation oncology is to identify agents that can improve chemoradiation therapy. Nanoparticle (NP) chemotherapeutics possess several properties, such as preferential accumulation in tumors, that are uniquely suited for chemoradiation therapy. To facilitate the clinical translation of NP chemotherapeutics in chemoradiation therapy, we conducted preclinical evaluation of Genexol-PM, the only clinically approved NP chemotherapeutic with a controlled drug release profile, as a radiosensitizer using non-small cell lung cancer (NSCLC) as a model disease. Methods and Materials: The physical characteristics and drug release profile of Genexol-PM were characterized. Genexol-PM's efficacy as a radiosensitizer was evaluated in vitro using NSCLC cell lines and in vivo using mouse xenograft models of NSCLC. Paclitaxel dose to normal lung and liver after Genexol-PM administration were quantified and compared with that after Taxol administration. Results: Genexol-PM has a size of 23.91 ± 0.41 nm and surface charge of ?8.1 ± 3.1 mV. It releases paclitaxel in a controlled release profile. In vitro evaluation of Genexol-PM as a radiosensitizer showed it is an effective radiosensitizer and is more effective than Taxol, its small molecule counterpart, at the half maximal inhibitory concentration. In vivo study of Genexol-PM as a radiosensitizer demonstrated that it is more effective as a radiosensitizer than Taxol. We also found that Genexol-PM leads to lower paclitaxel exposure to normal lung tissue than Taxol at 6 hours postadministration. Conclusions: We have demonstrated that Genexol-PM is more effective than Taxol as a radiosensitizer in the preclinical setting and holds high potential for clinical translation. Our data support the clinical evaluation of Genexol-PM in chemoradiation therapy for NSCLC.

  10. Neoadjuvant Chemoradiation With Paclitaxel/Carboplatin for Selected Stage III Non-Small-Cell Lung Cancer: Long-Term Results of a Trimodality Phase II Protocol

    SciTech Connect

    Hehr, Thomas; Friedel, Godehard; Steger, Volker; Spengler, Werner; Eschmann, Susanne M.; Bamberg, Michael; Budach, Wilfried

    2010-04-15

    Purpose: To evaluate, in a Phase II trial conducted August 1998 through January 2001, the efficacy of neoadjuvant chemotherapy followed by chemoradiotherapy and definitive surgery in patients with locally advanced non-small-cell lung cancer (LA-NSCLC), Stages IIIA bulky and selected Stage IIIB. Patients and Methods: Staging of LA-NSCLC included computed tomography of cranium, thorax, and abdomen, whole-body positron emission tomography, and video mediastinoscopy. Induction chemotherapy with weekly paclitaxel and carboplatin was followed by hyperfractionated accelerated thoracic radiotherapy (45 Gy) with simultaneous weekly paclitaxel and carboplatin. Four to six weeks after completion of induction therapy, restaging and resection of primary tumor and lymph nodes was intended. Results: A total of 59 consecutive patients were enrolled, 25% with Stage IIIA bulky disease, 65% with Stage IIIB, and 10% with Stage IV (excluded from further analysis). Forty-one patients completed induction therapy; in 52.4% a functional (positron emission tomography) downstaging was proven. Thirty-two patients (59.3%) underwent complete tumor resection, and 5 patients had an exploratory thoracotomy only. Histopathologic downstaging was proven in 59.4% and complete response in 21.9%. Hospital mortality was 5.4%. Median duration of follow-up for living patients was 62.1 months. Overall median survival was 22.6 months, 58.2 months for completely resected patients. During induction chemotherapy, Grade 3/4 granulocytopenia occurred in 8% of patients; the most common Grade 3/4 toxicity of chemoradiation was esophagitis, in 26.4% of patients. Conclusions: Induction paclitaxel/carboplatin with hyperfractionated accelerated chemoradiotherapy followed by complete tumor resection demonstrates high efficacy in LA-NSCLC and offers a promising chance of long-term survival.

  11. BEAM: A Randomized Phase II Study Evaluating the Activity of Bevacizumab in Combination With Carboplatin Plus Paclitaxel in Patients With Previously Untreated Advanced Melanoma

    PubMed Central

    Kim, Kevin B.; Sosman, Jeffrey A.; Fruehauf, John P.; Linette, Gerald P.; Markovic, Svetomir N.; McDermott, David F.; Weber, Jeffrey S.; Nguyen, Hoa; Cheverton, Peter; Chen, Daniel; Peterson, Amy C.; Carson, William E.; O'Day, Steven J.

    2012-01-01

    Purpose Metastatic melanoma, a highly vascularized tumor with strong expression of vascular endothelial growth factor, has an overall poor prognosis. We conducted a placebo-controlled, double-blind phase II study of carboplatin plus paclitaxel with or without bevacizumab in patients with previously untreated metastatic melanoma. Patients and Methods Patients were randomly assigned in a two-to-one ratio to carboplatin (area under the curve, 5) plus paclitaxel (175 mg/m2) and bevacizumab (15 mg/kg; CPB) or placebo (CP) administered intravenously once every 3 weeks. Progression-free survival (PFS) was the primary end point. Secondary end points included overall survival (OS) and safety. Results Two hundred fourteen patients (73% with M1c disease) were randomly assigned. With a median follow-up of 13 months, median PFS was 4.2 months for the CP arm (n = 71) and 5.6 months for the CPB arm (n = 143; hazard ratio [HR], 0.78; P = .1414). Overall response rates were 16.4% and 25.5%, respectively (P = .1577). With 13-month follow-up, median OS was 8.6 months in the CP arm versus 12.3 months in the CPB arm (HR, 0.67; P = .0366), whereas in an evaluation 4 months later, it was 9.2 versus 12.3 months, respectively (HR, 0.79; P = .1916). In patients with elevated serum lactate dehydrogenase (n = 84), median PFS and OS were longer in the CPB arm (PFS: 4.4 v 2.7 months; HR, 0.62; OS: 8.5 v 7.5 months; HR, 0.52). No new safety signals were observed. Conclusion The study did not meet the primary objective of statistically significant improvement in PFS with the addition of bevacizumab to carboplatin plus paclitaxel. A larger phase III study will be necessary to determine whether there is benefit to the addition of bevacizumab to carboplatin plus paclitaxel in this disease setting. PMID:22124101

  12. Continuous-Course Reirradiation With Concurrent Carboplatin and Paclitaxel for Locally Recurrent, Nonmetastatic Squamous Cell Carcinoma of the Head-and-Neck

    SciTech Connect

    Kharofa, Jordan; Choong, Nicholas; Wang, Dian; Firat, Selim; Schultz, Christopher; Sadasiwan, Chitra; Wong, Stuart

    2012-06-01

    Purpose: To examine the efficacy and toxicity of continuous-course, conformal reirradiation with weekly paclitaxel and carboplatin for the treatment of locally recurrent, nonmetastatic squamous cell carcinoma of the head and neck (SCCHN) in a previously irradiated field. Methods and Materials: Patients treated with continuous course-reirradiation with concurrent carboplatin and paclitaxel at the Medical College of Wisconsin and the Clement J. Zablocki VA from 2001 through 2009 were retrospectively reviewed. Patients included in the analysis had prior radiation at the site of recurrence of at least 45 Gy. The analysis included patients who received either intensity-modulated radiotherapy (RT) or three-dimensional conformal RT techniques. All patients received weekly concurrent carboplatin (AUC2) and paclitaxel (30-50 mg/m{sup 2}). Results: Thirty-eight patients with nonmetastatic SCCHN met the entry criteria for analysis. The primary sites at initial diagnosis were oropharyngeal or laryngeal in most patients (66%). Median reirradiation dose was 60 Gy (range, 54-70 Gy). Acute toxicity included Grade 2 neutropenia (5%), Grade 3 neutropenia (15%), and Grade 1/2 thrombocytopenia (8%). No deaths occurred from hematologic toxicity. Chemotherapy doses held (50%) was more prevalent than radiation treatment break (8%). Sixty-eight percent of patients required a gastrostomy tube in follow-up. Significant late toxicity was experienced in 6 patients (16%): 1 tracheoesophageal fistula, 1 pharyngocutaneous fistula, 3 with osteoradionecrosis, and 1 patient with a lingual artery bleed. Patients treated with three-dimensional conformal RT had more frequent significant late toxicites than patients treated with intensity-modulated RT (44% and 7% respectively, p < 0.05). The median time to progression was 7 months and progression-free rates at 1, 2, and 5 years was 44%, 34%, and 29% respectively. The median overall survival was 16 months. Overall survival at 1, 3, and 5 years was 54%, 31%, and 20% respectively. Conclusions: Continuous-course, conformal reirradiation with weekly paclitaxel and carboplatin has an acceptable toxicity profile and offers a potentially curative option in a subset of patients with few other options.

  13. Polymer Nanocomposites Based Thermo-Sensitive Gel for Paclitaxel and Temozolomide Co-Delivery to Glioblastoma Cells.

    PubMed

    Xu, Yuanyuan; Shen, Ming; Sun, Ying; Gao, Pei; Duan, Yourong

    2015-12-01

    In this work, we have reported the preparation and optimization of paclitaxel (PTX) and temozolomide (TMZ) loaded monomethoxy (polyethylene glycol)-poly(D, L-lactide-co-glycolide) (mPEG-PLGA) nanocomposite which is a thermo-sensitive gel delivery system to glioblastoma. We utilized the orthogonal design and homogeneous design for the optimal drug-loaded nanoparticles (NPs) and composite gel prescription, respectively. The physicochemical characteristics of NPs and rheological properties of the gel were analyzed. Then the in vitro release of the gel was determined with a membrane-less diffusion system. Finally, the cytotoxic and apoptosis-inducing effects of the gel on the human malignant glioblastoma cell line U87 and C6 rat glioblastoma cell line were evaluated by MTT and flow cytometry apoptosis assay, respectively. The transmission electron microscopy (TEM) analysis revealed the optimized NPs with a relatively uniform diameter and distribution. The homogeneous design and rheological determination showed that the optimized gel prescription was 250 mg/mL Pluronic F127 (F127), 0.5% hydroxy propyl methylcellulose (HPMC-100M), 0.5% Pluronic F68 (F68), 0.5% sodium alginate (SA) and suitable NPs, which possessed the appropriate gelation behaviors: gelation temperature 28.01 degrees C, gelation time 127.1 s and corrosion speed 0.1892 g/cm2 x hr; and rheological properties: suitable elasticity modulus, viscosity modulus and low phase angle. The in vitro results suggested that the PTX and TMZ were sustainedly released from nanoparticles or the composite gel, and the release and elimination time greatly prolonged; and the composite gel possessed much higher growth-inhibiting effect and apoptosis-inducing rate in U87 and C6 cells than other formulations. These findings demonstrated that the optimal gel was a promising delivery system for the interstitial chemotherapy to glioblastoma. PMID:26682412

  14. Paclitaxel combined with harmine inhibits the migration and invasion of gastric cancer cells through downregulation of cyclooxygenase-2 expression

    PubMed Central

    SUN, KUN; TANG, XIAO-HE; XIE, YI-KUI

    2015-01-01

    Cyclooxygenase-2 (COX-2) has a critical role in the invasiveness and metastasis of gastric cancer. In addition, paclitaxel (PTX) and harmine (HM) were reported to be potential therapeutic drug candidates for cancer therapy; however, the synergistic antitumor effect of PTX and HM combined treatment on the human gastric cancer cells remains to be elucidated. The aim of the present study was to evaluate the effects of PTX and/or HM on the cell migration and invasion in two human gastric cancer cell lines, SGC-7901 and MKN-45. MTT assay was used to detect the growth inhibition induced by PTX and HM. The Transwell assay was employed to assess the effects of PTX and HM on the cell migration and invasion. The expression levels of COX-2 and matrix metalloproteinase-9 (MMP-9) were analyzed by western blot analysis. The results demonstrated that PTX and HM inhibited cell proliferation in a dose-dependent manner. Individually PTX and HM were able to inhibit the migration and invasion of two human gastric cancer cells; however, the combination of PTX and HM exerted synergistic effects on migration and invasion inhibition, with downregulation of COX-2 and matrix metalloproteinase (MMP)-9. In conclusion, the results of the present study indicated that combination chemotherapy using PTX with HM exerted an antitumor effect, which may be implicated for the treatment of gastric cancer. Of note, the combination of the two drugs inhibited migration and invasion more effectively compared with each drug alone, the mechanism of which proceeded via the downregulation of COX-2 expression. PMID:26622726

  15. Biochemical characterization of the interactions between doxorubicin and lipidic GM1 micelles with or without paclitaxel loading

    PubMed Central

    Leonhard, Victoria; Alasino, Roxana V; Bianco, Ismael D; Garro, Ariel G; Heredia, Valeria; Beltramo, Dante M

    2015-01-01

    Doxorubicin (Dox) is an anthracycline anticancer drug with high water solubility, whose use is limited primarily due to significant side effects. In this study it is shown that Dox interacts with monosialoglycosphingolipid (GM1) ganglioside micelles primarily through hydrophobic interactions independent of pH and ionic strength. In addition, Dox can be incorporated even into GM1 micelles already containing highly hydrophobic paclitaxel (Ptx). However, it was not possible to incorporate Ptx into Dox-containing GM1 micelles, suggesting that Dox could be occupying a more external position in the micelles. This result is in agreement with a higher hydrolysis of Dox than of Ptx when micelles were incubated at alkaline pH. The loading of Dox into GM1 micelles was observed over a broad range of temperature (4°C–55°C). Furthermore, Dox-loaded micelles were stable in aqueous solutions exhibiting no aggregation or precipitation for up to 2 months when kept at 4°C–25°C and even after freeze–thawing cycles. Upon exposure to blood components, Dox-containing micelles were observed to interact with human serum albumin. However, the amount of human serum albumin that ended up being associated to the micelles was inversely related to the amount of Dox, suggesting that both could share their binding sites. In vitro studies on Hep2 cells showed that the cellular uptake and cytotoxic activity of Dox and Ptx from the micellar complexes were similar to those of the free form of these drugs, even when the micelle was covered with albumin. These results support the idea of the existence of different nano-domains in a single micelle and the fact that this micellar model could be used as a platform for loading and delivering hydrophobic and hydrophilic active pharmaceutical ingredients. PMID:26005348

  16. Development of a hazel cell culture-based paclitaxel and baccatin III production process on a benchtop scale.

    PubMed

    Gallego, Ana; Imseng, Nicole; Bonfill, Mercedes; Cusido, Rosa M; Palazon, Javier; Eibl, Regine; Moyano, Elisabeth

    2015-02-10

    The growing demand for the antitumorous agent paclitaxel and the difficulty in increasing its production by genetic engineering has prompted a search for new sources of taxanes. It has been reported that taxanes can be extracted from the angiosperm Corylus avellana L. Our aim was to improve taxane production by scaling up the process from mL-level to benchtop bioreactors, optimizing culture conditions and comparing the effect of two elicitors, 1 ?M coronatine (Cor) and 100 ?M methyl jasmonate (MeJA). Orbitally shaken flask cultures achieved a maximum fresh cell weight of 11.54 gDCW/L under control conditions, and MeJA- and Cor-treatment produced a statistically significant reduction in growth to 4.28 gDCW/L and 5.69 gDCW/L, while increasing the taxane content 3- and 27-fold, respectively. The enhancing effect of these elicitors on taxane production, despite affecting growth, was confirmed in orbitally shaken TubeSpin Bioreactors 50, where the highest taxane content (8583.3 ?g/L) was obtained when 1?M Cor was used and elicitation took place at a packed cell volume of 50%. Two benchtop stirred bioreactors, BIOSTAT B plus and UniVessel SU, were compared, the latter providing a higher biomass of C. avellana cell suspension cultures. Transferring the established optimum culture conditions for taxane production to the UniVessel SU resulted in a total taxane content of 6246.1 ?g/L, a 10-fold increase compared with shake flask experiments. PMID:25558804

  17. Biochemical characterization of the interactions between doxorubicin and lipidic GM1 micelles with or without paclitaxel loading.

    PubMed

    Leonhard, Victoria; Alasino, Roxana V; Bianco, Ismael D; Garro, Ariel G; Heredia, Valeria; Beltramo, Dante M

    2015-01-01

    Doxorubicin (Dox) is an anthracycline anticancer drug with high water solubility, whose use is limited primarily due to significant side effects. In this study it is shown that Dox interacts with monosialoglycosphingolipid (GM1) ganglioside micelles primarily through hydrophobic interactions independent of pH and ionic strength. In addition, Dox can be incorporated even into GM1 micelles already containing highly hydrophobic paclitaxel (Ptx). However, it was not possible to incorporate Ptx into Dox-containing GM1 micelles, suggesting that Dox could be occupying a more external position in the micelles. This result is in agreement with a higher hydrolysis of Dox than of Ptx when micelles were incubated at alkaline pH. The loading of Dox into GM1 micelles was observed over a broad range of temperature (4°C-55°C). Furthermore, Dox-loaded micelles were stable in aqueous solutions exhibiting no aggregation or precipitation for up to 2 months when kept at 4°C-25°C and even after freeze-thawing cycles. Upon exposure to blood components, Dox-containing micelles were observed to interact with human serum albumin. However, the amount of human serum albumin that ended up being associated to the micelles was inversely related to the amount of Dox, suggesting that both could share their binding sites. In vitro studies on Hep2 cells showed that the cellular uptake and cytotoxic activity of Dox and Ptx from the micellar complexes were similar to those of the free form of these drugs, even when the micelle was covered with albumin. These results support the idea of the existence of different nano-domains in a single micelle and the fact that this micellar model could be used as a platform for loading and delivering hydrophobic and hydrophilic active pharmaceutical ingredients. PMID:26005348

  18. Design of a paclitaxel prodrug conjugate for active targeting of an enzyme upregulated in breast cancer cells.

    PubMed

    Satsangi, Arpan; Roy, Sudipa S; Satsangi, Rajiv K; Vadlamudi, Ratna K; Ong, Joo L

    2014-06-01

    Breast cancer is the second most common cause of cancer-related deaths in women. Chemotherapy is an important treatment modality, and paclitaxel (PTX) is often the first-line therapy for its metastatic form. The two most notable limitations related to PTX-based treatment are the poor hydrophilicity of the drug and the systemic toxicity due to the drug's nonspecific and indiscriminate distribution among the tissues. The present work describes an approach to counter both challenges by designing a conjugate of PTX with a hydrophilic macromolecule that is coupled through a biocleavable linker, thereby allowing for active targeting to an enzyme significantly upregulated in cancer cells. The resultant strategy would allow for the release of the active ingredient preferentially at the site of action in related cancer cells and spare normal tissue. Thus, PTX was conjugated to the hydrophilic poly(amdioamine) [PAMAM] dendrimer through the cathepsin B-cleavable tetrapeptide Gly-Phe-Leu-Gly. The PTX prodrug conjugate (PGD) was compared to unbound PTX through in vitro evaluations against breast cancer cells and normal kidney cells as well as through in vivo evaluations using xenograft mice models. As compared to PTX, PGD demonstrated a higher cytotoxicity specific to cell lines with moderate-to-high cathepsin B activity; cells with comparatively lower cathepsin B activity demonstrated an inverse of this relationship. Regression analysis between the magnitude of PGD-induced cytotoxic increase over PTX and cathepsin B expression showed a strong, statistically significant correlation (r(2) = 0.652, p < 0.05). The PGD conjugate also demonstrated a markedly higher tumor reduction as compared to PTX treatment alone in MDA-MB-231 tumor xenograft models, with PGD-treated tumor volumes being 48% and 34% smaller than PTX-treated volumes at weeks 2 and 3 after treatment initiation. PMID:24847940

  19. A comparative study of thermo-sensitive hydrogels with water-insoluble paclitaxel in molecule, nanocrystal and microcrystal dispersions.

    PubMed

    Lin, Zhiqiang; Mei, Dong; Chen, Meiwan; Wang, Yitao; Chen, Xianhui; Wang, Zhaoyang; He, Bing; Zhang, Hua; Wang, Xueqing; Dai, Wenbing; Yin, Yuxin; Zhang, Qiang

    2015-09-28

    In situ thermo-sensitive hydrogels have attracted increasing attention for alternative cancer therapies due to their long-term and effective drug levels at local sites. Besides synthesizing new thermo-sensitive polymers, we can also fabricate this delivery system by combining a hydrogel with a thermo-response and drug in a different dispersion state, such as drug nanocrystals. However, the impact of the drug dispersion state or dimension on the quality of such a local injectable system is still unknown. So, here we developed and compared three types of F127 hydrogel systems with either paclitaxel or the near infra-red probe DiR in molecules (MOs), nanocrystals (NCs) and microcrystals (MCs), respectively. With 120 nm rod-shape nanocrystals, the NCs-Gel achieved a high drug loading, moderate drug release rate and gel erosion in vitro and in vivo, medium intratumoral drug residue but the best anti-tumor efficacy in 4T1 tumor bearing BALB/c mice. With the free drug solubilized in 20 nm micelles of the gel, the MOs-Gel system demonstrated the least drug loading and the fastest drug release and gel erosion, leading to the least intratumoral residue as well as the lowest anti-tumor effect. Finally, when dispersed in micron-grade rod-shape drug crystals, the MCs-Gel exhibited a high drug loading but poor stability, precipitating in vitro and in vivo, the highest intratumoral residue but the least drug release, resulting in moderate tumor inhibition. In conclusion, this study clarifies the effect of the drug dispersion state and scale on the behavior of a thermo-sensitive hydrogel, indicating the advantage of the NCs-Gel system, and it provides a basis for the future design of the local delivery of hydrophobic anti-cancer agents. PMID:26224484

  20. A comparative study of thermo-sensitive hydrogels with water-insoluble paclitaxel in molecule, nanocrystal and microcrystal dispersions

    NASA Astrophysics Data System (ADS)

    Lin, Zhiqiang; Mei, Dong; Chen, Meiwan; Wang, Yitao; Chen, Xianhui; Wang, Zhaoyang; He, Bing; Zhang, Hua; Wang, Xueqing; Dai, Wenbing; Yin, Yuxin; Zhang, Qiang

    2015-09-01

    In situ thermo-sensitive hydrogels have attracted increasing attention for alternative cancer therapies due to their long-term and effective drug levels at local sites. Besides synthesizing new thermo-sensitive polymers, we can also fabricate this delivery system by combining a hydrogel with a thermo-response and drug in a different dispersion state, such as drug nanocrystals. However, the impact of the drug dispersion state or dimension on the quality of such a local injectable system is still unknown. So, here we developed and compared three types of F127 hydrogel systems with either paclitaxel or the near infra-red probe DiR in molecules (MOs), nanocrystals (NCs) and microcrystals (MCs), respectively. With 120 nm rod-shape nanocrystals, the NCs-Gel achieved a high drug loading, moderate drug release rate and gel erosion in vitro and in vivo, medium intratumoral drug residue but the best anti-tumor efficacy in 4T1 tumor bearing BALB/c mice. With the free drug solubilized in 20 nm micelles of the gel, the MOs-Gel system demonstrated the least drug loading and the fastest drug release and gel erosion, leading to the least intratumoral residue as well as the lowest anti-tumor effect. Finally, when dispersed in micron-grade rod-shape drug crystals, the MCs-Gel exhibited a high drug loading but poor stability, precipitating in vitro and in vivo, the highest intratumoral residue but the least drug release, resulting in moderate tumor inhibition. In conclusion, this study clarifies the effect of the drug dispersion state and scale on the behavior of a thermo-sensitive hydrogel, indicating the advantage of the NCs-Gel system, and it provides a basis for the future design of the local delivery of hydrophobic anti-cancer agents.

  1. The preparation, characterization, and pharmacokinetic studies of chitosan nanoparticles loaded with paclitaxel/dimethyl-?-cyclodextrin inclusion complexes

    PubMed Central

    Ye, Ya-Jing; Wang, Yun; Lou, Kai-Yan; Chen, Yan-Zuo; Chen, Rongjun; Gao, Feng

    2015-01-01

    A novel biocompatible and biodegradable drug-delivery nanoparticle (NP) has been developed to minimize the severe side effects of the poorly water-soluble anticancer drug paclitaxel (PTX) for clinical use. PTX was loaded into the hydrophobic cavity of a hydrophilic cyclodextrin derivative, heptakis (2,6-di-O-methyl)-?-cyclodextrin (DM-?-CD), using an aqueous solution-stirring method followed by lyophilization. The resulting PTX/DM-?-CD inclusion complex dramatically enhanced the solubility of PTX in water and was directly incorporated into chitosan (CS) to form NPs (with a size of 323.9–407.8 nm in diameter) using an ionic gelation method. The formed NPs had a zeta potential of +15.9–23.3 mV and showed high colloidal stability. With the same weight ratio of PTX to CS of 0.7, the loading efficiency of the PTX/DM-?-CD inclusion complex-loaded CS NPs was 30.3-fold higher than that of the PTX-loaded CS NPs. Moreover, it is notable that PTX was released from the DM-?-CD/CS NPs in a sustained-release manner. The pharmacokinetic studies revealed that, compared with reference formulation (Taxol®), the PTX/DM-?-CD inclusion complex-loaded CS NPs exhibited a significant increase in AUC0?24h (the area under the plasma drug concentration–time curve over the period of 24 hours) and mean residence time by 2.7-fold and 1.4-fold, respectively. Therefore, the novel drug/DM-?-CD inclusion complex-loaded CS NPs have promising applications for the significantly improved delivery and controlled release of the poorly water-soluble drug PTX or its derivatives, thus possibly leading to enhanced therapeutic efficacy and less severe side effects. PMID:26170666

  2. D-?-tocopherol polyethylene glycol succinate-based derivative nanoparticles as a novel carrier for paclitaxel delivery

    PubMed Central

    Wu, Yupei; Chu, Qian; Tan, Songwei; Zhuang, Xiangting; Bao, Yuling; Wu, Tingting; Zhang, Zhiping

    2015-01-01

    Paclitaxel (PTX) is one of the most effective antineoplastic drugs. Its current clinical administration Taxol® is formulated in Cremophor EL, which causes serious side effects. Nanoparticles (NP) with lower systemic toxicity and enhanced therapeutic efficiency may be an alternative formulation of the Cremophor EL-based vehicle for PTX delivery. In this study, novel amphipathic 4-arm-PEG-TPGS derivatives, the conjugation of D-?-tocopherol polyethylene glycol succinate (TPGS) and 4-arm-polyethylene glycol (4-arm-PEG) with different molecular weights, have been successfully synthesized and used as carriers for the delivery of PTX. These 4-arm-PEG-TPGS derivatives were able to self-assemble to form uniform NP with PTX encapsulation. Among them, 4-arm-PEG5K-TPGS NP exhibited the smallest particle size, highest drug-loading efficiency, negligible hemolysis rate, and high physiologic stability. Therefore, it was chosen for further in vitro and in vivo investigations. Facilitated by the effective uptake of the NP, the PTX-loaded 4-arm-PEG5K-TPGS NP showed greater cytotoxicity compared with free PTX against human ovarian cancer (A2780), non-small cell lung cancer (A549), and breast adenocarcinoma cancer (MCF-7) cells, as well as a higher apoptotic rate and a more significant cell cycle arrest effect at the G2/M phase in A2780 cells. More importantly, PTX-loaded 4-arm-PEG5K-TPGS NP resulted in a significantly improved tumor growth inhibitory effect in comparison to Taxol® in S180 sarcoma-bearing mice models. This study suggested that 4-arm-PEG5K-TPGS NP may have the potential as an anticancer drug delivery system. PMID:26316751

  3. Pluronic-based functional polymeric mixed micelles for co-delivery of doxorubicin and paclitaxel to multidrug resistant tumor.

    PubMed

    Chen, Yanzuo; Zhang, Wei; Huang, Yukun; Gao, Feng; Sha, Xianyi; Fang, Xiaoling

    2015-07-01

    Although doxorubicin (DOX) and paclitaxel (PTX) are widely used in clinic as chemotherapeutics, both drug substances are found to be glycoprotein P (P-gp) substrates which are liable to develop the multidrug resistance (MDR). Additionally, the use of single chemotherapeutic drug has known limitations such as high toxicity profile due to the relatively high doses and limited regimen of clinical application. To this end, Pluronic P105-DOX conjugate was successfully designed and developed which can be further used as a hydrophobic core to entrap another anti-cancer drug PTX with Pluronic F127 to form the dual drug-loaded mixed micelles (PF-DP) in our study, which would offer great advantages over conventional micelles, including easy fabrication, high loading capacity, and co-delivery of hydrophilic DOX and hydrophobic PTX to achieve synergistic effect of these two drug substances. Results showed that PF-DP possessed a good polydispersity and sustained release profile for both DOX and PTX in vitro. Studies on cellular uptake demonstrated both anti-cancer drugs in PF-DP can effectively accumulate in MDR cancer cells. Furthermore, in vitro cytotoxicity, cell apoptosis and cell cycle arrest studies indicated that PF-DP had better antitumor efficacy in MDR cancer cells compared to those of single-drug loaded micelles. It was also found that PF-DP can suppress the growth of tumor cells more efficiently than single drug formulations at the equivalent drug concentrations, suggesting synergistic effect could be achieved. More importantly, a much stronger antitumor efficacy in MCF-7/ADR tumor-bearing mice was observed in PF-DP group than that of combined administration of free DOX and PTX. Collectively, the dual drug-loaded Pluronic-based functional mixed micelles developed in this study might be a potential nano-drug delivery system for MDR cancer chemotherapy. PMID:25899286

  4. Interfacial stabilization of the antitumoral drug Paclitaxel in monolayers of GM1 and GD1a gangliosides.

    PubMed

    Heredia, Valeria; Maggio, Bruno; Beltramo, Dante M; Dupuy, Fernando G

    2015-10-01

    Molecular interactions between the anti-cancer agent Paclitaxel (Ptx), and two gangliosides with different sialic acid content, GM1 and GD1a, were investigated using the Langmuir film balance technique. Ptx showed interfacial activity reducing the air/water surface tension by 18 mN·m(-1). However, the drug was able to insert into preformed ganglioside monolayers at much higher surface pressures, indicating a preferential interaction of Ptx with GM1 and GD1a. Compression isotherms of binary mixtures of Ptx and GM1 or GD1a also indicated non-ideal mixed monolayers in which the drug became stabilized at the interface in the presence of gangliosides. Ptx reached much higher surface pressure values in the mixed monolayers than those sustained in pure Ptx, although partial desorption of the drug from the interface into the subphase was also observed at high Ptx contents. The mean molecular area of the mixtures showed condensation, mainly in the case of GD1a, whereas Ptx induced a decrease in the compressibility of monolayers when mixed with either GM1 or GD1a. Additionally, Brewster angle microscopy analysis indicated that higher amounts of Ptx are present at the mixed ganglioside/Ptx interface when compared to pure drug monolayers. Finally, GD1a micelles increased in size in the presence of Ptx, whereas GM1 micelles kept their diameter, according to dynamic light scattering measurements, which could be explained by the different properties of ganglioside monolayers. The results obtained on ganglioside-Ptx interactions allowed interpreting the different Ptx loading capacity of GM1 and GD1a, enabling them to act as potential drug carriers. PMID:26119566

  5. Anti-tumor and anti-angiogenic effect of metronomic cyclic NGR-modified liposomes containing paclitaxel.

    PubMed

    Luo, Li-Min; Huang, Yue; Zhao, Bing-Xiang; Zhao, Xin; Duan, Yu; Du, Ruo; Yu, Ke-Fu; Song, Ping; Zhao, Yang; Zhang, Xuan; Zhang, Qiang

    2013-01-01

    In the present study, we prepared NGR-modified sterically stabilized liposomes containing paclitaxel (NGR-SSL-PTX) in order to evaluate their potential targeting to aminopeptidase N receptors expressed on tumor endothelial cells and the tumor cell surface and its anti-angiogenic activity following metronomic administration. NGR-SSL-PTX was prepared by a thin-film hydration method. The in vitro targeting characteristics of NGR-modified liposomes on HUVEC (human umbilical vein endothelial cells), HT1080 (human ?brosarcoma cells) and MCF-7 (human breast adenocarcinoma cells) were then investigated. The effect of NGR-SSL-PTX on HUVEC proliferation and migration was also tested. The pharmacokinetics of NGR-SSL-PTX was studied in rats. The in vivo targeting activity of NGR-modified liposomes was investigated in HT1080 tumor-bearing mice. The anti-tumor activity of NGR-SSL-PTX following metronomic administration was evaluated in HT1080 tumor-bearing mice in vivo. The targeting activity of the NGR-modified liposomes was demonstrated by in vitro flow cytometry and confocal microscopy as well as in vivo confocal immunofluorescence microscopy and bio-distribution experiments. The results of endothelial cell proliferation and migration and microvessel density (MVD) confirmed the anti-angiogenic activity of NGR-SSL-PTX in vitro and in vivo. The sustained circulation of NGR-SSL-PTX was shown in the pharmacokinetic study. NGR-SSL-PTX is able to improve treatment efficacy producing the most significant anti-tumor activity and anti-angiogenic following metronomic administration. PMID:23127332

  6. Amplification of chromosome 8q21-qter associated with the acquired paclitaxel resistance of nasopharyngeal caricinoma cells

    PubMed Central

    Li, Wei; You, Yating; Zhang, Xiaowei; Song, Yexun; Xiang, Hong; Peng, Xiaowei; Qin, Jiangbo; Tan, Guolin

    2015-01-01

    Objective: to observe relationship between chromosome imbalance and taxol resistance in nasopharyngeal carcinoma (NPC). Methods: three taxol-resistant sub-lines were established through repeated exposure of escalating doses of paclitaxel to NPC cell lines (CNE-1, HNE-2 and 5-8F). The change of copy number of chromosomes was investigated by the genome-wide analyses of comparative genomic hybridization (CGH). Gene profiles of both parental and resistant cell lines were determined by cDNA microarray. Cell viability was assayed by colony formation assay. Results: The taxol resistant sub-lines (CNE1/Taxol, HNE2/Taxol and 5-8F/Taxol) developed displayed an average 5~8-fold higher IC50 value than their parental cells. The common losses of chromosome 18, 10q11-qter and gains of chromosome 12, 3q21-qter, 5p13-pter and 20q11-qter were observed by CGH in all of 6 NPC cell lines. A common gain region of chromosome 8q21-qter was identified in taxol resistant sub-lines. 15 genes of 762 transcripts on this chromosome region were consistently up-regulated detected by cDNA microarray in three taxol resistant sub-lines, and functionally clustered into various groups, including genes related to vascular formation vascular formation (ANGPT1), apoptosis (MYC, TOP1MT), cell adhesion and cell cycle (PPP1R16A, SDC2, CA2, ANKRD46), gene regulation (HRSP12, ZNF696, SLC39A4, POP1), metabolism (PYCRL). Inhibition of ANGPT1 expression significantly increased the sensitivity of CNE-1/taxol to paclitaxol. Conclusion: The common gain of chromosome 8q21-qter in taxol resistant sublines predicates that potential candidate genes on this region may contribute to taxol resistant phenotype. ANGPT1 may be associated with taxol resistance of NPC cells. PMID:26722421

  7. Delivery of baicalein and paclitaxel using self-assembled nanoparticles: synergistic antitumor effect in vitro and in vivo

    PubMed Central

    Wang, Wei; Xi, Mei; Duan, Xuezhong; Wang, Yong; Kong, Fansheng

    2015-01-01

    Purpose Combination anticancer therapy is promising to generate synergistic anticancer effects to maximize the treatment effect and overcome multidrug resistance. The aim of the study reported here was to develop multifunctional, dual-ligand, modified, self-assembled nanoparticles (NPs) for the combination delivery of baicalein (BCL) and paclitaxel (PTX) prodrugs. Methods Prodrug of PTX and prodrug of BCL, containing dual-targeted ligands of folate (FA) and hyaluronic acid (HA), were synthesized. Multifunctional self-assembled NPs for combination delivery of PTX prodrug and BCL prodrug (PTX-BCL) were prepared and the synergistic antitumor effect was evaluated in vitro and in vivo. The in vitro transfection efficiency of the novel modified vectors was evaluated in human lung cancer A549 cells and drug-resistant lung cancer A549/PTX cells. The in vivo antitumor efficiency and systemic toxicity of different formulations were further investigated in mice bearing A549/PTX drug-resistant human lung cancer xenografts. Results The size of the PTX-BCL NPs was approximately 90 nm, with a positive zeta potential of +3.3. The PTX-BCL NPs displayed remarkably better antitumor activity over a wide range of drug concentrations, and showed an obvious synergism effect with CI50 values of 0.707 and 0.513, indicating that double-ligand modification and the co-delivery of PTX and BCL prodrugs with self-assembled NPs had remarkable superiority over other formulations. Conclusion The prepared PTX-BCL NP drug-delivery system was proven efficient by its targeting of drug-resistant human lung cancer cells and delivering of BCL and PTX prodrugs. Enhanced synergistic anticancer effects were achieved by PTX-BCL NPs, and multidrug resistance of PTX was overcome by this promising targeted nanomedicine. PMID:26045664

  8. Octa-ammonium POSS-conjugated single-walled carbon nanotubes as vehicles for targeted delivery of paclitaxel

    PubMed Central

    Naderi, Naghmeh; Madani, Seyed Y.; Mosahebi, Afshin; Seifalian, Alexander M.

    2015-01-01

    Background Carbon nanotubes (CNTs) have unique physical and chemical properties. Furthermore, novel properties can be developed by attachment or encapsulation of functional groups. These unique properties facilitate the use of CNTs in drug delivery. We developed a new nanomedicine consisting of a nanocarrier, cell-targeting molecule, and chemotherapeutic drug and assessed its efficacy in vitro. Methods The efficacy of a single-walled carbon nanotubes (SWCNTs)-based nanoconjugate system is assessed in the targeted delivery of paclitaxel (PTX) to cancer cells. SWCNTs were oxidized and reacted with octa-ammonium polyhedral oligomeric silsesquioxanes (octa-ammonium POSS) to render them biocompatible and water dispersable. The functionalized SWCNTs were loaded with PTX, a chemotherapeutic agent toxic to cancer cells, and Tn218 antibodies for cancer cell targeting. The nanohybrid composites were characterized with transmission electron microscopy (TEM), Fourier transform infrared (FTIR), and ultraviolet–visible–near-infrared (UV–Vis–NIR). Additionally, their cytotoxic effects on Colon cancer cell (HT-29) and Breast cancer cell (MCF-7) lines were assessed in vitro. Results TEM, FTIR, and UV–Vis–NIR studies confirmed side-wall functionalization of SWCNT with COOH-groups, PTX, POSS, and antibodies. Increased cell death was observed with PTX–POSS–SWCNT, PTX–POSS–Ab–SWCNT, and free PTX compared to functionalized-SWCNT (f-SWCNT), POSS–SWCNT, and cell-only controls at 48 and 72 h time intervals in both cell lines. At all time intervals, there was no significant cell death in the POSS–SWCNT samples compared to cell-only controls. Conclusion The PTX-based nanocomposites were shown to be as cytotoxic as free PTX. This important finding indicates successful release of PTX from the nanocomposites and further reiterates the potential of SWCNTs to deliver drugs directly to targeted cells and tissues. PMID:26356347

  9. Copy number changes of 4-gene set may predict early relapse in advanced epithelial ovarian cancer after initial platinum-paclitaxel chemotherapy

    PubMed Central

    Li, Ning; Hou, Jin-Lin; Shi, Zhi-Zhou; Li, Xiao-Guang; Li, Nan; Sun, Yang-Chun; Xu, Xin; Cai, Yan; Zhang, Xun; Zhang, Kai-Tai; Wang, Ming-Rong; Wu, Ling-Ying

    2014-01-01

    For advanced epithelial ovarian cancer (EOC), time to recurrence (TTR) is an important indicator to gauge the therapeutic efficacy of postoperative adjuvant chemotherapy. Our objective was to determine the genes that could potentially distinguish patients with short versus long TTR after initial administration of platinum-paclitaxel combination chemotherapy in advanced EOC. Tumor samples of 159 patients were obtained during the primary cytoreduction. Array comparative genomic hybridization (CGH) was carried with genomic DNA from 17 EOC samples (8 with TTR > 15 months and 9 with TTR ? 6 months) to screen candidate gene set, copy-number changes (CNC) of which were significantly different between early and late relapse cases. Seventeen candidate genes were identified by array CGH. The analysis of consistency between real-time PCR and array CGH revealed that 4 genes displayed consistent results, namely GSTT1, ISG20L1, STARD5 and FREM1. In a 142-case validation set, CNC of 4 candidate genes was evaluated and verified by real-time PCR. Sixty five point five percent of the patients were correctly divided into early (TTR ? 10 months) and late (TTR > 10 months) recurrent group by CNC of the 4 genes using discriminant analysis. The results showed that CNC of 4-gene set could potentially determine early (TTR ? 10 months) or late relapse (TTR > 10 months) after initial platinum-paclitaxel combination chemotherapy in advanced EOC. PMID:24959383

  10. MiR-125b regulates epithelial-mesenchymal transition via targeting Sema4C in paclitaxel-resistant breast cancer cells

    PubMed Central

    Zhao, Zunlan; Zhu, Lihua; Chen, Sulian; Wu, Qiong; Chen, Changjie; Wang, Zhiwei

    2015-01-01

    Emerging evidence has demonstrated that microRNAs (miRNA) play a critical role in chemotherapy-induced epithelial-mesenchymal transition (EMT) in breast cancer. However, the underlying mechanism of chemotherapy-mediated EMT has not been fully understood. To address this concern, we explored the role of miR-125b in regulation of EMT in stable paclitaxel-resistant (PR) breast cancer cells, namely MCF-7 PR and SKBR3 PR, which have displayed mesenchymal features. Our results illustrated that miR-125b was significantly downregulated in PR cells. Moreover, ectopic expression of miR-125b by its mimics reversed the phenotype of EMT in PR cells. Furthermore, we found that miR-125b governed PR-mediate EMT partly due to governing its target Sema4C. More importantly, overexpression of miR-125b or depletion of Sema4C sensitized PR cells to paclitaxel. These findings suggest that up-regulation of miR-125b or targeting Sema4C could serve as novel approaches to reverse chemotherapy resistance in breast cancers. PMID:25605244

  11. Brassinin inhibits STAT3 signaling pathway through modulation of PIAS-3 and SOCS-3 expression and sensitizes human lung cancer xenograft in nude mice to paclitaxel

    PubMed Central

    Lee, Jong Hyun; Kim, Chulwon; Sethi, Gautam; Ahn, Kwang Seok

    2015-01-01

    Persistent phosphorylation of signal transducers and activators of transcription 3 (STAT3) is frequently observed in tumor cells. We found that brassinin (BSN) suppressed both constitutive and IL-6-inducible STAT3 activation in lung cancer cells. Moreover, BSN induced PIAS-3 protein and mRNA, whereas the expression of SOCS-3 was reduced. Knockdown of PIAS-3 by small interfering RNA prevented inhibition of STAT3 and cytotoxicity by BSN. Overexpression of SOCS-3 in BSN-treated cells increased STAT3 phosphorylation and cell viability. BSN down-regulated STAT3-regulated gene products, inhibited proliferation, invasion, as well as induced apoptosis. Most importantly, when administered intraperitoneally, combination of BSN and paclitaxel significantly decreased the tumor development in a xenograft lung cancer mouse model associated with down-modulation of phospho-STAT3, Ki-67 and CD31. We suggest that BSN inhibits STAT3 signaling through modulation of PIAS-3 and SOCS-3, thereby attenuating tumor growth and increasing sensitivity to paclitaxel. PMID:25788267

  12. Gemcitabine and Oxaliplatin, but Not Sorafenib or Paclitaxel, Have a Synergistic Effect with Yttrium-90 in Reducing Hepatocellular Carcinoma and Cholangiocarcinoma Cell Line Viability.

    PubMed

    Edeline, Julien; Coulouarn, Cédric; Crouzet, Laurence; Pracht, Marc; Lepareur, Nicolas; Clément, Bruno; Garin, Etienne

    2015-12-01

    Synergy between yttrium-90 ((90)Y) and antineoplastic drugs was investigated. Viability of HepaRG (hepatocellular carcinoma) and HuCCT1 (cholangiocarcinoma) cells was studied through a tetrazolium dye reduction assay. A combination index (CI) was calculated, with CI < 1 denoting synergy and CI > 1 denoting antagonism. In HepaRG cells, gemcitabine showed synergy with (90)Y (CI = 0.70 [95% confidence interval = 0.65-0.75]), whereas oxaliplatin (CI = 1.15 [1.08-1.21]), paclitaxel (CI = 1.26 [1.15-1.37]), and sorafenib (CI = 1.77 [1.65-1.89]) showed antagonism. In HuCCT1 cells, gemcitabine (CI = 0.54 [0.50-0.58]) and oxaliplatin (CI = 0.86 [0.82-0.90]) showed synergy with (90)Y, whereas paclitaxel (CI = 1.18 [1.09-1.27]) and sorafenib (CI = 1.21 [1.12-1.30]) showed antagonism. These results suggest that gemcitabine and oxaliplatin should be tested in combination with (90)Y radioembolization for treatment of liver cancer. PMID:26596183

  13. Enhanced oral delivery of paclitaxel using acetylcysteine functionalized chitosan-vitamin E succinate nanomicelles based on a mucus bioadhesion and penetration mechanism.

    PubMed

    Lian, He; Zhang, Tianhong; Sun, Jin; Liu, Xiaohong; Ren, Guolian; Kou, Longfa; Zhang, Youxi; Han, Xiaopeng; Ding, Wenya; Ai, Xiaoyu; Wu, Chunnuan; Li, Lin; Wang, Yongjun; Sun, Yinghua; Wang, Siling; He, Zhonggui

    2013-09-01

    In addition to being a physiological protective barrier, the gastrointestinal mucosal membrane is also a primary obstacle that hinders the oral absorption of many therapeutic compounds, especially drugs with a poor permeability. In order to resolve this impasse, we have designed multifunctional nanomicelles based on the acetylcysteine functionalized chitosan-vitamin E succinate copolymer (CS-VES-NAC, CVN), which exhibit marked bioadhesion, possess the ability to penetrate mucus, and enhance the oral absorption of a hydrophobic drug with a poor penetrative profile, paclitaxel. The intestinal absorption (Ka = 0.38 ± 0.04 min(-1), Papp = 0.059 cm · min(-1)) of CVN nanomicelles was greatly improved (4.5-fold) in comparison with paclitaxel solution, and CLSM (confocal laser scanning microscope) pictures also showed not only enhanced adhesion to the intestinal surface but improved accumulation within intestinal villi. The in vivo pharmacokinetics indicated that the AUC0-t (586.37 ng/mL · h) of CVN nanomicelles was markedly enhanced compared with PTX solution. In summary, the novel multifunctional CVN nanomicelles appear to be a promising nanocarrier for insoluble and poorly permeable drugs due to their high bioadhesion and permeation-enhancing capability. PMID:23909663

  14. [Inhospital and 12-months results of percutaneous coronary interventions with implantation of Paclitaxel eluting stents in patients with long de novo coronary artery lesions].

    PubMed

    Batyraliev, T A; Fettser, D V; Sidorenko, B A; Preobrazhenski?, D V; Niyazova-Karben, Z A; Abdramanov, K A; Belenkov, Iu N

    2010-01-01

    We implanted 59 paclitaxel eluting Apollo stents to 48 patients with ischemic heart disease (IHD) and long de novo coronary artery lesions in 2007 with 100% immediate success rate without inhospital major cardiac complications. One patient developed hematoma at femoral artery puncture site. There were no cases of restenosis among 18 patients subjected to control angiography after 6 months. One patient had acute myocardial infarction in area supplied by nontarget artery. Control angiography after 12 months was carried out in 81.3% of patients while 14.6% of patients who refused angiography were examined with stress tests. Restenosis of stented segments was found in 3 (5.3%) patients, diameter loss was 0.32+/-0.45 mm. All these patients were subjected to repeat PCI. During follow up myocardial infarctions were registered in 4.2% of patients, overall rate of serious cardiac complications was 11.6%. PCI with implantation of paclitaxel was safe and effective with acceptable rate of major cardiac complications. Our results evidence in favor of further use of these stents. PMID:21118174

  15. MDR1 siRNA loaded hyaluronic acid-based CD44 targeted nanoparticle systems circumvent paclitaxel resistance in ovarian cancer

    NASA Astrophysics Data System (ADS)

    Yang, Xiaoqian; Lyer, Arun K.; Singh, Amit; Choy, Edwin; Hornicek, Francis J.; Amiji, Mansoor M.; Duan, Zhenfeng

    2015-02-01

    Development of multidrug resistance (MDR) is an almost universal phenomenon in patients with ovarian cancer, and this severely limits the ultimate success of chemotherapy in the clinic. Overexpression of the MDR1 gene and corresponding P-glycoprotein (Pgp) is one of the best known MDR mechanisms. MDR1 siRNA based strategies were proposed to circumvent MDR, however, systemic, safe, and effective targeted delivery is still a major challenge. Cluster of differentiation 44 (CD44) targeted hyaluronic acid (HA) based nanoparticle has been shown to successfully deliver chemotherapy agents or siRNAs into tumor cells. The goal of this study is to evaluate the ability of HA-PEI/HA-PEG to deliver MDR1 siRNA and the efficacy of the combination of HA-PEI/HA-PEG/MDR1 siRNA with paclitaxel to suppress growth of ovarian cancer. We observed that HA-PEI/HA-PEG nanoparticles can efficiently deliver MDR1 siRNA into MDR ovarian cancer cells, resulting in down-regulation of MDR1 and Pgp expression. Administration of HA-PEI/HA-PEG/MDR1 siRNA nanoparticles followed by paclitaxel treatment induced a significant inhibitory effect on the tumor growth, decreased Pgp expression and increased apoptosis in MDR ovarian cancer mice model. Our findings suggest that CD44 targeted HA-PEI/HA-PEG/MDR1 siRNA nanoparticles can serve as a therapeutic tool with great potentials to circumvent MDR in ovarian cancer.

  16. Window of opportunity: A new insight into sequential bevacizumab and paclitaxel in two cases of metastatic triple-negative breast cancer

    PubMed Central

    CHEN, DAR-REN; LIN, CHE; WANG, YU-FEN

    2015-01-01

    Bevacizumab, an antiangiogenic monoclonal antibody against vascular endothelial growth factor, was designed to normalize tumor vasculature and reduce intratumoral pressure. It can create a ‘normalization window’ during which the cancer can be attacked the most effectively, and the effects of chemotherapeutic drugs are enhanced. Representative trials (E2100, AVADO, RIBBON-1, RIBBON-2 and TURANDOT) have shown that the addition of bevacizumab to chemotherapy has significant benefits on progression-free survival for metastatic breast cancer, but not on overall survival. The present study describes two patients with metastatic triple-negative breast cancer who received 6 courses of bevacizumab-containing chemotherapy. Each course comprised 5–7.5 mg/kg bevacizumab administered on days 1 and 15, and 20–24 h after bevacizumab delivery, 80 mg/m2 paclitaxel was administered for 3 weeks on days 2, 9 and 16, followed by 1 week of rest. Following sequential treatment with bevacizumab and paclitaxel, the results of computed tomography showed that the tumors were rapidly reduced in size. Based on the imaging findings from three-dimension power Doppler ultrasonography in one of the breast cancer patients who received neoadjuvant chemotherapy with bevacizumab, the possible timing of the normalization window was 20–24 h after the administration of bevacizumab. The normalization window may provide an opportunity to enhance the effect of chemotherapy with the aid of bevacizumab.

  17. Induction chemotherapy with cetuximab, carboplatin and paclitaxel for the treatment of locally advanced squamous cell carcinoma of the head and neck

    PubMed Central

    BAUMAN, JESSICA; LANGER, COREY; QUON, HARRY; ALGAZY, KENNETH; LIN, ALEXANDER; DESAI, ARATI; MUTALE, FAITH; WEISS, JARED

    2013-01-01

    Although controversy exists in the management of locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN), clinicians often use induction chemotherapy for treatment of the most advanced cases. One promising regimen combines weekly cetuximab (400 mg/m2 loading dose followed by 250 mg/m2) with carboplatin (AUC of 2) and paclitaxel (90 mg/m2). We retrospectively evaluated patients treated with this regimen prior to definitive chemoradiation or surgery between May 2008 and December 2011. The primary endpoint used for this retrospective analysis was feasibility. Thirty consecutive, unselected patients were included. Median follow-up was 13.7 months (range, 5.0–38.7 months). All but one patient had stage IV SCCHN. Dose intensity was high for carboplatin (92%), paclitaxel (93%) and cetuximab (85%). Grade 3–4 toxicities occurred in <7% of the study population and were limited to rash, neutropenia and infusion reactions. Response rate (RR) to induction chemotherapy was 97% (30% complete response, 67% partial response). All patients completed subsequent chemoradiotherapy or surgery. Nineteen patients (63%) demonstrated a complete response and 11 patients (37%) demonstrated a partial response. Median overall survival and progression-free survival data are not yet mature. The RR to therapy in our off-protocol experience is at least comparable to that observed in the two phase II studies of this regimen and appears superior to that observed with docetaxel, cisplatin and fluorouracil (TPF). PMID:23599744

  18. Inhibition of autophagy enhances the effects of the AKT inhibitor MK-2206 when combined with paclitaxel and carboplatin in BRAF wild-type melanoma.

    PubMed

    Rebecca, Vito W; Massaro, Renato R; Fedorenko, Inna V; Sondak, Vernon K; Anderson, Alexander R A; Kim, Eunjung; Amaravadi, Ravi K; Maria-Engler, Silvya S; Messina, Jane L; Gibney, Geoffrey T; Kudchadkar, Ragini R; Smalley, Keiran S M

    2014-05-01

    This study investigates the mechanism of action behind the long-term responses (12-16 months) of two BRAF WT melanoma patients to the AKT inhibitor MK-2206 in combination with paclitaxel and carboplatin. Although single agent MK-2206 inhibited phospho-AKT signaling, it did not impact in vitro melanoma growth or survival. The combination of MK-2206 with paclitaxel and carboplatin was cytotoxic in long-term colony formation and 3D spheroid assays, and induced autophagy. Autophagy was initially protective with autophagy inhibitors and deletion of ATG5 found to enhance cytotoxicity. Although prolonged autophagy induction (>6 days) led to caspase-dependent apoptosis, drug resistant clones still emerged. Autophagy inhibition enhanced the cell death response through reactive oxygen species and could be reversed by anti-oxidants. We demonstrate for the first time that AKT inhibition in combination with chemotherapy may have clinical activity in BRAF WT melanoma and show that an autophagy inhibitor may prevent resistance to these drugs. PMID:24490764

  19. Cancer Associated Fibroblast-Derived Hepatocyte Growth Factor Inhibits the Paclitaxel-Induced Apoptosis of Lung Cancer A549 Cells by Up-Regulating the PI3K/Akt and GRP78 Signaling on a Microfluidic Platform

    PubMed Central

    Xu, Zhiyun; He, Tianrui; Li, Encheng; Guo, Zhe; Liu, Fen; Jiang, Chunmeng; Wang, Qi

    2015-01-01

    Tumor stroma and growth factors provide a survival environment to tumor cells and can modulate their chemoresistance by dysregulating several signal pathways. In this study, we fabricated a three-dimensional (3D) microfluidic chip using polydimethylsiloxane (PDMS) to investigate the impact of hepatocyte growth factor (HGF) from cancer-associated fibroblasts (CAF) on the Met/PI3K/AKT activation, glucose regulatory protein (GRP78) expression and the paclitaxel-induced A549 cell apoptosis. With a concentration gradient generator, the assembled chip was able to reconstruct a tumor microenvironment in vitro. We found high levels of HGF in the supernatants of CAF and the CAF matrix from the supernatants of activated HFL1 fibroblasts or HGF enhanced the levels of Met, PI3K and AKT phosphorylation and GRP78 expression in A549 cells cultured in a 3D cell chamber, which was abrogated by anti-HGF. Inhibition of Met attenuated the CAF matrix-enhanced PI3K/AKT phosphorylation and GRP78 expression while inhibition of PI3K reduced GRP78 expression, but not Met phosphorylation in A549 cells. Inhibition of GRP78 failed to modulate the CAF matrix-enhanced Met/PI3K/AKT phosphorylation in A549 cells. Furthermore, inhibition of PI3K or GRP78 enhanced spontaneous and paclitaxel-induced A549 cell apoptosis. Moreover, treatment with the CAF matrix inhibited spontaneous and medium or high dose of paclitaxel-induced A549 cell apoptosis. Inhibition of PI3K or GRP78 attenuated the CAF matrix-mediated inhibition on paclitaxel-induced A549 cell apoptosis. Our data indicated that HGF in the CAF matrix activated the Met/PI3K/AKT and up-regulated GRP78 expression, promoting chemoresistance to paclitaxel-mediated apoptosis in A549 cells. Our findings suggest that the microfluidic system may represent an ideal platform for signaling research and drug screening. PMID:26115510

  20. Effect of lipid bilayer alteration on transdermal delivery of a high-molecular-weight and lipophilic drug: studies with paclitaxel.

    PubMed

    Panchagnula, Ramesh; Desu, Hariraghuram; Jain, Amit; Khandavilli, Sateesh

    2004-09-01

    Skin forms an excellent barrier against drug permeation, due to the rigid lamellar structure of the stratum corneum (SC) lipids. Poor permeability of drugs can be enhanced through alteration in partition and diffusion coefficients, or concentration gradient of drug with an appropriate choice of solvent system, along with penetration enhancers. The aim of the current investigation was to assess applicability of lipid bilayer alteration by fatty acids and terpenes toward the permeation enhancement of a high-molecular-weight, lipophilic drug, paclitaxel (PCL) through rat skin. From among the fatty acids studied using ethanol/isopropyl myristate (1:1) vehicle, no significant enhancement in flux of PCL was observed (p > 0.05). In the case of cis mono and polyunsaturated fatty acids lag time was found to be similar to control (p > 0.05). This suggests that the permeation of a high-molecular-weight, lipophilic drug may not be enhanced by the alteration of the lipid bilayer, or the main barrier to permeation could lie in lower hydrophilic layers of skin. A significant increase in lag time was observed with trans unsaturated fatty acids unlike the cis isomers, and this was explained on the basis of conformation and preferential partitioning of fatty acids into skin. From among the terpenes, flux of PCL with cineole was significantly different from other studied terpenes and controls, and after treatment with menthol and menthone permeability was found to be reduced. Menthol and menthone cause loosening of the SC lipid bilayer due to breaking of hydrogen bonding between ceramides, resulting in penetration of water into the lipids of the SC lipid bilayer that leads to creation of new aqueous channels and is responsible for increased hydrophilicity of SC. This increased hydrophilicity of the SC bilayer might have resulted in unfavorable conditions for ethanol/isopropyl myristate (1:1) along with PCL to penetrate into skin, therefore permeability was reduced. The findings of this study suggest that the permeation of a high-molecular-weight and lipophilic drug cannot be enhanced through bilayer alteration by penetration enhancers, and alteration in partitioning of drug into skin could be a feasible mode to enhance the permeation of drug. PMID:15295779

  1. [Evaluation of short-time premedication with d-chlorpheniramine maleate injection for paclitaxel-induced hypersensitivity reaction].

    PubMed

    Harada, Tomohiko; Doi, Masakazu; Yamada, Yasuhiko; Akase, Tomohide

    2008-08-01

    Paclitaxel(referred to hereinafter as PTX )is used in ovarian cancer, non-small cell lung cancer, breast cancer, gastric cancer, and endometrial cancer with positive treatment result reports. However, severe allergic reactions such as decreases in blood pressure and impaired breathing occur with relatively high frequency. For the prevention of such allergic reactions, administration of a premedication composed of the three components, dexamethasone sodium phosphate injection, diphenhydramine hydrochloride tablet, and ranitidine hydrochloride injection solution(or injectable famodine), is advised in the appended documentation. Administration is difficult because, among these three components, only diphenhydramine hydrochloride is administered orally and thus must be provided through the internal medicine department. Particularly when this combined dosage is administered as outpatient chemotherapy, the doctor must prescribe diphenhydramine hydrochloride tablets, and the patient must not forget to bring them on the day in which chemotherapy is administered. Also, checks by the medical staff such as pharmacists and nurses are required, complicating the administration of this therapy further. Taking this situation into consideration, our hospital uses a short-time premedication method wherein d-Chlorpheniramine Maleate injections are substituted for diphenhydramine hydrochloride tablets, and the time required for premedication is reduced to 15 minutes. This study investigated the allergic reaction ratio to consider the safety and usefulness of the short-time premedication method used at our hospital. The chemotherapy regimens conducted for the subject patients were 9 cases of PTX+CBDCA, 6 cases of biweekly- PTX, and 5 cases of weekly-PTX. A total of 67 PTX injections were given, 15 of them being first-time administrations. The ratio of allergic/hypersensitivity reactions was 10.0%(2 cases in 20). The short-time premedication method using d-Chlorpheniramine Maleate injections did not display a significant difference from the conventional method used for prevention of allergic and hypersensitivity reactions. Also, since this method of medication proves useful for is easy for the patient, reduces treatment time, is safe, economical, and helps reduce the workload of doctors, pharmacists, and nurses. PMID:18701846

  2. Synthesis and evaluation of a backbone biodegradable multiblock HPMA copolymer nanocarrier for the systemic delivery of paclitaxel.

    PubMed

    Zhang, Rui; Luo, Kui; Yang, Jiyuan; Sima, Monika; Sun, Yongen; Janát-Amsbury, Margit M; Kope?ek, Jind?ich

    2013-02-28

    The performance and safety of current antineoplastic agents, particularly water-insoluble drugs, are still far from satisfactory. For example, the currently widely used Cremophor EL®-based paclitaxel (PTX) formulation exhibits pharmacokinetic concerns and severe side effects. Thus, the concept of a biodegradable polymeric drug-delivery system, which can significantly improve therapeutic efficacy and reduce side effects is advocated. The present work aims to develop a new-generation of long-circulating, biodegradable carriers for effective delivery of PTX. First, a multiblock backbone biodegradable N-(2-hydroxypropyl)methacrylamide(HPMA) copolymer-PTX conjugate (mP-PTX) with molecular weight (Mw) of 335 kDa was synthesized by RAFT (reversible addition-fragmentation chain transfer) copolymerization, followed by chain extension. In vitro studies on human ovarian carcinoma A2780 cells were carried out to investigate the cytotoxicity of free PTX, HPMA copolymer-PTX conjugate with Mw of 48 kDa (P-PTX), and mP-PTX. The experiments demonstrated that mP-PTX has a similar cytotoxic effect against A2780 cells as free PTX and P-PTX. To further compare the behavior of this new biodegradable conjugate (mP-PTX) with free PTX and P-PTX in vivo evaluation was performed using female nu/nu mice bearing orthotopic A2780 ovarian tumors. Pharmacokinetics study showed that high Mw mP-PTX was cleared more slowly from the blood than commercial PTX formulation and low Mw P-PTX. SPECT/CT imaging and biodistribution studies demonstrated biodegradability as well as elimination of mP-PTX from the body. The tumors in the mP-PTX treated group grew more slowly than those treated with saline, free PTX, and P-PTX (single dose at 20 mg PTX/kg equivalent). Moreover, mice treated with mP-PTX had no obvious ascites and body-weight loss. Histological analysis indicated that mP-PTX had no toxicity in liver and spleen, but induced massive cell death in the tumor. In summary, this biodegradable drug delivery system has a great potential to improve performance and safety of current antineoplastic agents. PMID:23262201

  3. High-performance liquid chromatographic separation of paclitaxel intermediate phenylisoserine derivatives on macrocyclic glycopeptide and cyclofructan-based chiral stationary phases.

    PubMed

    Ilisz, István; Grecsó, Nóra; Forró, Enik?; Fülöp, Ferenc; Armstrong, Daniel W; Péter, Antal

    2015-10-10

    High-performance liquid chromatographic methods were developed for the separation of enantiomers of four unnatural paclitaxel precursor phenylisoserine analogs on chiral stationary phases containing macrocyclic glycopeptides and cyclofructans as chiral selectors. The effects of the mobile phase composition, the nature and concentration of different mobile phase additives (alcohols, amines and acids) in different chromatographic modes, temperature and the structures of the analytes on the separations were investigated. Separations were carried out at constant mobile phase compositions in the temperature range 10-50°C on macrocyclic antibiotic-based and 5-35°C on cyclofructan-based columns and the changes in enthalpy, ?(?H°), entropy, ?(?S°), and free energy, ?(?G°), were calculated. The elution sequence was determined in most cases; no general rule could be observed. PMID:26099260

  4. Overexpression of the microRNA miR-433 promotes resistance to paclitaxel through the induction of cellular senescence in ovarian cancer cells.

    PubMed

    Weiner-Gorzel, Karolina; Dempsey, Eugene; Milewska, Malgorzata; McGoldrick, Aloysius; Toh, Valerie; Walsh, Aoibheann; Lindsay, Sinead; Gubbins, Luke; Cannon, Aoife; Sharpe, Daniel; O'Sullivan, Jacintha; Murphy, Madeline; Madden, Stephen F; Kell, Malcolm; McCann, Amanda; Furlong, Fiona

    2015-05-01

    Annually, ovarian cancer (OC) affects 240,000 women worldwide and is the most lethal gynecological malignancy. High-grade serous OC (HGSOC) is the most common and aggressive OC subtype, characterized by widespread genome changes and chromosomal instability and is consequently poorly responsive to chemotherapy treatment. The objective of this study was to investigate the role of the microRNA miR-433 in the cellular response of OC cells to paclitaxel treatment. We show that stable miR-433 expression in A2780 OC cells results in the induction of cellular senescence demonstrated by morphological changes, downregulation of phosphorylated retinoblastoma (p-Rb), and an increase in ?-galactosidase activity. Furthermore, in silico analysis identified four possible miR-433 target genes associated with cellular senescence: cyclin-dependent kinase 6 (CDK6), MAPK14, E2F3, and CDKN2A. Mechanistically, we demonstrate that downregulation of p-Rb is attributable to a miR-433-dependent downregulation of CDK6, establishing it as a novel miR-433 associated gene. Interestingly, we show that high miR-433 expressing cells release miR-433 into the growth media via exosomes which in turn can induce a senescence bystander effect. Furthermore, in relation to a chemotherapeutic response, quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed that only PEO1 and PEO4 OC cells with the highest miR-433 expression survive paclitaxel treatment. Our data highlight how the aberrant expression of miR-433 can adversely affect intracellular signaling to mediate chemoresistance in OC cells by driving cellular senescence. PMID:25684390

  5. The use of ?-conotoxin ImI to actualize the targeted delivery of paclitaxel micelles to ?7 nAChR-overexpressing breast cancer.

    PubMed

    Mei, Dong; Lin, Zhiqiang; Fu, Jijun; He, Bing; Gao, Wei; Ma, Ling; Dai, Wenbing; Zhang, Hua; Wang, Xueqing; Wang, Jiancheng; Zhang, Xuan; Lu, Wanliang; Zhou, Demin; Zhang, Qiang

    2015-02-01

    Alpha7 nicotinic acetylcholine receptor (?7 nAChR), a ligand-gated ion channel, is increasingly emerging as a new tumor target owing to its expression specificity and significancy for cancer. In an attempt to increase the targeted drug delivery to the ?7 nAChR-overexpressing tumors, herein, ?-conotoxin ImI, a disulfide-rich toxin with highly affinity for ?7 nAChR, was modified on the PEG-DSPE micelles (ImI-PMs) for the first time. The DLS, TEM and HPLC detections showed the spherical nanoparticle morphology about 20 nm with negative charge and high drug encapsulation. The ligand modification did not induce significant differences. The immunofluorescence assay confirmed the expression level of ?7 nAChR in MCF-7 cells. In vitro and in vivo experiments demonstrated that the ?7 nAChR-targeted nanomedicines could deliver more specifically and faster into ?7 nAChR-overexpressing MCF-7 cells. Furthermore, fluo-3/AM fluorescence imaging technique indicated that the increased specificity was attributed to the ligand-receptor interaction, and the inducitivity for intracellular Ca(2+) transient by ImI was still remained after modification. Moreover, paclitaxel, a clinical frequently-used anti-tumor drug for breast cancer, was loaded in ImI-modified nanomedicines to evaluate the targeting efficacy. Besides of exhibiting greater cytotoxicity and inducing more cell apoptosis in vitro, paclitaxel-loaded ImI-PMs displayed stronger anti-tumor efficacy in MCF-7 tumor-bearing nu/nu mice. Finally, the active targeting system showed low systemic toxicity and myelosuppression evidenced by less changes in body weight, white blood cells, neutrophilic granulocyte and platelet counts. In conclusion, ?7 nAChR is also a promising target for anti-tumor drug delivery and in this case, ?-conotoxin ImI-modified nanocarrier is a potential delivery system for targeting ?7 nAChR-overexpressing tumors. PMID:25542793

  6. pH-Sensitive Biocompatible Nanoparticles of Paclitaxel-Conjugated Poly(styrene-co-maleic acid) for Anticancer Drug Delivery in Solid Tumors of Syngeneic Mice.

    PubMed

    Dalela, Manu; Shrivastav, T G; Kharbanda, Surender; Singh, Harpal

    2015-12-01

    In the present study, we have synthesized poly(styrene-co-maleic anhydride), a biocompatible copolymer that was further conjugated with paclitaxel (PTX) via ester linkage and self-assembled to form poly(styrene-co-maleic acid)-paclitaxel (PSMAC-PTX) nanoparticles (NPs). The in vitro release of PTX from PSMAC-PTX NPs showed a higher release at lower pH than at the physiological pH of 7.4, confirming its pH-dependent release. The cell viability of PSMAC-PTX nanoparticles was evaluated using MTT assay. IC50 values of 9.05-18.43 ng/mL of PTX equivalent were observed in various cancer cell lines after 72 h of incubation. Confocal microscopy, Western blotting, and Flow cytometry results further supported that the cellular uptake and apoptosis of cancer cells with PSMAC-PTX NPs. Pharmacokinetic studies revealed that the conjugation of PTX to the PSMAC co-polymer not only increased the plasma and tumor Cmax of PTX but also prolonged its plasma half-life and retention in tumor via enhanced permeability and retention (EPR) effect. Administration of PSMAC-PTX NPs showed significant tumor growth inhibition with improved apoptosis effects in vivo on Ehrlich Ascites Tumor (EAT)-bearing BALB/c syngeneic mice in comparison with Taxol, without showing any cytotoxicity. On the basis of preliminary results, no subacute toxicity was observed in major organs, tissues and hematological system up to a dosage of 60 mg/kg body weight in mice. Therefore, PSMAC-PTX NPs may be considered as an alternative nanodrug delivery system for the delivery of PTX in solid tumors. PMID:26528585

  7. Efficacy and Safety of Paclitaxel-Coated Balloon for the Treatment of In-Stent Restenosis in High-Risk Patients.

    PubMed

    Miglionico, Marco; Mangiacapra, Fabio; Nusca, Annunziata; Scordino, Domenico; Gallo, Paolo; Campanale, Marco; Melfi, Rosetta; Di Sciascio, Germano

    2015-12-01

    In-stent restenosis (ISR) is a major cause of failure of percutaneous coronary intervention. The efficacy and safety of drug-coated balloon (DCB) in patients with high-risk clinical features are largely unknown. We enrolled 82 consecutive patients at high risk of bleeding with angiographically significant (diameter stenosis ?50%) ISR of bare metal stent (BMS) or drug-eluting stent (DES), treated with paclitaxel-coated balloon. All patients presented at least one of the following criteria: high bleeding risk, neoplasm, chronic inflammatory disease, and need for noncardiac surgery. Dual antiplatelet therapy was indicated for 4 weeks after the procedure. At angiographic follow-up, overall late lumen loss was 0.24 ± 0.32 mm, with no significant difference between BMS-ISR and DES-ISR (0.25 ± 0.35 vs 0.22 ± 0.30 mm, p = 0.714). The Kaplan-Meier estimate for major adverse clinical events-free survival at 3 years was 81.4% (82.3% in BMS-ISR vs 79.4% in DES-ISR, log-rank p = 0.866). No stent thrombosis has been recorded. In conclusion, the use of paclitaxel-coated balloon seems to be associated with favorable outcomes after percutaneous coronary intervention for BMS-ISR or DES-ISR in patients with high-risk clinical features and could be considered as a reasonable option in the presence of systemic co-morbidities and contraindications to long-term dual antiplatelet therapy. PMID:26428021

  8. Overexpression of the microRNA miR-433 promotes resistance to paclitaxel through the induction of cellular senescence in ovarian cancer cells

    PubMed Central

    Weiner-Gorzel, Karolina; Dempsey, Eugene; Milewska, Malgorzata; McGoldrick, Aloysius; Toh, Valerie; Walsh, Aoibheann; Lindsay, Sinead; Gubbins, Luke; Cannon, Aoife; Sharpe, Daniel; O'Sullivan, Jacintha; Murphy, Madeline; Madden, Stephen F; Kell, Malcolm; McCann, Amanda; Furlong, Fiona

    2015-01-01

    Annually, ovarian cancer (OC) affects 240,000 women worldwide and is the most lethal gynecological malignancy. High-grade serous OC (HGSOC) is the most common and aggressive OC subtype, characterized by widespread genome changes and chromosomal instability and is consequently poorly responsive to chemotherapy treatment. The objective of this study was to investigate the role of the microRNA miR-433 in the cellular response of OC cells to paclitaxel treatment. We show that stable miR-433 expression in A2780 OC cells results in the induction of cellular senescence demonstrated by morphological changes, downregulation of phosphorylated retinoblastoma (p-Rb), and an increase in ?-galactosidase activity. Furthermore, in silico analysis identified four possible miR-433 target genes associated with cellular senescence: cyclin-dependent kinase 6 (CDK6), MAPK14, E2F3, and CDKN2A. Mechanistically, we demonstrate that downregulation of p-Rb is attributable to a miR-433-dependent downregulation of CDK6, establishing it as a novel miR-433 associated gene. Interestingly, we show that high miR-433 expressing cells release miR-433 into the growth media via exosomes which in turn can induce a senescence bystander effect. Furthermore, in relation to a chemotherapeutic response, quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed that only PEO1 and PEO4 OC cells with the highest miR-433 expression survive paclitaxel treatment. Our data highlight how the aberrant expression of miR-433 can adversely affect intracellular signaling to mediate chemoresistance in OC cells by driving cellular senescence. PMID:25684390

  9. Intraperitoneal delivery of a novel liposome-encapsulated paclitaxel redirects metabolic reprogramming and effectively inhibits cancer stem cells in Taxol®-resistant ovarian cancer

    PubMed Central

    Shen, Yao-An; Li, Wai-Hou; Chen, Po-Hung; He, Chun-Lin; Chang, Yen-Hou; Chuang, Chi-Mu

    2015-01-01

    Taxol® remained as the mainstay therapeutic agent in the treatment of ovarian cancer, however recurrence rate is still high. Cancer stem cells (CSCs) represent a subset of cells in the bulk of tumors and play a central role in inducing drug resistance and recurrence. Furthermore, cancer metabolism has been an area under intensive investigation, since accumulating evidence has shown that CSCs and cancer metabolism are closely linked, an effect named as metabolic reprogramming. In this work, we aimed to investigate the impacts of a novel liposome-encapsulated paclitaxel (Nano-Taxol) on the stemness phenotype and metabolic reprogramming. A paclitaxel-resistant cell line (TR) was established at first. Tumor growth was induced in the mice peritoneal cavity by inoculation of TR cells. A 2x2 factorial experiment was designed to test the therapeutic efficacy in which factor 1 represented the comparison of drugs (Taxol® versus Nano-Taxol), while factor 2 represented the delivery route (intravenous versus intraperitoneal delivery). In this work, we found that intraperitoneal delivery of Nano-Taxol redirects metabolic reprogramming, from glycolysis to oxidative phosphorylation, and effectively suppresses cancer stem cells. Also, intraperitoneal delivery of Nano-Taxol led to a significantly better control of tumor growth compared with intravenous delivery of Taxol® (current standard treatment). This translational research may serve as a novel pathway for the drug development of nanomedicine. In the future, this treatment modality may be extended to treat several relevant cancers that have been proved to be suitable for the loco-regional delivery of therapeutic agents, including colon cancer, gastric cancer, and pancreatic cancer. PMID:26175846

  10. Synthesis, characterization, and paclitaxel release from a biodegradable, elastomeric, poly(ester urethane)urea bearing phosphorylcholine groups for reduced thrombogenicity.

    PubMed

    Hong, Yi; Ye, Sang-Ho; Pelinescu, Anca L; Wagner, William R

    2012-11-12

    Biodegradable polymers with high elasticity, low thrombogenicity, and drug loading capacity continue to be pursued for vascular engineering applications, including vascular grafts and stents. A biodegradable elastomeric polyurethane was designed as a candidate material for use as a drug-eluting stent coating, such that it was nonthrombogenic and could provide antiproliferative drug release to inhibit smooth muscle cell proliferation. A phosphorylcholine containing poly(ester urethane) urea (PEUU-PC) was synthesized by grafting aminated phosphorylcholine onto backbone carboxyl groups of a polyurethane (PEUU-COOH) synthesized from a soft segment blend of polycaprolactone and dimethylolpropionic acid, a hard segment of diisocyanatobutane and a putrescine chain extender. Poly(ester urethane) urea (PEUU) from a soft segment of polycaprolactone alone was employed as a control material. All of the synthesized polyurethanes showed high distensibility (>600%) and tensile strengths in the 20-35 MPa range. PEUU-PC experienced greater degradation than PEUU or PEUU-COOH in either a saline or lipase enzyme solution. PEUU-PC also exhibited markedly inhibited ovine blood platelet deposition compared with PEUU-COOH and PEUU. Paclitaxel loaded in all of the polymers during solvent casting continued to release for 5 d after a burst release in a 10% ethanol/PBS solution, which was utilized to increase the solubility of the releasate. Rat smooth muscle cell proliferation was significantly inhibited in 1 wk cell culture when releasate from the paclitaxel-loaded films was present. Based on these results, the synthesized PEUU-PC has promising functionality for use as a nonthrombogenic, drug eluting coating on metallic vascular stents and grafts. PMID:23035885

  11. Synthesis, Characterization, and Paclitaxel Release from a Biodegradable, Elastomeric, Poly(ester urethane)urea Bearing Phosphorylcholine Groups for Reduced Thrombogenicity

    PubMed Central

    Hong, Yi; Ye, Sang-Ho; Pelinescu, Anca L.; Wagner, William R.

    2013-01-01

    Biodegradable polymers with high elasticity, low thrombogenicity, and drug loading capacity continue to be pursued for vascular engineering applications, including vascular grafts and stents. A biodegradable elastomeric polyurethane was designed as a candidate material for use as a drug-eluting stent coating, such that it was nonthrombogenic and could provide antiproliferative drug release to inhibit smooth muscle cell proliferation. A phosphorylcholine containing poly(ester urethane) urea (PEUU-PC) was synthesized by grafting aminated phosphorylcholine onto backbone carboxyl groups of a polyurethane (PEUU-COOH) synthesized from a soft segment blend of polycaprolactone and dimethylolpropionic acid, a hard segment of diisocyanatobutane and a putrescine chain extender. Poly(ester urethane) urea (PEUU) from a soft segment of polycaprolactone alone was employed as a control material. All of the synthesized polyurethanes showed high distensibility (>600%) and tensile strengths in the 20–35 MPa range. PEUUPC experienced greater degradation than PEUU or PEUU-COOH in either a saline or lipase enzyme solution. PEUU-PC also exhibited markedly inhibited ovine blood platelet deposition compared with PEUU-COOH and PEUU. Paclitaxel loaded in all of the polymers during solvent casting continued to release for 5 d after a burst release in a 10% ethanol/PBS solution, which was utilized to increase the solubility of the releasate. Rat smooth muscle cell proliferation was significantly inhibited in 1 wk cell culture when releasate from the paclitaxel-loaded films was present. Based on these results, the synthesized PEUU-PC has promising functionality for use as a nonthrombogenic, drug eluting coating on metallic vascular stents and grafts. PMID:23035885

  12. Participation of non-neuronal muscarinic receptors in the effect of carbachol with paclitaxel on human breast adenocarcinoma cells. Roles of nitric oxide synthase and arginase.

    PubMed

    Español, Alejandro Javier; Salem, Agustina; Rojo, Daniela; Sales, María Elena

    2015-11-01

    Breast cancer is the most common type of cancer in women and represents a major issue in public health. The most frequent methods to treat these tumors are surgery and/or chemotherapy. The latter can exert not only beneficial effects by reducing tumor growth and metastasis, but also toxic actions on normal tissues. Metronomic therapy involves the use of low doses of cytotoxic drugs alone or in combination to improve efficacy and to reduce adverse effects. We have previously reported that breast tumors highly express functional muscarinic acetylcholine receptors (mAChRs) that regulate tumor progression. For this reason, mAChRs could be considered as therapeutic targets in breast cancer. In this paper, we investigated the ability of a combination of the cytotoxic drug paclitaxel plus carbachol, a cholinergic agonist, at low doses, to induce death in breast tumor MCF-7 cells, via mAChR activation, and the role of nitric oxide synthase (NOS) and arginase in this effect. We observed that the combination of carbachol plus paclitaxel at subthreshold doses significantly increased cytotoxicity in tumor cells without affecting MCF-10A cells, derived from human normal mammary gland. This effect was reduced in the presence of the muscarinic antagonist atropine. The combination also increased nitric oxide production by NOS1 and NOS3 via mAChR activation, concomitantly with an up-regulation of NOS3 expression. The latter effects were accompanied by a reduction in arginase II activity. In conclusion, our work demonstrates that mAChRs expressed in breast tumor cells could be considered as candidates to become targets for metronomic therapy in cancer treatment. PMID:25812766

  13. Association of the Charcot-Marie-Tooth disease gene ARHGEF10 with paclitaxel induced peripheral neuropathy in NCCTG N08CA (Alliance).

    PubMed

    Boora, Ganesh K; Kulkarni, Amit A; Kanwar, Rahul; Beyerlein, Peter; Qin, Rui; Banck, Michaela S; Ruddy, Kathryn J; Pleticha, Josef; Lynch, Cynthia A; Behrens, Robert J; Züchner, Stephan; Loprinzi, Charles L; Beutler, Andreas S

    2015-10-15

    The predisposition of patients to develop polyneuropathy in response to toxic exposure may have a genetic basis. The previous study Alliance N08C1 found an association of the Charcot-Marie-Tooth disease (CMT) gene ARHGEF10 with paclitaxel chemotherapy induced peripheral neuropathy (CIPN) related to the three non-synonymous, recurrent single nucleotide variants (SNV), whereby rs9657362 had the strongest effect, and rs2294039 and rs17683288 contributed only weakly. In the present report, Alliance N08CA was chosen to attempt to replicate the above finding. N08CA was chosen because it is the methodologically most similar study (to N08C1) performed in the CIPN field to date. N08CA enrolled patients receiving the neurotoxic chemotherapy agent paclitaxel. Polyneuropathy was assessed by serial repeat administration of the previously validated patient reported outcome instrument CIPN20. A study-wide, Rasch type model was used to perform extreme phenotyping in n=138 eligible patients from which "cases" and "controls" were selected for genetic analysis of SNV performed by TaqMan PCR. A significant association of ARHGEF10 with CIPN was found under the pre-specified primary endpoint, with a significance level of p=0.024. As in the original study, the strongest association of a single SNV was seen for rs9657362 (odds ratio=3.56, p=0.018). To further compare results across the new and the previous study, a statistical "classifier" was tested, which achieved a ROC area under the curve of 0.60 for N08CA and 0.66 for N08C1, demonstrating good agreement. Retesting of the primary endpoint of N08C1 in the replication study N08CA validated the association of ARHGEF10 with CIPN. PMID:26143528

  14. Survival, quality-adjusted survival, and other clinical end points in older advanced non-small-cell lung cancer patients treated with albumin-bound paclitaxel

    PubMed Central

    Langer, C J; Hirsh, V; Okamoto, I; Lin, F-J; Wan, Y; Whiting, S; Ong, T J; Renschler, M F; Botteman, M F

    2015-01-01

    Background: This analysis compared the quality-adjusted survival and clinical outcomes of albumin-bound paclitaxel+carboplatin (nab-PC) vs solvent-based paclitaxel+carboplatin (sb-PC) as first-line therapy in advanced non-small-cell lung cancer (NSCLC) in older patients. Methods: Using age-based subgroup data from a randomised Phase-3 clinical trial, nab-PC and sb-PC were compared with respect to overall response rate (ORR), overall survival (OS), progression-free survival (PFS), quality of life (QoL), safety/toxicity, and quality-adjusted time without symptoms or toxicity (Q-TWiST) with ages ?60 and ?70 years as cut points. Results: Among patients aged ?60 years (N=546), nab-PC (N=265) significantly increased ORR and prolonged OS, despite a non-significant improvement in PFS, vs sb-PC (N=281). Nab-PC improved QoL and was associated with less neuropathy, arthralgia, and myalgia but resulted in more anaemia and thrombocytopenia. Nab-PC yielded significant Q-TWiST benefits (11.1 vs 9.8 months; 95% CI of gain: 0.2–2.6), with a relative Q-TWiST gain of 10.8% (ranging from 6.4% to 15.1% in threshold analysis). In the ?70 years age group, nab-PC showed similar, but non-significant, ORR, PFS, and Q-TWiST benefits and significantly improved OS and QoL. Conclusion: Nab-PC as first-line therapy in older patients with advanced NSCLC increased ORR, OS, and QoL and resulted in quality-adjusted survival gains compared with standard sb-PC. PMID:26035702

  15. Paclitaxel, Carboplatin, and Trastuzumab

    PubMed Central

    Lee, Jennifer; Solimando, Dominic A.; Waddell, J. Aubrey

    2014-01-01

    The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, e-mail: OncRxSvc@comcast.net; or J. Aubrey Waddell, Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 E. Lamar Alexander Parkway, Maryville, TN 37804, e-mail: waddfour@charter.net. PMID:25477563

  16. A Randomized Phase III Trial in Advanced Endometrial Carcinoma of Surgery and Volume Directed Radiation Followed by Cisplatin and Doxorubicin with or without Paclitaxel: A Gynecologic Oncology Group Study

    PubMed Central

    Homesley, Howard D.; Filiaci, Virginia; Gibbons, Susan K.; Long, Harry J.; Cella, David; Spirtos, Nick M.; Morris, Robert T.; DeGeest, Koen; Lee, Roger; Montag, Anthony

    2009-01-01

    Objectives After surgical debulking and volume-directed irradiation of the pelvis/para-aortic lymph nodes, treatment was randomized to compare recurrence-free survival (RFS) and toxicity between two chemotherapy regimens for the treatment of women with advanced stage endometrial carcinoma. Methods Treatment was randomized between 6 cycles of cisplatin [C] (50 mg/m2) and doxorubicin [D] (45 mg/m2) with or without paclitaxel [P] (160 mg/m2). Initially in paclitaxel treated patients and, after May 2002, all patients received granulocyte growth factor with each cycle. Results Of 659 patients enrolled following surgery, 552 eligible patients were randomized to chemotherapy after irradiation. Accrual closed to Stage IV patients in June, 2003. Approximately 80% completed six cycles of chemotherapy. Three deaths resulted from bowel complications and one death was due to renal failure. Hematologic adverse events, sensory neuropathy and myalgia, were more frequent and severe in the paclitaxel arm (p< 0.01) which was confirmed by Quality of Life assessments. Percentage of patients alive and recurrence-free at 36 months was 62% for CD vs. 64% for CDP. The hazard of recurrence or death relative to the CD arm stratified by stage is 0.90 (95% CI is 0.69 to 1.17, p=0.21, one-tail). However, in subgroup analysis, CDP was associated with a 50% reduction in the risk of recurrence or death among patients with gross residual disease (95% CI: 0.26 to 0.92). Stage, residual disease, histology/grade, positive para-aortic node and cytology, pelvic metastases and age were significantly associated with RFS. Conclusion The addition of paclitaxel to cisplatin and doxorubicin following surgery and radiation was not associated with a significant improvement in RFS but was associated with increased toxicity. PMID:19108877

  17. A prospective evaluation of the safety and efficacy of the TAXUS Element paclitaxel-eluting coronary stent system for the treatment of de novo coronary artery lesions: Design and statistical methods of the PERSEUS clinical program

    PubMed Central

    2010-01-01

    Background Paclitaxel-eluting stents decrease angiographic and clinical restenosis following percutaneous coronary intervention compared to bare metal stents. TAXUS Element is a third-generation paclitaxel-eluting stent which incorporates a novel, thinner-strut, platinum-enriched metal alloy platform. The stent is intended to have enhanced radiopacity and improved deliverability compared to other paclitaxel-eluting stents. The safety and efficacy of the TAXUS Element stent are being evaluated in the pivotal PERSEUS clinical trials. Methods/Design The PERSEUS trials include two parallel studies of the TAXUS Element stent in single, de novo coronary atherosclerotic lesions. The PERSEUS Workhorse study is a prospective, randomized (3:1), single-blind, non-inferiority trial in subjects with lesion length ?28 mm and vessel diameter ?2.75 mm to ?4.0 mm which compares TAXUS Element to the TAXUS Express2 paclitaxel-eluting stent system. The Workhorse study employs a novel Bayesian statistical approach that uses prior information to limit the number of study subjects exposed to the investigational device and thus provide a safer and more efficient analysis of the TAXUS Element stent. PERSEUS Small Vessel is a prospective, single-arm, superiority trial in subjects with lesion length ?20 mm and vessel diameter ?2.25 mm to <2.75 mm that compares TAXUS Element with a matched historical bare metal Express stent control. Discussion The TAXUS PERSEUS clinical trial program uses a novel statistical approach to evaluate whether design and metal alloy iterations in the TAXUS Element stent platform provide comparable safety and improved procedural performance compared to the previous generation Express stent. PERSEUS trial enrollment is complete and primary endpoint data are expected in 2010. PERSEUS Workhorse and Small Vessel are registered at http://www.clinicaltrials.gov, identification numbers NCT00484315 and NCT00489541. PMID:20059766

  18. Effect of the association of 1-methyl-DL-tryptophan with paclitaxel on the expression of indoleamine 2,3-dioxygenase in cultured cancer cells from patients with breast cancer.

    PubMed

    Salvadori, Maria Letícia Baptista; da Cunha Bianchi, Pedro Kastein Faria; Gebrim, Luiz Henrique; Silva, Renata Santos; Kfoury, José Roberto

    2015-11-01

    Breast cancer is the most common type of cancer among women and the survival of patients affected by it is increasing, mainly due to several new approaches in early diagnosis and more effective treatments. The enzyme indoleamine 2,3-dioxygenase (IDO) is expressed in many cells, including tumor cells. IDO acts by inhibiting the proliferation of T lymphocytes, thus compromising their cytotoxic activity. 1-Methyl-DL-tryptophan (1MT) is a competitive inhibitor of IDO, which blocks its immunosuppressive effect. Paclitaxel is an antineoplastic drug largely used in breast cancer therapy. Thus, this study aimed to determine the in vitro effect of the association of 1MT and paclitaxel chemotherapy, as an approach to reduce tumor growth. It is believed that this would allow the restoration of T lymphocyte proliferation capability and its cytotoxic response. The supplemented cultures showed that the most significant differences in the expression of IDO were observed in the group treated with paclitaxel associated with 1-MT continuous supplementation, reducing enzyme expression from 12.06 to 3.56 %. This association was more effective in reducing IDO expression and could collaborate in developing a new therapeutic strategy for breast cancer treatment. PMID:26442514

  19. Randomised phase 3 open-label trial of first-line treatment with gemcitabine in association with docetaxel or paclitaxel in women with metastatic breast cancer: a comparison of different schedules and treatments

    PubMed Central

    2013-01-01

    Background This open-label study compared docetaxel/gemcitabine vs. paclitaxel/gemcitabine and a weekly (W) vs. 3-weekly (3 W) schedule in metastatic breast cancer (MBC). Methods Patients relapsed after adjuvant/neoadjuvant anthracycline-containing chemotherapy were randomized to: A) gemcitabine 1000 mg/m2 Day 1,8 + docetaxel 75 mg/m2 Day 1 q3W; B) gemcitabine 1250 mg/m2 Day 1,8 + paclitaxel 175 mg/m2 Day 1 q3W; C) gemcitabine 800 mg/m2 Day 1,8,15 + docetaxel 30 mg/m2 Day 1,8,15 q4W; D) gemcitabine 800 mg/m2 Day 1,15 + paclitaxel 80 mg/m2 Day 1,8,15 q4W. Primary endpoint was time-to-progression (TTP). Secondary endpoints were overall survival (OS) and overall response rate (ORR). Results Interim analysis led to accrual interruption (241 patients enrolled of 360 planned). Median TTP (months) was 8.33 (95% CI: 6.19-10.16) with W and 7.51 (95% CI: 5.93-8.33) with 3 W (p=0.319). No differences were observed in median TTP between docetaxel and paclitaxel, with 85.6% and 87.0% of patients progressing, respectively. OS did not differ between regimens/schedules. ORR was comparable between regimens (HR: 0.882; 95% CI: 0.523-1.488; p=0.639), while it was significantly higher in W than in the 3 W (HR: 0.504; 95% CI: 0.299-0.850; p=0.010) schedule. Grade 3/4 toxicities occurred in 69.2% and 71.9% of patients on docetaxel and paclitaxel, and in 65.8% and 75.2% in W and 3 W. Conclusions Both treatment regimens showed similar TTP. W might be associated with a better tumour response compared with 3 W. Trial registration Clinicaltrial.gov ID NCT00236899 PMID:23537313

  20. Comparative study analyzing survival and safety of bevacizumab/carboplatin/paclitaxel and cisplatin/pemetrexed in chemotherapy-naïve patients with advanced non-squamous bronchogenic carcinoma not harboring EGFR mutation

    PubMed Central

    Kader, Yasser Abdel; Le Chevalier, Thierry; El-Nahas, Tamer; Sakr, Amr

    2013-01-01

    Purpose The majority of Egyptian patients with lung cancer present at a late stage of the disease. Bevacizumab/carboplatin/paclitaxel, as well as cisplatin plus pemetrexed, are both standard regimens for advanced non-squamous bronchogenic cancer. This study compares both regimens, in terms of efficacy and toxicity profile, in Egyptian patients. Patients and methods This is a randomized Phase II study comparing toxicity profile and survival in 41 chemotherapy-naïve patients with stage IIIB or IV non-squamous NSCLC, with an ECOG performance status of 0 to 2. The epidermal growth factor receptor (EGFR) mutation detection was performed prior to treatment of all patients. Patients in the first group received: bevacizumab 7.5 mg/m2 on Day 1 and Day 15; carboplatin area under the curve-5 on Day 1; and paclitaxel 60 mg/m2 on Day 1, Day 8, and Day 15 every 4 weeks. In the second group, patients received cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 every 3 weeks. Results The combination of bevacizumab/carboplatin/paclitaxel demonstrated higher Grade III–IV toxicity than cisplatin/pemetrexed regarding sensory/motor neuropathy (P = 0.06), DVT (P = 0.23), proteinuria (P = 0.23), and hypertension (P = 0.11), as well as Grade II alopecia (P = 0.001); however, no significant difference in toxicities between both arms was recorded regarding nausea and vomiting (P = 0.66), hematological toxicity, febrile neutropenia (P = 1) and fatigue (P = 0.66). Progression-free survival was similar for both treatment arms with a median of 6 months (P = 0.978). Overall median survival was comparable in both arms, 16.07 months versus 16.01 months (P = 0.89). Conclusion Bevacizumab/carboplatin/paclitaxel and cisplatin/pemetrexed provided meaningful and comparable efficacy in advanced non-squamous bronchogenic carcinoma not harboring EGFR mutation. No significant difference in toxicity was observed between both treatment arms, apart from bevacizumab/carboplatin/paclitaxel-related risks as DVT, hypertension, proteinuria, sensory/motor neuropathy, and alopecia. PMID:23836994

  1. Efficacy and safety of concurrent trastuzumab plus weekly paclitaxel-FEC as primary therapy for HER2-positive breast cancer in everyday clinical practice.

    PubMed

    Pernas, Sonia; Gil-Gil, Miguel; de Olza, María Ochoa; Gumà, Anna; Climent, Fina; Petit, Anna; Pla, María Jesús; García-Tejedor, Amparo; López-Ojeda, Ana; Falo, Cati; Fernandez-Otega, Adela; Mesia, Carlos; Pérez-Martin, Francisco Javier; Urruticoechea, Ander; Germà, Josep Ramon

    2012-08-01

    One of the most efficacious primary therapies in HER2-positive breast cancer was published by the M.D. Anderson group in 2005. This randomized trial evaluated the addition of trastuzumab to a taxane-anthracycline based chemotherapy. Despite largely significant differences in pathological complete response (pCR) in the trastuzumab group (65 vs. 26 %) this regimen did not become a common standard due to toxicity concerns and its premature closure with a small sample size. In order to evaluate the efficacy and safety of this regimen in an off-trial setting we conducted a prospectively monitorized series of consecutive patients with early or locally advanced Her-2 positive breast cancer following the same treatment strategy. Stage II-IIIC HER2-positive breast cancer patients, including inflammatory disease, were treated with weekly-trastuzumab for 24 weeks administered concurrently with all primary chemotherapy containing paclitaxel (80 mg/m(2)) for 12 weeks and 4 cycles of FEC-75 (fluorouracil 500 mg/m(2), epirubicine 75 mg/m(2), and cyclophosphamide 500 mg/m(2)) followed by surgery. The objectives were efficacy, in terms of pCR in both the breast and lymph nodes, and safety, with close cardiac monitoring during and after treatment. From August 2004 to February 2009, 83 patients were included. Most patients (73.5 %) had node involvement and 13.2 % had inflammatory disease. Fifty-one patients (61.4 %) achieved a pCR in breast and axilla (95 % CI 50-72 %). HR-negative tumors were associated with higher pCR rate than HR-positive tumors (77 vs. 48 %, P = 0.006). At a median follow-up of 50.2 months no patient developed symptomatic cardiac failure, and 9 patients (10.8 %) presented a transient asymptomatic decrease in left ventricular ejection fraction. Primary therapy with concurrent trastuzumab plus paclitaxel-FEC for HER2-positive breast cancer in everyday practice is highly effective and safe confirming the results observed in a randomized trial stopped prematurely. PMID:22772380

  2. Combination of single walled carbon nanotubes/graphene oxide with paclitaxel: a reactive oxygen species mediated synergism for treatment of lung cancer

    NASA Astrophysics Data System (ADS)

    Arya, Neha; Arora, Aditya; Vasu, K. S.; Sood, A. K.; Katti, Dhirendra S.

    2013-03-01

    Heterogeneity in tumors has led to the development of combination therapies that enable enhanced cell death. Previously explored combination therapies mostly involved the use of bioactive molecules. In this work, we explored a non-conventional strategy of using carbon nanostructures (CNs) [single walled carbon nanotube (SWNT) and graphene oxide (GO)] for potentiating the efficacy of a bioactive molecule [paclitaxel (Tx)] for the treatment of lung cancer. The results demonstrated enhanced cell death following combination treatment of SWNT/GO and Tx indicating a synergistic effect. In addition, synergism was abrogated in the presence of an anti-oxidant, N-acetyl cysteine (NAC), and was therefore shown to be reactive oxygen species (ROS) dependent. It was further demonstrated using bromodeoxyuridine (BrdU) incorporation assay that treatment with CNs was associated with enhanced mitogen associated protein kinase (MAPK) activation that was ROS mediated. Hence, these results for the first time demonstrated the potential of SWNT/GO as co-therapeutic agents with Tx for the treatment of lung cancer.Heterogeneity in tumors has led to the development of combination therapies that enable enhanced cell death. Previously explored combination therapies mostly involved the use of bioactive molecules. In this work, we explored a non-conventional strategy of using carbon nanostructures (CNs) [single walled carbon nanotube (SWNT) and graphene oxide (GO)] for potentiating the efficacy of a bioactive molecule [paclitaxel (Tx)] for the treatment of lung cancer. The results demonstrated enhanced cell death following combination treatment of SWNT/GO and Tx indicating a synergistic effect. In addition, synergism was abrogated in the presence of an anti-oxidant, N-acetyl cysteine (NAC), and was therefore shown to be reactive oxygen species (ROS) dependent. It was further demonstrated using bromodeoxyuridine (BrdU) incorporation assay that treatment with CNs was associated with enhanced mitogen associated protein kinase (MAPK) activation that was ROS mediated. Hence, these results for the first time demonstrated the potential of SWNT/GO as co-therapeutic agents with Tx for the treatment of lung cancer. Electronic supplementary information (ESI) available. See DOI: 10.1039/c3nr33190c

  3. A phase 2 study of everolimus combined with trastuzumab and paclitaxel in patients with HER2-overexpressing advanced breast cancer that progressed during prior trastuzumab and taxane therapy.

    PubMed

    Hurvitz, Sara A; Dalenc, Florence; Campone, Mario; O'Regan, Ruth M; Tjan-Heijnen, Vivianne C; Gligorov, Joseph; Llombart, Antonio; Jhangiani, Haresh; Mirshahidi, Hamid R; Tan-Chiu, Elizabeth; Miao, Sara; El-Hashimy, Mona; Lincy, Jeremie; Taran, Tetiana; Soria, Jean-Charles; Sahmoud, Tarek; André, Fabrice

    2013-10-01

    Increased activation of the PI3K/Akt/mTOR pathway is a common factor in putative mechanisms of trastuzumab resistance, resulting in dysregulation of cell migration, growth, proliferation, and survival. Data from preclinical and phase 1/2 clinical studies suggest that adding everolimus (an oral mTOR inhibitor) to trastuzumab plus chemotherapy may enhance the efficacy of, and restore sensitivity to, trastuzumab-based therapy. In this phase 2 multicenter study, adult patients with HER2-positive advanced breast cancer resistant to trastuzumab and pretreated with a taxane received everolimus 10 mg/day in combination with paclitaxel (80 mg/m(2) days 1, 8, and 15 every 4 weeks) and trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly), administered in 28-day cycles. Endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients were enrolled; one remained on study treatment at the time of data cutoff. The median number of prior chemotherapy lines for advanced disease was 3.5 (range 1-11). The ORR was 21.8 %, the clinical benefit rate was 36.4 %, the median PFS estimate was 5.5 months (95 % confidence interval [CI]: 4.99-7.69 months), and the median OS estimate was 18.1 months (95 % CI: 12.85-24.11 months). Hematologic grade 3/4 adverse events (AEs) included neutropenia (25.5 % grade 3, 3.6 % grade 4), anemia (7.3 % grade 3), and thrombocytopenia (5.5 % grade 3, 1.8 % grade 4). Nonhematologic grade 3/4 AEs included stomatitis (20.0 %), diarrhea (5.5 %), vomiting (5.5 %), fatigue (5.5 %), and pneumonia (5.5 %), all grade 3. These findings suggest that the combination of everolimus plus trastuzumab and paclitaxel is feasible, with promising activity in patients with highly resistant HER2-positive advanced breast cancer. This combination is currently under investigation in the BOLERO-1 phase 3 trial. PMID:24101324

  4. Anti-proliferative activity and cell cycle arrest induced by evodiamine on paclitaxel-sensitive and -resistant human ovarian cancer cells.

    PubMed

    Zhong, Zhang-Feng; Tan, Wen; Wang, Sheng-Peng; Qiang, Wen-An; Wang, Yi-Tao

    2015-01-01

    Chemo-resistance is the main factor for poor prognosis in human ovarian epithelial cancer. Active constituents derived from Chinese medicine with anti-cancer potential might circumvent this obstacle. In our present study, evodiamine (EVO) derived from Evodia rutaecarpa (Juss.) Benth suppressed the proliferation of human epithelial ovarian cancer, A2780 and the related paclitaxel-resistant cell lines and did not cause cytotoxicity, as confirmed by the significant decline of clone formation and the representative alterations of CFDA-SE fluorescence. Meanwhile, EVO induced cell cycle arrest in a dose- and time-dependent manner. This disturbance might be mediated by the cooperation of Cyclin B1 and Cdc2, including the up-regulation of Cyclin B1, p27, and p21, and activation failure of Cdc2 and pRb. MAPK signaling pathway regulation also assisted in this process. Furthermore, chemo-sensitivity potential was enhanced as indicated in A2780/PTX(R) cells by the down-regulation of MDR-1 expression, accompanied by MDR-1 function suppression. Taken together, we confirmed initially that EVO exerted an anti-proliferative effect on human epithelial ovarian cancer cells, A2780/WT and A2780/PTX(R), induced G2/M phase cell cycle arrest, and improved chemo-resistance. Overall, we found that EVO significantly suppressed malignant proliferation in human epithelial ovarian cancer, thus proving to be a potential anti-cancer agent in the future. PMID:26553648

  5. Thrombotic thrombocytopenic purpura following salvage chemotherapy with paclitaxel, ifosfamide and cisplatin in a patient with a refractory germ cell tumor: A case report and review of the literature

    PubMed Central

    ULAS, ARIFE; SILAY, KAMILE; AKINCI, SEMA; AKINCI, MUHAMMED BULENT; SENDUR, MEHMET ALI; DEDE, DIDEM SENER; POLAT, YUNUS HALIL; YALCIN, BULENT

    2015-01-01

    Thrombotic thrombocytopenic purpura (TTP) is a rare form of thrombotic microangiopathy that is characterized by microvascular thrombosis, thrombocytopenia, hemolysis and end organ damage. An extensive variety of drugs, including certain chemotherapeutic agents, have been associated with TTP. However, paclitaxel, cisplatin and ifosfamide regimen (TIP)-induced TTP has not previously been described. The present study reports the case of a 43-year-old patient with a refractory testicular germ cell tumor who developed acute TTP during TIP chemotherapy. Following the third cycle of TIP chemotherapy, the patient developed fever, anemia, thrombocytopenia and confusion. A diagnosis of TTP was established. Plasmapheresis was initiated as daily treatment in the first week, then continued every other day for 4 weeks. TIP chemotherapy was discontinued. The patient's clinical and neurological symptoms improved markedly after a week. Renal function and hemolysis improved, and the patient was discharged in a stable condition. The patient did not develop any complications and has been in remission for 5 months. The Naranjo adverse drug reaction probability scale indicated a likely association between TTP and the TIP chemotherapy regimen in this patient. This case is also investigated with regard to the associated literature to increase the awareness of TTP following chemotherapy.

  6. To Study the Effect of Paclitaxel on the Cytoplasmic Viscosity of Murine Macrophage Immune Cell RAW 264.7 Using Self-Developed Optical Tweezers System

    NASA Astrophysics Data System (ADS)

    Chen, Ying-chun; Wu, Chien-ming

    2012-12-01

    In recent years, optical tweezers have become one of the tools to measure the mechanical properties of living cells. In this study, we first constructed an optical tweezers to investigate the cytoplasmic viscosity of immune cells. In addition to measuring viscosity of cells in a normal condition, we also treated cells with anti-cancer drug, Paclitaxel, and in order to study its effect on the cytoplasmic viscosity. The results showed that the viscosity decreased dramatically during the first 3 h. After 3 h, the change started to slow down and it remained nearly flat by the end of the experiment. In addition, we used the confocal laser scanning microscope to observe the cytoskeleton of the cell after drug treatment for 3 and 5 h, respectively, and found that actin filaments were disrupted and that the nucleus had disintegrated in some drug-treated cells, similar to the process of apoptosis. This study presents a new way for measuring the changes in cytoplasmic viscosity, and to determine if a cell is going into apoptosis as a result of a drug treatment.

  7. Intraperitoneal delivery of paclitaxel by poly(ether-anhydride) microspheres effectively suppresses tumor growth in a murine metastatic ovarian cancer model

    PubMed Central

    Yang, Ming; Yu, Tao; Wood, Joseph; Wang, Ying-Ying; Tang, Benjamin C.; Zeng, Qi; Simons, Brian W.; Fu, Jie; Chuang, Chi-Mu; Lai, Samuel K.; Wu, T.-C.; Hung, Chien-Fu; Hanes, Justin

    2014-01-01

    Intraperitoneal (IP) chemotherapy is more effective than systemic chemotherapy for treating advanced ovarian cancer, but is typically associated with severe complications due to high dose, frequent administration schedule, and use of non-biocompatible excipients/delivery vehicles. Here, we developed paclitaxel (PTX)-loaded microspheres composed of di-block copolymers of poly(ethylene glycol) and poly(sebacic acid) (PEG-PSA) for safe and sustained IP chemotherapy. PEG-PSA microspheres provided efficient loading (~ 13% w/w) and prolonged release (~ 13 days) of PTX. In a murine ovarian cancer model, a single dose of IP PTX/PEG-PSA particles effectively suppressed tumor growth for more than 40 days and extended the median survival time to 75 days compared to treatments with Taxol® (47 days) or IP placebo particles (34 days). IP PTX/PEG-PSA was well tolerated, with only minimal to mild inflammation. Our findings support PTX/PEG–PSA microspheres as a promising drug delivery platform for IP therapy of ovarian cancer, and potentially other metastatic peritoneal cancers. PMID:24816829

  8. Ecdysteroids Sensitize MDR and Non-MDR Cancer Cell Lines to Doxorubicin, Paclitaxel, and Vincristine but Tend to Protect Them from Cisplatin

    PubMed Central

    Sipos, Péter; Dér, Katalin; Csábi, József; Miklos, Walter; Berger, Walter; Zalatnai, Attila; Amaral, Leonard; Molnár, Joseph; Szabó-Révész, Piroska

    2015-01-01

    Ecdysteroids, analogs of the insect molting hormone, are known for their various mild, nonhormonal bioactivities in mammals. Previously, we reported that less-polar ecdysteroids can modulate the doxorubicin resistance of a multidrug resistant (MDR) mouse lymphoma cell line expressing the human ABCB1 transporter. Here, we describe the ability of 20-hydroxyecdysone (1) and its mono- (2) and diacetonide (3) derivatives to sensitize various MDR and non-MDR cancer cell lines towards doxorubicin, paclitaxel, vincristine, or cisplatin. Drug IC50 values with or without ecdysteroid were determined by MTT assay. Compound 3 significantly sensitized all cell lines to each chemotherapeutic except for cisplatin, whose activity was decreased. In order to overcome solubility and stability issues for the future in vivo administration of compound 3, liposomal formulations were developed. By means of their combination index values obtained via checkerboard microplate method, a formulation showed superior activity to that of compound 3 alone. Because ecdysteroids act also on non-ABCB1 expressing (sensitive) cell lines, our results demonstrate that they do not or not exclusively exert their adjuvant anticancer activity as ABCB1 inhibitors, but other mechanisms must be involved, and they opened the way towards their in vivo bioactivity testing against various cancer xenografts. PMID:26075272

  9. Genetic variations of orosomucoid genes associated with serum alpha-1-acid glycoprotein level and the pharmacokinetics of paclitaxel in Japanese cancer patients.

    PubMed

    Katori, Noriko; Sai, Kimie; Saito, Yoshiro; Fukushima-Uesaka, Hiromi; Kurose, Kouichi; Yomota, Chikako; Kawanishi, Toru; Nishimaki-Mogami, Tomoko; Naito, Mikihiko; Sawada, Jun-Ichi; Kunitoh, Hideo; Nokihara, Hiroshi; Sekine, Ikuo; Ohe, Yuichiro; Yoshida, Teruhiko; Matsumura, Yasuhiro; Saijo, Nagahiro; Yamamoto, Noboru; Okuda, Haruhiro; Tamura, Tomohide

    2011-10-01

    Alpha-1-acid glycoprotein (AGP) encoded by orosomucoid genes (ORM1 and ORM2) is an acute-phase response protein and functions as a drug-binding protein that affects pharmacokinetics (PK)/pharmacodynamics of binding drugs. To explore the effects of genetic variations of ORMs and a role of AGP on paclitaxel (PTX) therapy, we analyzed the duplication and genetic variations/haplotypes of ORMs in 165 Japanese cancer patients and then investigated their associations with serum AGP levels and the PK parameters of PTX. No effects of ORM duplications on serum AGP levels at baseline or PK of PTX were observed, but close associations of ORM1 -559T > A with the increases of AGP levels and area under the curve (AUC) of PTX metabolites were detected. In addition, a significant correlation between the serum AGP level and the AUCs of PTX metabolites was observed, suggesting that AGP may function as a carrier of PTX from the blood into the liver via putative receptors. This study provided useful information on the possible clinical importance of ORM genetic polymorphisms and a novel role of AGP in PTX therapy. PMID:21638284

  10. Self-aggregated nanoparticles of linoleic acid-modified glycol chitosan conjugate as delivery vehicles for paclitaxel: preparation, characterization and evaluation.

    PubMed

    Yu, Jingmou; Liu, Yonghua; Zhang, Lei; Zhao, Jianguo; Ren, Jin; Zhang, Lifang; Jin, Yi

    2015-12-01

    A series of linoleic acid-modified glycol chitosan (LAGC) conjugates were synthesized and characterized by FTIR and (1)H NMR. The effect of the amount of linoleic acid (LA) on the physicochemical properties of LAGC conjugates was investigated. The mean diameters of three LAGC nanoparticles determined by dynamic light scattering ranged from 204 to 289 nm. The critical aggregation concentration values of LAGC conjugates in aqueous solution were 0.0148, 0.0348, and 0.0807 mg/ml, respectively. Paclitaxel (PTX) was physically loaded into the LAGC nanoparticles by a dialysis method. The drug loading content and encapsulation efficiency of PTX-loaded LAGC (PTX-LAGC) nanoparticles increased with an increasing ratio of the hydrophobic LA to hydrophilic glycol chitosan in the conjugates. PTX-LAGC nanoparticles were almost spherical in shape observed by transmission electron microscopy. In vitro release revealed that PTX release from the nanoparticles was reduced as the LA substitution degree of LAGC conjugates increased. Compared with the commercial formulation Taxol, PTX-LAGC-1 nanoparticles exhibited comparable cellular uptake and cytotoxicity against HepG2 cells in vitro. Importantly, PTX-LAGC-1 nanoparticles demonstrated the stronger antitumor efficacy against hepatic H22 tumor-bearing mice than Taxol (p < 0.05). Therefore, glycolipid-like LAGC nanoparticles had a potential as delivery vehicles for tumor therapy. PMID:26489688

  11. A toxic organic solvent-free technology for the preparation of PEGylated paclitaxel nanosuspension based on human serum albumin for effective cancer therapy

    PubMed Central

    Yin, Tingjie; Dong, Lihui; Cui, Bei; Wang, Lei; Yin, Lifang; Zhou, Jianping; Huo, Meirong

    2015-01-01

    Clinically, paclitaxel (PTX) is one of most commonly prescribed therapies against a wide range of solid neoplasms. Despite its success, the clinical applicability of PTX (Taxol®) is severely hampered by systemic toxicities induced by Cremophor EL. While attempts to bypass the need for Cremophor EL have been developed through platforms such as Abraxane™, nab™ relies heavily on the use of organic solvents, namely, chloroform. The toxicity introduced by residual chloroform poses a potential risk to patient health. To mitigate the toxicities of toxic organic solvent-based manufacture methods, we have designed a method for the formulation of PTX nanosuspensions (PTX-PEG [polyethylene glycol]-HSA [human serum albumin]) that eliminates the dependence on toxic organic solvents. Coined the solid-dispersion technology, this technique permits the dispersion of PTX into PEG skeleton without the use of organic solvents or Cremophor EL as a solubilizer. Once the PTX-PEG dispersion is complete, the dispersion can be formulated with HSA into nanosuspensions suitable for intravenous administration. Additionally, the incorporation of PEG permits the prolonged circulation through the steric stabilization effect. Finally, HSA-mediated targeting permits active receptor-mediated endocytosis for enhanced tumor uptake and reduced side effects. By eliminating the need for both Cremophor EL and organic solvents while simultaneously increasing antitumor efficacy, this method provides a superior alternative to currently accepted methods for PTX delivery. PMID:26715846

  12. Ecdysteroids sensitize MDR and non-MDR cancer cell lines to doxorubicin, paclitaxel, and vincristine but tend to protect them from cisplatin.

    PubMed

    Martins, Ana; Sipos, Péter; Dér, Katalin; Csábi, József; Miklos, Walter; Berger, Walter; Zalatnai, Attila; Amaral, Leonard; Molnár, Joseph; Szabó-Révész, Piroska; Hunyadi, Attila

    2015-01-01

    Ecdysteroids, analogs of the insect molting hormone, are known for their various mild, nonhormonal bioactivities in mammals. Previously, we reported that less-polar ecdysteroids can modulate the doxorubicin resistance of a multidrug resistant (MDR) mouse lymphoma cell line expressing the human ABCB1 transporter. Here, we describe the ability of 20-hydroxyecdysone (1) and its mono- (2) and diacetonide (3) derivatives to sensitize various MDR and non-MDR cancer cell lines towards doxorubicin, paclitaxel, vincristine, or cisplatin. Drug IC50 values with or without ecdysteroid were determined by MTT assay. Compound 3 significantly sensitized all cell lines to each chemotherapeutic except for cisplatin, whose activity was decreased. In order to overcome solubility and stability issues for the future in vivo administration of compound 3, liposomal formulations were developed. By means of their combination index values obtained via checkerboard microplate method, a formulation showed superior activity to that of compound 3 alone. Because ecdysteroids act also on non-ABCB1 expressing (sensitive) cell lines, our results demonstrate that they do not or not exclusively exert their adjuvant anticancer activity as ABCB1 inhibitors, but other mechanisms must be involved, and they opened the way towards their in vivo bioactivity testing against various cancer xenografts. PMID:26075272

  13. Anti-proliferative activity and cell cycle arrest induced by evodiamine on paclitaxel-sensitive and -resistant human ovarian cancer cells

    PubMed Central

    Zhong, Zhang-Feng; Tan, Wen; Wang, Sheng-Peng; Qiang, Wen-An; Wang, Yi-Tao

    2015-01-01

    Chemo-resistance is the main factor for poor prognosis in human ovarian epithelial cancer. Active constituents derived from Chinese medicine with anti-cancer potential might circumvent this obstacle. In our present study, evodiamine (EVO) derived from Evodia rutaecarpa (Juss.) Benth suppressed the proliferation of human epithelial ovarian cancer, A2780 and the related paclitaxel-resistant cell lines and did not cause cytotoxicity, as confirmed by the significant decline of clone formation and the representative alterations of CFDA-SE fluorescence. Meanwhile, EVO induced cell cycle arrest in a dose- and time-dependent manner. This disturbance might be mediated by the cooperation of Cyclin B1 and Cdc2, including the up-regulation of Cyclin B1, p27, and p21, and activation failure of Cdc2 and pRb. MAPK signaling pathway regulation also assisted in this process. Furthermore, chemo-sensitivity potential was enhanced as indicated in A2780/PTXR cells by the down-regulation of MDR-1 expression, accompanied by MDR-1 function suppression. Taken together, we confirmed initially that EVO exerted an anti-proliferative effect on human epithelial ovarian cancer cells, A2780/WT and A2780/PTXR, induced G2/M phase cell cycle arrest, and improved chemo-resistance. Overall, we found that EVO significantly suppressed malignant proliferation in human epithelial ovarian cancer, thus proving to be a potential anti-cancer agent in the future. PMID:26553648

  14. Modification of paclitaxel-loaded solid lipid nanoparticles with 2-hydroxypropyl-?-cyclodextrin enhances absorption and reduces nephrotoxicity associated with intravenous injection

    PubMed Central

    Baek, Jong-Suep; Kim, Ju-Heon; Park, Jeong-Sook; Cho, Cheong-Weon

    2015-01-01

    Background Paclitaxel (PTX) solid lipid nanoparticles (SLNs) modified with 2-hydroxypropyl-?-cyclodextrin (HPCD) were evaluated for their ability to enhance PTX absorption and reduce the nephrotoxicity accompanying intravenous administration. Methods PTX-loaded SLNs (PS) and PTX-loaded SLNs modified using HPCD (PSC) were prepared by hot-melted sonication. The anticancer activity of PSC was evaluated in MCF-7 cells, and confocal microscopy was used to quantify the cellular uptake. The pharmacokinetic profiles of PTX released from PSC after intravenous administration were studied in rats. Furthermore, kidney toxicity was determined by measuring the kidney size and plasma creatinine level. Results PSC were successfully prepared by hot-melted sonication and had smaller diameters than PS. PSC exhibited improved anticancer activity and cellular uptake in MCF-7 cells. Furthermore, PSC showed higher bioavailability in rats after intravenous administration than PTX solution; however, no significant differences in kidney toxicity were observed. Conclusion Based on these results, PSC could be considered as a potential therapeutic PTX delivery system for breast cancer with low renal toxicity. PMID:26347363

  15. Liver Metastasis of a Triple-Negative Breast Cancer and Complete Remission for 5 Years After Treatment With Combined Bevacizumab/Paclitaxel/Carboplatin

    PubMed Central

    Ogata, Hideaki; Kikuchi, Yoshihiro; Natori, Kazuhiko; Shiraga, Nobuyuki; Kobayashi, Masahiro; Magoshi, Shunsuke; Saito, Fumi; Osaku, Tadatoshi; Kanazawa, Shinsaku; Kubota, Yorichika; Murakami, Yoshie; Kaneko, Hironori

    2015-01-01

    Abstract Triple-negative breast cancer (TNBC) is aggressive, with high risk of visceral metastasis and death. A substantial proportion of patients with TNBC is associated with BRCA mutations, implying that these tumors are sensitive to DNA-damaging agents. We report successful treatment of a metastatic TNBC in a woman with a BRCA2 germline mutation using combined bevacizumab/paclitaxel/carboplatin (BPC) therapy. The patient was pregnant and had liver metastases, and a complete clinical response was sustained for approximately 5 years. Mastectomy was performed during the 29th week of pregnancy, and the baby was later delivered by caesarean section. Subsequently, multiple metastases in both liver lobes were detected using computed tomography and magnetic resonance imaging and the patient was treated with a BPC regimen, which led to complete disappearance of metastatic lesions in the liver. No additional treatment was provided, and after 5 years the patient consented to direct sequencing of BRCA2 and a 6781delG mutation was identified. At the most recent (5-year) follow-up, the patient was alive with good quality of life and no evidence of metastases. This finding suggests that BPC therapy might be considered a good therapeutic option for the treatment of metastatic TNBC in a woman with a BRCA2 germline mutation. PMID:26496295

  16. Intraperitoneal delivery of paclitaxel by poly(ether-anhydride) microspheres effectively suppresses tumor growth in a murine metastatic ovarian cancer model.

    PubMed

    Yang, Ming; Yu, Tao; Wood, Joseph; Wang, Ying-Ying; Tang, Benjamin C; Zeng, Qi; Simons, Brian W; Fu, Jie; Chuang, Chi-Mu; Lai, Samuel K; Wu, T-C; Hung, Chien-Fu; Hanes, Justin

    2014-04-01

    Intraperitoneal (IP) chemotherapy is more effective than systemic chemotherapy for treating advanced ovarian cancer, but is typically associated with severe complications due to high dose, frequent administration schedule, and use of non-biocompatible excipients/delivery vehicles. Here, we developed paclitaxel (PTX)-loaded microspheres composed of di-block copolymers of poly(ethylene glycol) and poly(sebacic acid) (PEG-PSA) for safe and sustained IP chemotherapy. PEG-PSA microspheres provided efficient loading (~ 13% w/w) and prolonged release (~ 13 days) of PTX. In a murine ovarian cancer model, a single dose of IP PTX/PEG-PSA particles effectively suppressed tumor growth for more than 40 days and extended the median survival time to 75 days compared to treatments with Taxol(®) (47 days) or IP placebo particles (34 days). IP PTX/PEG-PSA was well tolerated, with only minimal to mild inflammation. Our findings support PTX/PEG-PSA microspheres as a promising drug delivery platform for IP therapy of ovarian cancer, and potentially other metastatic peritoneal cancers. PMID:24816829

  17. Co-delivery of pEGFP-hTRAIL and paclitaxel to brain glioma mediated by an angiopep-conjugated liposome.

    PubMed

    Sun, Xiyang; Pang, Zhiqing; Ye, Hongxing; Qiu, Bo; Guo, Liangran; Li, Jingwei; Ren, Jinfeng; Qian, Yong; Zhang, Qizhi; Chen, Jun; Jiang, Xinguo

    2012-01-01

    In this study, we report an angiopep-2 modified cationic liposome (ANG-CLP) for the efficient co-delivery of a therapeutic gene encoding the human tumour necrosis factor-related apoptosis-inducing ligand (pEGFP-hTRAIL) and paclitaxel (PTX) to glioma. The dual targeting co-delivery system (ANG-CLP/PTX/pEGFP-hTRAIL) improved uptake and gene expression not only in U87 MG cells and BCECs, but also in the glioma bed and infiltrating margin of intracranial U87 MG glioma-bearing models. The system selectively induces apoptosis in U87 MG cells while reducing toxicity to BCECs. The results of the pharmacodynamics studies showed that the apoptosis of glioma cells in in vitro BBB models and in U87 MG glioma-bearing mice induced by ANG-CLP/PTX/pEGFP-hTRAIL was more apparent and widespread than that induced by single medication systems and unmodified co-delivery system. More importantly, the median survival time of brain tumour-bearing mice treated with ANG-CLP/PTX/pEGFP-hTRAIL was 69.5 days, significantly longer than that of other groups, even longer than the commercial temozolomide group (47 days). Therefore, the dual targeting co-delivery system is a promising drug delivery strategy against glioma. PMID:22048008

  18. Overexpression of Lin28 Decreases the Chemosensitivity of Gastric Cancer Cells to Oxaliplatin, Paclitaxel, Doxorubicin, and Fluorouracil in Part via microRNA-107

    PubMed Central

    Teng, Rongyue; Hu, Yan; Zhou, Jichun; Seifer, Benjamin; Chen, Yongxia

    2015-01-01

    Higher Lin28 expression is associated with worse pathologic tumor responses in locally advanced gastric cancer patients undergoing neoadjuvant chemotherapy. However, the characteristics of Lin28 and its mechanism of action in chemotherapy resistance is still unclear. In this study, we found that transfection of Lin28 into gastric cancer cells (MKN45 and MKN28) increased their resistance to the chemo-drugs oxaliplatin (OXA), paclitaxel (PTX), doxorubicin (ADM), and fluorouracil (5-Fu) compared with gastric cancer cells transfected with a control vector. When knockdown Lin28 expression by Lin28 small interfering RNA (siRNA) was evaluated in vitro, we found that the resistance to chemo-drugs was reduced. Furthermore, we found that Lin28 up-regulates C-myc and P-gp and down-regulates Cylin D1. Finally, we found that miR-107 is a target microRNA of Lin28 and that it participates in the mechanism of chemotherapy resistance. Our results suggest that the Lin28/miR-107 pathway could be one of many signaling pathways regulated by Lin28 and associated with gastric cancer chemo-resistance. PMID:26636340

  19. Synthesis and optimization of a novel polymeric micelle based on hyaluronic acid and phospholipids for delivery of paclitaxel, in vitro and in-vivo evaluation.

    PubMed

    Saadat, Ebrahim; Amini, Mohsen; Khoshayand, Mohammad Reza; Dinarvand, Rassoul; Dorkoosh, Farid A

    2014-11-20

    Novel polymeric micelles were synthesized based on hyaluronic acid (HA) and phospholipids (PEs) including 1,2-dimiristoyl phosphatidylethanolamine (DMPE) and 1,2-distearoyl phosphatidylethanolamine (DSPE). The newly developed micelles evaluated for the physicochemical properties including structural analysis by means of FTIR. Micelles were optimized for delivery of paclitaxel (PTX). The D-optimal design was applied in order to reach micelles with high entrapment efficiency (EE %) and minimum size, simultaneously. In this design the independent variables were the co-polymer type, the drug to polymer ratio and the formulation temperature, whereas the dependent variables were EE% and micelle size. The EE% of the optimized micelles was 46.8% and 59.9% for HA-DMPE and HA-DSPE micelles, respectively. The size of the optimized micelles was in the range of around 250 nm. In vitro release study of the optimized micelles showed that PTX was released from HA-DMPE and HA-DSPE micelles as long as 23 h and 34 h, respectively. Differential scanning calorimetry (DSC) studies showed a conversion of the crystalline PTX molecules into the amorphous form in the micelles. In vivo real time image analysis showed that micellar system was mostly accumulated in the liver, spleen and heart. Accelerated stability studies represented that PTX loaded micelle formulations were stable both physically and chemically at least in 6 months' time. PMID:25148729

  20. Pluronic F127 polymeric micelles for co-delivery of paclitaxel and lapatinib against metastatic breast cancer: preparation, optimization and in vitro evaluation.

    PubMed

    Dehghan Kelishady, Pooya; Saadat, Ebrahim; Ravar, Fatemeh; Akbari, Hamid; Dorkoosh, Farid

    2014-09-29

    Abstract The aim of this study was to develop and characterize the paclitaxel (PTX)-lapatinib (LPT) loaded micelles for simultaneous delivery against metastatic breast cancer. Efflux pump-mediated drug resistance influences the efficacy of chemotherapeutic regimens. However, in the newly developed delivery system, LPT was selected to act as chemosensetizer. LPT increases the intracellular level of PTX by inhibition of efflux pumps. Pluronic F127 was selected for the preparation of the micelles, and its critical micelle concentration was determined to be 0.012?mg/ml. D-optimal design was used to analyze the impact of different experimental parameters on PTX and LPT encapsulation ratio. PTX encapsulation ratio was optimized at 68.3%, while LPT encapsulation ratio found to be 70.1%. Transmission electron microscope analyses demonstrate that micelles possess a good core-shell structure without any sharp edge. Laser scattering method results indicated that size of the optimized micelles is 64.81?nm with acceptable polydispersity index (0.309). In vitro release studies showed a sustain release pattern. PTX-LPT-loaded micelles suppressed the proliferation of resistant T-47D cell line (IC50?=?0.6?±?0.1?µg/ml) compared to binary mixture of PTX and LPT (IC50?=?6.7?±?1.2?µg/ml). Therefore, it is concluded that the developed formulation might increase the therapeutic efficacy in drug resistant metastatic breast cancer. PMID:25265388

  1. Oral delivery of paclitaxel nanocrystal (PNC) with a dual Pgp-CYP3A4 inhibitor: preparation, characterization and antitumor activity.

    PubMed

    Patel, Ketan; Patil, Anand; Mehta, Miten; Gota, Vikram; Vavia, Pradeep

    2014-09-10

    Several molecular inheritances have severely restrained the peroral delivery of taxanes. The main objective of the present investigation was to develop a paclitaxel (PTX) formulation which can circumvent the hurdles of its extremely poor solubility and permeability, Pgp efflux and high pre-systemic metabolism. Positively charged PTX nanocrystals of 209 nm were prepared by sonoprecipitation with high pressure homogenization technique, wherein an arginine based surfactant was explored as a stabilizer. The BET surface area analysis revealed that the surface area of PNC was 8.53 m(2)/gm, reflecting significant rise in surface area with nanonization of PTX. The DSC and XRD pattern suggested that the PTX is in the form of the most stable dihydrate crystal. The PNC showed very rapid dissolution profile compared to plain PTX in both sinks and non-sink conditions. Clarithromycin (CLM) was evaluated as a better alternative to cyclosporin A in improving PTX permeability. The PNC-CLM showed remarkable enhancement of 453% in relative bioavailability along with maintaining the therapeutic concentration of PTX for 8h. Efficacy data in B16 F10 melanoma tumor bearing mice showed substantial reduction in tumor volume and improvement in percentage survival compared to the control group. PMID:24954663

  2. Expressions of Thymidylate Synthase,Thymidine Phosphorylase, Class III ?-tubulin, and Excision Repair Cross-complementing Group 1predict Response in Advanced Gastric Cancer Patients Receiving Capecitabine Plus Paclitaxel or Cisplatin

    PubMed Central

    Lu, Ming; Gao, Jing; Wang, Xi-cheng

    2011-01-01

    Objective Toevaluate the role of class III ?-tubulin (TUBB3), thymidylate synthase (TS), thymidine phosphorylase (TP), and excision repair cross-complementing group 1 (ERCC1) in clinical outcome of advanced gastric cancer patients receiving capecitabine plus paclitaxel or cisplatin. Methods The clinical data and tumor specimens from 57 advanced gastric cancer patients receiving first-line capecitabine plus paclitaxel (cohort 1, n=36) and capecitabine plus cisplatin (cohort 2, n=21) were retrospectively collected, and TUBB3, TS, TP, and ERCC1 expressions were detected by real-time quantitative PCR. The associations between expressions of biomarkers and response or survival were analyzed statistically. Results The median age of 57 patients was 57 years (range: 27–75 years) with 38 males and 19 females. Of all patients, the response rates of patients with high TP, low TP and high TS, low TS expressions were 57.1%, 27.6% (P=0.024), and 55.2%, 28.6% (P=0.042), respectively. Among cohort 1, the response rates and median overall survivals of patients with low and high TUBB3 expressions were 61.1% vs. 33.3% (P=0.095) and 13.8 months vs. 6.6 months (P=0.019), respectively; the response rate (87.5%) of patients with low TUBB3 and high TP expressions was higher than that (14.3%) of patients with high TUBB3 and low TP expressions (P=0.01). Among cohort 2, the response rates of patients with low ERCC1 and high ERCC1 expressions were 45.5% and 20.0% respectively (P=0.361). Conclusion TUBB3, TS and TP expressions could predict the response of advanced gastric cancer patients receiving capecitabine-based and paclitaxel-based chemotherapy. These results will be further confirmed in future large samples. PMID:23358102

  3. Cannabidiol inhibits paclitaxel-induced neuropathic pain through 5-HT1A receptors without diminishing nervous system function or chemotherapy efficacy

    PubMed Central

    Ward, Sara Jane; McAllister, Sean D; Kawamura, Rumi; Murase, Ryuchi; Neelakantan, Harshini; Walker, Ellen A

    2014-01-01

    Background and Purpose Paclitaxel (PAC) is associated with chemotherapy-induced neuropathic pain (CIPN) that can lead to the cessation of treatment in cancer patients even in the absence of alternate therapies. We previously reported that chronic administration of the non-psychoactive cannabinoid cannabidiol (CBD) prevents PAC-induced mechanical and thermal sensitivity in mice. Hence, we sought to determine receptor mechanisms by which CBD inhibits CIPN and whether CBD negatively effects nervous system function or chemotherapy efficacy. Experimental Approach The ability of acute CBD pretreatment to prevent PAC-induced mechanical sensitivity was assessed, as was the effect of CBD on place conditioning and on an operant-conditioned learning and memory task. The potential interaction of CBD and PAC on breast cancer cell viability was determined using the MTT assay. Key Results PAC-induced mechanical sensitivity was prevented by administration of CBD (2.5 – 10?mg·kg?1) in female C57Bl/6 mice. This effect was reversed by co-administration of the 5-HT1A antagonist WAY 100635, but not the CB1 antagonist SR141716 or the CB2 antagonist SR144528. CBD produced no conditioned rewarding effects and did not affect conditioned learning and memory. Also, CBD + PAC combinations produce additive to synergistic inhibition of breast cancer cell viability. Conclusions and Implications Our data suggest that CBD is protective against PAC-induced neurotoxicity mediated in part by the 5-HT1A receptor system. Furthermore, CBD treatment was devoid of conditioned rewarding effects or cognitive impairment and did not attenuate PAC-induced inhibition of breast cancer cell viability. Hence, adjunct treatment with CBD during PAC chemotherapy may be safe and effective in the prevention or attenuation of CIPN. PMID:24117398

  4. A phase II clinical trial of palonosetron for the management of delayed vomiting in gynecological cancer patients receiving paclitaxel/carboplatin therapy

    PubMed Central

    TAKATORI, ERIKO; SHOJI, TADAHIRO; MIURA, YUKI; NAGAO, MIYUKI; TAKADA, ANNA; NAGASAWA, TAKAYUKI; OMI, HIDEO; KAGABU, MASAHIRO; HONDA, TATSUYA; SUGIYAMA, TORU

    2015-01-01

    There are currently no studies demonstrating the effects of palonosetron on delayed chemotherapy-induced nausea and vomiting (CINV) in gynecological cancer patients receiving chemotherapy with moderately emetogenic chemotherapeutic agents. We conducted a phase II clinical trial to assess the efficacy and safety of palonosetron in patients receiving paclitaxel/carboplatin (TC) therapy. The study population consisted of 42 patients who had been diagnosed with gynecological malignancies and treated with TC. On day 1, 0.75 mg/body palonosetron and 19.8 mg/body dexamethasone were administered intravenously immediately prior to TC therapy. Dexamethasone in daily doses of 6.6 mg/body was also administered intravenously on days 2 and 3. The efficacy and safety of palonosetron + dexamethasone were evaluated by the self-completion method using the Multinational Association of Supportive Care in Cancer Antiemesis Tool during an observation period lasting from day 1 through day 8 of the initial cycle of TC therapy. The severity of the nausea was assessed using a visual analog scale. During the acute (0–24 h), delayed (24–96 h) and overall (0–96 h) periods, the complete response rates were 95.2, 90.5 and 85.7%, respectively, whereas the complete control rates were 90.5, 85.7 and 78.6%, respectively. Grade ? 2 constipation and diarrhea developed in 1 patient (2.4%) each. The palonosetron + dexamethasone regimen proved to be effective for delayed CINV in gynecological cancer patients receiving TC therapy. This combined antiemetic regimen was associated with only mild adverse reactions and may serve as supportive therapy, allowing cancer chemotherapy to be continued while maintaining an adequate quality of life. PMID:25798254

  5. Concurrent chemotherapy (carboplatin, paclitaxel, etoposide) and involved-field radiotherapy in limited stage small cell lung cancer: a Dutch multicenter phase II study

    PubMed Central

    Baas, P; Belderbos, J S A; Senan, S; Kwa, H B; van Bochove, A; van Tinteren, H; Burgers, J A; van Meerbeeck, J P

    2006-01-01

    To improve the prognosis of limited stage small cell lung cancer (LS-SCLC) the addition of concurrent thoracic radiotherapy to a platinum-containing regimen is important. In the Netherlands, we initiated a multicenter, phase II study, of the combination of four cycles of carboplatin (AUC 5), paclitaxel (200?mg?m?2) and etoposide (2 × 50?mg orally for 5 days) combined with 45?Gy (daily fractions of 1.8?Gy). The radiation was given to the involved field and concurrently with the second and third chemotherapy cycle. Patients with a partial or complete response received prophylactic cranial irradiation to a dose of 30?Gy. From January 1999 to December 2001, 37 of the 38 patients with LS-SCLC entered were eligible for toxicity analysis and response. Grade 3 and 4 haematological toxicity occurred in 57% (21/37) with febrile neutropenia in 24% (9/37). There were no treatment-related deaths or other grade 4 toxicity. Grade 3 toxicities were oesophagitis (27%), radiation pneumonitis (6%), anorexia (14%), nausea (16%), dyspnea (19%) and lethargy (22%). The objective response rate was 92% (95% confidence interval (CI) 80–98%) with a median survival time of 19.5 months (95% CI 12.8–29.2). The 1-, 2- and 5-year survival rate was 70, 47 and 27%, respectively. In field local recurrences occurred in six patients. Distant metastases were observed in 19 patients of which 13 in the brain. This study indicates that combination chemotherapy with concurrent involved-field radiation therapy is an effective treatment for LS-SCLC. Despite PCI, the brain remained the most important site of recurrence. PMID:16465191

  6. Paclitaxel is incorporated by mesenchymal stromal cells and released in exosomes that inhibit in vitro tumor growth: a new approach for drug delivery.

    PubMed

    Pascucci, Luisa; Coccè, Valentina; Bonomi, Arianna; Ami, Diletta; Ceccarelli, Piero; Ciusani, Emilio; Viganò, Lucia; Locatelli, Alberta; Sisto, Francesca; Doglia, Silvia Maria; Parati, Eugenio; Bernardo, Maria Ester; Muraca, Maurizio; Alessandri, Giulio; Bondiolotti, Gianpietro; Pessina, Augusto

    2014-10-28

    Mesenchymal stromal cells (MSCs) have been proposed for delivering anticancer agents because of their ability to home in on tumor microenvironment. We found that MSCs can acquire strong anti-tumor activity after priming with Paclitaxel (PTX) through their capacity to uptake and then release the drug. Because MSCs secrete a high amount of membrane microvesicles (MVs), we here investigated the role of MVs in the releasing mechanism of PTX. The murine SR4987 line was used as MSC model. The release of PTX from SR4987 in the conditioned medium (CM) was checked by HPLC and the anti-tumor activity of both CM and MVs was tested on the human pancreatic cell line CFPAC-1. MVs were isolated by ultracentrifugation, analyzed by transmission (TEM) and scanning electron microscopy (SEM), and the presence of PTX by the Fourier transformed infrared (FTIR) microspectroscopy. SR4987 loaded with PTX (SR4987PTX) secreted a significant amount of PTX and their CM possessed strong anti-proliferative activity on CFPAC-1. At TEM and SEM, SR4987PTX showed an increased number of "vacuole-like" structures and shed a relevant number of MVs, but did not differ from untreated SR4987. However, SR4987PTX-derived-MVs (SR4987PTX-MVs) demonstrated a strong anti proliferative activity on CFPAC-1. FTIR analysis of SR4987PTX-MVs showed the presence of an absorption spectrum in the corresponding regions of the PTX marker, absent in MVs from SR4987. Our work is the first demonstration that MSCs are able to package and deliver active drugs through their MVs, suggesting the possibility of using MSCs as a factory to develop drugs with a higher cell-target specificity. PMID:25084218

  7. Molecular and Clinical Responses in a Pilot Study of Gefitinib With Paclitaxel and Radiation in Locally Advanced Head-and-Neck Cancer

    SciTech Connect

    Van Waes, Carter; Allen, Clint T.; Citrin, Deborah; Gius, David; Colevas, A. Dimetrios; Harold, Nancy A.; Rudy, Susan; Nottingham, Liesl; Muir, Christine; Chen, Zhong; Singh, Anurag K.; Dancey, Janet; Morris, John C.

    2010-06-01

    Purpose: Epidermal growth factor receptor (EGFR) overexpression in head-and-neck squamous cell carcinoma (HNSCC) stimulates tumor cell proliferation, inhibits apoptosis, and increases chemotherapy and radiation resistance. We examined the toxicity, safety and the effects on EGFR signaling in tumor biopsy samples from patients with locally advanced HNSCC treated with the EGFR signaling inhibitor gefitinib (GEF) combined with weekly intravenous paclitaxel (PAC) and radiation therapy (RT). Methods and Materials: This was a pilot Phase I dose-escalation study. Eligibility included Stage III to IVB HNSCC, age >=18 years, no prior RT or chemotherapy, adequate organ function, and informed consent. Endpoints included determination of maximum tolerated dose (MTD) and analysis of treatment effect on EGFR signaling, tumor cell proliferation, and apoptosis in biopsy samples. Results: Ten patients were treated. The MTD of this combination was GEF 250 mg/d with PAC 36 mg/m{sup 2} intravenously weekly x 6 with concurrent RT. Grade 3/4 toxicities included prolonged (>8 weeks) stomatitis (7 patients), infection (2 patients), and interstitial pneumonitis (1 patient). There were five complete responses (CR) and two partial responses (PR). Of 7 patients undergoing serial biopsies, only 1 patient demonstrated a reduction in phosphorylated EGFR, decreased downstream signaling, and reduced cellular proliferation after initiating GEF. Conclusions: Inhibition of EGFR by GEF was observed in only one of seven tumors studied. The addition of GEF to PAC and RT did not appear to improve the response of locally advanced HNSCC compared with our prior experience with PAC and RT alone. This treatment appeared to delay recovery from stomatitis.

  8. Combined paclitaxel, cisplatin and fluorouracil therapy enhances ionizing radiation effects, inhibits migration and induces G0/G1 cell cycle arrest and apoptosis in oral carcinoma cell lines

    PubMed Central

    ELIAS, SILVIA TAVEIRA; BORGES, GABRIEL ALVARES; RÊGO, DANIELA FORTUNATO; E SILVA, LUIS FELIPE OLIVEIRA; AVELINO, SAMUEL; DE MATOS NETO, JOÃO NUNES; SIMEONI, LUIZ ALBERTO; GUERRA, ELIETE NEVES SILVA

    2015-01-01

    Although taxels (in particular paclitaxel), cisplatin and fluorouracil (TPF) chemotherapy has been approved for use in the treatment of head and neck squamous cell carcinoma (HNSCC), little is known with regard to the cellular mechanisms of this novel drug association. In order to investigate the reaction of cells to this novel treatment, the present study aimed to examine the cytotoxic effect of TPF in HNSCC cell lines in combination with irradiation, to analyze its effect on cell cycle progression and cell death, and to evaluate its ability to alter cell migration. An MTT assay was used to determine cell viability following TPF and cisplatin treatments in two human HNSCC cell lines (FaDu and SCC-9) and one keratinocyte cell line (HaCaT). The concurrent use of TPF or cisplatin and irradiation was also analyzed. Flow cytometric analysis was utilized to determine the cell cycle distribution and to verify the induction of apoptosis. The capacity of the drugs to alter oral cancer cell migration was also evaluated using a Transwell migration assay. The results indicated that TPF and cisplatin were cytotoxic to all cell lines, and enhanced the effects of ionizing radiation. FaDu cells were significantly more sensitive to the two treatments, and TPF was more cytotoxic than cisplatin for all cells. Flow cytometric analysis revealed that TPF increased the number of cells in G0/G1 phase in the SCC-9 cell line, and indicated apoptotic cell death. The results of the Transwell assay demonstrated that TPF inhibited migration in oral carcinoma cell lines. The results of the present study indicated that TPF functions in oral carcinoma cell lines through the enhancement of ionizing radiation effects, inducing cell cycle arrest at G0/G1 and apoptosis, in addition to inhibiting migration. PMID:26622739

  9. Potentiation of cytotoxicity of paclitaxel in combination with Cl-IB-MECA in human C32 metastatic melanoma cells: A new possible therapeutic strategy for melanoma.

    PubMed

    Soares, Ana S; Costa, Vera M; Diniz, Carmen; Fresco, Paula

    2013-10-01

    Metastatic melanoma monotherapies with drugs such as dacarbazine, cisplatin or paclitaxel (PXT) are associated with significant toxicity and low efficacy rates. These facts reinforce the need for development of novel agents or combinatory strategies. Cl-IB-MECA is a small molecule, orally bioavailable, well tolerated and currently under clinical trials as an anticancer agent. Our aim was to investigate a possible combinatory therapeutic strategy using PXT and Cl-IB-MECA on human C32 melanoma cells and its underlying mechanisms. Cytotoxicity was evaluated using MTT reduction, lactate dehydrogenase leakage and neutral red uptake assays, for different concentrations and combinations of both agents, at 24 and 48 h. Apoptosis was also assessed using fluorescence microscopy and through the evaluation of caspases 8, 9, and 3 activities. We demonstrated, for the first time, that combination of PXT and Cl-IB-MECA significantly increases cytotoxicity for clinically relevant concentrations. This combination seems to act synergistically in disrupting membrane integrity, but also causing lysosomal and mitochondrial dysfunction. When using the lowest PTX concentration (10 ng/mL), co-incubation with CI-IB-MECA (micromolar concentrations) potentiated overall cytotoxic effects and morphological signs of apoptosis. All combinations studied enhanced caspase 8, 9, and 3 activities, suggesting the involvement of both intrinsic and extrinsic apoptotic pathways. The possibility that cytotoxicity elicited by Cl-IB-MECA, alone or in combination with PXT, involves adenosine receptor activation was discarded and results confirmed that oxidative stress is only involved in cytotoxicity after treatment with PXT, alone. Being melanoma a very apoptosis-resistance cancer, this combination seems to hold promise as a new therapeutic strategy for melanoma. PMID:24035253

  10. Prognostic factors of survival in patients treated with nab-paclitaxel plus gemcitabine regimen for advanced or metastatic pancreatic cancer: A single institutional experience

    PubMed Central

    Lo Re, Giovanni; Santeufemia, Davide A.; Foltran, Luisa; Bidoli, Ettore; Basso, Stefano M.M.; Lumachi, Franco

    2015-01-01

    Purpose The objectives of this study were to evaluate the effectiveness of nab-paclitaxel plus gemcitabine (NAB-P/GEM) regimen in an unselected population of patients with advanced inoperable or metastatic pancreatic cancer (PC), and to identify the prognostic factors influencing overall survival (OS). Experimental design Patients with age < 85 years, ECOG-performance status (PS) < 3, and adequate renal, hepatic and hematologic function were eligible. NAB-P (125 mg/m2) and GEM (1000 mg/m2) day 1,8,15 every 4 weeks were employed for 3–6 cycles or until highest response. Results Overall, 147 cycles (median 4, range 1–11 cycles) were administered on thirty-seven consecutive patients (median 66 years old, range 40–82) treated. The median overall progression-free survival and OS were 6.2 and 9.2 months, respectively. The G 3–4 dose-limiting toxicity were neutropenia (20.7%), severe anemia (17.2%), and cardiovascular toxicity (10.3%). PS, number of cycles, baseline CA 19–9 and LDH serum levels, were found to be significantly related to OS. The multivariate analysis showed that both number of cycles (HR = 9.14, 95% CI 1.84–45.50, p = 0.001) and PS (HR = 13.18, 95% CI 2.73–63.71, p = 0.001) were independently associated with OS. Conclusion NAB-P/GEM regimen should be used in all patients with advanced or metastatic PC, with the exception of those with serious contraindications to chemotherapy, such as severe renal or hepatic impairment or major cardiovascular diseases. PMID:25779664

  11. Overcoming drug-resistant lung cancer by paclitaxel loaded dual-functional liposomes with mitochondria targeting and pH-response.

    PubMed

    Jiang, Lei; Li, Li; He, Xiaodan; Yi, Qiangying; He, Bin; Cao, Jun; Pan, Weisan; Gu, Zhongwei

    2015-06-01

    Mitochondrion-orientated transportation of smart liposomes has been developed as a promising strategy to deliver anticancer drugs directly to tumor sites, and these have a tremendous potential for killing cancer cells, especially those with multidrug resistance (MDR). Herein we report a novel dual-functional liposome system possessing both extracellular pH response and mitochondrial targeting properties to enhance drug accumulation in mitochondria and trigger apoptosis of drug-resistant cancer cells. Briefly, peptide D[KLAKLAK]2 (KLA) was modified with 2, 3-dimethylmaleic anhydride (DMA) and combined with 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) to yield a DSPE-KLA-DMA (DKD) lipid. This dual-functional DKD was then mixed with other commercially available lipids to fabricate liposomes. In vitro anticancer efficacy of this liposome system was evaluated in human lung cancer A549 cells and drug-resistant lung cancer A549/Taxol cells. At tumor extracellular pH (?6.8), liposomes could reverse their surface charge (negative to positive), facilitating liposome internalization. After cellular uptake, KLA peptide directed delivery-enabled selective accumulation of these liposomes into mitochondria and favored release of their cargo paclitaxel (PTX) into desired sites. Specifically, enhanced apoptosis of MDR cancer cells through mitochondrial signaling pathways was evidenced by release of cytochrome c and increased activity of caspase-9 and -3. These dual-functional liposomes had the greatest efficacy for treating A549 cells and A549/Taxol cells in vitro, and in treating drug-resistant lung cancer A549/Taxol cells xenografted onto nude mice (tumor growth inhibition 86.7%). In conclusion, dual-functional liposomes provide a novel and versatile approach for overcoming MDR in cancer treatment. PMID:25818419

  12. Enhanced anti-tumor efficacy by co-delivery of doxorubicin and paclitaxel with amphiphilic methoxy PEG-PLGA copolymer nanoparticles.

    PubMed

    Wang, Hai; Zhao, Ying; Wu, Yan; Hu, Yu-lin; Nan, Kaihui; Nie, Guangjun; Chen, Hao

    2011-11-01

    The use of single chemotherapeutic drug has shown some limitations in anti-tumor treatment, such as development of drug resistance, high toxicity and limited regime of clinical uses. The combination of two or more therapeutic drugs is feasible means to overcome the limitations. Co-delivery strategy has been proposed to minimize the amount of each drug and to achieve the synergistic effect for cancer therapies. Attempts have been made to deliver chemotherapeutic drugs simultaneously using drug carriers, such as micelles, liposomes, and inorganic nanoparticles (NPs). Here we reported core-shell NPs that were doubly emulsified from an amphiphilic copolymer methoxy poly(ethylene glycol)-poly(lactide-co-glycolide) (mPEG-PLGA). These NPs offered advantages over other nanocarriers, as they were easy to fabricate by improved double emulsion method, biocompatible, and showed high loading efficacy. More importantly, these NPs could co-deliver hydrophilic doxorubicin (DOX) and hydrophobic paclitaxel (TAX). The drug-loaded NPs possessed a better polydispersity, indicating that they are more readily subject to controlled size distribution. Studies on drug release and cellular uptake of the co-delivery system demonstrated that both drugs were effectively taken up by the cells and released simultaneously. Furthermore, the co-delivery nanocarrier suppressed tumor cells growth more efficiently than the delivery of either DOX or TAX at the same concentrations, indicating a synergistic effect. Moreover, the NPs loading drugs with a DOX/TAX concentration ratio of 2:1 showed the highest anti-tumor activity to three different types of tumor cells. This nanocarrier might have important potential in clinical implications for co-delivery of multiple anti-tumor drugs with different properties. PMID:21807411

  13. A Phase II Study of a Paclitaxel-Based Chemoradiation Regimen With Selective Surgical Salvage for Resectable Locoregionally Advanced Esophageal Cancer: Initial Reporting of RTOG 0246

    SciTech Connect

    Swisher, Stephen G.; Winter, Kathryn A.; Komaki, Ritsuko U.; Ajani, Jaffer A.; Wu, Tsung T.; Hofstetter, Wayne L.; Konski, Andre A.; Willett, Christopher G.

    2012-04-01

    Purpose: The strategy of definitive chemoradiation with selective surgical salvage in locoregionally advanced esophageal cancer was evaluated in a Phase II trial in Radiation Therapy Oncology Group (RTOG)-affiliated sites. Methods and Materials: The study was designed to detect an improvement in 1-year survival from 60% to 77.5% ({alpha} = 0.05; power = 80%). Definitive chemoradiation involved induction chemotherapy with 5-fluorouracil (5-FU) (650 mg/mg{sup 2}/day), cisplatin (15 mg/mg{sup 2}/day), and paclitaxel (200 mg/mg{sup 2}/day) for two cycles, followed by concurrent chemoradiation with 50.4 Gy (1.8 Gy/fraction) and daily 5-FU (300 mg/mg{sup 2}/day) with cisplatin (15 mg/mg{sup 2}/day) over the first 5 days. Salvage surgical resection was considered for patients with residual or recurrent esophageal cancer who did not have systemic disease. Results: Forty-three patients with nonmetastatic resectable esophageal cancer were entered from Sept 2003 to March 2006. Forty-one patients were eligible for analysis. Clinical stage was {>=}T3 in 31 patients (76%) and N1 in 29 patients (71%), with adenocarcinoma histology in 30 patients (73%). Thirty-seven patients (90%) completed induction chemotherapy followed by concurrent chemoradiation. Twenty-eight patients (68%) experienced Grade 3+ nonhematologic toxicity. Four treatment-related deaths were noted. Twenty-one patients underwent surgery following definitive chemoradiation because of residual (17 patients) or recurrent (3 patients) esophageal cancer,and 1 patient because of choice. Median follow-up of live patients was 22 months, with an estimated 1-year survival of 71%. Conclusions: In this Phase II trial (RTOG 0246) evaluating selective surgical salvage after definitive chemoradiation in locoregionally advanced esophageal cancer, the hypothesized 1-year RTOG survival rate (77.5%) was not achieved (1 year, 71%; 95% confidence interval< 54%-82%).

  14. A stent for co-delivering paclitaxel and nitric oxide from abluminal and luminal surfaces: Preparation, surface characterization, and in vitro drug release studies

    NASA Astrophysics Data System (ADS)

    Gallo, Annemarie; Mani, Gopinath

    2013-08-01

    Most drug-eluting stents currently available are coated with anti-proliferative drugs on both abluminal (toward blood vessel wall) and luminal (toward lumen) surfaces to prevent neointimal hyperplasia. While the abluminal delivery of anti-proliferative drugs is useful for controlling neointimal hyperplasia, the luminal delivery of such drugs impairs or prevents endothelialization which causes late stent thrombosis. This research is focused on developing a bidirectional dual drug-eluting stent to co-deliver an anti-proliferative agent (paclitaxel - PAT) and an endothelial cell promoting agent (nitric oxide - NO) from abluminal and luminal surfaces of the stent, respectively. Phosphonoacetic acid, a polymer-free drug delivery platform, was initially coated on the stents. Then, the PAT and NO donor drugs were co-coated on the abluminal and luminal stent surfaces, respectively. The co-coating of drugs was collectively confirmed by the surface characterization techniques such as Fourier transform infrared spectroscopy, scanning electron microscopy (SEM), 3D optical surface profilometry, and contact angle goniometry. SEM showed that the integrity of the co-coating of drugs was maintained without delamination or cracks formation occurring during the stent expansion experiments. In vitro drug release studies showed that the PAT was released from the abluminal stent surfaces in a biphasic manner, which is an initial burst followed by a slow and sustained release. The NO was burst released from the luminal stent surfaces. Thus, this study demonstrated the co-delivery of PAT and NO from abluminal and luminal stent surfaces, respectively. The stent developed in this study has potential applications in inhibiting neointimal hyperplasia as well as encouraging luminal endothelialization to prevent late stent thrombosis.

  15. Reversal of multidrug resistance by co-delivery of paclitaxel and lonidamine using a TPGS and hyaluronic acid dual-functionalized liposome for cancer treatment.

    PubMed

    Assanhou, Assogba G; Li, Wenyuan; Zhang, Lei; Xue, Lingjing; Kong, Lingyi; Sun, Hongbin; Mo, Ran; Zhang, Can

    2015-12-01

    Multidrug resistance (MDR) remains the primary issue in cancer therapy, which is characterized by the overexpressed P-glycoprotein (P-gp)-included efflux pump or the upregulated anti-apoptotic proteins. In this study, a D-alpha-tocopheryl poly (ethylene glycol 1000) succinate (TPGS) and hyaluronic acid (HA) dual-functionalized cationic liposome containing a synthetic cationic lipid, 1,5-dioctadecyl-N-histidyl-l-glutamate (HG2C18) was developed for co-delivery of a small-molecule chemotherapeutic drug, paclitaxel (PTX) with a chemosensitizing agent, lonidamine (LND) to treat the MDR cancer. It was demonstrated that the HG2C18 lipid contributes to the endo-lysosomal escape of the liposome following internalization for efficient intracellular delivery. The TPGS component was confirmed able to elevate the intracellular accumulation of PTX by inhibiting the P-gp efflux, and to facilitate the mitochondrial-targeting of the liposome. The intracellularly released LND suppressed the intracellular ATP production by interfering with the mitochondrial function for enhanced P-gp inhibition, and additionally, sensitized the MDR breast cancer (MCF-7/MDR) cells to PTX for promoted induction of apoptosis through a synergistic effect. Functionalized with the outer HA shell, the liposome preferentially accumulated at the tumor site and showed a superior antitumor efficacy in the xenograft MCF-7/MDR tumor mice models. These findings suggest that this dual-functional liposome for co-delivery of a cytotoxic drug and an MDR modulator provides a promising strategy for reversal of MDR in cancer treatment. PMID:26426537

  16. Efficacy and safety analysis of trastuzumab and paclitaxel based regimen plus carboplatin or epirubicin as neoadjuvant therapy for clinical stage II-III, HER2-positive breast cancer patients: a phase 2, open-label, multicenter, randomized trial.

    PubMed

    Huang, Liang; Chen, Sheng; Yang, Wentao; Xu, Binghe; Huang, Tao; Yang, Hongjian; Zheng, Hong; Wang, Yongsheng; Song, Erwei; Zhang, Jin; Cui, Shude; Pang, Da; Tang, Lili; Lei, Yutao; Geng, Cuizhi; Shao, Zhiming

    2015-07-30

    This trial was designed to compare the efficacy and safety between epirubicin (E) and carboplatin (C) in combination with paclitaxel (P) and trastuzumab (H) in neoadjuvant setting. In 13 Chinese cancer centers, 100 patients with HER2-positive, locally advanced breast cancer were 1:1 randomized to receive medication as follows: trastuzumab and paclitaxel weekly combined with carboplatin weekly for PCH group, or epirubicin every 3 weeks for PEH group. Patients were given 4 to 6 cycles of chemotherapy. The primary endpoint was pathologic complete response (pCR) rate, which was no significant difference in PCH and PEH regimen (39.1% vs. 48.8%; p=0.365). However, PEH regimen achieved higher pCR in luminal-B (HER2-poitive) subgroup (55.0% vs. 24.0%; p = 0.033), but not in ERBB2+ subgroup (42.9% vs. 57.1%; p = 0.355). PEH regimen showed a favorable efficacy in PIK3CA mutated subgroup (69.2% vs.23.5%, p=0.012). No significant difference was observed in the subgroup analysis of TP53 mutation status, PTEN expression, FCGR2A SNP and FCGR3A SNP. Both regimens as neoadjuvant chemotherapy achieve similar efficacy and safety. PEH might improve pCR rate, especially in the luminal-B subtype and PIK3CA mutation subtype. PEH is feasible and less likely to increase the incidence of acute cardiac events compared to PCH. PMID:26084292

  17. Efficacy and safety analysis of trastuzumab and paclitaxel based regimen plus carboplatin or epirubicin as neoadjuvant therapy for clinical stage II-III, HER2-positive breast cancer patients: a phase 2, open-label, multicenter, randomized trial

    PubMed Central

    Yang, Wentao; Xu, Binghe; Huang, Tao; Yang, Hongjian; Zheng, Hong; Wang, Yongsheng; Song, Erwei; Zhang, Jin; Cui, Shude; Pang, Da; Tang, Lili; Lei, Yutao; Geng, Cuizhi; Shao, Zhiming

    2015-01-01

    This trial was designed to compare the efficacy and safety between epirubicin (E) and carboplatin (C) in combination with paclitaxel (P) and trastuzumab (H) in neoadjuvant setting. In 13 Chinese cancer centers, 100 patients with HER2-positive, locally advanced breast cancer were 1:1 randomized to receive medication as follows: trastuzumab and paclitaxel weekly combined with carboplatin weekly for PCH group, or epirubicin every 3 weeks for PEH group. Patients were given 4 to 6 cycles of chemotherapy. The primary endpoint was pathologic complete response (pCR) rate, which was no significant difference in PCH and PEH regimen (39.1% vs. 48.8%; p=0.365). However, PEH regimen achieved higher pCR in luminal-B (HER2-poitive) subgroup (55.0% vs. 24.0%; p = 0.033), but not in ERBB2+ subgroup (42.9% vs. 57.1%; p = 0.355). PEH regimen showed a favorable efficacy in PIK3CA mutated subgroup (69.2% vs.23.5%, p=0.012). No significant difference was observed in the subgroup analysis of TP53 mutation status, PTEN expression, FCGR2A SNP and FCGR3A SNP. Both regimens as neoadjuvant chemotherapy achieve similar efficacy and safety. PEH might improve pCR rate, especially in the luminal-B subtype and PIK3CA mutation subtype. PEH is feasible and less likely to increase the incidence of acute cardiac events compared to PCH. PMID:26084292

  18. A recurrent ovarian cancer patient with a history of nine prior chemotherapy regimens who was safely treated with weekly paclitaxel plus bevacizumab and achieved a complete response: a case report

    PubMed Central

    Takatori, Eriko; Shoji, Tadahiro; Nagasawa, Takayuki; Takeuchi, Satoshi; Hosoyachi, Akira; Sugiyama, Toru

    2015-01-01

    Herein, we describe our experience with a recurrent ovarian cancer patient who was treated safely with bevacizumab and who achieved a complete response despite receiving nine prior chemotherapy regimens. The patient was a 54-year-old woman with stage IIIC recurrent ovarian serous adenocarcinoma (grade 3). Computed tomography (CT) revealed that no evidence of ascites, multiple intraperitoneal dissemination, or intrapelvic lymph node metastases was present. The absence of bowel obstruction and disseminated lesions involving the intestinal tract was confirmed by CT. Performance status was 0, and a blood test also indicated preservation of major organ function. In our hospital, weekly paclitaxel plus bevacizumab therapy (paclitaxel at 80 mg/m2 on days 1, 8, and 15; bevacizumab at 15/mg/kg on day 1 and every 21 days thereafter) was started. Eight cycles were administered, with no signs of gastrointestinal perforation, and the antitumor effect was evaluated as a complete response. The observed adverse events included grade 1 hyponatremia and grade 1 hypochloremia, and there was one grade 1 sensory peripheral neuropathy. These adverse events neither delayed treatment nor necessitated any dosage reductions. This case suggests that bevacizumab can be safely administered even to patients with recurrent ovarian cancer who have received three or more prior chemotherapy regimens if there are neither symptoms of bowel obstruction nor lesions suggestive of intestinal invasion on diagnostic imaging. PMID:26316778

  19. A Phase I/II Study of Bortezomib in Combination with Paclitaxel, Carboplatin and Concurrent Thoracic Radiation Therapy for Non-Small Cell Lung Cancer: NCCTG-N0321

    PubMed Central

    Zhao, Yujie; Foster, Nathan R.; Meyers, Jeffrey P.; Thomas, Sachdev P.; Northfelt, Donald W.; Rowland, Kendrith M.; Mattar, Bassam I.; Johnson, David B.; Molina, Julian R.; Mandrekar, Sumithra J.; Schild, Steven E.; Bearden, James D.; Aubry, Marie-Christine; Adjei, Alex A.

    2014-01-01

    Introduction Despite the advances in radiation techniques and chemotherapy, survival with current platinum-based chemotherapy and concomitant thoracic radiation remains dismal. Bortezomib, a proteasome inhibitor, modulates apoptosis and cell cycle through disruption of protein degradation. The combination of bortezomib and carboplatin/paclitaxel and concurrent radiation in unresectable stage III NSCLC was evaluated in this phase I/II study. Methods Patients with histologic or cytologic confirmed stage III non-metastatic NSCLC who were candidates for radiation therapy were eligible. In the phase I portion, patients received escalating doses of bortezomib, paclitaxel and carboplatin concomitantly with thoracic radiation(60 Gy/30 daily fractions) using a modified 3 + 3 design. The primary endpoint for the phase II portion was the 12-month survival rate (12MS). A 1-stage design with an interim analysis yielded 81% power to detect a true 12MS of 75%, with a .09 level of significance if the true 12MS was 60% using a sample size of 60 patients. Secondary endpoints consisted of adverse events (AEs), overall survival (OS), progression-free survival (PFS), and the confirmed response rate (RR). Results Thirty-one patients enrolled during the phase I portion of the trial, of which 4 cancelled prior to receiving treatment, leaving 27 evaluable patients. Of these 27 patients, 2 dose-limiting toxicities (DLTs) were observed, one (grade 3 pneumonitis) at dose level 1 (bortezomib at 0.5 mg/m2;, paclitaxel at 150 mg/m2 and carboplatin at area under the curve (AUC) of 5) and one (grade 4 neutropenia lasting ?8 days) at dose level 6 (bortezomib 1.2 mg/m2, paclitaxel 175 mg/m2, and carboplatin at AUC of 6). During the phase I portion, the most common grade 3/4 AEs were leukopenia (44% %), dyspnea (22%), and dysphagia (11%). Dose level 6 was declared to be there commended phase II dose (RP2D) and the phase II portion of the study opened. After the first 26 evaluable patients were enrolled to the RP2D, a per protocol interim analysis occurred. Of these 26 patients, 23 (88%) survived at least 6 months (95% CI: 70 to 98%), which was enough to continue to full accrual per study design. However, due to slow accrual, the study was stopped after 27 evaluable patients were enrolled (6 - phase I RP2D; 21 - phase II). Of these 27 patients, the 12MS was 73% (95% CI: 58 - 92%), the median OS was 25.0 months (95% CI: 15.6 to 35.8), and the median PFS was 8.4 months (95% CI: 4.1 to 10.5). The confirmed RR was 26% (7/27; 95% CI: 11% to 46%), consisting of 4 partial responses and 3 complete responses. Grade 3+ and Grade 4+AEsoccurred in 82%and 56%of patients, respectively. One patient experienced grade 5 pneumonitis that was possibly related to the treatment. Grade 3 and 4 hematological toxicities were observed in 82% and 56% patients, respectively. Conclusions The addition of bortezomib to concurrent carboplatin/paclitaxel and radiation appeared to be feasible, although associated with increased hematological toxicities. A favorable median overall survival of 25 months suggests a potential benefit for this regimen. PMID:25247339

  20. ?-Lapachone and Paclitaxel Combination Micelles with Improved Drug Encapsulation and Therapeutic Synergy as Novel Nanotherapeutics for NQO1-Targeted Cancer Therapy.

    PubMed

    Zhang, Ling; Chen, Zhen; Yang, Kuan; Liu, Chun; Gao, Jinming; Qian, Feng

    2015-11-01

    ?-Lapachone (LPC) is a novel cytotoxic agent that is bioactivated by NADP(H): quinone oxidoreductase 1 (NQO1), an enzyme elevated in a variety of tumors, such as non-small cell lung cancer (NSCLC), pancreatic cancer, liver cancer, and breast cancer. Despite its unique mechanism of action, its clinical evaluation has been largely hindered by low water solubility, short blood half-life, and narrow therapeutic window. Although encapsulation into poly(ethylene glycol)-b-poly(d,l-lactic acid) (PEG-PLA) micelles could modestly improve its solubility and prolong its half-life, the extremely fast intrinsic crystallization tendency of LPC prevents drug loading higher than ?2 wt %. The physical stability of the LPC-loaded micelles is also far from satisfactory for further development. In this study, we demonstrate that paclitaxel (PTX), a front-line drug for many cancers, can provide two functions when coencapsulated together with LPC in the PEG-PLA micelles; first, as a strong crystallization inhibitor for LPC, thus to significantly increase the LPC encapsulation efficiency in the micelle from 11.7 ± 2.4% to 100.7 ± 2.2%. The total drug loading efficiency of both PTX and LPC in the combination polymeric micelle reached 100.3 ± 3.0%, and the drug loading density reached 33.2 ± 1.0%. Second, the combination of LPC/PTX demonstrates strong synergistic cytotoxicity effect against the NQO1 overexpressing cancer cells, including A549 NSCLC cells, and several pancreatic cancer cells (combination index <1). In vitro drug release study showed that LPC was released faster than PTX either in phosphate-buffered saline (PH = 7.4) or in 1 M sodium salicylate, which agrees with the desired dosing sequence of the two drugs to exert synergistic pharmacologic effect at different cell checkpoints. The PEG-PLA micelles coloaded with LPC and PTX offer a novel nanotherapeutic, with high drug loading, sufficient physical stability, and biological synergy to increase drug delivery efficiency and optimize the therapeutic window for NOQ1-targeted therapy of cancer. PMID:26415823

  1. Preparation of Polymeric Prodrug Paclitaxel-Poly(lactic acid)-b-Polyisobutylene and Its Application in Coatings of a Drug Eluting Stent.

    PubMed

    Ren, Kai; Zhang, Mingzu; He, Jinlin; Wu, Yixian; Ni, Peihong

    2015-06-01

    To develop a novel biodegradable and quite adhesive coating material for fabricating a paclitaxel (PTX)-containing eluting stent, herein, we report two kinds of drug eluting stent (DES) materials. One of them is a prodrug, PTX end-capped poly(lactic acid)-b-polyisobutylene (PTX-PLA-b-PIB) diblock copolymer, which possesses favorable biodegradability and biocompatibility. The other is a mixture of PIB-b-PLA diblock copolymer and PTX. PIB-b-PLA was synthesized via the ring-opening polymerization (ROP) using hydroxyl-terminated polyisobutylene (PIB-OH) as the initiator, while the PTX-PLA-b-PIB prodrug was prepared through a combination of ROP and Cu(I)-catalyzed azide-alkyne cycloaddition "click" reaction. The chemical structures and compositions as well as the molecular weights and molecular weight distributions of these copolymers have been fully characterized by (1)H nuclear magnetic resonance, Fourier transform infrared, and gel permeation chromatography measurements. The thermal degradation behavior and glass transition temperature (Tg) of the copolymers were studied by thermogravimetric analysis and differential scanning calorimetry, respectively. The solutions of PTX-PLA-b-PIB and the PIB-b-PLA/PTX mixture were separately coated onto the bare metal stents to form the PTX-containing DES. Subsequently, the surface structures and morphologies of the bare stent and DES were studied by atomic force microscopy and scanning electron microscopy, respectively. The in vitro release of PTX from these stents was conducted in a buffer medium (PBS 7.4) at 37 °C. The results showed that the coating formed by a blend of PTX-PLA-b-PIB, PIB-b-PLA, and PTX yielded a release that was better sustained than those of the individual PTX-PLA-b-PIB prodrug or PIB-b-PLA/PTX mixture. MTT assays demonstrated that the stent coated with PTX-PLA-b-PIB displayed a cytotoxicity lower than that of the PIB-b-PLA/PTX mixed layer, and the biocompatibility of coatings can be effectively improved by the prodrug. PMID:25955234

  2. Use of a Lipid-Coated Mesoporous Silica Nanoparticle Platform for Synergistic Gemcitabine and Paclitaxel Delivery to Human Pancreatic Cancer in Mice

    PubMed Central

    2015-01-01

    Recently, a commercial albumin-bound paclitaxel (PTX) nanocarrier (Abraxane) was approved as the first new drug for pancreatic ductal adenocarcinoma in almost a decade. PTX improves the pharmaceutical efficacy of the first-line pancreatic cancer drug, gemcitabine (GEM), through suppression of the tumor stroma and inhibiting the expression of the GEM-inactivating enzyme, cytidine deaminase (CDA). We asked, therefore, whether it was possible to develop a mesoporous silica nanoparticle (MSNP) carrier for pancreatic cancer to co-deliver a synergistic GEM/PTX combination. High drug loading was achieved by a custom-designed coated lipid film technique to encapsulate a calculated dose of GEM (40 wt %) by using a supported lipid bilayer (LB). The uniform coating of the 65 nm nanoparticles by a lipid membrane allowed incorporation of a sublethal amount of hydrophobic PTX, which could be co-delivered with GEM in pancreatic cells and tumors. We demonstrate that ratiometric PTX incorporation and delivery by our LB-MSNP could suppress CDA expression, contemporaneous with induction of oxidative stress as the operating principle for PTX synergy. To demonstrate the in vivo efficacy, mice carrying subcutaneous PANC-1 xenografts received intravenous (IV) injection of PTX/GEM-loaded LB-MSNP. Drug co-delivery provided more effective tumor shrinkage than GEM-loaded LB-MSNP, free GEM, or free GEM plus Abraxane. Comparable tumor shrinkage required coadministration of 12 times the amount of free Abraxane. High-performance liquid chromatography analysis of tumor-associated GEM metabolites confirmed that, compared to free GEM, MSNP co-delivery increased the phosphorylated DNA-interactive GEM metabolite 13-fold and decreased the inactivated and deaminated metabolite 4-fold. IV injection of MSNP-delivered PTX/GEM in a PANC-1 orthotopic model effectively inhibited primary tumor growth and eliminated metastatic foci. The enhanced in vivo efficacy of the dual delivery carrier could be achieved with no evidence of local or systemic toxicity. In summary, we demonstrate the development of an effective LB-MSNP nanocarrier for synergistic PTX/GEM delivery in pancreatic cancer. PMID:25776964

  3. A randomized phase II study of temozolomide and bevacizumab or nab-paclitaxel, carboplatin, and bevacizumab in patients with unresectable stage IV melanoma: A North Central Cancer Treatment Group Study, N0775

    PubMed Central

    Kottschade, Lisa A.; Suman, Vera J.; Perez, Domingo G.; McWilliams, Robert R.; Kaur, Judith S.; Amatruda, Thomas T.; Geoffroy, Francois J.; Gross, Howard M.; Cohen, Peter A.; Jaslowski, Anthony J.; Kosel, Matthew L.; Markovic, Svetomir N.

    2014-01-01

    Background Increasing evidence shows chemotherapy in combination with VEGF inhibition is a clinically active therapy for patients with metastatic melanoma (MM). Methods A phase II trial was conducted in chemotherapy naïve patients with unresectable stage IV MM who were randomized to temozolomide (200 mg/m2 on d. 1–5) and bevacizumab (10mg/kg IV d. 1 and 15) every 28 days (Regimen temozolomide/bevacizumab [TB]) or nab-paclitaxel (100mg/m2 [80 mg/m2 post addendum 5-secondary to toxicity] days 1, 8 and 15), bevacizumab (10mg/kg on days 1 and 15), and carboplatin (AUC 6 day 1 [ AUC 5 post addendum 5]) every 28 days (Regimen ABC). Accrual goal was 41 patients per regimen. The primary aim of this study was to estimate progression-free survival rate at 6 months (PFS6) in each regimen. A regimen would be considered promising if its PFS6 rate was > 60%. Results Ninety-three eligible patients (42 TB and 51 ABC) were enrolled. The majority of patients had M1c disease (20- TB & 26 ABC). The median PFS and overall survival (OS) times with ABC were 6.7 months and 13.9 months, respectively. Median PFS time and median OS with TB were 3.8 months and 12.3 months, respectively. The most common severe toxicities (?grade 3) in both regimens were cytopenias, fatigue, and thrombosis. Among the first 41 patients enrolled onto each regimen, PFS6 rate was 32.8% (95% CI: 21.1–51.2%) for TB and 56.1% (90% CI: 44.7–70.4%) for ABC. Conclusions The addition of bevacizumab to nab-paclitaxel and carboplatin shows promising activity despite tolerability issues. PMID:22915053

  4. Comparison of outcomes after percutaneous coronary intervention for chronic total occlusion using everolimus- versus sirolimus- versus paclitaxel-eluting stents (from the Korean National Registry of Chronic Total Occlusion Intervention).

    PubMed

    Lee, Min-Ho; Lee, Joo M; Kang, Si-Hyuck; Yoon, Chang-Hwan; Jang, Yangsoo; Yu, Cheol W; Park, Hun S; Lee, Seung-Hwan; Hur, Seung-Ho; Kim, Moo H; Rha, Seung-Woon; Gwon, Hyeon-Cheol; Chae, In-Ho; Kim, Hyo-Soo

    2015-07-15

    For the treatment of chronic total occlusion (CTO), the efficacy and safety of the everolimus-eluting stent (EES) remain less well defined. Also, there are limited data for the predictors of outcome after CTO intervention. The purpose of this study was to compare clinical outcomes of the EES with the first-generation drug-eluting stent (DES) in CTO intervention and to investigate the predictors of clinical outcome. The Korean National Registry of CTO Intervention is a retrospective cohort of 26 centers from the past 5 years. The primary end point was major adverse cardiovascular events (MACE) defined as a composite of cardiac death, nonfatal myocardial infarction, and target lesion revascularization. Of the 1,754 all-comer patients, 1,509 patients (EES 311, sirolimus-eluting stent [SES] 642, paclitaxel-eluting stent 556) were finally analyzed after excluding 245 patients (mixed DESs in 46 and follow-up loss in 199). In the inverse probability weighting-adjusted population, the 1-year MACE rate of the EES was comparable with that of the SES (5.8% vs 3.4%, p = 0.796) and the paclitaxel-eluting stent (5.8% vs 6.9%, p = 0.740). Each component of MACE was also comparable among the 3 stents. Importantly, the independent predictors of MACE were diabetes mellitus, previous congestive heart failure, and left circumflex CTO. In conclusion, for the first time in the largest CTO cohort, the EES showed good 1-year clinical outcomes that were comparable with the SES. Independent predictors of MACE after CTO intervention were clinical factors (diabetes and congestive heart failure) and lesion location. PMID:26001819

  5. Randomized Phase II Trial Comparing Carboplatin Plus Weekly Paclitaxel and Docetaxel Alone in Elderly Patients With Advanced Non-Small Cell Lung Cancer: North Japan Lung Cancer Group Trial 0801

    PubMed Central

    Maemondo, Makoto; Sugawara, Shunichi; Harada, Toshiyuki; Minegishi, Yuji; Usui, Kazuhiro; Miwa, Koji; Morikawa, Naoto; Kambe, Mariko; Ube, Kenji; Watanabe, Kana; Ishimoto, Osamu; Sakakibara, Tomohiro; Gemma, Akihiko; Nukiwa, Toshihiro

    2014-01-01

    Background. Standard first-line chemotherapy for elderly non-small cell lung cancer (NSCLC) patients has been monotherapy with vinorelbine or gemcitabine. Docetaxel has also been considered as an alternative option for the elderly population in Japan. We have previously demonstrated the high efficacy of carboplatin plus weekly paclitaxel for elderly NSCLC patients. Consequently, we conducted a randomized phase II study to select the proper regimen for a future phase III trial. Methods. Eligible patients were aged 70 years or older with newly diagnosed advanced NSCLC. Patients were randomly assigned either to a combination of carboplatin (area under the curve: 6 mg/mL per minute) with weekly paclitaxel (70 mg/m2) (CP regimen) or to single-agent docetaxel (60 mg/m2). The primary endpoint of this study was objective response rate. Secondary endpoints were progression-free survival, overall survival, and toxicity profile. Results. Among 83 eligible patients (41 to CP, 42 to docetaxel), the objective response rates were 54% (95% confidence interval: 39%–69%) and 24% (95% confidence interval: 11%–37%) and median progression-free survival was 6.6 months and 3.5 months in the CP arm and the docetaxel arm, respectively. Severe neutropenia, febrile neutropenia, and nausea were significantly frequent in the docetaxel arm, whereas toxicities in the CP arm were generally moderate. One treatment-related death was observed in the docetaxel arm. Conclusion. The CP regimen achieved higher activity with less toxicity than single-agent docetaxel. Considering the results of this phase II trial and the IFCT-0501 trial, we have selected the CP regimen for a future phase III trial in elderly patients with advanced NSCLC. PMID:24682465

  6. Phase II Study Evaluating the Addition of Cetuximab to the Concurrent Delivery of Weekly Carboplatin, Paclitaxel, and Daily Radiotherapy for Patients With Locally Advanced Squamous Cell Carcinomas of the Head and Neck

    SciTech Connect

    Suntharalingam, Mohan; Kwok, Young; Goloubeva, Olga; Parekh, Arti; Taylor, Rodney; Wolf, Jeffrey; Zimrin, Ann; Strome, Scott; Ord, Robert; Cullen, Kevin J.

    2012-04-01

    Purpose: To report the mature data of a prospective Phase II trial designed to evaluate the efficacy of an epidermal growth factor receptor inhibitor cetuximab (CTX) added to the concurrent therapy of weekly paclitaxel/carboplatin (PC) and daily radiation therapy (RT). Methods and Materials: From 2005 to 2009, a total of 43 patients were enrolled in the study. The median follow-up was 31 months (range, 9-59 months). All patients had Stage III/IV disease at presentation, and 67% had oropharyngeal primaries. The weekly IV dose schedules were CTX 250 mg/m{sup 2} (400 mg/m{sup 2} IV loading dose 1 week before RT), paclitaxel 40 mg/m{sup 2}, and carboplatin AUC 2. RT was given at 1.8 Gy per day to 70.2 Gy. Intensity-modulated RTwas used in 70% of cases. Results: All patients completed the planned RT dose, 74% without any treatment breaks. The planned CTX and PC cycles were completed in 70% (91% with at least seven of planned nine cycles) and 56% (93% with at least seven of planned eight cycles) of patients, respectively. Toxicity included Grade 3 mucositis (79%), rash (9%), leucopenia (19%), neutropenia (19%), and RT dermatitis (16%). The complete response (CR) rate at the completion of therapy was 84%. The estimated 3-year local regional control rate was 72%. Six patients with an initial CR subsequently experienced a local recurrence, 10 patients experienced distant progression. The median overall survival and disease-free survivals have not been reached. The 3-year actuarial overall survival and disease-free survival were 59% and 58%, respectively. Conclusions: The addition of CTX to weekly PC and daily RT was well tolerated and resulted in encouraging local control and survival rates.

  7. PRONOUNCE: Randomized, Open-Label, Phase III Study of First-Line Pemetrexed + Carboplatin Followed by Maintenance Pemetrexed versus Paclitaxel + Carboplatin + Bevacizumab Followed by Maintenance Bevacizumab in Patients ith Advanced Nonsquamous Non–Small-Cell Lung Cancer

    PubMed Central

    Zinner, Ralph G.; Obasaju, Coleman K.; Spigel, David R.; Weaver, Robert W.; Beck, J. Thaddeus; Waterhouse, David M.; Modiano, Manuel R.; Hrinczenko, Borys; Nikolinakos, Petros G.; Liu, Jingyi; Koustenis, Andrew G.; Winfree, Katherine B.; Melemed, Symantha A.; Guba, Susan C.; Ortuzar, Waldo I.; Desaiah, Durisala; Treat, Joseph A.; Govindan, Ramaswamy; Ross, Helen J.

    2015-01-01

    Introduction: PRONOUNCE compared the efficacy and safety of pemetrexed+carboplatin followed by pemetrexed (Pem+Cb) with paclitaxel+carboplatin+bevacizumab followed by bevacizumab (Pac+Cb+Bev) in patients with advanced nonsquamous non–small-cell lung cancer (NSCLC). Methods: Patients ?18 years of age with stage IV nonsquamous NSCLC (American Joint Committee on Cancer v7.0), and Eastern Cooperative Oncology Group performance status 0/1 were randomized (1:1) to four cycles of induction Pem+Cb (pemetrexed, 500 mg/m2, carboplatin, area under the curve = 6) followed by Pem maintenance or Pac+Cb+Bev (paclitaxel, 200 mg/m2, carboplatin, area under the curve = 6, and bevacizumab, 15 mg/kg) followed by Bev maintenance in the absence of progressive disease or discontinuation. The primary objective was progression-free survival (PFS) without grade 4 toxicity (G4PFS). Secondary end points were PFS, overall survival (OS), overall response rate (ORR), disease control rate (DCR), and safety. Resource utilization was also assessed. Results: Baseline characteristics of the patients randomized to Pem+Cb (N = 182) and Pac+Cb+Bev (N = 179) were well balanced between the arms. Median (months) G4PFS was 3.91 for Pem+Cb and 2.86 for Pac+Cb+Bev (hazard ratio = 0.85, 90% confidence interval, 0.7–1.04; p = 0.176); PFS, OS, ORR, or DCR did not differ significantly between the arms. Significantly more drug-related grade 3/4 anemia (18.7% versus 5.4%) and thrombocytopenia (24.0% versus 9.6%) were reported for Pem+Cb. Significantly more grade 3/4 neutropenia (48.8% versus 24.6%), grade 1/2 alopecia (28.3% versus 8.2%), and grade 1/2 sensory neuropathy were reported for Pac+Cb+Bev. Number of hospitalizations and overall length of stay did not differ significantly between the arms. Conclusions: Pem+Cb did not produce significantly better G4PFS compared with Pac+Cb+Bev. Pem+Cb was not superior in PFS, OS, ORR, or DCR compared with Pac+Cb+Bev. Both regimens were well tolerated, although, toxicity profiles differed. PMID:25371077

  8. Phase II Evaluation of Early Oral Estramustine, Oral Etoposide and Intravenous Paclitaxel in Combination with Hormone Therapy in Patients with High-Risk Metastatic Adenocarcinoma of the Prostate: Southwest Oncology Group (SWOG) S0032

    PubMed Central

    Smith, David C.; Tangen, Cathy M.; Hussain, Maha H.A.; Van Veldhuizen, Peter J.; Harrer, Grant W.; Stuart, Robert K.; Mills, Glenn M.; Vogelzang, Nicholas J.; Thompson, Ian M.

    2012-01-01

    Background This multicenter cooperative group single arm trial assessed the efficacy of a multiagent taxane-based chemotherapy in combination with hormonal therapy in men with metastatic androgen-dependent prostate cancer. Methods Forty-one patients with newly diagnosed metastatic prostate cancer involving both the axial and appendicular skeletons or viscera were enrolled. Thirty-five were treated with combined androgen blockade and up to 4 cycles of oral estramustine (280 mg orally 3 times per day) and etoposide (50 mg/m2 daily) for 14 days of each 21 day cycle, with paclitaxel (135 mg/m2 IV over 1 hour) on day 2 of each cycle. Chemotherapy was started within 30 days of initiation of hormonal therapy. Patients were followed to determine progression-free survival. Results The median progression-free survival for the evaluable population was 13 months (95% CI 10–16 mo) with a median overall survival of 38 months (95% CI 28–49 mo). The main toxicities were myelosuppression with 9 patients with ? grade 3 neutropenia, and 1 with grade 4 thrombocytopenia. One patient died with neutropenic infection. Four episodes of thrombosis embolism occurred (3 grade 4, 1 grade 3) with one episode of grade 4 cardiac ischemia. Conclusions Administration of chemotherapy to this population is feasible with moderate toxicity. This is a high-risk population with poor prognosis and this study serves as a basis for ongoing phase III trials assessing this approach in metastatic prostate cancer. PMID:21334731

  9. The effect of co-delivery of paclitaxel and curcumin by transferrin-targeted PEG-PE-based mixed micelles on resistant ovarian cancer in 3-D spheroids and in vivo tumors

    PubMed Central

    Sarisozen, Can; Abouzeid, Abraham H.; Torchilin, Vladimir P.

    2014-01-01

    Multicellular 3D cancer cell culture (spheroids) resemble to in vivo tumors in terms of shape, cell morphology, growth kinetics, gene expression and drug response. However, these characteristics cause very limited drug penetration into deeper parts of the spheroids. In this study, we used multi drug resistant (MDR) ovarian cancer cell spheroid and in vivo tumor models to evaluate the co-delivery of paclitaxel (PCL) and a potent NF-?B inhibitor curcumin (CUR). PCL and CUR were co-loaded into the polyethylene glycol-phosphatidyl ethanolamine (PEG-PE) based polymeric micelles modified with Transferrin (TF) as the targeting ligand. Cytotoxicity, cellular association and accumulation into the deeper layers were investigated in the spheroids and compared with the monolayer cell culture. Comparing to non-targeted micelles, flow cytometry and confocal imaging proved significantly deeper and higher micelle penetration into the spheroids with TF-targeting. Both in monolayers and spheroids, PCL cytotoxicity was significantly increased when co-delivered with CUR in non-targeted micelles or as single agent in TF-targeted micelles, whereas TF-modification of co-loaded micelles did not further enhance the cytotoxicity. In vivo tumor inhibition studies showed good correlation with the 3D cell culture experiments, which suggests the current spheroid model can be used as an intermediate model for evaluation of co-delivery of anticancer compounds in targeted micelles. PMID:25016976

  10. Down-Regulation of Nucleolar and Spindle-Associated Protein 1 (NUSAP1) Expression Suppresses Tumor and Cell Proliferation and Enhances Anti-Tumor Effect of Paclitaxel in Oral Squamous Cell Carcinoma

    PubMed Central

    Okamoto, Atsushi; Higo, Morihiro; Shiiba, Masashi; Nakashima, Dai; Koyama, Tomoyoshi; Miyamoto, Isao; Kasama, Hiroki; Kasamatsu, Atsushi; Ogawara, Katsunori; Yokoe, Hidetaka; Tanzawa, Hideki; Uzawa, Katsuhiro

    2015-01-01

    Background Nucleolar and spindle-associated protein 1 (NUSAP1) is an important mitotic regulator. In addition to its crucial function in mitosis, NUSAP1 has recently received attention due to the interesting roles in carcinogenesis. The aim of this study was to reveal functional mechanisms of NUSAP1 in oral squamous cell carcinoma (OSCC). Methods mRNA and protein expression levels of NUSAP1 in 9 OSCC-derived cells were analyzed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and immunoblotting analyses. The correlation between the NUSAP1 expression profile and the clinicopathological factors was evaluated by immunohistochemistry (IHC) in clinical OSCC samples (n = 70). The NUSAP1 knockdown cells were established with short hairpin RNA (shRNA) in OSCC cells, and functional assays were performed using these cells. In addition to the evaluation of cellular proliferation and cell cycle, we also investigated the potential role of NUSAP1 in paclitaxel (PTX)-induced cellular responses. Results mRNA and protein expression of NUSAP1 were significantly up-regulated in OSCC-derived cells compared with human normal oral keratinocytes (P < 0.05). IHC revealed that NUSAP-1 expression is closely associated with primary advanced T stage (P<0.05). Suppression of NUSAP1 expression levels led to significant (P < 0.05) inhibition of cellular proliferation. Furthermore, apoptosis induced by PTX was enhanced in NUSAP1 knockdown OSCC cells. Conclusions NUSAP1 may be a crucial biomarker for OSCC. Moreover, down-regulated NUSAP1 expression suppresses tumor proliferation and also enhances anti-tumor effect of PTX by activating apoptotic pathways. Thus, the present study strongly suggests that regulating NUSAP1 expression should contribute to the therapy for OSCC. PMID:26554377

  11. Quality of life (QoL) in metastatic breast cancer patients with maintenance paclitaxel plus gemcitabine (PG) chemotherapy: results from phase III, multicenter, randomized trial of maintenance chemotherapy versus observation (KCSG-BR07-02).

    PubMed

    Park, Yeon Hee; Jung, Kyung Hae; Im, Seock-Ah; Sohn, Joo Hyuk; Ro, Jungsil; Ahn, Jin-Hee; Kim, Sung-Bae; Nam, Byung-Ho; Oh, Do Youn; Han, Sae-Won; Lee, Soohyeon; Park, In Hae; Lee, Keun Seok; Kim, Jee Hyun; Kang, Seok Yun; Lee, Moon Hee; Park, Hee Sook; Woo, Sook Young; Jung, Sin-Ho; Ahn, Jin Seok; Im, Young-Hyuck

    2015-07-01

    The therapeutic goals are palliative for metastatic breast cancer (MBC) and include prolongation of survival with good quality of life (QoL) and symptom control. The purpose of this study was to examine QoL among women with MBC treated on KCSG-BR07-02 with maintenance of paclitaxel plus gemcitabine (PG) chemotherapy after achieving disease control to initial six cycles of PG chemotherapy or observation. Patients were randomized to either maintenance chemotherapy or observation until progression. QoL was assessed using EORTC QLQ-C30 and BR-23. QoL at each cycle was compared between the two treatment arms using the 2-sample t test. Generalized estimating equation method was used to examine the overall difference between the two treatments in QoL. All reported p-values are 2 sided. There were no statistically significant differences between two arms in most of the component of the EORTC QLQ-C30 and BR-23 (p > 0.05). There was no significant difference between two treatments (p = 0.6094 for QLQ-C30, p = 0.5516 for BR23) at baseline, and there did not exist significant change over the cycle (p = 0.0914 for QLQ-C30, p = 0.7981 for BR23). There was no significant interaction effect between treatment and cycle (p = 0.5543 for QLQ-C30. p = 0.5817 for BR23). Maintenance PG chemotherapy in patients with MBC achieving disease control with an initial six cycles of PG chemotherapy resulted in better PFS and OS compared to observation without impeding QoL. PMID:26033708

  12. Phase II randomized clinical trial evaluating neoadjuvant chemotherapy regimens with weekly paclitaxel or eribulin followed by doxorubicin and cyclophosphamide in women with locally advanced HER2-negative breast cancer: NSABP Foundation Study FB-9.

    PubMed

    Abraham, Jame; Robidoux, André; Tan, Antoinette R; Limentani, Steven; Sturtz, Keren; Shalaby, Ibrahim; Alcorn, Hope; Buyse, Marc E; Wolmark, Norman; Jacobs, Samuel A

    2015-07-01

    Locally advanced breast cancer (LABC) is a good setting in which to monitor response to neoadjuvant chemotherapy, to downsize the tumor (which facilitates breast-conserving surgery), and to test newer agents in untreated patients. Eribulin (E) has shown activity in patients who have undergone previous taxane, anthracycline, and capecitabine treatment. We aimed to evaluate the neoadjuvant use of E followed by doxorubicin and cyclophosphamide (AC) in patients with HER2-negative LABC, using as a control a randomized group of women who received weekly paclitaxel (WP). Fifty women with LABC were accrued January-August 2013. Patients were randomized (1:2) to receive either WP (N = 19) for 12 treatments or E (N = 31) every 3 weeks for 4 cycles followed by AC every 3 weeks for 4 cycles before surgery. 17/19 patients who took WP and 25/30 who took E completed all cycles. Patients were evaluated by clinical examination and breast MRI at baseline and after completion of E or WP. Surgical pCR in breast and lymph nodes was determined by a local pathologist following chemotherapy. Forty-nine patients received ?1 dose of neoadjuvant chemotherapy and are included in this analysis. Forty-eight underwent surgery; one had disease that was inoperable (on E) and is included as no-pCR patient. 17/19 of these patients who took WP completed 12 doses; 28/30 on E completed 4 cycles. Six discontinued treatment on WP, E, or AC. Both treatments were well tolerated. pCR on WP = 5/19(26 %) and on E = 5/30(17 %). Both regimens were equally well tolerated with no unexpected toxicities. pCR did not suggest higher activity with E than with other standard regimens in these LABC patients. PMID:26126970

  13. Selective tissue distribution and long circulation endowed by paclitaxel loaded PEGylated poly(?-caprolactone-co-L-lactide) micelles leading to improved anti-tumor effects and low systematic toxicity.

    PubMed

    Wang, Feihu; Shen, Yuanyuan; Xu, Xiaofen; Lv, Li; Li, Yanggong; Liu, Jieying; Li, Min; Guo, Aijie; Guo, Shengrong; Jin, Fang

    2013-11-01

    High tumor targeting and sustained drug concentration are key points for successful anti-tumor therapy, however, it is a challenging task. In this work, a novel micelle formulation of paclitaxel (PTX) has been prepared for the purpose of prolonging the blood circulation time as well as improving the accumulation of the drug within the tumor tissue. PEGylated P(CL-co-LLA) (poly(?-caprolactone-co-L-lactide)) micelles containing PTX were prepared by solid dispersion-sonication method with a higher drug-loading efficiency and encapsulation ratio (28.4% and 94.7%, respectively). Pharmacokinetic study revealed that the drug-loading micelles exhibited a higher AUC values and a prolonged residence time of drug in the blood circulation than those of PTX injection. As demonstrated by tissue distribution and anti-tumor study in S180 tumor-bearing mice, the PEG-P(CL-co-LLA)/PTX micelles displayed modified tissue distribution of PTX and increased accumulation of PTX in tumor, therefore, resulted in anti-tumor effects enhancement and drug concentration in the normal tissues reduction. Furthermore, the preliminary safety tests were performed by measuring the body weight, histopathology, blood cell counts and clinical chemistry parameters, and the results showed no subacute toxicity to hematological system, major organs or tissues in mice. Taken together, our valuation shows that PEG-P(CL-co-LLA) micelles is a potential drug delivery system of PTX for the effective treatment of the tumor and systematic toxicity reduction, thus, the micellar formulation can provide a useful alternative dosage form for i.v. administration of PTX. PMID:23968782

  14. Ultrasound contrast-enhanced imaging and in vitro antitumor effect of paclitaxel-poly(lactic-co-glycolic acid)-monomethoxypoly (ethylene glycol) nanocapsules with ultrasound-targeted microbubble destruction

    PubMed Central

    MA, JING; XING, LING XI; SHEN, MING; LI, FAN; ZHU, MING JIE; JIN, LI FANG; LI, ZHAOJUN; GAO, FENG; SU, YIJIN; DUAN, YOU RONG; DU, LIAN FANG

    2015-01-01

    A combination of diagnostic and therapeutic ultrasound (US) techniques may be able to provide the basis of specific therapeutic protocols, particularly for the treatment of tumors. Nanotechnology may aid the progression towards the use of US for tumor diagnosis and targeted therapy. The current study investigated in vivo and in vitro US contrast imaging using nanocapsules (NCs), and also US and US-targeted microbubble destruction (UTMD) therapy using drug-loaded NCs for pancreatic cancer in vitro. In the current study, the NCs were made from the polymer nanomaterial poly(lactic-co-glycolic acid)-monomethoxypoly(ethylene glycol) (PLGA-mPEG), encapsulated with paclitaxel (PTX), to create PTX-PLGA-mPEG NCs. The PTX-PLGA-mPEG NCs were used as a US contrast agent (UCA), which produced satisfactory US contrast-enhanced images in vitro and in vivo of the rabbit kidneys, with good contrast compared with lesions in the peripheral regions. However, clear contrast-enhanced images were not obtained using PTX-PLGA-mPEG NCs as a UCA, when imaging the superficial pancreatic tumors of nude mice in vivo. Subsequently, fluorescence and flow cytometry were used to measure the NC uptake rate of pancreatic tumor cells under various US or UTMD conditions. An MTT assay was used to evaluate the efficiency of PTX and PTX-PLGA-mPEG NCs in killing tumor cells following 24 or 48 h of US or UTMD therapy, compared with controls. The specific US or UTMD conditions had been previously demonstrated to be optimal through repeated testing, to determine the conditions by which cells were not impaired and the efficiency of uptake of nanoparticles was highest. The current study demonstrated high cellular uptake rates of PLGA-mPEG NCs and high tumor cell mortality with PTX-PLGA-mPEG NCs under US or UTMD optimal conditions. It was concluded that the use of NCs in US-mediated imaging and antitumor therapy may provide a novel application for US. PMID:25500683

  15. Ultrasound contrast-enhanced imaging and in vitro antitumor effect of paclitaxel-poly(lactic-co-glycolic acid)-monomethoxypoly (ethylene glycol) nanocapsules with ultrasound-targeted microbubble destruction.

    PubMed

    Ma, Jing; Xing, Ling Xi; Shen, Ming; Li, Fan; Zhu, Ming Jie; Jin, Li Fang; Li, Zhaojun; Gao, Feng; Su, Yijin; Duan, You Rong; Du, Lian Fang

    2015-04-01

    A combination of diagnostic and therapeutic ultrasound (US) techniques may be able to provide the basis of specific therapeutic protocols, particularly for the treatment of tumors. Nanotechnology may aid the progression towards the use of US for tumor diagnosis and targeted therapy. The current study investigated in vivo and in vitro US contrast imaging using nanocapsules (NCs), and also US and US?targeted microbubble destruction (UTMD) therapy using drug?loaded NCs for pancreatic cancer in vitro. In the current study, the NCs were made from the polymer nanomaterial poly(lactic?co?glycolic acid)?monomethoxypoly(ethylene glycol) (PLGA?mPEG), encapsulated with paclitaxel (PTX), to create PTX?PLGA?mPEG NCs. The PTX?PLGA?mPEG NCs were used as a US contrast agent (UCA), which produced satisfactory US contrast?enhanced images in vitro and in vivo of the rabbit kidneys, with good contrast compared with lesions in the peripheral regions. However, clear contrast?enhanced images were not obtained using PTX?PLGA?mPEG NCs as a UCA, when imaging the superficial pancreatic tumors of nude mice in vivo. Subsequently, fluorescence and flow cytometry were used to measure the NC uptake rate of pancreatic tumor cells under various US or UTMD conditions. An MTT assay was used to evaluate the efficiency of PTX and PTX?PLGA?mPEG NCs in killing tumor cells following 24 or 48 h of US or UTMD therapy, compared with controls. The specific US or UTMD conditions had been previously demonstrated to be optimal through repeated testing, to determine the conditions by which cells were not impaired and the efficiency of uptake of nanoparticles was highest. The current study demonstrated high cellular uptake rates of PLGA?mPEG NCs and high tumor cell mortality with PTX?PLGA?mPEG NCs under US or UTMD optimal conditions. It was concluded that the use of NCs in US?mediated imaging and antitumor therapy may provide a novel application for US. PMID:25500683

  16. 21 CFR 516.1684 - Paclitaxel.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...mammary carcinoma in dogs that have not received previous chemotherapy or radiotherapy. For the treatment of resectable and nonresectable...squamous cell carcinoma in dogs that have not received previous chemotherapy or radiotherapy. (3) Limitations. Federal...

  17. Paclitaxel and Carboplatin Before Radiation Therapy With Paclitaxel in Treating HPV-Positive Patients With Stage III-IV Oropharynx, Hypopharynx, or Larynx Cancer

    ClinicalTrials.gov

    2015-09-03

    Human Papilloma Virus Infection; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Verrucous Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Verrucous Carcinoma of the Larynx; Stage IVA Squamous Cell Carcinoma of the Larynx; Stage IVA Squamous Cell Carcinoma of the Oropharynx; Stage IVA Verrucous Carcinoma of the Larynx; Stage IVB Squamous Cell Carcinoma of the Larynx; Stage IVB Squamous Cell Carcinoma of the Oropharynx; Stage IVB Verrucous Carcinoma of the Larynx; Stage IVC Squamous Cell Carcinoma of the Larynx; Stage IVC Squamous Cell Carcinoma of the Oropharynx; Stage IVC Verrucous Carcinoma of the Larynx

  18. Study Comparing Nanoparticle-based Paclitaxel With Solvent-based Paclitaxel as Part of Neoadjuvant Chemotherapy for Patients With Early Breast Cancer (GeparSepto)

    ClinicalTrials.gov

    2014-02-10

    Tubular Breast Cancer Stage II; Mucinous Breast Cancer Stage II; Breast Cancer Female NOS; Invasive Ductal Breast Cancer; Tubular Breast Cancer Stage III; HER-2 Positive Breast Cancer; Inflammatory Breast Cancer Stage IV; Inflammatory Breast Cancer

  19. Paclitaxel or Polyglutamate Paclitaxel or Observation in Treating Patients With Stage III or Stage IV Ovarian Epithelial or Peritoneal Cancer or Fallopian Tube Cancer

    ClinicalTrials.gov

    2014-12-23

    Malignant Ovarian Mixed Epithelial Tumor; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer; Undifferentiated Ovarian Carcinoma

  20. Paclitaxel, Nab-paclitaxel, or Ixabepilone With or Without Bevacizumab in Treating Patients With Stage IIIC or Stage IV Breast Cancer

    ClinicalTrials.gov

    2015-06-05

    Estrogen Receptor Negative; Estrogen Receptor Positive; HER2/Neu Negative; HER2/Neu Positive; Male Breast Carcinoma; Progesterone Receptor Negative; Progesterone Receptor Positive; Recurrent Breast Carcinoma; Stage IIIC Breast Cancer AJCC v6; Stage IV Breast Cancer