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  1. Rethinking production of Taxol® (paclitaxel) using endophyte biotechnology.

    PubMed

    Kusari, Souvik; Singh, Satpal; Jayabaskaran, Chelliah

    2014-06-01

    Taxol® (generic name paclitaxel) represents one of the most clinically valuable natural products known to mankind in the recent past. More than two decades have elapsed since the notable discovery of the first Taxol®-producing endophytic fungus, which was followed by a plethora of reports on other endophytes possessing similar biosynthetic potential. However, industrial-scale Taxol® production using fungal endophytes, although seemingly promising, has not seen the light of the day. In this opinion article, we embark on the current state of knowledge on Taxol® biosynthesis focusing on the chemical ecology of its producers, and ask whether it is actually possible to produce Taxol® using endophyte biotechnology. The key problems that have prevented the exploitation of potent endophytic fungi by industrial bioprocesses for sustained production of Taxol® are discussed.

  2. Medium chain triglyceride (MCT) rich, paclitaxel loaded self nanoemulsifying preconcentrate (PSNP): a safe and efficacious alternative to Taxol.

    PubMed

    Patel, Ketan; Patil, Anand; Mehta, Miten; Gota, Vikram; Vavia, Pradeep

    2013-12-01

    The current work was aimed to develop Medium Chain Triglyceride (MCT) rich self nanoemulsifying preconcentrate of paclitaxel (PTX) for parenteral delivery. Very high concentrations of Cremophor EL and ethanol in Taxol have rendered patients to severe side effects. Years of extensive research on development of cost effective and safer vehicle for PTX, have failed to provide a promising replacement for Taxol. MCT was selected as oil owing to its parenteral acceptability, high solubilization capacity and multiple therapeutic benefits in cancer cachexia. PTX precipitation kinetics and reported toxicity profile of Kolliphor HS15 has favored its selection for PTX Self Nanoemulsifying Preconcentrate (PSNP). Presence of 30% free PEG in Kolliphor HS15 (PEG-15-hydroxystearate) restricts its miscibility with MCT, imposing significant challenge in development of MCT rich self nanoemulsifying preconcentrate. Removal of PEG layer from oil-surfactant mixture facilitated the formulation of PSNP with 51% w/w MCT. PSNP exhibited better precipitation kinetic profile, higher PTX loading with negligible hemolysis and histamine release compared to Taxol. PSNP was bioequivalent to Taxol, though V(d) and MRT was significantly higher than Taxol. PSNP showed distinctly better profile in inhibiting tumor growth and maintaining body weight with significantly higher % survival. Thus, PSNP can be a safer vehicle with potential clinical benefits.

  3. New Taxol (paclitaxel) prodrugs designed for ADEPT and PMT strategies in cancer chemotherapy.

    PubMed

    Alaoui, Abdessamad El; Saha, Nabendu; Schmidt, Frédéric; Monneret, Claude; Florent, Jean-Claude

    2006-07-15

    Two new glucuronide paclitaxel prodrugs have been synthesized. Linked to the 2'-OH of the drug by a carbonate function, they include a self-immolative spacer bearing an arylnitro or arylamino group between the drug and the glucuronic acid residue. Both prodrugs were well detoxified and easily cleaved in the presence of beta-D-glucuronidase with fast removal of the spacer, releasing paclitaxel. The arylamino spacer-containing prodrug, more stable than the corresponding nitro analogue, was selected for further studies.

  4. Pharmacodynamics of non-break weekly paclitaxel (Taxol) and pharmacokinetics of Cremophor-EL vehicle: results of a dose-escalation study.

    PubMed

    Briasoulis, Evangelos; Karavasilis, Vasilis; Tzamakou, Eleftheria; Haidou, Constantina; Piperidou, Christina; Pavlidis, Nicholas

    2002-06-01

    We characterized the toxicity and determined the maximum tolerated dose of non-break weekly paclitaxel (Taxol) in chemotherapy-naive cancer patients, and studied pharmacokinetics of the formulation vehicle Cremophor-EL with this schedule. Twenty-three patients with primary refractory solid tumors received weekly paclitaxel at the dose range of 70-200 mg/m2. As dose-limiting toxicity we defined granulocytopenia grade > or =2 causing a treatment delay for more than 2 weeks, or febrile neutropenia or grade >2 organ-specific toxicity. Plasma kinetics of Cremophor-EL were analyzed over the first five courses of treatment. Non-break weekly paclitaxel was feasible at doses up to 110 mg/m2, while granulocytopenia precluded scheduled administration of doses > or =130 mg/m2. Clinically relevant peripheral neurotoxicity tended to occur at around 1500 mg/m2 cumulative dosage at weekly doses > or =110 mg/m2. Detectable Cremophor-EL levels were found in all pre-dose samples, but there was no evidence of accumulation up to the sixth course. Our results, discussed in the light of an overview of published data, suggest that chronic weekly administration of paclitaxel is feasible and with a lack of significant accumulation of Cremophor-EL levels at doses up to 90 mg/m2.

  5. Cremophor EL pharmacokinetics in a phase I study of paclitaxel (Taxol) and carboplatin in non-small cell lung cancer patients.

    PubMed

    Meerum Terwogt, J; van Tellingen, O; Nannan Panday, V R; Huizing, M T; Schellens, J H; ten Bokkel Huinink, W W; Boschma, M U; Giaccone, G; Veenhof, C H; Beijnen, J H

    2000-10-01

    The purpose of our study was to investigate the pharmacokinetics of Cremophor EL following administration of escalating doses of Taxol (paclitaxel dissolved in Cremophor EL/ethanol) to non-small cell lung cancer (NSCLC) patients. Patients with NSCLC stage IIIb or IV without prior chemotherapy treatment were eligible for treatment with paclitaxel and carboplatin in a dose-finding phase I study. The starting dose of paclitaxel was 100 mg/m2 and doses were escalated with steps of 25 mg/m2, which is equal to a starting dose of Cremophor EL of 8.3 ml/m2 with dose increments of 2.1 ml/m2. Carboplatin dosages were 300, 350 or 400 mg/m2. Pharmacokinetic sampling was performed during the first and the second course, and the samples were analyzed using a validated high-performance liquid chromatographic assay. A total of 39 patients were included in this pharmacokinetic part of the study. The doses of paclitaxel were escalated up to 250 mg/m2 (20.8 ml/m2 Cremophor EL). Pharmacokinetic analyses revealed a low elimination-rate of Cremophor EL (CI=37.8-134 ml/h/m2; t 1/2=34.4-61.5 h) and a volume of distribution similar to the volume of the central blood compartment (Vss=4.96-7.85 l). In addition, a dose-independent clearance of Cremophor EL was found indicating linear kinetics. Dose adjustment using the body surface area, however, resulted in a non-linear increase in systemic exposure. The use of body surface area in calculations of Cremophor EL should therefore be re-evaluated.

  6. Vitamin E TPGS used as emulsifier in the solvent evaporation/extraction technique for fabrication of polymeric nanospheres for controlled release of paclitaxel (Taxol).

    PubMed

    Mu, L; Feng, S S

    2002-04-23

    The D-alpha-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) was applied in the present investigation as surfactant stabiliser to fabricate paclitaxel-loaded PLGA nanospheres in the solvent evaporation/extraction technique with successful achievement. Laser light scattering system (LLS), scanning electron microscopy (SEM), atomic force microscopy (AFM), differential scanning calorimetry (DSC), Fourier transform infra-red spectroscopy (FTIR), and X-ray photoelectron spectroscopy (XPS) were employed to characterise the nanopsheres fabricated in various recipes under various preparation conditions for size and size distribution, surface morphology, thermogram property and surface chemistry. Encapsulation efficiency and in vitro release was measured by the high-performance liquid chromatography (HPLC). The outcomes were discussed with respect to the development of polymeric nanospheres delivery system of the anticancer drug, paclitaxel (Taxol((R))). The produced nanospheres were found in fine spherical shape with smooth surfaces and without aggregation or adhesion. There was no significant difference in morphology between the vitamin E TPGS emulsified and PVA emulsified PLGA nanospheres. However, it was found that, in comparison with the traditional chemical emulsifier PVA, the TPGS could significantly improve the encapsulation efficiency of the drug in the PLGA nanospheres, which could be as high as 100%. The size of the vitamin E TPGS emulsified nanospheres ranged from 300 to 800 nm and the size distribution was narrow with polydispersity of 0.005-0.045. XPS investigation demonstrated that there were residual surfactant molecules remained on the surface although the TPGS could be washed out relatively thoroughly in the process of nanospheres formation. This finding was also confirmed by FTIR-PAS investigation of the nanospheres. The in vitro release indicated that the release property of paclitaxel from the nanospheres strongly depends on the emulsifier

  7. Paclitaxel-resistant HeLa cells have up-regulated levels of reactive oxygen species and increased expression of taxol resistance gene 1.

    PubMed

    Bi, Wenxiang; Wang, Yuxia; Sun, Gaoying; Zhang, Xiaojin; Wei, Yongqing; Li, Lu; Wang, Xiaoyuan

    2014-07-01

    This study is to establish a paclitaxel (PTX)-resistant human cervical carcinoma HeLa cell line (HeLa/PTX) and to investigate its redox characteristics and the expression of taxol resistance gene 1 (Txr1). HeLa cells were treated with PTX and effects of PTX on cell proliferation were detected through cell counting and the MTT assay. Levels of cellular reactive oxygen species (ROS), reduced glutathione (GSH), and oxidized glutathione (GSSG) as well as the ratio of GSH to GSSG were measured by the 2,7-difluorescein diacetate (DCFH-DA) method and the 5,5'dithiobis(2-nitrobenzoic acid) (DTNB) method. Activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were determined by the nitrite formation method, the molybdate colorimetric method, and the DTNB colorimetric method, respectively. The level of Txr1 mRNA was determined by real-time PCR. Compared with the regular HeLa cells, HeLa/PTX cells were larger in size and had more cytoplasmic granules. The population doubling time for HeLa/PTX cells was 1.32 times of that of HeLa cells (P<0.01). HeLa/PTX cells showed stronger resistance to PTX than HeLa cells with a resistance index of 122.69. HeLa/PTX cells had higher levels of ROS (P<0.01) and Txr1 mRNA (P<0.01), lower level of GSH (P < 0.05), and lower activities of SOD (P<0.01) and GPx (P < 0.05) than HeLa cells. HeLa/PTX cells, with higher levels of ROS and Txr1 mRNA expression, are more resistant to PTX than HeLa cells.

  8. Current and emerging options for taxol production.

    PubMed

    Li, Yi; Zhang, Guojian; Pfeifer, Blaine A

    2015-01-01

    Paclitaxel (trademark "Taxol") is a plant-derived isoprenoid natural product that exhibits potent anticancer activity. Taxol was originally isolated from the Pacific yew tree in 1967 and triggered an intense scientific and engineering venture to provide the compound reliably to cancer patients. The choices available for production include synthetic and biosynthetic routes (and combinations thereof). This chapter focuses on the currently utilized and emerging biosynthetic options for Taxol production. A particular emphasis is placed on the biosynthetic production hosts including macroscopic and unicellular plant species and more recent attempts to elucidate, transfer, and reconstitute the Taxol pathway within technically advanced microbial hosts. In so doing, we provide the reader with relevant background related to Taxol and more general information related to producing valuable, but structurally complex, natural products through biosynthetic strategies.

  9. Polysaccharide-based Noncovalent Assembly for Targeted Delivery of Taxol

    NASA Astrophysics Data System (ADS)

    Yang, Yang; Zhang, Ying-Ming; Chen, Yong; Chen, Jia-Tong; Liu, Yu

    2016-01-01

    The construction of synthetic straightforward, biocompatible and biodegradable targeted drug delivery system with fluorescent tracking abilities, high anticancer activities and low side effects is still a challenge in the field of biochemistry and material chemistry. In this work, we constructed targeted paclitaxel (Taxol) delivery nanoparticles composed of permethyl-β-cyclodextrin modified hyaluronic acid (HApCD) and porphyrin modified paclitaxel prodrug (PorTaxol), through host-guest and amphiphilic interactions. The obtained nanoparticles (HATXP) were biocompatible and enzymatic biodegradable due to their hydrophilic hyaluronic acid (HA) shell and hydrophobic Taxol core, and exhibited specific targeting internalization into cancer cells via HA receptor mediated endocytosis effects. The cytotoxicity experiments showed that the HATXP exhibited similar anticancer activities to, but much lower side effects than commercial anticancer drug Taxol. The present work would provide a platform for targeted paclitaxel drug delivery and a general protocol for the design of advanced multifunctional nanoscale biomaterials for targeted drug/gene delivery.

  10. The Shape of Things to Come: Structural and Synthetic Studies of Taxol and Related Compounds

    PubMed Central

    Kingston, David G. I.

    2007-01-01

    The history of the development of TaxolTM (paclitaxel) as an anticancer drug is reviewed, and some aspects of the phytochemistry of Taxus species and of the medicinal chemistry of taxol are discussed. The nature of the taxol-tubulin interaction is then described, with an emphasis on studies that led to the discovery and experimental proof of the T-taxol conformation as the tubulin-binding conformation of taxol. The implications of this conformation for future drug development are also briefly covered. PMID:17184797

  11. Toxicity studies of cremophor-free paclitaxel solid dispersion formulated by a supercritical antisolvent process.

    PubMed

    Park, Jae-Hyun; Chi, Sang-Cheol; Lee, Won Seok; Lee, Won Mo; Koo, Yoon Bon; Yong, Chul Soon; Choi, Han Gon; Woo, Jong Soo

    2009-01-01

    To evaluate the acute toxicity of a paclitaxel solid dispersion formulation, single dose studies in ICR mice were carried out for injectable excipients, paclitaxel solid dispersion powder, and Taxol. In the dose range of excipients used for preparing paclitaxel solid dispersion, each excipient was clinically safe, and the LD(50) for exicipients was higher than 2,000 mg/kg for both males and females. In this study, there were no remarkable clinical signs or deaths related to paclitaxel solid dispersion even at doses up to 160 mg/kg of paclitaxel. But Taxol resulted in clinical signs when it contained more than 30 mg/mL paclitaxel. The LD(50) for paclitaxel solid dispersion was above 160 mg/kg and the LD(50) for Taxol was 31.3 mg/kg, more than 5 times lower than that of paclitaxel solid dispersion. However, paclitaxel solid dispersion could not be administered i.v. at a dose exceeding 160 mg/kg, because of high viscosity. To evaluate the nephrotoxicity of paclitaxel solid dispersion, plasma level of creatinine and kidney weight were measured and compared to Taxol. At the doses administered, paclitaxel solid dispersion did not change creatinine clearance, while Taxol killed all animals at doses >15 mg/kg. To investigate membrane damage when paclitaxel formulations were injected, hemolytic activity was determined for different concentrations. Paclitaxel solid dispersion showed about 10% hemolytic activity, whereas Taxol showed about 40% hemolytic activity when it contained 2 mg of paclitaxel. Comparisons with the LD(50) value, nephrotoxicity, and hemolytic activity of Taxol suggested that Cremophor-free paclitaxel solid dispersion as an injectable formulation is a promising approach to increasing the safety and clinical efficacy of paclitaxel for treatment of cancer.

  12. Systematic Analysis of the Anticancer Agent Taxol-Producing Capacity in Colletotrichum Species and Use of the Species for Taxol Production

    PubMed Central

    Choi, Jinhee; Park, Jae Gyu; Ali, Md. Sarafat

    2016-01-01

    Paclitaxel (taxol) has long been used as a potent anticancer agent for the treatment of many cancers. Ever since the fungal species Taxomyces andreanae was first shown to produce taxol in 1993, many endophytic fungal species have been recognized as taxol accumulators. In this study, we analyzed the taxol-producing capacity of different Colletotrichum spp. to determine the distribution of a taxol biosynthetic gene within this genus. Distribution of the taxadiene synthase (TS) gene, which cyclizes geranylgeranyl diphosphate to produce taxadiene, was analyzed in 12 Colletotrichum spp., of which 8 were found to contain the unique skeletal core structure of paclitaxel. However, distribution of the gene was not limited to closely related species. The production of taxol by Colletotrichum dematium, which causes pepper anthracnose, depended on the method in which the fungus was stored, with the highest production being in samples stored under mineral oil. Based on its distribution among Colletotrichum spp., the TS gene was either integrated into or deleted from the bacterial genome in a species-specific manner. In addition to their taxol-producing capacity, the simple genome structure and easy gene manipulation of these endophytic fungal species make them valuable resources for identifying genes in the taxol biosynthetic pathway. PMID:27433121

  13. Design and synthesis of simplified taxol analogs based on the T-Taxol bioactive conformation

    PubMed Central

    Zhao, Jielu; Bane, Susan; Snyder, James P.; Hu, Haipeng; Mukherjee, Kamalika; Slebodnick, Carla; Kingston, David G. I.

    2011-01-01

    A series of compounds designed to adopt a conformation similar to the tubulin-binding T-Taxol conformation of the anticancer drug paclitaxel has been synthesized. Both the internally bridged analogs 37-39, 41 and the open-chain analogs 27-29 and 43 were prepared. The bridged analogs 37-39 and 41 were synthesized by Grubbs' metatheses of compounds 30-32 and 33, which, in turn, were prepared by coupling β-lactams 24-26 with alcohols 22 and 23. Both the bridged and the open-chain analogs showed moderate to good cytotoxicity. PMID:22071526

  14. Effect of unpurified Cremophor EL on the solution stability of paclitaxel.

    PubMed

    Gogate, Uday S; Schwartz, Philip A; Agharkar, Shreeram N

    2009-01-01

    Taxol for Injection Concentrate contains a solution of paclitaxel in a 50:50 v/v mixture of Cremophor EL (cleaned):ethanol. Cleaned, rather than unpurified, Cremophor EL is used as a cosolvent because paclitaxel was observed to be less stable in the presence of unpurified Cremophor. In order to understand the cause of this paclitaxel instability, various studies were performed. The results of these studies, coupled with the examination of degradation products, suggested that carboxylate anions present in the unpurified Cremophor catalyze the degradation of paclitaxel by general base catalyzed ethanolysis. Stabilization of Taxol for Injection Concentrate prepared with unpurified Cremophor can be achieved by addition of strong acids, resulting in neutralization of the carboxylate anions. Separately, a quality control test for the cleaning procedure of Cremophor is needed to insure stability of Taxol for Injection Concentrate. A colorimetric indicator test was identified which can distinguish between good and poor quality cleaned Cremophor as it pertains to paclitaxel stability.

  15. Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel.

    PubMed

    Desai, Neil; Trieu, Vuong; Yao, Zhiwen; Louie, Leslie; Ci, Sherry; Yang, Andrew; Tao, Chunlin; De, Tapas; Beals, Bridget; Dykes, Donald; Noker, Patricia; Yao, Rosie; Labao, Elizabeth; Hawkins, Michael; Soon-Shiong, Patrick

    2006-02-15

    ABI-007, an albumin-bound, 130-nm particle form of paclitaxel, was developed to avoid Cremophor/ethanol-associated toxicities in Cremophor-based paclitaxel (Taxol) and to exploit albumin receptor-mediated endothelial transport. We studied the antitumor activity, intratumoral paclitaxel accumulation, and endothelial transport for ABI-007 and Cremophor-based paclitaxel. Antitumor activity and mortality were assessed in nude mice bearing human tumor xenografts [lung (H522), breast (MX-1), ovarian (SK-OV-3), prostate (PC-3), and colon (HT29)] treated with ABI-007 or Cremophor-based paclitaxel. Intratumoral paclitaxel concentrations (MX-1-tumored mice) were compared for radiolabeled ABI-007 and Cremophor-based paclitaxel. In vitro endothelial transcytosis and Cremophor inhibition of paclitaxel binding to cells and albumin was compared for ABI-007 and Cremophor-based paclitaxel. Both ABI-007 and Cremophor-based paclitaxel caused tumor regression and prolonged survival; the order of sensitivity was lung > breast congruent with ovary > prostate > colon. The LD(50) and maximum tolerated dose for ABI-007 and Cremophor-based paclitaxel were 47 and 30 mg/kg/d and 30 and 13.4 mg/kg/d, respectively. At equitoxic dose, the ABI-007-treated groups showed more complete regressions, longer time to recurrence, longer doubling time, and prolonged survival. At equal dose, tumor paclitaxel area under the curve was 33% higher for ABI-007 versus Cremophor-based paclitaxel, indicating more effective intratumoral accumulation of ABI-007. Endothelial binding and transcytosis of paclitaxel were markedly higher for ABI-007 versus Cremophor-based paclitaxel, and this difference was abrogated by a known inhibitor of endothelial gp60 receptor/caveolar transport. In addition, Cremophor was found to inhibit binding of paclitaxel to endothelial cells and albumin. Enhanced endothelial cell binding and transcytosis for ABI-007 and inhibition by Cremophor in Cremophor-based paclitaxel may account in

  16. Paclitaxel Injection

    MedlinePlus

    Paclitaxel injection manufactured with human albumin is used to treat breast cancer that has not improved or that has come back after treatment with other medications. Paclitaxel injection manufactured with polyoxyethylated castor oil is used to ...

  17. Liposomal paclitaxel formulations.

    PubMed

    Koudelka, Stěpán; Turánek, Jaroslav

    2012-11-10

    Over the past three decades, taxanes represent one of the most important new classes of drugs approved in oncology. Paclitaxel (PTX), the prototype of this class, is an anti-cancer drug approved for the treatment of breast and ovarian cancer. However, notwithstanding a suitable premedication, present-day chemotherapy employing a commercial preparation of PTX (Taxol®) is associated with serious side effects and hypersensitivity reactions. Liposomes represent advanced and versatile delivery systems for drugs. Generally, both in vivo mice tumor models and human clinical trials demonstrated that liposomal PTX formulations significantly increase a maximum tolerated dose (MTD) of PTX which outperform that for Taxol®. Liposomal PTX formulations are in various stages of clinical trials. LEP-ETU (NeoPharm) and EndoTAG®-1 (Medigene) have reached the phase II of the clinical trials; Lipusu® (Luye Pharma Group) has already been commercialized. Present achievements in the preparation of various liposomal formulations of PTX, the development of targeted liposomal PTX systems and the progress in clinical testing of liposomal PTX are discussed in this review summarizing about 30 years of liposomal PTX development.

  18. 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

  19. Isolation of Taxol-Producing Endophytic Fungi from Iranian Yew Through Novel Molecular Approach and Their Effects on Human Breast Cancer Cell Line.

    PubMed

    Kasaei, Abdollah; Mobini-Dehkordi, Mohsen; Mahjoubi, Foruzandeh; Saffar, Behnaz

    2017-03-23

    Taxol or paclitaxel, an approved drug by the Food and Drug Administration, is being used for the treatment of human cancers. This study aimed to isolate and determine different species of native endophytic fungi from Iranian Taxus baccata (yew) plants located in the northern forests of Iran. To do so, a novel molecular screening approach was performed for 50 isolated endophytic fungi through amplification of exon No. 1 of taxadine synthase as a key gene in taxol production pathway. We used effective colony-polymerase chain reaction technique for rapid screening of potent taxol-producing fungi instead of genomic DNA extraction. Production of taxol was performed in batch culture by selected fungi individually and produced taxol was assayed quantitatively by high-performance liquid chromatography using standard taxanes. We found that only six fungi could produce taxol and baccatin III. Interestingly, after 7 days of incubation, the highest level of taxol was found to be 129 and that of baccatin 139.2 mg/kg dw for two native isolated Cladosporium sp. named F1 and F3. The fungal taxols could decrease cell viability in MTT assay same as commercial taxol. The fungal taxols semi-quantitatively showed antimitotic effects on MCF-7 cells as human breast cancer cell line. The expression of bcl-2 anti-apoptotic gene, in contrast to bax pro-apoptotic gene, significantly decreased after treatment by standard and fungal taxols. As fungal taxol was produced simpler than other methods and could significantly affect viability and specific genes expression profile, it is recommended that using of taxol-producing fungi from Iranian yew could be a safe and confident procedure to overcome challenges of using other methods.

  20. Anti-proliferative effect of Jesridonin on paclitaxel-resistant EC109 human esophageal carcinoma cells

    PubMed Central

    Wang, Cong; Guo, Liubin; Wang, Saiqi; Wang, Junwei; Li, Yongmei; Dou, Yinhui; Wang, Ran; Shi, Hongge; Ke, Yu; Liu, Hongmin

    2017-01-01

    Chemoresistance to anticancer drugs is a major obstacle in the efforts to develop a successful treatment strategy for esophageal squamous carcinoma (ESCC). Thus, the exploration of new drugs and treatment strategies for combating resistance are of utmost importance. In this study, we investigated the antitumor drug resistance activity of Jesridonin, a new ent-kaurene diterpenoid, and its possible mechanisms of action using the resistant cancer cell line, EC109/Taxol. MTT assay revealed that Jesridonin had similar IC50 values against EC109 paclitaxel-sensitive cells and drug-resistant EC109/Taxol cells in vitro. In mice, Jesridonin effectively prevented the growth of EC109/Taxol tumor xenografts without exerting any significant toxicity. In addition, Jesridonin significantly inhibited the proliferation of EC109/Taxol cells, induced apoptosis and arrested the cell cycle at the G2/M phase. Furthermore, western blot analysis revealed that Jesridonin upregulated the expression of p53, p53 upregulated modulator of apoptosis (PUMA), cleaved-caspase-9 and cleaved-caspase-3 in EC109/Taxol cells, and downregulated the expression of procaspase-3, procaspase-9 and Bcl-2 in the EC109/Taxol cells in a concentration-dependent manner. Overall, our results demonstrate that Jesridonin may have potential for use in the treatment of paclitaxel-resistant ESCC. The data of the present study may lead to the development of novel treatment strategies for paclitaxel-resistant tumors. PMID:28204832

  1. Ototoxicity of paclitaxel in rat cochlear organotypic cultures

    SciTech Connect

    Dong, Yang; Ding, Dalian; Jiang, Haiyan; Shi, Jian-rong; Salvi, Richard; Roth, Jerome A.

    2014-11-01

    Paclitaxel (taxol) is a widely used antineoplastic drug employed alone or in combination to treat many forms of cancer. Paclitaxel blocks microtubule depolymerization thereby stabilizing microtubules and suppressing cell proliferation and other cellular processes. Previous reports indicate that paclitaxel can cause mild to moderate sensorineural hearing loss and some histopathologic changes in the mouse cochlea; however, damage to the neurons and the underlying cell death mechanisms are poorly understood. To evaluate the ototoxicity of paclitaxel in more detail, cochlear organotypic cultures from postnatal day 3 rats were treated with paclitaxel for 24 or 48 h with doses ranging from 1 to 30 μM. No obvious histopathologies were observed after 24 h treatment with any of the paclitaxel doses employed, but with 48 h treatment, paclitaxel damaged cochlear hair cells in a dose-dependent manner and also damaged auditory nerve fibers and spiral ganglion neurons (SGN) near the base of the cochlea. TUNEL labeling was negative in the organ of Corti, but positive in SGN with karyorrhexis 48 h after 30 μM paclitaxel treatment. In addition, caspase-6, caspase-8 and caspase-9 labeling was present in SGN treated with 30 μM paclitaxel for 48 h. These results suggest that caspase-dependent apoptotic pathways are involved in paclitaxel-induced damage of SGN, but not hair cells in cochlea. - Highlights: • Paclitaxel was toxic to cochlear hair cells and spiral ganglion neurons. • Paclitaxel-induced spiral ganglion degeneration was apoptotic. • Paclitaxel activated caspase-6, -8 and -8 in spiral ganglion neurons.

  2. Taxol induces concentration-dependent phosphatidylserine (PS) externalization and cell cycle arrest in ASTC-a-1 cells

    NASA Astrophysics Data System (ADS)

    Guo, Wen-jing; Chen, Tong-sheng

    2010-02-01

    Taxol (Paclitaxel) is an important natural product for the treatment of solid tumors. Different concentrations of taxol can trigger distinct effects on both the cellular microtubule network and biochemical pathways. Apoptosis induced by low concentrations (5-30 nM) of taxol was associated with mitotic arrest, alteration of microtubule dynamics and/or G2/M cell cycle arrest, whereas high concentrations of this drug (0.2-30 μM) caused significant microtubule damage, and was found recently to induce cytoplasm vacuolization in human lung adenocarcinoma (ASTC-a-1) cells. In present study, cell counting kit (CCK-8) assay, confocal microscope, and flow cytometry analysis were used to analyze the cell death form induced by 35 nM and 70 μM of taxol respectively in human lung adenocarcinoma (ASTC-a-1) cells. After treatment of 35 nM taxol for 48 h, the OD450 value was 0.80, and 35 nM taxol was found to induce dominantly cell death in apoptotic pathway such as phosphatidylserine (PS) externalization, G2/M phase arrest after treatment for 24 h, and nuclear fragmentation after treatment for 48 h. After 70 μM taxol treated the cell for 24 h, the OD450 value was 1.01, and 70 μM taxol induced cytoplasm vacuolization programmed cell death (PCD) and G2/M phase as well as the polyploidy phase arrest in paraptotic-like cell death. These findings imply that the regulated signaling pathway of cell death induced by taxol is dependent on taxol concentration in ASTC-a-1 cells.

  3. Paclitaxel Nano-Delivery Systems: A Comprehensive Review

    PubMed Central

    Ma, Ping; Mumper, Russell J.

    2013-01-01

    Paclitaxel is one of the most effective chemotherapeutic drugs ever developed and is active against a broad range of cancers, such as lung, ovarian, and breast cancers. Due to its low water solubility, paclitaxel is formulated in a mixture of Cremophor EL and dehydrated ethanol (50:50, v/v) a combination known as Taxol. However, Taxol has some severe side effects related to Cremophor EL and ethanol. Therefore, there is an urgent need for the development of alternative Taxol formulations. The encapsulation of paclitaxel in biodegradable and non-toxic nano-delivery systems can protect the drug from degradation during circulation and in-turn protect the body from toxic side effects of the drug thereby lowering its toxicity, increasing its circulation half-life, exhibiting improved pharmacokinetic profiles, and demonstrating better patient compliance. Also, nanoparticle-based delivery systems can take advantage of the enhanced permeability and retention (EPR) effect for passive tumor targeting, therefore, they are promising carriers to improve the therapeutic index and decrease the side effects of paclitaxel. To date, paclitaxel albumin-bound nanoparticles (Abraxane®) have been approved by the FDA for the treatment of metastatic breast cancer and non-small cell lung cancer (NSCLC). In addition, there are a number of novel paclitaxel nanoparticle formulations in clinical trials. In this comprehensive review, several types of developed paclitaxel nano-delivery systems will be covered and discussed, such as polymeric nanoparticles, lipid-based formulations, polymer conjugates, inorganic nanoparticles, carbon nanotubes, nanocrystals, and cyclodextrin nanoparticles. PMID:24163786

  4. Screening of paclitaxel-binding molecules from a library of random peptides displayed on T7 phage particles using paclitaxel-photoimmobilized resin.

    PubMed

    Aoki, Sota; Morohashi, Kengo; Sunoki, Takashi; Kuramochi, Kouji; Kobayashi, Susumu; Sugawara, Fumio

    2007-01-01

    Paclitaxel (Taxol), an effective anticancer agent, is known to bind to tubulin and induce tubulin polymerization. Several other binding proteins of paclitaxel, such as Bcl-2, heat shock proteins, and NSC-1, have also been reported. Here, we describe a T7 phage-based display to screen for paclitaxel-binding molecules from a random peptide library using paclitaxel-photoimmobilized TentaGel resin. Specific phage particles that bind the paclitaxel-immobilized resin were obtained. Among them, two phage clones included the same consensus amino acid sequence (KACGRTRVTS). Analysis of the protein database using BLAST revealed that a portion of this sequence is conserved in the zinc finger domain of human NFX1. Binding affinity of paclitaxel against the partial recombinant protein of NFX1 (424aa-876aa) was confirmed by pull-down assays and surface plasmon resonance analyses.

  5. Independent evaluation of the anatomical and behavioral effects of Taxol in rat models of spinal cord injury.

    PubMed

    Popovich, Phillip G; Tovar, C Amy; Lemeshow, Stanley; Yin, Qin; Jakeman, Lyn B

    2014-11-01

    The goal of the current manuscript was to replicate published data that show intrathecal infusions of Taxol® (paclitaxel), an anti-neoplastic microtubule stabilizing agent, reduce fibrogliotic scarring caused by a dorsal spinal hemisection (DHx) injury and increase functional recovery and growth of serotonergic axons after moderate spinal contusion injury. These experiments were completed as part of an NIH-NINDS contract entitled "Facilities of Research Excellence in Spinal Cord Injury (FORE-SCI) - Replication". Here, data are presented that confirm the anti-scarring effects of Taxol after DHx injury; however, Taxol did not confer neuroprotection or promote serotonergic axon growth nor did it improve functional recovery in a model of moderate spinal contusion injury. Thus, only partial replication was achieved. Possible explanations for disparate results in our studies and published data are discussed.

  6. Hypersensitivity reaction studies of a polyethoxylated castor oil-free, liposome-based alternative paclitaxel formulation.

    PubMed

    Wang, Hongbo; Cheng, Guang; Du, Yuan; Ye, Liang; Chen, Wenzhong; Zhang, Leiming; Wang, Tian; Tian, Jingwei; Fu, Fenghua

    2013-03-01

    The commercial drug paclitaxel (Taxol) may introduce hypersensitivity reactions associated with the polyethoxylated castor oil-ethanol solvent. To overcome these problems, we developed a polyethoxylated castor oil-free, liposome-based alternative paclitaxel formulation, known as Lipusu. In this study, we performed in vitro and in vivo experiments to compare the safety profiles of Lipusu and Taxol, with special regard to hypersensitivity reactions. First, Swiss mice were used to determine the lethal dosages, and then to evaluate hypersensitivity reactions, followed by histopathological examination and enzyme-linked immunosorbent assays (ELISAs) of serum SC5b-9 and lung histamine. Additionally, healthy human serum was used to analyze in vitro complement activation. Finally, an MTT assay was used to determine the in vitro anti-proliferation activity. Our data clearly showed that Lipusu displayed a much higher safety margin and did not induce hypersensitivity or hypersensitivity-related lung lesions, which may be associated with the fact that Lipusu did not activate complement or increase histamine release in vivo. Moreover, Lipusu did not promote complement activation in healthy human serum in vitro, and demonstrated anti-proliferative activity against human cancer cells, similar to that of Taxol. Therefore, the improved formulation of paclitaxel, which exhibited a much better safety profile and comparable cytotoxic activity to Taxol, may bring a number of benefits to cancer patients.

  7. Anticancer activity of fungal taxol derived from Botryodiplodia theobromae Pat., an endophytic fungus, against 7, 12 dimethyl benz(a)anthracene (DMBA)-induced mammary gland carcinogenesis in Sprague Dawley rats.

    PubMed

    Pandi, M; Manikandan, R; Muthumary, J

    2010-01-01

    Breast cancer is the second most prevalent cancer worldwide and their incidence increases gradually. Taxol (paclitaxel), a potent anticancer drug, is naturally isolated from the bark of the Pacific yew. Taxol is widely used in the treatment of ovarian, lung and breast cancer. The increased demand for taxol, coupled with its limited availability from the protected Pacific yew, has had researchers scrambling for alternate sources. The purpose of the present study is to investigate chemopreventive effect of fungal taxol derived from a novel endophytic fungus Botryodiplodia theobromae Pat., isolated from a medicinal plant Morinda citrifolia Linn. The fungal taxol is found to be active against the 7, 12 dimethyl benz(a)anthracene (DMBA)-induced mammary gland carcinogenesis in Sprague dawley rats. The enzymic and non-enzymic antioxidants i.e. superoxide dismutase (SOD), catalase (CAT), glutatione peroxidase (GPx), glutatione-S-transferase (GST), reduced glutathione (GSH), vitamin C and vitamin E were evaluated in control and experimental groups. Lipid peroxides levels (LPO) were also tested. Histological analysis of breast tissue was analyzed by haematoxylin and eosin staining to assess the cytoprotective role of fungal taxol active against breast cancer. Immunohistochemical analyses were also performed to evaluate the effect of fungal taxol on the inflammatory marker such as Cyclooxygenase-2 (COX-2) in control and experimental groups. The results showed that the fungal taxol significantly suppresses the DMBA-induced breast cancer in Sprague dawley rats.

  8. Cremophor-free intravenous microemulsions for paclitaxel II. Stability, in vitro release and pharmacokinetics.

    PubMed

    Nornoo, Adwoa O; Chow, Diana S-L

    2008-02-12

    Two cremophor-free microemulsion systems LBMW (lecithin:butanol:myvacet:water) and CMW (capmul:myvacet:water), for intravenous (IV) administration of paclitaxel (PAC) were previously developed and characterized. Their chemical stability, in vitro release and pharmacokinetics of PAC were assessed using Taxol (cremophor:ethanol 1:1, 6 mg/ml) as a reference. The shelf-lives of PAC at 25 degrees C in Taxol, LBMW and CMW, in an accelerated stability study, were 71, 57 and 31 days, respectively. The activation energy (Ea) for PAC in Taxol, LBMW and CMW was 23, 16 and 14 kcal/mol, respectively. PAC released from LBMW and CMW using a dialysis technique was significantly slower than that from Taxol. The extents of release of PAC from LBMW and CMW were 25 and 50% of that from Taxol. In vivo pharmacokinetic studies in male Sprague-Dawley rats after IV administration revealed that PAC in LBMW and CMW remained in the systemic circulation five and two times longer and was eight and three times more widely distributed than PAC from Taxol. LBMW and CMW offer a significant clinical advantage in terms of the prolonged half-life and wide tissue distribution, indicating that PAC delivered by these systems intravenously may result in prolonged exposure of PAC to the tumor and subsequently an improved clinical efficacy.

  9. Drug-induced subacute cutaneous lupus erythematosus associated with nab-paclitaxel therapy.

    PubMed

    Lamond, N W D; Younis, T; Purdy, K; Dorreen, M S

    2013-10-01

    Drug-induced lupus erythematosus (dile) syndromes are documented complications of chemotherapeutic agents, including paclitaxel. Subacute cutaneous lupus erythematosus (scle) is a distinct dile syndrome presenting with characteristic annular or papulosquamous skin lesions in a photosensitive distribution with associated high anti-ssa titres. Previously, dile syndromes complicating paclitaxel therapy have been attributed to polyethoxylated castor oil (Kolliphor EL: BASF, Ludwigshafen, Germany), the biologic solvent included in the drug's original formulation (Taxol: Bristol-Myers Squibb, Montreal, QC), rather than the parent chemotherapy molecule. Here, we report a characteristic case of drug-induced scle complicating treatment with nanoparticle albumin bound (nab)-paclitaxel (Abraxane: Celgene, Summit, NJ, U.S.A.), a solvent-free taxane formulation. The pertinent English-language literature is also discussed. This case report is the first to link solvent-free paclitaxel with scle, and it suggests that the parent molecule is responsible for the reaction.

  10. STAT3-dependent TXNDC17 expression mediates Taxol resistance through inducing autophagy in human colorectal cancer cells.

    PubMed

    Zhang, Zhongde; Wang, Aihua; Li, Hui; Zhi, Hui; Lu, Feng

    2016-06-10

    Taxol (paclitaxel) is one of the taxane class of anticancer drugs as a first-line chemotherapeutic agent against many cancers including colorectal cancer, breast cancer, non-small cell lung cancer, ovarian cancer and so on. It is verified to induce cytotoxicity in a concentration and time-dependent manner. Numerous novel formulations of Taxol have been remanufactured for better therapeutic effect. Though Taxol works as a common anticancer drug for a long time in clinical practice, drug resistance is a major limitation of its long-term administration. In-depth research on drug resistance is still in progress and researchers have made some achievements, however, the mechanism or key molecule related to Taxol resistance in colorectal cancer still remains to be explored. In the present study, we observed that the high expression of TXNDC17 (thioredoxin domain containing 17) was associated with Taxol resistance in colorectal cancer cells. And TXNDC17 mediated Taxol resistance was related with increased basal autophagy level. Taxol exposure induced high levels of phospho-STAT3 (Tyr 705) and TXNDC17; and increase of basal autophagy in colorectal cancer cells. TXNDC17 overexpression cells obtained Taxol resistance and a high level of autophagy, and it is not surprising that stable downregulation of TXNDC17 accordingly reversed these phenomena. Interestingly, STAT3 could similarly work as TXNDC17 in spite of slighter effect compared to TXNDC17. And it has been proved that phospho-STAT3 (Tyr 705) possesses transcriptional regulation activity through forming dimmers. Many research revealed that transcription factor STAT3 affected more than 1000 gene products, and TXNDC17 is predicted to be a target gene of STAT3 at UCSC database. For the first time, we found STAT3 could bind promoter region of TXNDC17 (-623 bp to -58 bp relative to the transcription start site (TSS)) for regulating its expression. These results suggest the possibility that TXNDC17 could play an important role

  11. Integrated modeling methodology for microtubule dynamics and Taxol kinetics with experimentally identifiable parameters.

    PubMed

    Zhao, He; Sokhansanj, Bahrad A

    2007-10-01

    Microtubule dynamics play a critical role in cell function and stress response, modulating mitosis, morphology, signaling, and transport. Drugs such as paclitaxel (Taxol) can impact tubulin polymerization and affect microtubule dynamics. While theoretical methods have been previously proposed to simulate microtubule dynamics, we develop a methodology here that can be used to compare model predictions with experimental data. Our model is a hybrid of (1) a simple two-state stochastic formulation of tubulin polymerization kinetics and (2) an equilibrium approximation for the chemical kinetics of Taxol drug binding to microtubule ends. Model parameters are biologically realistic, with values taken directly from experimental measurements. Model validation is conducted against published experimental data comparing optical measurements of microtubule dynamics in cultured cells under normal and Taxol-treated conditions. To compare model predictions with experimental data requires applying a "windowing" strategy on the spatiotemporal resolution of the simulation. From a biological perspective, this is consistent with interpreting the microtubule "pause" phenomenon as at least partially an artifact of spatiotemporal resolution limits on experimental measurement.

  12. Anti-nociceptive roles of the glia-specific metabolic inhibitor fluorocitrate in paclitaxel-evoked neuropathic pain.

    PubMed

    Xu, Yongming; Cheng, Guangxia; Zhu, Yanrong; Zhang, Xin; Pu, Shaofeng; Wu, Junzhen; Lv, Yingying; Du, Dongping

    2016-10-01

    Paclitaxel (Taxol) is a powerful chemotherapy drug used in breast cancers, but it often causes neuropathic pain, leading to the early cessation of therapy and poor treatment outcomes. Approaches for the management of paclitaxel-induced neuropathic pain are urgently needed. The involvement of spinal astrocytes in the pathogenesis of paclitaxel-induced neuropathy has been reported, but little is known about the role of fluorocitrate (FC), a selective inhibitor of astrocyte activation, during neuropathic pain related to paclitaxel treatment. In this study, we investigated the effects of FC on paclitaxel-induced neuropathic pain. Glial fibrillary acidic protein (GFAP) expression was determined to assess astrocyte activation. To explore the mechanisms involved, the expression of glial glutamate transporter 1 (GLT-1) and the activation of mitogen-activated protein kinases in the spinal dorsal horn were analyzed. The results showed that paclitaxel decreased the mechanical nociceptive thresholds and increased GFAP expression, leading to spinal astrocyte activation. After paclitaxel treatment, GLT-1 was significantly down-regulated, and the phosphorylation of ERK1/2 and JNK were obviously up-regulated. However, paclitaxel treatment did not increase p38 phosphorylation. Additional studies showed that paclitaxel-evoked mechanical hypersensitivity was reduced by FC treatment. Moreover, FC treatment inhibited the activation of astrocytes and reversed the changes in GLT-1 expression and MAPK phosphorylation. Further study indicated that FC did not influence the antitumor effect of paclitaxel, suggesting that FC blocked paclitaxel-induced neuropathic pain without antagonizing its antitumor effect. Together, these results suggested that paclitaxel induced astrocyte-specific activation, which may contribute to mechanical allodynia and hyperalgesia, and that FC could be a potential therapeutic agent for paclitaxel-induced neuropathic pain.

  13. Moderate intensity static magnetic fields affect mitotic spindles and increase the antitumor efficacy of 5-FU and Taxol.

    PubMed

    Luo, Yan; Ji, Xinmiao; Liu, Juanjuan; Li, Zhiyuan; Wang, Wenchao; Chen, Wei; Wang, Junfeng; Liu, Qingsong; Zhang, Xin

    2016-06-01

    Microtubules are the fundamental components in mitotic spindle, which plays essential roles in cell division. It was well known that purified microtubules could be affected by static magnetic fields (SMFs) in vitro because of the diamagnetic anisotropy of tubulin. However, whether these effects lead to cell division defects was unknown. Here we find that 1T SMFs induce abnormal mitotic spindles and increase mitotic index. Synchronization experiments show that SMFs delay cell exit from mitosis and cause mitotic arrest. These mimic the cellular effects of a microtubule-targeting drug Paclitaxel (Taxol), which is frequently used in combination with 5-Fluorouracil (5-FU) and Cisplatin in cancer treatment. Using four different human cancer cell lines, HeLa, HCT116, CNE-2Z and MCF7, we find that SMFs increase the antitumor efficacy of 5-FU or 5-FU/Taxol, but not Cisplatin, which indicates that the SMF-induced combinational effects with chemodrugs are drug-specific. Our study not only reveals the effect of SMFs on microtubules to cause abnormal mitotic spindles and delay cells exit from mitosis, but also implies the potential applications of SMFs in combination with chemotherapy drugs 5-FU or 5-FU/Taxol, but not with Cisplatin in cancer treatment.

  14. Prodrug Strategies for Paclitaxel

    PubMed Central

    Meng, Ziyuan; Lv, Quanxia; Lu, Jun; Yao, Houzong; Lv, Xiaoqing; Jiang, Feng; Lu, Aiping; Zhang, Ge

    2016-01-01

    Paclitaxel is an anti-tumor agent with remarkable anti-tumor activity and wide clinical uses. However, it is also faced with various challenges especially for its poor water solubility and low selectivity for the target. To overcome these disadvantages of paclitaxel, approaches using small molecule modifications and macromolecule modifications have been developed by many research groups from all over the world. In this review, we discuss the different strategies especially prodrug strategies that are currently used to make paclitaxel more effective. PMID:27223283

  15. Paclitaxel-associated reticulate hyperpigmentation: Report and review of chemotherapy-induced reticulate hyperpigmentation

    PubMed Central

    Cohen, Philip R

    2016-01-01

    Drug-induced reticulate hyperpigmentation is uncommon. Including the patient described in this report, chemotherapy-associated reticulate hyperpigmentation has only been described in ten individuals. This paper describes the features of a woman with recurrent and metastatic breast cancer who developed paclitaxel-induced reticulate hyperpigmentation and reviews the characteristics of other oncology patients who developed reticulate hyperpigmentation from their antineoplastic treatment. A 55-year-old Taiwanese woman who developed reticulate hyperpigmentation on her abdomen, back and extremities after receiving her initial treatment for metastatic breast cancer with paclitaxel is described. The hyperpigmentation became darker with each subsequent administration of paclitaxel. The drug was discontinued after five courses and the pigment faded within two months. PubMed was searched with the key words: Breast, cancer, chemotherapy, hyperpigmentation, neoplasm, reticulate, tumor, paclitaxel, taxol. The papers generated by the search, and their references, were reviewed. Chemotherapy-induced reticulate hyperpigmentation has been described in four men and six women. Bleomycin, cytoxan, 5-fluorouracil, idarubacin, and paclitaxel caused the hyperpigmentation. The hyperpigmentation faded in 83% of the patients between two to six months after the associated antineoplastic agent was discontinued. In conclusion, chemotherapy-induced reticulate hyperpigmentation is a rare reaction that may occur during treatment with various antineoplastic agents. The hyperpigmentation fades in most individuals once the treatment is discontinued. Therefore, cancer treatment with the associated drug can be continued in patients who experience this cutaneous adverse event. PMID:28035312

  16. Paclitaxel Through the Ages of Anticancer Therapy: Exploring Its Role in Chemoresistance and Radiation Therapy

    PubMed Central

    Barbuti, Anna Maria; Chen, Zhe-Sheng

    2015-01-01

    Paclitaxel (Taxol®) is a member of the taxane class of anticancer drugs and one of the most common chemotherapeutic agents used against many forms of cancer. Paclitaxel is a microtubule-stabilizer that selectively arrests cells in the G2/M phase of the cell cycle, and found to induce cytotoxicity in a time and concentration-dependent manner. Paclitaxel has been embedded in novel drug formulations, including albumin and polymeric micelle nanoparticles, and applied to many anticancer treatment regimens due to its mechanism of action and radiation sensitizing effects. Though paclitaxel is a major anticancer drug which has been used for many years in clinical treatments, its therapeutic efficacy can be limited by common encumbrances faced by anticancer drugs. These encumbrances include toxicities, de novo refraction, and acquired multidrug resistance (MDR). This article will give a current and comprehensive review of paclitaxel, beginning with its unique history and pharmacology, explore its mechanisms of drug resistance and influence in combination with radiation therapy, while highlighting current treatment regimens, formulations, and new discoveries. PMID:26633515

  17. 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; 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.

  18. 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

  19. 2′-(2-bromohexadecanoyl)-paclitaxel conjugate nanoparticles for the treatment of non-small cell lung cancer in an orthotopic xenograft mouse model

    PubMed Central

    Peng, Lei; Schorzman, Allison N; Ma, Ping; Madden, Andrew J; Zamboni, William C; Benhabbour, Soumya Rahima; Mumper, Russell J

    2014-01-01

    A nanoparticle (NP) formulation with 2′-(2-bromohexadecanoyl)-paclitaxel (Br-16-PX) conjugate was developed in these studies for the treatment of non-small cell lung cancer (NSCLC). The lipophilic paclitaxel conjugate Br-C16-PX was synthesized and incorporated into lipid NPs where the 16-carbon chain enhanced drug entrapment in the drug delivery system and improved in vivo pharmacokinetics. The electron-withdrawing bromine group was used to facilitate the conversion of Br-C16-PX to paclitaxel at the tumor site. The developed system was evaluated in luciferase-expressing A549 cells in vitro and in an orthotopic NSCLC mouse model. The results demonstrated that the Br-C16-PX NPs had a higher maximum tolerated dose (75 mg/kg) than Taxol® (19 mg/kg) and provided significantly longer median survival (88 days versus 70 days, P<0.05) in the orthotopic NSCLC model. An improved pharmacokinetic profile was observed for the Br-C16-PX NPs at 75 mg/kg compared to Taxol at 19 mg/kg. The area under the concentration versus time curve (AUC)0–96 h of Br-C16-PX from the NPs was 91.7-fold and 49.6-fold greater than Taxol in plasma and tumor-bearing lungs, respectively, which provided sustained drug exposure and higher antitumor efficacy in the NP-treated group. PMID:25114529

  20. Preparation and characterization of paclitaxel nanosuspension using novel emulsification method by combining high speed homogenizer and high pressure homogenization.

    PubMed

    Li, Yong; Zhao, Xiuhua; Zu, Yuangang; Zhang, Yin

    2015-07-25

    The aim of this study was to develop an alternative, more bio-available, better tolerated paclitaxel nanosuspension (PTXNS) for intravenous injection in comparison with commercially available Taxol(®) formulation. In this study, PTXNS was prepared by emulsification method through combination of high speed homogenizer and high pressure homogenization, followed by lyophilization process for intravenous administration. The main production parameters including volume ratio of organic phase in water and organic phase (Vo:Vw+o), concentration of PTX, content of PTX and emulsification time (Et), homogenization pressure (HP) and passes (Ps) for high pressure homogenization were optimized and their effects on mean particle size (MPS) and particle size distribution (PSD) of PTXNS were investigated. The characteristics of PTXNS, such as, surface morphology, physical status of paclitaxel (PTX) in PTXNS, redispersibility of PTXNS in purified water, in vitro dissolution study and bioavailability in vivo were all investigated. The PTXNS obtained under optimum conditions had an MPS of 186.8 nm and a zeta potential (ZP) of -6.87 mV. The PTX content in PTXNS was approximately 3.42%. Moreover, the residual amount of chloroform was lower than the International Conference on Harmonization limit (60 ppm) for solvents. The dissolution study indicated PTXNS had merits including effect to fast at the side of raw PTX and sustained-dissolution character compared with Taxol(®) formulation. Moreover, the bioavailability of PTXNS increased 14.38 and 3.51 times respectively compared with raw PTX and Taxol(®) formulation.

  1. Paclitaxel-loaded hyaluronan solid nanoemulsions for enhanced treatment efficacy in ovarian cancer

    PubMed Central

    Kim, Joo-Eun; Park, Young-Joon

    2017-01-01

    Paclitaxel-loaded hyaluronan solid nanoemulsions (PTX-HSNs) were successfully fabricated for the delivery of PTX to improve ovarian cancer treatment via active tumor targeting. PTX-HSNs were fabricated using high-pressure homogenization with a microfluidizer and were lyophilized with d-mannitol. Hyaluronan was coated on the outside of the PTX-HSN sphere. The mean size of the PTX-HSNs was maintained less than 100 nm, with a relatively narrow size distribution. The PTX loading content was 3 mg/mL, and encapsulation efficiency (EE) was close to 100%. In vitro cell affinity studies using SK-OV-3 (cluster of differentiation 44 [CD44+]) and OVCAR-3 (CD44−) cells showed that PTX-HSN had a targeting capability hundredfold higher than that of PTX-loaded solid nanoemulsions (PTX-SNs) without hyaluronan. Further, the in vitro PTX release by PTX-SNs and PTX-HSNs lasted more than 6 days without showing a release burst, which was more sustained than that of Taxol®, suggesting a more constant effect on cancer cells at the tumor site than was observed for Taxol. The in vivo toxicity, in vivo antitumor effects, and pharmacokinetics of PTX-HSNs and Taxol were evaluated in nude mice and rats. The maximum tolerated dose (MTD) for PTX-HSNs, PTX-SNs, and Taxol was determined by measuring changes in clinical symptoms after administering 20–50 mg/kg PTX via the caudal vein. The MTD of PTX-HSNs had a dosing capacity greater than 50 mg PTX/kg, which was 2.5-fold higher than that of Taxol when administered as a PTX injection. In vivo, PTX-HSN treatment effectively inhibited tumor growth and showed less toxicity in tumor-transplanted mice compared to that observed for Taxol treatments. The pharmacokinetic parameters of PTX-HSNs were more desirable than those of Taxol. After PTX-HSN treatment, the circulation time of PTX was prolonged and retention of PTX in ovarian tumor tissues increased. Therefore, PTX-HSN is a highly effective nanosystem with a high MTD for delivering PTX to ovarian

  2. 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

    2015-04-06

    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.

  3. Combination between Taxol-Encapsulated Liposomes and Eruca sativa Seed Extract Suppresses Mammary Tumors in Female Rats Induced by 7,12 Dimethylbenz(α)anthracene.

    PubMed

    Shaban, Nadia; Abdel-Rahman, Salah; Haggag, Amany; Awad, Doaa; Bassiouny, Ahmad; Talaat, Iman

    2016-01-01

    Taxol (paclitaxel) is a powerful anti-cancer drug widely used against several types of malignant tumors. Because Taxol may exert several side effects, a variety of formulations have been developed. One of these features liposomes, regarded as one of the most promising drug carriers, biocompatible and best able to reduce drug toxicity without changing efficacy against tumor cells. Eruca sativa seed extract (SE) is considered a promising natural product from cruciferous vegetables against breast cancer, increasing chemotherapeutic and eliminating harmful side effects. The effects of Taxol-encapsulated liposomes (T) alone and in combination between Eruca sativa seed extract on nuclear factor kappa B (NF-κB), cyclooxygenase-2 (COX-2) and B-cell lymphoma-2 (Bcl-2) gene expression levels were investigated in rat mammary gland carcinogenesis induced by 7,12 dimethylbenz(α) anthracene (DMBA) using qRT-PCR. The results showed that DMBA increased NF-κB, COX-2 and Bcl-2 gene expression levels and lipid peroxidation (LP), while decreasing glutathione-S-transferase (GST) and superoxide dismutase (SOD) activities and total antioxidant concentration (TAC) compared to the control group. T and T-SE treatment reduced NF-κB, COX-2 and Bcl-2 gene expression levels and LP. Hence, T and T-SE treatment appeared to reduce inflammation and cell proliferation, while increasing apoptosis, GST and SOD activities and TAC.

  4. Hydrophobically modified inulin as an amphiphilic carbohydrate polymer for micellar delivery of paclitaxel for intravenous route.

    PubMed

    Muley, Pratik; Kumar, Sunny; El Kourati, Fadoua; Kesharwani, Siddharth S; Tummala, Hemachand

    2016-03-16

    Micellization offers several advantages for the delivery of water insoluble drugs including a nanoparticulate 'core-shell' delivery system for drug targeting. Recently, hydrophobically modified polysaccharides (HMPs) are gaining recognition as micelle forming polymers to encapsulate hydrophobic drugs. In this manuscript, for the first time, we have evaluated the self-assembling properties of a lauryl carbamate derivative of the poly-fructose natural polymer inulin (Inutec SP1(®) (INT)) to form paclitaxel (PTX) loaded micelles. INT self-assembled into well-defined micellar structures in aqueous environment with a low critical micellar concentration of 27.8 μg/ml. INT micelles exhibited excellent hemocompatibility and low toxicity to cultured cells. PTX loaded INT micelles exhibited a mean size of 256.37 ± 10.45 nm with excellent drug encapsulation efficiency (95.66 ± 2.25%) and loading (8.69 ± 0.22%). PTX loaded micelles also displayed sustained release of PTX and enhanced anti-cancer efficacy in-vitro in mouse melanoma cells (B16F10) compared to Taxol formulation with Cremophor EL as solvent. In addition, PTX loaded INT micelles exhibited comparable in-vivo antitumor activity in B16F10 allograft mouse model at half the dose of Taxol. In conclusion, INT offers safe, inexpensive and natural alternative to widely used PEG-modified polymers for the formulation of micellar delivery systems for paclitaxel.

  5. 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

  6. Induction of monocyte chemoattractant protein-1 (MCP-1) and its receptor CCR2 in primary sensory neurons contributes to paclitaxel-induced peripheral neuropathy

    PubMed Central

    Zhang, Haijun; Boyette-Davis, Jessica A.; Kosturakis, Alyssa K.; Li, Yan; Yoon, Seo-Yeon; Walters, Edgar T.; Dougherty, Patrick M.

    2013-01-01

    The use of paclitaxel (Taxol®), a microtubule stabilizer, for cancer treatment is often limited by its associated peripheral neuropathy (chemotherapy-induced peripheral neuropathy, CIPN) which predominantly results in sensory dysfunction including chronic pain. Here we show that paclitaxel CIPN was associated with an induction of chemokine monocyte chemoattractant protein-1 (MCP-1) and its cognate receptor CCR2 in primary sensory neurons of dorsal root ganglia (DRG). Immunostaining revealed that MCP-1 was mainly expressed in small nociceptive neurons while CCR2 was expressed in large and medium-sized myelinated neurons. Direct application of MCP-1 consistently induced intracellular calcium increases in DRG large and medium-sized but not small neurons mainly dissociated from paclitaxel- but not vehicle-treated animals. Paclitaxel also induced increased expression of MCP-1 in spinal astrocytes but no CCR2 signal was detected in spinal cord. Local blockade of MCP-1/CCR2 signaling by anti-MCP-1 antibody or CCR2 antisense oligodeoxynucleotides significantly attenuated paclitaxel CIPN phenotypes including mechanical hypersensitivity and loss of intraepidermal nerve fibers (IENFs) in hindpaw glabrous skin. These results suggest that activation of paracrine MCP-1/CCR2 signaling between DRG neurons plays a critical role in the development of paclitaxel CIPN and targeting MCP-1/CCR2 signaling could be a novel therapeutic approach. PMID:23726937

  7. Cremophor-free intravenous microemulsions for paclitaxel I: formulation, cytotoxicity and hemolysis.

    PubMed

    Nornoo, Adwoa O; Osborne, David W; Chow, Diana S-L

    2008-02-12

    Two cremophor-free microemulsions, lecithin:butanol:myvacet oil:water (LBMW) and capmul:myvacet oil:water (CMW) for paclitaxel (PAC) were developed for intravenous (i.v.) administration. Six surfactants and four oils were screened with various combinations for maximal water incorporation and PAC solubility. Microemulsion regions were subsequently determined in ternary phase diagrams. Cytotoxicity in an MDA-M231 human breast cancer cell line and hemolytic potential were assessed in these systems compared to Taxol (cremophor EL:ethanol, 1:1, 6 mgPAC/ml). The maximal water incorporation into the lecithin:butanol surfactant blend was greater than that incorporated into capmul when combined with the oils screened. PAC solubility in myvacet oil was increased 1389-fold over its aqueous solubility. LBMW had a larger microemulsion region (46.5% of total ternary phase diagram) than that seen with CMW (18.6%). The droplet size of the dispersed phase was 111.5 (4.18)nm for LBMW and 110.3 (8.09)nm for CMW. Cytotoxicity of PAC was in decreasing order of: Taxol>LBMW>CMW. The IC50 values for LBMW and CMW ranged from 4.5 to 5.7 and >10 microM, respectively, as compared to that of Taxol (1.3 to 1.8 microM). Eighty-three percent, 68%, and 63% of red blood cells remain unlysed at a formulation volume to blood ratio of 0.035 in LBMW, CMW and Taxol. Promising microemulsions, LBMW and CMW were developed that can incorporate approximately 12 mg/g of PAC, substantially higher than its aqueous solubility (10.8 microg/ml) and that in the Taxol vehicle (6 mg/ml). PAC retained its cytotoxicity in the LBMW and CMW and was less likely to cause hemolysis compared to Taxol. This higher drug loading results in a smaller vehicle volume in required doses of these formulations and potentially less vehicle-related side effects are anticipated.

  8. 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, T5αH, 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

  9. Influence of Cremophor EL and genetic polymorphisms on the pharmacokinetics of paclitaxel and its metabolites using a mechanism-based model.

    PubMed

    Fransson, Martin N; Gréen, Henrik; Litton, Jan-Eric; Friberg, Lena E

    2011-02-01

    The formulation vehicle Cremophor EL has previously been shown to affect paclitaxel kinetics, but it is not known whether it also affects the kinetics of paclitaxel metabolites. This information may be important for understanding paclitaxel metabolism in vivo and in the investigation of the role of genetic polymorphisms in the metabolizing enzymes CYP2C8 and CYP3A4/CYP3A5 and the ABCB1 transporter. In this study we used the population pharmacokinetic approach to explore the influence of predicted Cremophor EL concentrations on paclitaxel (Taxol) metabolites. In addition, correlations between genetic polymorphisms and enzyme activity with clearance of paclitaxel, its two primary metabolites, 6α-hydroxypaclitaxel and p-3'-hydroxypaclitaxel, and its secondary metabolite, 6α-p-3'-dihydroxypaclitaxel were investigated. Model building was based on 1156 samples from a study with 33 women undergoing paclitaxel treatment for gynecological cancer. Total concentrations of paclitaxel were fitted to a model described previously. One-compartment models characterized unbound metabolite concentrations. Total concentrations of 6α-hydroxypaclitaxel and p-3'-hydroxypaclitaxel were strongly dependent on predicted Cremophor EL concentrations, but this association was not found for 6α-p-3'-dihydroxypaclitaxel. Clearance of 6α-hydroxypaclitaxel (fraction metabolized) was significantly correlated (p < 0.05) to the ABCB1 allele G2677T/A. Individuals carrying the polymorphisms G/A (n = 3) or G/G (n = 5) showed a 30% increase, whereas individuals with polymorphism T/T (n = 8) showed a 27% decrease relative to those with the polymorphism G/T (n = 17). The correlation of G2677T/A with 6α-hydroxypaclitaxel has not been described previously but supports other findings of the ABCB1 transporter playing a part in paclitaxel metabolism.

  10. Enzyme-instructed self-assembly of taxol promotes axonal branching

    NASA Astrophysics Data System (ADS)

    Mei, Bin; Miao, Qingqing; Tang, Anming; Liang, Gaolin

    2015-09-01

    Axonal branching is important for vertebrate neuron signaling. Taxol has a biphasic effect on axonal branching (i.e., high concentration inhibits axonal growth but low concentration restores it). To the best of our knowledge, low concentration of taxol to promote axonal branching has not been reported yet. Herein, we rationally designed a taxol derivative Fmoc-Phe-Phe-Lys(taxol)-Tyr(H2PO4)-OH (1) which could be subjected to alkaline phosphatase (ALP)-catalyzed self-assembly to form taxol nanofibers. We found that, at 10 μM, 1 has a microtubule (MT) condensation effect similar to that of taxol on mammalian cells but with more chronic toxicity than taxol on the cells. At a low concentration of 10 nM, 1 not only promoted neurite elongation as taxol did but also promoted axonal branching which was not achieved by using taxol. We propose that self-assembly of 1 along the MTs prohibited their lateral contacts and thus promoted axonal branching. Our strategy of enzyme-instructed self-assembly (EISA) of a taxol derivative provides a new tool for scientists to study the morphology of neurons, as well as their behaviours.Axonal branching is important for vertebrate neuron signaling. Taxol has a biphasic effect on axonal branching (i.e., high concentration inhibits axonal growth but low concentration restores it). To the best of our knowledge, low concentration of taxol to promote axonal branching has not been reported yet. Herein, we rationally designed a taxol derivative Fmoc-Phe-Phe-Lys(taxol)-Tyr(H2PO4)-OH (1) which could be subjected to alkaline phosphatase (ALP)-catalyzed self-assembly to form taxol nanofibers. We found that, at 10 μM, 1 has a microtubule (MT) condensation effect similar to that of taxol on mammalian cells but with more chronic toxicity than taxol on the cells. At a low concentration of 10 nM, 1 not only promoted neurite elongation as taxol did but also promoted axonal branching which was not achieved by using taxol. We propose that self-assembly of 1

  11. Well-defined, size-tunable, multi-functional micelles for efficient paclitaxel delivery for cancer treatment

    PubMed Central

    Luo, Juntao; Xiao, Kai; Li, Yuanpei; Lee, Joyce S.; Shi, Lifang; Tan, Yih-Horng; Xing, Li; Cheng, R. Holland; Liu, Gang-Yu; Lam, Kit S.

    2010-01-01

    We have developed a well-defined and biocompatible amphiphilic telodendrimer system (PEG-b-dendritic oligo-cholic acid) which can self-assemble into multifunctional micelles in aqueous solution for efficient delivery of hydrophobic drugs such as paclitaxel. In this telodendrimer system, cholic acid is essential for the formation of stable micelles with high drug loading capacity, owing to its facial amphiphilicity. A series of telodendrimers with variable length of PEG chain and number of cholic acid in the dendritic blocks were synthesized. The structure and molecular weight of each of these telodendrimers were characterized, and their critical micellization concentration (CMC), drug-loading properties, particle sizes and cytotoxicity were examined and evaluated for further optimization for anticancer drug delivery. The sizes of the micelles, with and without paclitaxel loading, could be tuned from 11.5 to 21 nm and from 15 to 141 nm, respectively. Optical imaging studies in xenograft models demonstrated preferential uptakes of the smaller paclitaxel-loaded micelles (17–60 nm) by the tumor, and the larger micelles (150 nm) by the liver and lung. The toxicity and anti-tumor efficacy profiles of these paclitaxel-loaded micelles in xenograft models were found to be superior to those of Taxol® and Abraxane®. PMID:20536174

  12. Taxol production by an endophytic fungus, Fusarium redolens, isolated from Himalayan yew.

    PubMed

    Garyali, Sanjog; Kumar, Anil; Reddy, M Sudhakara

    2013-10-28

    Different endophytic fungi isolated from Himalayan Yew plants were tested for their ability to produce taxol. The BAPT gene (C-13 phenylpropanoid side chain-CoA acetyl transferase) involved in the taxol biosynthetic pathway was used as a molecular marker to screen taxol-producing endophytic fungi. Taxol extracted from fungal strain TBPJ-B was identified by HPLC and MS analysis. Strain TBPJ-B was identified as Fusarium redolens based on the morphology and internal transcribed spacer region of nrDNA analysis. HPLC quantification of fungal taxol showed that F. redolens was capable of producing 66 μg/l of taxol in fermentation broth. The antitumour activity of the fungal taxol was tested by potato disc tumor induction assay using Agrobacterium tumefaciens as the tumor induction agent. The present study results showed that PCR amplification of genes involved in taxol biosynthesis is an efficient and reliable method for prescreening taxol-producing fungi. We are reporting for the first time the production of taxol by F. redolens from Taxus baccata L. subsp. wallichiana (Zucc.) Pilger. This study offers important information and a new source for the production of the important anticancer drug taxol by endophytic fungus fermentation.

  13. Taxol-induced paraptosis-like A549 cell death is not senescence

    NASA Astrophysics Data System (ADS)

    Wang, Chao-yang; Chen, Tong-Sheng

    2011-03-01

    Our previous studies have shown that taxol, a potent anticancer agent, induces caspase-independent cell death and cytoplasmic vacuolization in human lung cancer cells. However, the mechanisms of taxol-induced cytoplasmic vacuolization are poorly understood. Cytoplasmic vacuolization have been reported to be a characteristic of cell senescence. Here, we employed confocal fluorescence microscopy imaging to study the reversibility of taxol-induced cytoplasmic vacuolization and whether taxol triggers senescence in A549 cells. We found that taxol-induced cytoplasmic vacuolization at 6 or 9 h after treatment with taxol did not decrease but increase at 24 h or 72 h after refreshing the culture medium without taxol, indicating taxol-induced cytoplasmic vacuolization is irreversible. We used SA-β-Gal (senescence-associated β-galactosidase) to assess whether taxol-induced cell death in cytoplasmic vacuolization fashion is senescence, and found that hydrogen peroxide (H2O2)-treated, but not taxol-treated cells is significantly stained by the SA-β-Gal, a senescence testing kit, indicating that the form of taxol-induced cell death is not senescence.

  14. A novel paclitaxel-loaded poly(d,l-lactide-co-glycolide)-Tween 80 copolymer nanoparticle overcoming multidrug resistance for lung cancer treatment

    PubMed Central

    Yuan, Xun; Ji, Wenxiang; Chen, Si; Bao, Yuling; Tan, Songwei; Lu, Shun; Wu, Kongming; Chu, Qian

    2016-01-01

    Drug resistance has become a main obstacle for the effective treatment of lung cancer. To address this problem, a novel biocompatible nanoscale package, poly(d,l-lactide-co-glycolide)-Tween 80, was designed and synthesized to overcome paclitaxel (PTX) resistance in a PTX-resistant human lung cancer cell line. The poly(d,l-lactide-co-glycolide) (PLGA)-Tween 80 nanoparticles (NPs) could efficiently load PTX and release the drug gradually. There was an increased level of uptake of PLGA-Tween 80 in PTX-resistant lung cancer cell line A549/T, which achieved a significantly higher level of cytotoxicity than both PLGA NP formulation and Taxol®. The in vivo antitumor efficacy also showed that PLGA-Tween 80 NP was more effective than Taxol®, indicating that PLGA-Tween 80 copolymer was a promising carrier for PTX in resistant lung cancer. PMID:27307727

  15. A novel paclitaxel-loaded poly(d,l-lactide-co-glycolide)-Tween 80 copolymer nanoparticle overcoming multidrug resistance for lung cancer treatment.

    PubMed

    Yuan, Xun; Ji, Wenxiang; Chen, Si; Bao, Yuling; Tan, Songwei; Lu, Shun; Wu, Kongming; Chu, Qian

    2016-01-01

    Drug resistance has become a main obstacle for the effective treatment of lung cancer. To address this problem, a novel biocompatible nanoscale package, poly(d,l-lactide-co-glycolide)-Tween 80, was designed and synthesized to overcome paclitaxel (PTX) resistance in a PTX-resistant human lung cancer cell line. The poly(d,l-lactide-co-glycolide) (PLGA)-Tween 80 nanoparticles (NPs) could efficiently load PTX and release the drug gradually. There was an increased level of uptake of PLGA-Tween 80 in PTX-resistant lung cancer cell line A549/T, which achieved a significantly higher level of cytotoxicity than both PLGA NP formulation and Taxol(®). The in vivo antitumor efficacy also showed that PLGA-Tween 80 NP was more effective than Taxol(®), indicating that PLGA-Tween 80 copolymer was a promising carrier for PTX in resistant lung cancer.

  16. Induction of taxol metabolism in the rat by dexamethasone

    SciTech Connect

    Anderson, C.D.; Gondi, K.N.; Walle, T.

    1994-12-31

    The antitumor drug taxol was metabolized to two major metabolites (RM1 and RM2) in adult male and female rat liver microsomes. The male rats produced RM1 2.6 fold faster than the females, and they produced RM2 3 fold faster than the females. This correlated well with the sex differences noticed in liver microsomal cytochrome P450 (CYP) 3A content (4.4 fold greater in male) and 6{beta}-hydroxylation of testosterone (2.4 fold greater in male). Taxol was metabolized to three major metabolites (RM1, RM2, and RM3) in adult male and female rat liver microsomes from rats pretreated with dexamethasone. Production of RM1 and RM2 was increased in these rats (2.3 and 3.3 fold respectively in males; 6.5 and 8.7 fold respectively in females) as compared to the untreated rats. These results compared well with the induction of CYP 3A proteins (3.5 fold in male, 10 fold in female) and induction of 6{beta}-hydroxylation (1.9 fold in males, 3.8 fold in females). RM3, which was produced only by the rats pretreated with dexamethasone, had a retention time of 0.58 relative to taxol which corresponds to 6{alpha}- hydroxytaxol, the major human metabolite of taxol. This study indicates that taxol metabolism in the rat is likely due to CYP 3A enzymes. Although the evidence points toward CYP 3A1 as the major isoform involved, it does not rule out others. The findings also suggest that CYP 3A1 is responsible for the induced metabolite, RM3.

  17. Enhancement of taxol-induced apoptosis by inhibition of NF-κB with ursorlic acid

    NASA Astrophysics Data System (ADS)

    Li, Yunlong; Xing, Da

    2007-05-01

    Taxol is known to inhibit cell growth and triggers significant apoptosis in various cancer cells, and activation of proliferation factor NF-κB during Taxol-induced apoptosis is regarded as a main reason resulting in tumor cells resistance to Taxol. It has been found that ursorlic acid can inhibit the activation of NF-κB. In order to study whether ursorlic acid can enhance the Taxol-induced apoptosis, we use fluorescence resonance energy transfer (FRET) technique and probe SCAT3 to compare the difference of caspase-3 activation between Taxol alone and Taxol combined ursorlic acid. With laser scanning confocal microscopy, we find that ursorlic acid, a nontoxic food component, sensitizes ASTC-a-1 cells more efficiently to Taxol-induced apoptosis by advanced activation of caspase 3. The result also suggests that there would be a synergistic effect between Taxol and ursorlic acid, and the more detailed mechanism of synergistic effect needs to be clarified further, such as the correlations among NF-κB, Akt, caspase 8, which leads to the advanced activation of caspase 3 during combined treatment of Taxol and ursorlic acid. Moreover, this may be a new way to improve Taxol-dependent tumor therapy.

  18. Greater taxol yield of fungus Pestalotiopsis hainanensis from dermatitic scurf of the giant panda (Ailuropoda melanoleuca).

    PubMed

    Gu, Yu; Wang, Yanlin; Ma, Xiaoping; Wang, Chengdong; Yue, Guizhou; Zhang, Yuetian; Zhang, Yunyan; Li, Shanshan; Ling, Shanshan; Liu, Xiaomin; Wen, Xintian; Cao, Sanjie; Huang, Xiaobo; Deng, Junliang; Zuo, Zhicai; Yu, Shumin; Shen, Liuhong; Wu, Rui

    2015-01-01

    While taxol yields of fungi from non-animal sources are still low, whether Pestalotiopsis hainanensis isolated from the scurf of a dermatitic giant panda, Ailuropoda melanoleuca, provides a greater taxol yield remains unknown. The objective of the study was to determine the corresponding taxol yield. The structure of the taxol produced by the fungus was evaluated by thin layer chromatography (TLC), ultraviolet (UV) spectroscopy, high-performance liquid chromatography (HPLC), (1)H and (13)C nuclear magnetic resonance spectroscopy ((1)H-NMR and (13)C-NMR), and time-of-flight mass spectrometry (TOF-MS), with standard taxol as a control. The results demonstrated that the P. hainanensis fungus produced taxol, which had the same structure as the standard taxol and yield of 1,466.87 μg/L. This fungal taxol yield from the dermatitic giant panda was significantly greater than those of fungus from non-animal sources. The taxol-producing fungus may be a potential candidate for the production of taxol on an industrial scale.

  19. EGFR-targeted poly(ethylene glycol)-distearoylphosphatidylethanolamine micelle loaded with paclitaxel for laryngeal cancer: preparation, characterization and in vitro evaluation.

    PubMed

    Ren, Henglei; Gao, Chunli; Zhou, Liang; Liu, Min; Xie, Cao; Lu, Weiyue

    2015-01-01

    The objective of this study was to evaluate the potential of using polymeric micelles modified with a peptide (termed GE11) ligand of epidermal growth factor receptor as the targeted carriers to achieve increased accumulation in laryngeal cancer and enhanced intracellular delivery for the encapsulated anticancer drugs. Poly (ethylene glycol)-distearoylphosphatidylethanolamine (PEG-DSPE) micelles containing paclitaxel were prepared via film-hydration method followed by investigation of in vitro release of paclitaxel in phosphate-buffered saline. The average size of GE11-PEG-DSPE/paclitaxel micelle and mPEG-DSPE/paclitaxel were 35 ± 2.8 nm [the polydispersity index (PDI) = 0.207] and 28 ± 2.1 nm (PDI = 0.154), respectively. Micelles with or without GE11-modified had similar physicochemical properties. Transmission electron microscopy showed that the micelles were homogeneous and spherical in shape. Encapsulation efficiency and drug loading of the micelle were 74.11 ± 3.89% and 3.58 ± 2.82%, respectively. The in vitro targeting characteristic of GE11-modified micelles was investigated by observing the level of cellular uptake of fluorescent coumarin-6-loaded micelles on EGFR over-expressed human laryngeal cancer cell line Hep-2 and EGFR low-expressed human leukemic cell line U-937. Hep-2 cell proliferation was significantly inhibited by GE11-PEG-DSPE/paclitaxel micelle compared to mPEG-DSPE/paclitaxel micelle and Taxol in vitro. Our results suggested that GE11-PEG-DSPE micelle could be a promising strategy for enhancing paclitaxel's chemotherapeutic effects on EGFR over-expressed cancer cells.

  20. PEG-Derivatized Embelin as a Nanomicellar Carrier For Delivery of Paclitaxel to Breast and Prostate Cancers

    PubMed Central

    Lu, Jianqin; Huang, Yixian; Zhao, Wenchen; Marquez, Rebecca T.; Meng, Xiaojie; Li, Jiang; Gao, Xiang; Venkataramanan, Raman; Wang, Zhou; Li, Song

    2012-01-01

    Paclitaxel (PTX) is one of the most effective chemotherapeutic agents for a wide spectrum of cancers, but its therapeutic benefit is often limited by severe side effects. We have developed a micelle-based PTX formulation based on a simple conjugate derived from polyethylene glycol 5000 (PEG5K) and embelin (EB). Embelin is a natural product and exhibits antitumor activity through blocking the activity of X-linked inhibitor of apoptosis protein (XIAP). PEG5K-EB2 conjugate self-assembles to form stable micelles in aqueous solution and efficiently encapsulates hydrophobic drugs such as PTX. PEG5K-EB2 micelles have a relatively low CMC of 0.002mg/mL (0.35μM) with sizes in the range of 20 ~ 30 nm with or without loaded PTX. In vitro cell uptake study showed that the PEG5K-EB2 micelles were efficiently taken up by tumor cells. In vitro release study showed that PTX formulated in PEG5K-EB2 micelles was slowly released over 5 days with much slower release kinetics than that of Taxol formulation. PTX formulated in PEG5K-EB2 micelles exhibited more potent cytotoxicity than Taxol in several cultured tumor cell lines. Total body near infrared fluorescence (NIRF) imaging showed that PEG5K-EB2 micelles were selectively accumulated at tumor site with minimal uptake in major organs including liver and spleen. PTX-loaded PEG5K-EB2 micelles demonstrated an excellent safety profile with a maximum tolerated dose (MTD) of 100–120 mg PTX/kg in mice, which was significantly higher than that for Taxol (15–20 mg PTX/kg). Finally, PTX formulated in PEG5K-EB2 micelles showed superior anti-tumor activity compared to Taxol in murine models of breast and prostate cancers. PMID:23182923

  1. Investigation of genotoxic effect of taxol plus radiation on mice bone marrow cells.

    PubMed

    Ozkan, Lütfi; Egeli, Unal; Tunca, Berrin; Aydemir, Nilüfer; Ceçener, Gülşah; Akpinar, Gürler; Ergül, Emel; Cimen, Ciğdem; Ozuysal, Sema; Kahraman-Cetintaş, Sibel; Engin, Kayihan; Ahmed, Mansoor M

    2002-01-01

    In this study, we investigated the genotoxic effect of taxol, radiation, or taxol plus radiation on highly proliferative normal tissue-bone marrow cells of Swiss albino mice. Swiss-albino mice, 3-4 months old, were used in this study. Taxol was administered bolus intravenously through the tail vein. Radiation was given by using a linear accelerator. There were four treatment categories, which had a total of 34 groups. Each group consisted of five animals. The first was the control category that had one group (n = 5). The second treatment category was taxol alone, which had three groups as per taxol dose alone (n = 15). The third treatment category was radiation alone, which had three groups as per the radiation dose (n = 15). The fourth treatment category was taxol plus radiation, which had 27 groups as per combined radiation dose plus taxol dose concentration and as per pre-treatment timing sequence of taxol before radiation (n = 135). Mice were sacrificed 24 h after taxol or radiation or combined administration using ether anesthesia. The cells were then dropped on two labeled slides, flamed, air dried, and stained in 7% Giemsa; 20-30 well-spread mitotic metaphases were analyzed for each animal; the cells with chromosome breaks, acentric fragments, and rearrangements were evaluated on x1,000 magnification with light microscope (Zeiss axioplan). The mitotic index was determined by counting the number of mitotic cells among 1,000 cells per animal. Differences between groups were evaluated with Student's t-test statistically. Taxol caused a dose-dependent increase in chromosomal aberrations (P = 0.027). Similarly, radiation caused a dose-dependent increase in chromosomal aberrations (P = 0.003) and decreased mitotic index (P = 0.002). In combination, there were a small enhancements at the 40 mg/kg taxol dose level and at 0.25 and 0.5 Gy radiation doses in the 48 h group. However, an increase in chromosomal aberrations was observed after 48 hours of taxol exposure

  2. Molecular recognition of taxol by microtubules. Kinetics and thermodynamics of binding of fluorescent taxol derivatives to an exposed site.

    PubMed

    Díaz, J F; Strobe, R; Engelborghs, Y; Souto, A A; Andreu, J M

    2000-08-25

    We have determined the kinetic scheme and the reaction rates of binding to microtubules of two fluorescent taxoids, 7-O-[N-(4'-fluoresceincarbonyl)-l-alanyl]Taxol (Flutax-1) and 7-O-[N-(2,7-difluoro-4'-fluoresceincarbonyl)-l-alanyl]Taxol (Flutax-2). Flutax-1 and Flutax-2 bind to microtubules with high affinity (K(a) approximately 10(7) m(-1), 37 degrees C). The binding mechanism consists of a fast bimolecular reaction followed by at least two monomolecular rearrangements, which were characterized with stopped-flow techniques. The kinetic constants of the bimolecular reaction were 6.10 +/- 0.22 x 10(5) m(-1) s(-1) and 13.8 +/- 1.8 x 10(5) m(-1) s(-1) at 37 degrees C, respectively. A second slow binding step has been measured employing the change of fluorescence anisotropy of the probe. The reversal of this reaction is the rate-limiting step of dissociation. A third step has been detected using small angle x-ray scattering and involves a 2-nm increase in the diameter of microtubules. It is suggested that the first step entails the binding of the Taxol moiety and the second a relative immobilization of the fluorescent probe. The equilibrium and some kinetic measurements required the use of stabilized cross-linked microtubules, which preserved taxoid binding. The results indicate that the Taxol binding site is directly accessible, in contrast with its location at lumen in the current model of microtubules. An alternative structural model is considered in which the binding site is located between protofilaments, accessible from the microtubule surface.

  3. Engineering isoprenoid biosynthesis in Artemisia annua L. for the production of taxadiene: a key intermediate of taxol.

    PubMed

    Li, Meiya; Jiang, Fusheng; Yu, Xiangli; Miao, Zhiqi

    2015-01-01

    Taxadiene is the first committed precursor to paclitaxel, marketed as Taxol, arguably the most important anticancer agent against ovarian and breast cancer. In Taxus, taxadiene is directly synthesized from geranylgeranyl diphosphate (GGPP) that is the common precursor for diterpenoids and is found in most plants and microbes. In this study, Artemisia annua L., a Chinese medicinal herb that grows fast and is rich in terpenoids, was used as a genetic engineering host to produce taxadiene. The TXS (taxadiene synthase) gene, cloned from Taxus and inserted into pCAMBIA1304, was transformed into Artemisia annua L. using the Agrobacterium tumefaciens-mediated method. Thirty independent transgenic plants were obtained, and GC-MS analysis was used to confirm that taxadiene was produced and accumulated up to 129.7 μg/g dry mass. However, the high expression of TXS did not affect plant growth or photosynthesis in transgenic Artemisia annua L. It is notable that artemisinin is produced and stored in leaves and most taxadiene accumulated in the stem of transgenic Artemisia annua L., suggesting a new way to produce two important compounds in one transgenic plant: leaves for artemisinin and stem for taxadiene. Overall, this study demonstrates that genetic engineering of the taxane biosynthetic pathway in Artemisia annua L. for the production of taxadiene is feasible.

  4. 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.

  5. Nab-paclitaxel: a flattering facelift.

    PubMed

    Viúdez, A; Ramírez, N; Hernández-García, I; Carvalho, F L; Vera, R; Hidalgo, M

    2014-12-01

    The application of nanotechnology in oncology has increased the efficacy and efficiency of some cytotoxic agents. The paradigm in this field is nab-paclitaxel, a soluble form of paclitaxel that is linked to albumin nanoparticles. The development of nanotechnology as a delivery system for paclitaxel has provided better pharmacokinetic and pharmacodynamic characteristics, neutralizing its hydrophobicity. This procedure significantly improves the treatment of metastatic breast cancer compared to conventional paclitaxel-based therapies, including other type of cancers such as metastatic pancreatic cancer, stage IIIB-IV non-small cell lung cancer (NSCLC) and metastatic melanoma. In these last cases, significant differences were found in primary end-points for patients treated with nab-paclitaxel-based chemotherapy compared to those treated with conventional treatments. The application of nanotechnology in cancer treatment may also improve the efficacy of other known drugs, as a result of improved pharmacokinetic and pharmacodynamic profiles, similarly to paclitaxel.

  6. Evaluation of the efficacy of paclitaxel with curcumin combination in ovarian cancer cells

    PubMed Central

    Liu, Zeng; Zhu, Yuan-Yuan; Li, Zhao-Yuan; Ning, Si-Qing

    2016-01-01

    The aim of the present study was to evaluate the efficacy of paclitaxel combined with curcumin (CUR) against drug resistance in ovarian cancer cells. PLGA-phospholipid-PEG nanoparticles were prepared using the nano precipitation method. The size and morphology of the nanoparticles were determined using a transmission electron microscope and particle size analyzer. The encapsulation efficiency of nanoparticles was determined using the ultrafiltration centrifugation method. The dialysis method was used to study the release of PLGA-phospholipid-PEG nanoparticles. ADM was used to induce the A2780 cell line (human ovarian cancer cell line) to establish the model of the multidrug-resistant (MDR) cell line, and the protein activity of P-glycoprotein (P-gp) in the A2780 cell line and A2780/ADM resistant cell line was determined using western blot analysis. The results showed that, the prepared nanoparticles were uniform in size, with a size of approximately 100 nm, and round in shape. Additionally, the nanoparticles had a more gentle and slow release than the free drug release. The results of the protein trace printing experiment showed that the P-gp content of the drug-resistant cell line was significantly reduced by the CUR nanoparticles. In conclusion, PLGA-phospholipid nanoparticles containing taxol and CUR have improved solubility and stability together with a slow release effect. In addition, CUR was able to overcome the MDR of tumor cells by elevating the paclitaxel concentration in the tumor cells to improve the antitumor activity of this combination. PMID:27895754

  7. Novel thermo-sensitive core-shell nanoparticles for targeted paclitaxel delivery

    NASA Astrophysics Data System (ADS)

    Li, Yuanpei; Pan, Shirong; Zhang, Wei; Du, Zhuo

    2009-02-01

    Novel thermo-sensitive nanoparticles self-assembled from poly(N,N-diethylacrylamide- co-acrylamide)-block-poly(γ-benzyl L-glutamate) were designed for targeted drug delivery in localized hyperthermia. The lower critical solution temperature (LCST) of nanoparticles was adjusted to a level between physiological body temperature (37 °C) and that used in local hyperthermia (about 43 °C). The temperature-dependent performances of the core-shell nanoparticles were systemically studied by nuclear magnetic resonance (NMR), circular dichroism (CD), fluorescence spectroscopy, dynamic light scattering (DLS), and atom force microscopy (AFM). The mean diameter of the nanoparticles increased slightly from 110 to 129 nm when paclitaxel (PTX), a poorly water-soluble anti-tumor drug, was encapsulated. A stability study in bovine serum albumin (BSA) solution indicated that the PTX loaded nanoparticles may have a long circulation time under physiological environments as the LCST was above physiological body temperature and the shell remained hydrophilic at 37 °C. The PTX release profiles showed thermo-sensitive controlled behavior. The proliferation inhibiting activity of PTX loaded nanoparticles was evaluated against Hela cells in vitro, compared with Taxol (a formulation of paclitaxel dissolved in Cremophor EL and ethanol). The cytotoxicity of PTX loaded nanoparticles increased obviously when hyperthermia was performed. The nanoparticles synthesized here could be an ideal candidate for thermal triggered anti-tumor PTX delivery system.

  8. Cytotoxic and anti-angiogenic paclitaxel solubilized and permeation-enhanced by natural product nanoparticles

    PubMed Central

    Liu, Zhijun; Zhang, Fang; Koh, Gar Yee; Dong, Xin; Hollingsworth, Javoris; Zhang, Jian; Russo, Paul S.; Yang, Peiying; Stout, Rhett W.

    2014-01-01

    Paclitaxel (PTX) is one of the most potent intravenous chemotherapeutic agents to date, yet an oral formulation has been problematic due to its low solubility and permeability. Using the recently discovered solubilizing properties of rubusoside (RUB), we investigated this unique PTX-RUB formulation. Paclitaxel was solubilized by RUB in water to levels of 1.6 to 6.3 mg/mL at 10 to 40% weight/volume. These, nanomicellar, PTX-RUB complexes were dried to a powder which was subsequently reconstituted in physiologic solutions. After 2.5 hrs in gastric fluid 85 to 99% of PTX-RUB remained soluble, while 79 to 96% remained soluble in intestinal fluid. The solubilization of PTX was mechanized by the formation of water-soluble spherical nanomicelles between PTX and RUB with an average diameter of 6.6 nm. Compared with Taxol®, PTX-RUB nanoparticles were nearly four times more permeable in Caco-2 cell monocultures. In a side-by-side comparison with DMSO-solubilized PTX, PTX-RUB maintained the same level of cytotoxicity against three human cancer cell lines with IC50 values ranging from 4 nM to 20 nM. Additionally, tubular formation and migration of HUVECs were inhibited at levels as low as 5 nM. These chemical and biological properties demonstrated by the PTX-RUB nanoparticles may improve oral bioavailability and enable further pharmacokinetic, toxicologic, and efficacy investigations. PMID:25243454

  9. Combined Delivery of Let-7b MicroRNA and Paclitaxel via Biodegradable Nanoassemblies for the Treatment of KRAS Mutant Cancer.

    PubMed

    Dai, Xin; Fan, Wei; Wang, Yingzhe; Huang, Lijie; Jiang, Ying; Shi, Lei; Mckinley, DeAngelo; Tan, Wen; Tan, Chalet

    2016-02-01

    In the present study, we synthesized a novel cationic copolymer composed of polyethylene glycol 5000 (PEG5K), vitamin E (VE), and diethylenetriamine (DET) at 1:4:20 molar ratio. The resulting PEG5K-VE4-DET20 copolymer formed nanoassemblies when mixed with the neutral PEG5K-VE4 copolymer at 1:8 weight ratio, which were investigated as the nanocarriers for combined delivery of paclitaxel and let-7b mimic. We found that the PEG5K-VE4-DET20 nanoassemblies could entrap paclitaxel for an extended period and burst release the drug in the presence of cathepsin B, demonstrating the biodegradability of the copolymers. At N/P ratio of 12:1, the PEG5K-VE4-DET20 nanoassemblies formed stable polyplexes with let-7b mimic, which were efficiently taken up by tumor cells and underwent endosomal escape. In non-small cell lung cancer A549 cells that harbor mutant KRAS, paclitaxel and let-7b mimic-loaded nanoassemblies (N-PTX/let-7b) markedly potentiated the cytotoxicity of paclitaxel, induced apoptosis, and diminished the invasiveness of tumor cells. In mice bearing subcutaneous A549 xenografts, intravenous administration of N-PTX/let-7b retarded tumor growth more efficaciously than Taxol. Our study demonstrates the promise of the PEG5K-VE4-DET20 nanoassemblies for concurrent delivery of hydrophobic drugs and miRNA mimics.

  10. Effects of Taxol on Regeneration in a Rat Sciatic Nerve Transection Model

    PubMed Central

    Hsu, Shih-Tien; Yao, Chun-Hsu; Hsu, Yuan-Man; Lin, Jia-Horng; Chen, Yung-Hsiang; Chen, Yueh-Sheng

    2017-01-01

    Recent studies describe taxol as a candidate treatment for promoting central nerve regeneration. However, taxol has serious side effects including peripheral neurotoxicity, and little information is known about the effect of taxol on peripheral nerve regeneration. We investigated the effects of taxol on regeneration in a rat sciatic nerve transection model. Rats were divided into four groups (n = 10): normal saline (i.p.) as the control, Cremophor EL vehicle, and 2 or 6 mg/kg of taxol in the Cremophor EL solution (four times in day-2, 4, 6, and 8), respectively. We evaluated neuronal electrophysiology, animal behaviour, neuronal connectivity, macrophage infiltration, location and expression levels of calcitonin gene-related peptide (CGRP), and expression levels of both nerve growth factors and immunoregulatory factors. In the high-dose taxol group (6 mg/kg), neuronal electrophysiological function was significantly impaired. Licking latencies were significantly changed while motor coordination was unaffected. Neuronal connectivity, macrophage density, and expression levels of CGRP was dramatically reduced. Expression levels of nerve growth factors and immunoregulatory factors was also reduced, while it was increased in the low-dose taxol group (2 mg/kg). These results indicate that taxol can modulate local inflammatory conditions, impair nerve regeneration, and impede recovery of a severe peripheral nerve injury. PMID:28181572

  11. Polymer-based paclitaxel-eluting coronary stents. Clinical results in de novo lesions.

    PubMed

    Chieffo, Alaide; Colombo, Antonio

    2004-03-01

    Drug-eluting stents (DES) represent one of the fastest-growing fields in interventional cardiology today. Paclitaxel (Taxol) is a potent antiproliferative agent that shifts the microtubule equilibrium toward assembly, favoring the formation of abnormally stable microtubules with blockage of the cell cycle in G2/M phases. A series of clinical trials (TAXUS I through VI) have been designed to test the safety and the efficacy of polymer- based paclitaxel-eluting stents (Taxus, Boston Scientific, Natick, MA, USA) at the dosage 1 microg/mm(2) in a variety of clinical settings. Except for TAXUS III and TAXUS V-ISR, in the TAXUS program de novo lesions have been evaluated. Two different release kinetics were evaluated: slow-release (SR) and moderate- release (MR) formulation. Very encouraging preliminary results also come from the "real world" data on Taxus SR stent collected in the "Web-based taxus Intercontinental obServational Data TransitiOnal registry prograM" (the WISDOM Registry) and in the "Real Life Polymer-Based Paclitaxel Registry" (the Real Life PBPaclitaxel Registry). The remarkable positive results obtained from the randomized trials offer the interventional cardiologist another effective option (besides the Cypher stent, Cordis a J & J, Warren, NJ, USA) to treat patients with a DES. This fact may certainly drive the competition and, ultimately, lower the cost. The final answer will probably come from the ongoing registries and prospective trials versus coronary artery bypass grafting (CABG), which will reveal the real impact of this new technology on everyday practice.

  12. Live-Cell Analysis of Mitotic Spindle Formation in Taxol-Treated Cells

    PubMed Central

    Hornick, Jessica E.; Bader, Jason R.; Tribble, Emily K.; Trimble, Kayleigh; Breunig, J. Scott; Halpin, Elizabeth S.; Vaughan, Kevin T.; Hinchcliffe, Edward H.

    2009-01-01

    Taxol functions to suppress the dynamic behavior of individual microtubules, and induces multipolar mitotic spindles. However, little is known about the mechanisms by which taxol disrupts normal bipolar spindle assembly in vivo. Using live imaging of GFP-α tubulin expressing cells, we examined spindle assembly after taxol treatment. We find that as taxol-treated cells enter mitosis, there is a dramatic redistribution of the microtubule network from the centrosomes to the cell cortex. As they align there, the cortical microtubules recruit NuMA to their embedded ends, followed by the kinesin motor HSET. These cortical microtubules then bud off to form cytasters, which fuse into multipolar spindles. Cytoplasmic dynein and dynactin do not re-localize to cortical microtubules, and disruption of dynein/dynactin interactions by over-expression of p50 “dynamitin” does not prevent cytaster formation. Taxol added well before spindle poles begin to form induces multipolarity, but taxol added after nascent spindle poles are visible—but before NEB is complete—results in bipolar spindles. Our results suggest that taxol prevents rapid transport of key components, such as NuMA, to the nascent spindle poles. The net result is loss of mitotic spindle pole cohesion, microtubule re-distribution, and cytaster formation. PMID:18481305

  13. Molecular and biomolecular-based nanomaterials: Tubulin and taxol as molecular constituents

    NASA Astrophysics Data System (ADS)

    Castro Carmona, Javier Servando

    The new field of protein-based nano-technology takes advantage of the complex interactions between proteins to form unique structures with properties that cannot be achieved with traditional components. Microtubules (MTs), self assembled proteinaceous hollow filaments, offer promise in the development of MT-based nano-systems. The compelling need for the controlled assembly of 3D MT arrays is the fundamental motivation for the first part of this research. We report on the morphology of MTs grown in a crowded environment in the form of high viscosity fluids containing agarose and a novel process that enables the assembly of MTs supported by gel-based 3D scaffolds. Our research on MTs and their interaction with other molecules lead us to discover extraordinary spherulitic structures that changed the course of the project. The novel subject situate us into a complicated dilemma that question the nature of MT asters reported in experiments carried out in cells. The second part of this research is focused in the crystallization of Taxol, a MT stabilizing molecule used as anti-cancer drug. It was confirmed via fluorescent and differential interference contrast microscopy that Taxol crystals can be decorated with fluorescent proteins and fluorochromes without perturbing their morphology. We used theoretical calculations to further investigate Taxol-fluorescent agent interactions. Furthermore, the crystallization of Taxol was studied in pure water, aqueous solutions containing tubulin proteins and tubulin-containing agarose gels. We demonstrated that tubulin is able to heterogeneously nucleate Taxol spherulites. To explain the formation of tubulin-Taxol nuclei a new, secondary Taxol-binding site within the tubulin heterodimer is suggested. Results presented in this work are important for in vivo and in vitro microtubule studies due to the possibility of mistaking these Taxol spherulites for microtubule asters. Thus, we are confirming the need for careful interpretation of

  14. In vitro cell cultures obtained from different explants of Corylus avellana produce Taxol and taxanes

    PubMed Central

    Bestoso, Federica; Ottaggio, Laura; Armirotti, Andrea; Balbi, Alessandro; Damonte, Gianluca; Degan, Paolo; Mazzei, Mauro; Cavalli, Francesca; Ledda, Bernardetta; Miele, Mariangela

    2006-01-01

    Background Taxol is an effective antineoplastic agent, originally extracted from the bark of Taxus brevifolia with a low yield. Many attempts have been made to produce Taxol by chemical synthesis, semi-synthesis and plant tissue cultures. However, to date, the availability of this compound is not sufficient to satisfy the commercial requirements. The aim of the present work was to produce suspension cell cultures from plants not belonging to Taxus genus and to verify whether they produced Taxol and taxanes. For this purpose different explants of hazel (Corylus avellana species) were used to optimize the protocol for inducing in vitro callus, an undifferentiated tissue from which suspension cell cultures were established. Results Calli were successfully induced from stems, leaves and seeds grown in various hormone concentrations and combinations. The most suitable callus to establish suspension cell cultures was obtained from seeds. Media recovered from suspension cell cultures contained taxanes, and showed antiproliferative activity on human tumour cells. Taxol, 10-deacetyltaxol and 10-deacetylbaccatin III were the main taxanes identified. The level of Taxol recovered from the media of hazel cultures was similar to that found in yew cultures. Moreover, the production of taxanes in hazel cell cultures increased when elicitors were used. Conclusion Here we show that hazel cell cultures produce Taxol and taxanes under controlled conditions. This result suggests that hazel possesses the enzymes for Taxol production, which until now was considered to be a pathway particular to Taxus genus. The main benefit of producing taxanes through hazel cell cultures is that hazel is widely available, grows at a much faster rate in vivo, and is easier to cultivate in vitro than yew. In addition, the production of callus directly from hazel seeds shortens the culture time and minimizes the probability of contamination. Therefore, hazel could become a commercial source of Taxol and

  15. 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(ε-caprolactone) hydrophobic core based on self-assembly of poly(ε-caprolactone)–poly(ethylene glycol)–poly(ε-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

  16. PEG-Farnesylthiosalicylate Conjugate as a Nanomicellar Carrier for Delivery of Paclitaxel

    PubMed Central

    Zhang, Xiaolan; Lu, Jianqin; Huang, Yixian; Zhao, Wenchen; Li, Jiang; Gao, Xiang; Venkataramanan, Raman; Sun, Min; Stolz, Donna D.; Zhang, Lin; Li, Song

    2013-01-01

    S-trans, trans-farnesylthiosalicylic acid (FTS) is a synthetic small molecule that acts as a potent and especially nontoxic Ras antagonist. It inhibits both oncogenically activated Ras and growth factor receptor-mediated Ras activation, resulting in the inhibition of Ras-dependent tumor growth. In this work, a FTS conjugate with polyethylene glycol (PEG) through a labile ester linkage, PEG5K-FTS2(L), was developed. PEG5K-FTS2 conjugate readily forms micelles in aqueous solutions with a critical micelle concentration of 0.68 μM and hydrophobic drugs such as paclitaxel (PTX) could be effectively loaded into these particles. Both drug-free and PTX- loaded micelles were spherical in shape with a uniform size of 20 ~ 30 nm. The release of PTX from PTX-loaded PEG5K-FTS2 micelles was significantly slower than that from Taxol formulation. In vitro cytotoxicity studies with several tumor cell lines showed that PEG5K-FTS2(L) was comparable to FTS in antitumor activity. Western immunoblotting showed that total Ras levels were downregulated in several cancer cell lines treated with FTS or PEG5K-FTS2(L). The micellar formulation of PTX exhibited more in vitro cytotoxic activity against several tumor cell lines compared with free PTX, suggesting a possible synergistic effect between the carrier and the codelivered drug. The anti-tumor activity of the PTX loaded PEG5K-FTS2(L) micelles in a syngeneic murine breast cancer model was found to be significantly higher than that of Taxol, which may be attributed to their preferential tumor accumulation and a possible synergistic effect between PEG5K-FTS2 carrier and loaded PTX. PMID:23425093

  17. Bile salt liposomes for enhanced lymphatic transport and oral bioavailability of paclitaxel.

    PubMed

    Zhang, Bin; Xue, Aiying; Zhang, Chen; Yu, Jinlong; Chen, Wen; Sun, Deqing

    2016-06-01

    Paclitaxel (PTX), a BCS class IV drug that is characterized by its poor solubility and is a substrate for P-glycoprotein, is one of the most widely used antineoplastic agents. However, oral administration of PTX for chemotherapy is highly challenging. The aim of this study was to develop bile-salt liposomes (BS-Lips) to enhance the absorption of PTX and thus improve its therapeutic outcome. The BS-Lips were prepared by the thin-film hydration method and characterized in terms of particle size and morphology. Drug release and in vitro stability in simulated gastrointestinal fluids and in media of different pH values were evaluated, as well as in vivo performance, including antitumor activity and pharmacokinetics in rats, with the plasma concentrations determined by a HPLC method. The PTX-loaded BS-Lips were successfully prepared with a diameter of approximately 150 nm and an entrapment efficiency of greater than 90 percent. Moreover, the BS-Lips were not affected by gastrointestinal enzymes or pH alternation, as evident from the unchanged particle size and the drug retained in BS-Lips after 6 h incubation. The insertion of bile salt into the lipid layer of liposomes increased the lymphatic transport of PTX by twofold. Importantly, BS-Lips increased the oral bioavailability of PTX by 2.5 and 4-fold, respectively, compared with conventional liposomes (Lips) and Taxol (free drug), thereby displaying a better inhibition of tumor growth that was similar to the group injected intravenously with Taxol. In conclusion, the BS-Lips represent promising vehicles for the oral delivery of PTX, thereby enabling an intravenous-to-oral switch for cancer chemotherapy.

  18. Development of paclitaxel-loaded liposomal nanocarrier stabilized by triglyceride incorporation

    PubMed Central

    Hong, Soon-Seok; Choi, Ju Yeon; Kim, Jong Oh; Lee, Mi-Kyung; Kim, So Hee; Lim, Soo-Jeong

    2016-01-01

    Studies have highlighted the challenge of developing injectable liposomes as a paclitaxel (PTX) carrier, a challenge attributable to the limitations in liposomal stability caused by PTX loading. Poor stability of PTX-loaded liposomes is caused by PTX-triggered aggregation or fusion of liposomal membranes and is exacerbated in the presence of PEGylated lipid. In the present study, the effect of triglyceride incorporation on the stability of PTX-loaded/PEGylated liposomes was explored. Incorporation of a medium chain triglyceride Captex 300 into saturated phosphatidylcholine (PC)-based liposomes (1,2-dimyristoyl-sn-glycero-3-phosphocholine [DMPC]:cholesterol [CHOL]:N-(Carbonyl-methoxypolyethyleneglycol 2000)-1, 2-distearoyl-sn-glycero-3-phospho-ethanolamine [PE-PEG]), produced a fine, homogeneous, and membrane-filterable PTX-loaded liposomes fulfilling the requirement of an injectable lipid formulation. Triglyceride incorporation also greatly inhibited the time-dependent leakage of PTX from saturated PC-based liposomes, which appears to be mediated by the inhibition of liposome fusion. In contrast, triglyceride incorporation induced the destabilization and PTX leakage of unsaturated PC-based liposomes, indicating the opposite effect of triglyceride depending on the fluidity status of PC constituting the liposomal membrane. PTX release profile and the in vitro and in vivo anticancer efficacy of triglyceride-incorporated DMPC:CHOL:PE-PEG liposomes were similar to Taxol® while the toxicity of liposomal PTX was significantly lower than that of Taxol. Taken together, triglyceride incorporation provided an injectable PTX formulation by functioning as a formulation stabilizer of PEGylated/saturated PC-based liposomes. PMID:27660440

  19. 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

  20. LPS and Taxol activate Lyn kinase autophosphorylation in Lps(n), but not in Lpsd), macrophages.

    PubMed Central

    Henricson, B. E.; Carboni, J. M.; Burkhardt, A. L.; Vogel, S. N.

    1995-01-01

    BACKGROUND: The anti-tumor agent, Taxol, has been shown in murine macrophages to stimulate tumor necrosis factor (TNF), modulate TNF receptors, induce a large panel of immediate-early genes, and induce protein tyrosine phosphorylation indistinguishably from LPS. These data, coupled with the finding that lipid A antagonists block Taxol-induced stimulation, support the hypothesis that these two structurally unrelated compounds activate a common, receptor-associated signaling apparatus. A very early event in LPS signaling of human monocytes is activation of lyn kinase activity. We therefore sought to evaluate the activation of lyn kinase by LPS and Taxol in LPS-responsive (Lps(n)) and LPS-hyporesponsive (Lps(d)) macrophages. MATERIALS AND METHODS: C3H/OuJ (Lps(n)) and C3H/HeJ (Lps(d)) macrophages were stimulated by LPS or Taxol. Cell lysates were subjected to immunoprecipitation with anti-lyn antibody, gel electrophoresis, and in vitro kinase assays. Autoradiography and Phosphor-Imager analysis were carried out to detect incorporation of 32P into lyn protein. RESULTS: Within seconds of stimulation, LPS and Taxol induce in Lps(n) macrophages a depression of autophosphorylation, followed within minutes by autophosphorylation of both p53 and p56 lyn species. Lps(d) macrophages respond to LPS and Taxol with the initial decrease in activity, but fail to respond to LPS with autophosphorylation, and respond only to a limited extent upon Taxol stimulation. Tyrosine phosphatase inhibitors exerted inhibitory effects on LPS stimulation of lyn autophosphorylation. CONCLUSIONS: Decreased lyn kinase activity within seconds and autophosphorylation within minutes of LPS or Taxol stimulation in Lps(n) macrophages strongly supports the hypothesis that LPS and Taxol share a common signaling pathway. The finding that C3H/HeJ macrophages respond to LPS and Taxol with a normal depression of lyn activity, but fail to autophosphorylate lyn normally in response to LPS or Taxol, suggests that

  1. 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.

  2. Paclitaxel in a novel formulation containing less Cremophor EL as first-line therapy for advanced breast cancer: a phase II trial.

    PubMed

    Chao, Ta-Chung; Chu, Zyting; Tseng, Ling-Ming; Chiou, Tzeon-Jye; Hsieh, Ruey-Kuen; Wang, Wei-Shu; Yen, Chueh-Chuan; Yang, Muh-Hwa; Hsiao, Liang-Tsai; Liu, Jin-Hwang; Chen, Po-Min

    2005-03-01

    Paclitaxel (Taxol) is formulated in 50% Cremophor EL (CrEL)/absolute ethanol for clinical use. In order to reduce vehicle-related side effects, Genetaxyl was developed to have paclitaxel formulated in a solution containing lesser amounts of CrEL and ethanol plus 2 other solvents. The purpose of the study was to evaluate the efficacy and safety of Genetaxyl as first-line therapy to treat breast cancer patients. Patients with newly diagnosed stage III (N = 8) or IV (N = 10), or recurrent (N = 11) breast cancer received single-agent Genetaxyl at 175 mg/m(2) administered in a 3-h infusion every 3 weeks for 3-6 cycles. A total of 148 cycles were delivered to 29 patients. The overall response rate was 41.4% (95% confidence interval, 23.4 to 59.2%), and that of patients with metastatic disease (N = 20) was 30%. Median survival for all patients was 32.4 months and 24.3 months for patients having metastatic disease. The toxicity profile seems favorable, especially regarding myelosuppression and myalgia/arthralgia. No severe hypersensitivity reaction occurred. These phase II trial results demonstrate that a 60% reduction of CrEL by Genetaxyl's formulation does not affect the activity of paclitaxel and could allow for better control of several CrEL-related toxicities.

  3. Paclitaxel improves outcome from traumatic brain injury

    PubMed Central

    Cross, Donna J.; Garwin, Gregory G.; Cline, Marcella M.; Richards, Todd L.; Yarnykh, Vasily; Mourad, Pierre D.; Ho, Rodney J.Y.; Minoshima, Satoshi

    2016-01-01

    Pharmacologic interventions for traumatic brain injury (TBI) hold promise to improve outcome. The purpose of this study was to determine if the microtubule stabilizing therapeutic paclitaxel used for more than 20 years in chemotherapy would improve outcome after TBI. We assessed neurological outcome in mice that received direct application of paclitaxel to brain injury from controlled cortical impact (CCI). Magnetic resonance imaging was used to assess injury-related morphological changes. Catwalk Gait analysis showed significant improvement in the paclitaxel group on a variety of parameters compared to the saline group. MRI analysis revealed that paclitaxel treatment resulted in significantly reduced edema volume at site-of-injury (11.92 ± 3.0 and 8.86 ± 2.2 mm3 for saline vs. paclitaxel respectively, as determined by T2-weighted analysis; p ≤ 0.05), and significantly increased myelin tissue preservation (9.45 ± 0.4 vs. 8.95 ± 0.3, p ≤ 0.05). Our findings indicate that paclitaxel treatment resulted in improvement of neurological outcome and MR imaging biomarkers of injury. These results could have a significant impact on therapeutic developments to treat traumatic brain injury. PMID:26086366

  4. Efficacy assessment of sustained intraperitoneal paclitaxel therapy in a murine model of ovarian cancer using bioluminescent imaging.

    PubMed

    Vassileva, V; Moriyama, E H; De Souza, R; Grant, J; Allen, C J; Wilson, B C; Piquette-Miller, M

    2008-12-16

    We evaluated the pre-clinical efficacy of a novel intraperitoneal (i.p.) sustained-release paclitaxel formulation (PTX(ePC)) using bioluminescent imaging (BLI) in the treatment of ovarian cancer. Human ovarian carcinoma cells stably expressing the firefly luciferase gene (SKOV3(Luc)) were injected i.p. into SCID mice. Tumour growth was evaluated during sustained or intermittent courses of i.p. treatment with paclitaxel (PTX). In vitro bioluminescence strongly correlated with cell survival and cytotoxicity. Bioluminescent imaging detected tumours before their macroscopic appearance and strongly correlated with tumour weight and survival. As compared with intermittent therapy with Taxol, sustained PTX(ePC) therapy resulted in significant reduction of tumour proliferation, weight and BLI signal intensity, enhanced apoptosis and increased survival times. Our results demonstrate that BLI is a useful tool in the pre-clinical evaluation of therapeutic interventions for ovarian cancer. Moreover, these results provide evidence of enhanced therapeutic efficacy with the sustained PTX(ePC) implant system, which could potentially translate into successful clinical outcomes.

  5. Enhanced antitumor efficacy by cyclic RGDyK-conjugated and paclitaxel-loaded pH-responsive polymeric micelles.

    PubMed

    Gao, Yajie; Zhou, Yanxia; Zhao, Lei; Zhang, Chao; Li, Yushu; Li, Jinwen; Li, Xinru; Liu, Yan

    2015-09-01

    Cyclic RGDyK (cRGDyK)-conjugated pH-sensitive polymeric micelles were fabricated for targeted delivery of paclitaxel to prostate cancer cells based on pH-sensitive copolymer poly(2-ethyl-2-oxazoline)-poly(D,L-lactide) (PEOz-PLA) and cRGDyK-PEOz-PLA to enhance antitumor efficacy. The prepared micelles with an average diameter of about 28nm exhibited rapid release behavior at endo/lysosome pH, effectively enhanced the cytotoxicity of paclitaxel to PC-3 cells by increasing the cellular uptake, which was correlated with integrin αvβ3 expression in tumor cells. The active targeting activity of the micelles was further confirmed by in vivo real time near-infrared fluorescence imaging in PC-3 tumor-bearing nude mice. Moreover, the active targeting and pH-sensitivity endowed cRGDyK-conjugated micelles with a higher antitumor effect in PC-3 xenograft-bearing nude mice compared with unmodified micelles and Taxol with negligible systemic toxicity. Therefore, these results suggested that cRGDyK-conjugated pH-sensitive polymeric micelles may be a promising delivery system for efficient delivery of anticancer drugs to treat integrin αvβ3-rich prostate cancers.

  6. Tumor targeting by conjugation of DHA to paclitaxel.

    PubMed

    Bradley, M O; Swindell, C S; Anthony, F H; Witman, P A; Devanesan, P; Webb, N L; Baker, S D; Wolff, A C; Donehower, R C

    2001-07-06

    Targeting an anti-cancer drug to tumors should increase the Area Under the drug concentration-time Curve (AUC) in tumors while decreasing the AUC in normal cells and should therefore increase the therapeutic index of that drug. Anti-tumor drugs typically have half-lives far shorter than the cell cycle transit times of most tumor cells. Tumor targeting, with concomitant long tumor exposure times, will increase the proportion of cells that move into cycle when the drug concentration is high, which should result in more tumor cell killing. In an effort to test that hypothesis, we conjugated a natural fatty acid, docosahexaenoic acid (DHA), through an ester bond to the paclitaxel 2'-oxygen. The resulting paclitaxel fatty acid conjugate (DHA-paclitaxel) does not assemble microtubules and is non-toxic. In the M109 mouse tumor model, DHA-paclitaxel is less toxic than paclitaxel and cures 10/10 tumored animals, whereas paclitaxel cures 0/10. One explanation for the conjugate's greater therapeutic index is that the fatty acid alters the pharmacokinetics of the drug to increase its AUC in tumors and decrease its AUC in normal cells. To test that possibility, we compared the pharmacokinetics of DHA-paclitaxel with paclitaxel in CD2F1 mice bearing approximately 125 mg sc M109 tumors. The mice were injected at zero time with a bolus of either DHA-paclitaxel or paclitaxel formulated in 10% cremophor/10% ethanol/80% saline. Animals were sacrificed as a function of time out to 14 days. Tumors and plasma were frozen and stored. The concentrations of paclitaxel and DHA-paclitaxel were analyzed by LC/MS/MS. The results show that DHA targets paclitaxel to tumors: tumor AUCs are 61-fold higher for DHA-paclitaxel than for paclitaxel at equitoxic doses and eight-fold higher at equimolar doses. Likewise, at equi-toxic doses, the tumor AUCs of paclitaxel derived from i.v. DHA-paclitaxel are 6.1-fold higher than for paclitaxel derived from i.v. paclitaxel. The tumor concentration of

  7. 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.

  8. Isolation of Chinese hamster ovary cell mutants requiring the continuous presence of taxol for cell division

    PubMed Central

    1983-01-01

    Chinese hamster ovary (CHO) cell mutants resistant to the cytotoxic effects of taxol and requiring the drug for normal growth were isolated in a single step. One of these mutant cell lines, Tax-18, fails to divide in the absence of taxol; instead, the cells become larger, rounder, flatter, and multinucleated. Analysis by flow cytometry indicates that during taxol deprivation there is an accumulation of cells in G2 + M phase but that the cells are able to leak through the block in the absence of cell division and further increase their DNA content beyond the tetraploid amount. This interpretation is confirmed by karyotype analysis and by time-lapse studies that show cells rounded for mitosis two to five times longer than in wild-type cultures or in Tax-18 cultures grown in taxol. The cells finally attempt to undergo cytokinesis, fail, and spread out again, but as larger cells than before. Tax-18 has a normal growth rate and morphology when grown in taxol even at concentrations three to five times below the selecting concentration of the drug. The cells, however, have increased sensitivity to microtubule-disrupting drugs such as colcemid, griseofulvin, and D2O. The mutation for taxol auxotrophy behaves recessively in somatic cell hybridization experiments, and the phenotypic reversion rate is approximately 10(-5) in a nonmutagenized population. Both alpha- and beta-tubulin are present in apparently normal amounts and with normal electrophoretic mobilities on two- dimensional gels. The results suggest that Tax-18 lacks a factor necessary for mitosis and that taxol may be able to substitute for this factor. PMID:6134736

  9. Targeting Paclitaxel-Loaded Nanoparticles to Ovarian Cancer

    DTIC Science & Technology

    2013-05-01

    Final Targeting Paclitaxel-Loaded Nanoparticles to Ovarian Cancer Stephen B. Howell showell@ucsd.edu University of California, San Diego La Jolla, CA...None provided. 24 3 Targeting paclitaxel-loaded nanoparticles to ovarian cancer W81XWH-09-1-0223 Table of Contents...N/A 4 Title: Targeting Paclitaxel-Loaded Nanoparticles to Ovarian Cancer Grant

  10. Oral microemulsions of paclitaxel: in situ and pharmacokinetic studies.

    PubMed

    Nornoo, Adwoa O; Zheng, Haian; Lopes, Luciana B; Johnson-Restrepo, Boris; Kannan, Kurunthachalam; Reed, Rachel

    2009-02-01

    The overall goal of this study was to develop cremophor-free oral microemulsions of paclitaxel (PAC) to enhance its permeability and oral absorption. The mechanism of this enhancement, as well as characteristics of the microemulsions relevant to the increase in permeability and absorption of the low solubility, low permeability PAC was investigated. Phase diagrams were used to determine the macroscopic phase behavior of the microemulsions and to compare the efficiency of different surfactant-oil mixtures to incorporate water. The microemulsion region on the phase diagrams utilizing surfactant-myvacet oil combinations was in decreasing order: lecithin: butanol: myvacet oil (LBM, 48.5%)>centromix CPS: 1-butanol: myvacet oil (CPS, 45.15%)>capmul MCM: polysorbate 80: myvacet oil (CPM, 27.6%)>capryol 90: polysorbate 80: myvacet oil (CP-P80, 23.9%)>capmul: myvacet oil (CM, 20%). Oil-in-water (o/w) microemulsions had larger droplet sizes (687-1010 nm) than the water-in-oil (w/o) microemulsions (272-363 nm) when measured using a Zetasizer nano series particle size analyzer. Utilizing nuclear magnetic resonance spectroscopy (NMR), the self-diffusion coefficient (D) of PAC in CM, LBM and CPM containing 10% of deuterium oxide (D(2)O) was 2.24x10(-11), 1.97x10(-11) and 0.51x10(-11) m(2)/s, respectively. These values indicate the faster molecular mobility of PAC in the two w/o microemulsions (CM and LBM) than the o/w microemulsion--CPM. The in situ permeability of PAC through male CD-IGS rat intestine was 3- and 11-fold higher from LBM and CM, respectively, than that from the control clinical formulation, Taxol (CE, cremophor: ethanol) in a single pass perfusion study. PAC permeability was significantly increased in the presence of the pgp/CYP3A4 inhibitor cyclosporine A (CsA). This enhancement may be attributed to the pgp inhibitory effect of the surfactants, oil and/or the membrane perturbation effect of the surfactants. The oral disposition of PAC in CM, LBM and CPM compared

  11. Herbal Medicine Goshajinkigan Prevents Paclitaxel-Induced Mechanical Allodynia without Impairing Antitumor Activity of Paclitaxel.

    PubMed

    Bahar, Muh Akbar; Andoh, Tsugunobu; Ogura, Keisuke; Hayakawa, Yoshihiro; Saiki, Ikuo; Kuraishi, Yasushi

    2013-01-01

    Chemotherapy-induced peripheral neuropathy is a major dose-limiting side effect of commonly used chemotherapeutic agents. However, there are no effective strategies to treat the neuropathy. We examined whether Goshajinkigan, a herbal medicine, would prevent paclitaxel-induced allodynia without affecting the anticancer action in mice. Murine breast cancer 4T1 cells were inoculated into the mammary fat pad. Paclitaxel (10 and 20 mg/kg, intraperitoneal, alternate day from day 7 postinoculation) inhibited the tumor growth, and Goshajinkigan (1 g/kg, oral, daily from day 2 postinoculation) did not affect the antitumor action of paclitaxel. Mechanical allodynia developed in the inoculated region due to tumor growth and in the hind paw due to paclitaxel-induced neuropathy. Paclitaxel-induced allodynia was markedly prevented by Goshajinkigan, although tumor-associated allodynia was not inhibited by Goshajinkigan. These results suggest that Goshajinkigan prevents paclitaxel-induced peripheral neuropathy without interfering with the anti-cancer action of paclitaxel.

  12. Paclitaxel-loaded star-shaped copolymer nanoparticles for enhanced malignant melanoma chemotherapy against multidrug resistance.

    PubMed

    Su, Yongsheng; Hu, Jian; Huang, Zhibin; Huang, Yubin; Peng, Bingsheng; Xie, Ni; Liu, Hui

    2017-01-01

    Malignant melanoma (MM) is the most dangerous type of skin cancer with annually increasing incidence and death rates. However, chemotherapy for MM is restricted by low topical drug concentration and multidrug resistance. In order to surmount the limitation and to enhance the therapeutic effect on MM, a new nanoformulation of paclitaxel (PTX)-loaded cholic acid (CA)-functionalized star-shaped poly(lactide-co-glycolide) (PLGA)-D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) nanoparticles (NPs) (shortly PTX-loaded CA-PLGA-TPGS NPs) was fabricated by a modified method of nanoprecipitation. The particle size, zeta potential, morphology, drug release profile, drug encapsulation efficiency, and loading content of PTX-loaded NPs were detected. As shown by confocal laser scanning, NPs loaded with coumarin-6 were internalized by human melanoma cell line A875. The cellular uptake efficiency of CA-PLGA-TPGS NPs was higher than those of PLGA NPs and PLGA-TPGS NPs. The antitumor effects of PTX-loaded NPs were evaluated by the MTT assay in vitro and by a xenograft tumor model in vivo, demonstrating that star-shaped PTX-loaded CA-PLGA-TPGS NPs were significantly superior to commercial PTX formulation Taxol(®). Such drug delivery nanocarriers are potentially applicable to the improvement of clinical MM therapy.

  13. Paclitaxel-loaded star-shaped copolymer nanoparticles for enhanced malignant melanoma chemotherapy against multidrug resistance

    PubMed Central

    Su, Yongsheng; Hu, Jian; Huang, Zhibin; Huang, Yubin; Peng, Bingsheng; Xie, Ni; Liu, Hui

    2017-01-01

    Malignant melanoma (MM) is the most dangerous type of skin cancer with annually increasing incidence and death rates. However, chemotherapy for MM is restricted by low topical drug concentration and multidrug resistance. In order to surmount the limitation and to enhance the therapeutic effect on MM, a new nanoformulation of paclitaxel (PTX)-loaded cholic acid (CA)-functionalized star-shaped poly(lactide-co-glycolide) (PLGA)-D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) nanoparticles (NPs) (shortly PTX-loaded CA-PLGA-TPGS NPs) was fabricated by a modified method of nanoprecipitation. The particle size, zeta potential, morphology, drug release profile, drug encapsulation efficiency, and loading content of PTX-loaded NPs were detected. As shown by confocal laser scanning, NPs loaded with coumarin-6 were internalized by human melanoma cell line A875. The cellular uptake efficiency of CA-PLGA-TPGS NPs was higher than those of PLGA NPs and PLGA-TPGS NPs. The antitumor effects of PTX-loaded NPs were evaluated by the MTT assay in vitro and by a xenograft tumor model in vivo, demonstrating that star-shaped PTX-loaded CA-PLGA-TPGS NPs were significantly superior to commercial PTX formulation Taxol®. Such drug delivery nanocarriers are potentially applicable to the improvement of clinical MM therapy. PMID:28293102

  14. 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.

  15. PEG-Farnesyl Thiosalicylic Acid Telodendrimer Micelles as an Improved Formulation for Targeted Delivery of Paclitaxel

    PubMed Central

    2015-01-01

    We have recently designed and developed a dual-functional drug carrier that is based on poly(ethylene glycol) (PEG)-derivatized farnesylthiosalicylate (FTS, a nontoxic Ras antagonist). PEG5K-FTS2 readily form micelles (20–30 nm) and hydrophobic drugs such as paclitaxel (PTX) could be effectively loaded into these micelles. PTX formulated in PEG5K-FTS2 micelles showed an antitumor activity that was more efficacious than Taxol in a syngeneic mouse model of breast cancer (4T1.2). In order to further improve our PEG-FTS micellar system, four PEG-FTS conjugates were developed that vary in the molecular weight of PEG (PEG2K vs PEG5K) and the molar ratio of PEG/FTS (1/2 vs 1/4) in the conjugates. These conjugates were characterized including CMC, drug loading capacity, stability, and their efficacy in delivery of anticancer drug PTX to tumor cells in vitro and in vivo. Our data showed that the conjugates with four FTS molecules were more effective than the conjugates with two molecules of FTS and that FTS conjugates with PEG5K were more effective than the counterparts with PEG2K in forming stable mixed micelles. PTX formulated in PEG5K-FTS4 micelles was the most effective formulation in inhibiting the tumor growth in vivo. PMID:24987803

  16. Somatostatin receptor-mediated specific delivery of paclitaxel prodrugs for efficient cancer therapy.

    PubMed

    Huo, Meirong; Zhu, Qinnv; Wu, Qu; Yin, Tingjie; Wang, Lei; Yin, Lifang; Zhou, Jianping

    2015-06-01

    In this study, a novel PTX prodrug, octreotide(Phe)-polyethene glycol-paclitaxel [OCT(Phe)-PEG-PTX], was successfully synthesized and used for targeted cancer therapy. A nontargeting conjugate, mPEG-PTX, was also synthesized and used as a control. Chemical structures of OCT(Phe)-PEG-PTX and mPEG-PTX were confirmed using (1) H nuclear magnetic resonance and circular dichroism. The drug contents in both the conjugates were 12.0% and 14.0%, respectively. Compared with the parent drug (PTX), OCT(Phe)-PEG-PTX, and mPEG-PTX prodrugs showed a 20,000- and 30,000-fold increase in water solubility, respectively. PTX release from mPEG-PTX and OCT(Phe)-PEG-PTX exhibited a pH-dependent profile. Moreover, compared with mPEG-PTX, OCT(Phe)-PEG-PTX exhibited significantly stronger cytotoxicity against NCI-H446 cells (SSTR overexpression) but comparable cytotoxicity against WI-38 cells (no SSTR expression). Results of confocal laser scanning microscopy revealed that the targeting prodrug labeled with fluorescence probe was selectively taken into tumor cells via SSTR-mediated endocytosis. In vivo investigation of prodrugs in nude mice bearing NCI-H446 cancer xenografts confirmed that OCT(Phe)-PEG-PTX prodrug exhibited stronger antitumor efficacy and lower systemic toxicity than mPEG-PTX and commercial Taxol. These results suggested that OCT(Phe)-PEG-PTX is a promising anticancer drug delivery system for targeted cancer therapy.

  17. Cytotoxic and antiangiogenic paclitaxel solubilized and permeation-enhanced by natural product nanoparticles.

    PubMed

    Liu, Zhijun; Zhang, Fang; Koh, Gar Yee; Dong, Xin; Hollingsworth, Javoris; Zhang, Jian; Russo, Paul S; Yang, Peiying; Stout, Rhett W

    2015-02-01

    Paclitaxel (PTX) is one of the most potent intravenous chemotherapeutic agents to date, yet an oral formulation has been problematic because of its low solubility and permeability. Using the recently discovered solubilizing properties of rubusoside (RUB), we investigated the unique PTX-RUB formulation. PTX was solubilized by RUB in water to levels of 1.6-6.3 mg/ml at 10-40% weight/volume. These nanomicellar PTX-RUB complexes were dried to a powder, which was subsequently reconstituted in physiologic solutions. After 2.5 h, 85-99% of PTX-RUB remained soluble in gastric fluid, whereas 79-96% remained soluble in intestinal fluid. The solubilization of PTX was mechanized by the formation of water-soluble spherical nanomicelles between PTX and RUB, with an average diameter of 6.6 nm. Compared with Taxol, PTX-RUB nanoparticles were nearly four times more permeable in Caco-2 cell monocultures. In a side-by-side comparison with dimethyl sulfoxide-solubilized PTX, PTX-RUB maintained the same level of cytotoxicity against three human cancer cell lines with IC50 values ranging from 4 to 20 nmol/l. In addition, tubule formation and migration of human umbilical vein endothelial cells were inhibited at levels as low as 5 nmol/l. These chemical and biological properties demonstrated by the PTX-RUB nanoparticles may improve oral bioavailability and enable further pharmacokinetic, toxicologic, and efficacy investigations.

  18. A3 adenosine receptor agonist prevents the development of paclitaxel-induced neuropathic pain by modulating spinal glial-restricted redox-dependent signaling pathways.

    PubMed

    Janes, Kali; Esposito, Emanuela; Doyle, Timothy; Cuzzocrea, Salvatore; Tosh, Dillip K; Jacobson, Kenneth A; Salvemini, Daniela

    2014-12-01

    Chemotherapy-induced peripheral neuropathy accompanied by chronic neuropathic pain is the major dose-limiting toxicity of several anticancer agents including the taxane paclitaxel (Taxol). A critical mechanism underlying paclitaxel-induced neuropathic pain is the increased production of peroxynitrite in spinal cord generated in response to activation of the superoxide-generating enzyme, NADPH oxidase. Peroxynitrite in turn contributes to the development of neuropathic pain by modulating several redox-dependent events in spinal cord. We recently reported that activation of the Gi/Gq-coupled A3 adenosine receptor (A3AR) with selective A3AR agonists (ie, IB-MECA) blocked the development of chemotherapy induced-neuropathic pain evoked by distinct agents, including paclitaxel, without interfering with anticancer effects. The mechanism or mechanisms of action underlying these beneficial effects has yet to be explored. We now demonstrate that IB-MECA attenuates the development of paclitaxel-induced neuropathic pain by inhibiting the activation of spinal NADPH oxidase and two downstream redox-dependent systems. The first relies on inhibition of the redox-sensitive transcription factor (NFκB) and mitogen activated protein kinases (ERK and p38) resulting in decreased production of neuroexcitatory/proinflammatory cytokines (TNF-α, IL-1β) and increased formation of the neuroprotective/anti-inflammatory IL-10. The second involves inhibition of redox-mediated posttranslational tyrosine nitration and modification (inactivation) of glia-restricted proteins known to play key roles in regulating synaptic glutamate homeostasis: the glutamate transporter GLT-1 and glutamine synthetase. Our results unravel a mechanistic link into biomolecular signaling pathways employed by A3AR activation in neuropathic pain while providing the foundation to consider use of A3AR agonists as therapeutic agents in patients with chemotherapy-induced peripheral neuropathy.

  19. Automated Synthesis of 18F Analogue of Paclitaxel (PAC): [18F]Paclitaxel (FPAC)

    PubMed Central

    Kalen, Joseph D.; Hirsch, Jerry I.; Kurdziel, Karen A.; Eckelman, William C.; Kiesewetter, Dale O.

    2007-01-01

    A positron-emitting paclitaxel (PAC) derivative could allow in-vivo measurement of multidrug resistance in tumors and, therefore, predict a potential chemotherapeutic benefit to patients. [18F]Paclitaxel was produced using a 2-reaction vessel automated synthesizer followed by HPLC purification. Optimized reaction conditions resulted in radiochemical yields of 21.2 ± 9.6% at end of bombardment, radiochemical purity > 99%, and specific activity of 159 ± 43 GBq/μmol. [18F]Paclitaxel activities of 1.33 ± 0.729 GBq (n=7) were obtained in sterile, pyrogen-free solution for IV administration. PMID:17161952

  20. Phantom limb pain as a manifestation of paclitaxel neurotoxicity.

    PubMed

    Khattab, J; Terebelo, H R; Dabas, B

    2000-07-01

    Paclitaxel is a chemotherapeutic agent with activity directed against several malignancies. It has multiple adverse effects including neurotoxicity. We describe 2 patients with prior amputation who experienced phantom limb pain (PLP) after receiving paclitaxel therapy. A third patient experienced disabling neurotoxicity in the extremity of a prior ulnar nerve and tendon transposition after receiving paclitaxel. This unique syndrome should be identified as a direct causal effect of paclitaxel. In this report, we review the pathophysiology of PLP and treatment options. Physicians should be aware that PLP can occur after initiation of paclitaxel.

  1. Function of Aurora kinase A in Taxol-resistant breast cancer and its correlation with P-gp.

    PubMed

    Li, Yan; Tang, Ke; Zhang, Haijing; Zhang, Yi; Zhou, Wanqi; Chen, Xiaoguang

    2011-01-01

    Breast cancer is one of the most common malignant diseases among women. In early and metastatic breast cancer, Taxane (Taxol) is widely used as an adjuvant and neoadjuvant therapies. Although breast cancer is initially responsive to Taxol, inherent or developed resistance to Taxol often limits the efficacy of the drug. The oncogene Aurora kinase A is frequently up-regulated in human cancer, and is associated with sensitivity to chemotherapy in certain types of cancer. In the present study, we aimed to clarify the functional role of Aurora kinase A in breast cancer resistance to Taxol, and to determine the means to overcome this resistance. The correlation between the expression levels of Aurora kinase A and chemoresistance to Taxol in breast cancer cells, and resistance to Taxol in a xenograft model were demonstrated. MTT assay was performed to determine cell viability. Subsequently, the relationship of Aurora kinase A with the expression and functional role of P-gp was clarified, as well as its relationship with p-ERK2, which regulates the expression of P-gp. The expression of Aurora A was determined to be capable of enhancing the sensitivity of cells resistant to Taxol in vitro and in vivo using stable knockdown Aurora kinase A cells. We propose that this kinase may be used as a target for overcoming chemoresistance and enhancing the chemosensitivity of breast cancer to Taxol.

  2. Initial experience with paclitaxel-coated stents.

    PubMed

    Grube, Eberhard; Büllesfeld, Lutz

    2002-12-01

    Local delivery of immunosuppressive or antiproliferative agents using a drug-eluting stent is a new technology that is supposed to inhibit in-stent restenosis, thus providing a biological and mechanical solution. This technique is a very promising. To date, several agents have been used, including paclitaxel, QP-2, rapamycin, actinomycin D, dexamethason, tacrolimus, and everolimus. Several studies, published recently or still ongoing, have evaluated these drugs as to their release kinetics, effective dosage, safety in clinical practice, and benefit. These studies include: SCORE (paclitaxel derivative), TAXUS I-VI, ELUTES, ASPECT, DELIVER (paclitaxel), RAVEL, SIRIUS (sirolimus), ACTION (actinomycin), EVIDENT, PRESENT (tacrolimus), EMPEROR (dexamethason), and FUTURE (everolimus). Paclitaxel was one of the first stent-based antiproliferative agents under clinical investigation that provided profound inhibition of neointimal thickening depending on delivery duration and drug dosage. The randomized, multicenter SCORE trail (Quanam stent, paclitaxel-coated) enrolled 266 patients at 17 sites. At 6-month's follow-up, a drop of 83% in stent restenosis using the drug-eluting stent could be achieved (6.4% drug-eluting stent vs 36.9% control group), which was attributable to a remarkable decrease in intimal proliferation. Unfortunately, due to frequent stent thrombosis and side-branch occlusions, the reported 30-day MACE rate was 10.2%. The randomized TAXUS-I safety trial (BSC, NIRx, paclitaxel-coated) also demonstrated beneficial reduction of restenotic lesions at 6-month's follow-up (0% vs 10%) but was associated with the absence of thrombotic events presumably due to less drug dosage. The ongoing TAXUS II-VI trials are addressing additional insight regarding the efficacy of the TAXUS paclitaxel-eluting stent. ASPECT and ELUTES evaluated paclitaxel-coated stents (i.e., Cook and Supra G), including subgroups with different drug dosages. With respect to stent restenosis and

  3. Effect of phenylalanine on Taxol production and antioxidant activity of extracts of suspension-cultured hazel (Corylus avellana L.) cells.

    PubMed

    Bemani, Ebrahim; Ghanati, Faezeh; Rezaei, Ayatollah; Jamshidi, Mitra

    2013-07-01

    Taxol is produced by a few microorganisms and plants such as yew (Taxus sp.). Recent researches have shown that hazel (Corylus avellana L.) is also able to produce Taxol. In the present study, effects of different concentrations of phenylalanine (Phe) on the production of Taxol, antioxidant activity, and cytotoxic effects of extracts of suspension-cultured hazel cells were investigated. The cells were treated with different concentrations of Phe on day 7 of subculture and were harvested on day 14. The results showed that the amounts of Taxol and antioxidant activity were increased by increasing the phenylalanine supply. Interestingly, the cytotoxic effects of hazel cell extract were even stronger than that of pure Taxol (standard), suggesting hazel cell extract as a novel and suitable probe for treating human cancer. Application of phenylalanine to hazel cells exaggerates their effects.

  4. Nature as a remarkable chemist: a personal story of the discovery and development of Taxol.

    PubMed

    Wani, Mansukh C; Horwitz, Susan Band

    2014-05-01

    The development of a new anticancer drug with a novel structure and unique mechanism of action is an important event, especially when the drug plays a clear role in improving the outcome for cancer patients. No drug fits this description better than Taxol. However, during the early phases of its development, there was little interest in the drug, particularly in the medical community. The story of Taxol is long and fascinating, and includes many examples in which the drug could have been dropped, resulting in its antitumor activity never being available to patients. It was 21 years between the original landmark paper on the isolation and structural determination of Taxol and its approval in 1992 by the FDA for its use in the treatment of ovarian cancer.

  5. 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.

  6. Surface modification of paclitaxel-loaded tri-block copolymer PLGA- b-PEG- b-PLGA nanoparticles with protamine for liver cancer therapy

    NASA Astrophysics Data System (ADS)

    Gao, Nansha; Chen, Zhihong; Xiao, Xiaojun; Ruan, Changshun; Mei, Lin; Liu, Zhigang; Zeng, Xiaowei

    2015-08-01

    In order to enhance the therapeutic effect of chemotherapy on liver cancer, a biodegradable formulation of protamine-modified paclitaxel-loaded poly(lactide- co-glycolide)- b-poly(ethylene glycol)- b-poly(lactide- co-glycolide) (PLGA- b-PEG- b-PLGA) nanoparticles (PTX-loaded/protamine NPs) was prepared. Tri-block copolymer PLGA- b-PEG- b-PLGA was synthesized by ring-opening polymerization and characterized by 1H NMR spectroscopy and gel permeation chromatography. PTX-loaded and PTX-loaded/protamine NPs were characterized in terms of size, size distribution, zeta potential, surface morphology, drug encapsulation efficiency, and drug release. Confocal laser scanning microscopy showed that coumarin 6-loaded/protamine NPs were internalized by hepatocellular carcinoma cell line HepG2. The cellular uptake efficiency of NPs was obviously elevated after protamine modification. With commercial formulation Taxol® as the reference, HepG2 cells were also used to study the cytotoxicity of the NPs. PTX-loaded/protamine NPs exhibited significantly higher cytotoxicity than PTX-loaded NPs and Taxol® did. All the results suggested that surface modification of PTX-loaded PLGA- b-PEG- b-PLGA NPs with protamine boosted the therapeutic efficacy on liver cancer.

  7. Biodistribution and pharmacokinetics in rats and antitumor effect in various types of tumor-bearing mice of novel self-assembled gelatin-oleic acid nanoparticles containing paclitaxel.

    PubMed

    Tran, Phuong Ha-Lien; Tran, Thao Truong-Dinh; Lee, Beom-Jin

    2014-01-01

    The aim of this study was to investigate the pharmacokinetics and biodistribution in Sprague-Dawley rats, anti-tumor activity and acute toxicity in different tumor-bearing mice of novel biocompatible nanoparticles. Paclitaxel (PTX) was selected as a model drug and loaded on different tumor types and at various doses. The nanoparticles were prepared using a newly synthesized gelatin-oleic acid conjugate via self-assembly in an aqueous solution. The nanoparticles were further functionalized using folic acid (FA) as a targeting ligand for cancer. The in vivo effects of the nanoparticles were compared with the commercially available Taxol (a solution form of PTX) as a reference dosage form. The in vivo studies confirmed that nanoparticles showed improved therapeutic effects on tumors and significantly reduced the toxic effects associated with Taxol, even at the 50% lethal dose (LD50). The in vivo pharmacokinetic parameters and biodistribution of the nanoparticles containing PTX also indicated slower clearance, longer blood circulation and higher tumor selectivity. Furthermore, the functionalized nanoparticles with FA were more effective than the non-functionalized nanoparticles. Thus, the suitable properties of gelatin-oleic nanoparticles (GON) as a drug carrier and the effective targeting ligand could synergistically maximize the in vivo anti-tumor efficacy resulting in delayed tumor volume growth and hence, providing versatile strategies in cancer therapy and drug delivery.

  8. Biological evaluation of redox-sensitive micelles based on hyaluronic acid-deoxycholic acid conjugates for tumor-specific delivery of paclitaxel.

    PubMed

    Li, Jing; Yin, Tingjie; Wang, Lei; Yin, Lifang; Zhou, Jianping; Huo, Meirong

    2015-04-10

    Tumor-targeted drug delivery and microenvironment-responsive drug release are attractive strategies in cancer treatment. Our previous study demonstrated that redox-sensitive micelles based on hyaluronic acid-deoxycholic acid (HA-ss-DOCA) conjugates exhibited excellent drug-loading capacities (34.1%) for paclitaxel (PTX) and rapid drug release in response to reducing agent, glutathione. In the present study, the physicochemical and biological properties of PTX-loaded HA-ss-DOCA (PTX-HA-ss-DOCA) micelles were investigated further. The micelles have an average size of about 120 nm and a zeta potential of about -36 mV. Transmission electron microscopy and wide-angle X-ray diffraction analysis demonstrated redox-sensitive degradation of micelles in the presence of glutathione. Moreover, the encapsulated payload was effectively released from HA-ss-DOCA micelles into cytoplasm and then rapidly transported into nuclei. In vitro cytotoxicity and cell apoptosis assay further revealed that HA significantly improved the tumor-specific drug delivery of HA-ss-DOCA micelles via receptor-mediated endocytosis, while efficient intracellular drug release and transportation lead to marked inhibition of tumor cell growth, as compared to Taxol(®) and insensitive micelles. More importantly, PTX-HA-ss-DOCA micelles demonstrated superior in vivo antitumor activity compared with Taxol(®) and insensitive control, and decreased systemic toxicity. Herein we present data which provide valuable insight into the design and development of tumor-specific drug delivery systems.

  9. Distinct pose of discodermolide in taxol binding pocket drives a complementary mode of microtubule stabilization.

    PubMed

    Khrapunovich-Baine, Marina; Menon, Vilas; Verdier-Pinard, Pascal; Smith, Amos B; Angeletti, Ruth Hogue; Fiser, Andras; Horwitz, Susan Band; Xiao, Hui

    2009-12-15

    The microtubule cytoskeleton has proven to be an effective target for cancer therapeutics. One class of drugs, known as microtubule stabilizing agents (MSAs), binds to microtubule polymers and stabilizes them against depolymerization. The prototype of this group of drugs, Taxol, is an effective chemotherapeutic agent used extensively in the treatment of human ovarian, breast, and lung carcinomas. Although electron crystallography and photoaffinity labeling experiments determined that the binding site for Taxol is in a hydrophobic pocket in beta-tubulin, little was known about the effects of this drug on the conformation of the entire microtubule. A recent study from our laboratory utilizing hydrogen-deuterium exchange (HDX) in concert with various mass spectrometry (MS) techniques has provided new information on the structure of microtubules upon Taxol binding. In the current study we apply this technique to determine the binding mode and the conformational effects on chicken erythrocyte tubulin (CET) of another MSA, discodermolide, whose synthetic analogues may have potential use in the clinic. We confirmed that, like Taxol, discodermolide binds to the taxane binding pocket in beta-tubulin. However, as opposed to Taxol, which has major interactions with the M-loop, discodermolide orients itself away from this loop and toward the N-terminal H1-S2 loop. Additionally, discodermolide stabilizes microtubules mainly via its effects on interdimer contacts, specifically on the alpha-tubulin side, and to a lesser extent on interprotofilament contacts between adjacent beta-tubulin subunits. Also, our results indicate complementary stabilizing effects of Taxol and discodermolide on the microtubules, which may explain the synergy observed between the two drugs in vivo.

  10. 2-(m-Azidobenzoyl)taxol binds differentially to distinct β-tubulin isotypes

    PubMed Central

    Yang, Chia-Ping Huang; Yap, Eng-Hui; Xiao, Hui; Fiser, Andras; Horwitz, Susan Band

    2016-01-01

    There are seven β-tubulin isotypes present in distinct quantities in mammalian cells of different origin. Altered expression of β-tubulin isotypes has been reported in cancer cell lines resistant to microtubule stabilizing agents (MSAs) and in human tumors resistant to Taxol. To study the relative binding affinities of MSAs, tubulin from different sources, with distinct β-tubulin isotype content, were specifically photolabeled with a tritium-labeled Taxol analog, 2-(m-azidobenzoyl)taxol, alone or in the presence of MSAs. The inhibitory effects elicited by these MSAs on photolabeling were distinct for β-tubulin from different sources. To determine the exact amount of drug that binds to different β-tubulin isotypes, bovine brain tubulin was photolabeled and the isotypes resolved by high-resolution isoelectrofocusing. All bands were analyzed by mass spectrometry following cyanogen bromide digestion, and the identity and relative quantity of each β-tubulin isotype determined. It was found that compared with other β-tubulin isotypes, βIII-tubulin bound the least amount of 2-(m-azidobenzoyl)taxol. Analysis of the sequences of β-tubulin near the Taxol binding site indicated that, in addition to the M-loop that is known to be involved in drug binding, the leucine cluster region of βIII-tubulin contains a unique residue, alanine, at 218, compared with other isotypes that contain threonine. Molecular dynamic simulations indicated that the frequency of Taxol-accommodating conformations decreased dramatically in the T218A variant, compared with other β-tubulins. Our results indicate that the difference in residue 218 in βIII-tubulin may be responsible for inhibition of drug binding to this isotype, which could influence downstream cellular events. PMID:27651486

  11. An Italian cost-effectiveness analysis of paclitaxel albumin (nab-paclitaxel) versus conventional paclitaxel for metastatic breast cancer patients: the COSTANza study

    PubMed Central

    Lazzaro, Carlo; Bordonaro, Roberto; Cognetti, Francesco; Fabi, Alessandra; De Placido, Sabino; Arpino, Grazia; Marchetti, Paolo; Botticelli, Andrea; Pronzato, Paolo; Martelli, Elisa

    2013-01-01

    Purpose Paclitaxel albumin (nab-paclitaxel) is a nanoparticle albumin-bound paclitaxel formulation aimed at increasing therapeutic index in metastatic breast cancer. When compared to conventional paclitaxel, nab-paclitaxel has a reported longer time to progression, higher response, lower incidence of neutropenia, no need for premedication, shorter time of administration, and in pretreated metastatic breast cancer patients, extended overall survival. This study investigates the cost-effectiveness of nab-paclitaxel versus conventional paclitaxel for pretreated metastatic breast cancer patients in Italy. Materials and methods A Markov model with progression-free, progressed, and dead states was developed to estimate costs, outcomes, and quality adjusted life years over 5 years from the Italian National Health Service viewpoint. Patients were assumed to receive nab-paclitaxel 260 mg/m2 three times weekly or conventional paclitaxel 175 mg/m2 three times weekly. Data on health care resource consumption was collected from a convenience sample of five Italian centers. Resources were valued at Euro (€) 2011. Published utility weights were applied to health states to estimate the impact of response, disease progression, and adverse events on quality adjusted life years. Three sensitivity analyses tested the robustness of the base case incremental cost-effectiveness ratio (ICER). Results and conclusion Compared to conventional paclitaxel, nab-paclitaxel gains an extra 0.165 quality adjusted life years (0.265 life years saved) and incurs additional costs of €2506 per patient treated. This translates to an ICER of €15,189 (95% confidence interval: €11,891–€28,415). One-way sensitivity analysis underscores that ICER for nab-paclitaxel remains stable despite varying taxanes cost. Threshold analysis shows that ICER for nab-paclitaxel exceeds €40,000 only if cost per mg of conventional paclitaxel is set to zero. Probabilistic sensitivity analysis highlights that nab-paclitaxel

  12. D-α-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-α-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

  13. Well-Defined Redox-Sensitive Polyethene Glycol-Paclitaxel Prodrug Conjugate for Tumor-Specific Delivery of Paclitaxel Using Octreotide for Tumor Targeting.

    PubMed

    Yin, Tingjie; Wu, Qu; Wang, Lei; Yin, Lifang; Zhou, Jianping; Huo, Meirong

    2015-08-03

    A redox-sensitive prodrug, octreotide(Phe)-polyethene glycol-disulfide bond-paclitaxel [OCT(Phe)-PEG-ss-PTX], was successfully developed for targeted intracellular delivery of PTX. The formulation emphasizes long-circulation-time polymer-drug conjugates, combined targeting based on EPR and OCT-receptor mediated endocytosis, sharp redox response, and programmed drug release. The nontargeted redox-sensitive prodrug, mPEG-ss-PTX, and the targeted insensitive prodrug, OCT(Phe)-PEG-PTX, were also synthesized as controls. These polymer-PTX conjugates, structurally confirmed by 1H NMR, exhibited approximately 23,000-fold increase in water solubility over parent PTX and possessed drug contents ranging from 11% to 14%. The redox-sensitivity of the objective OCT(Phe)-PEG-ss-PTX prodrug was verified by in vitro PTX release profile in simulated reducing conditions, and the SSTRs-mediated endocytosis was demonstrated by flow cytometry and confocal laser scanning microscopy analyses. Consequently, compared with mPEG-PTX and OCT(Phe)-PEG-PTX, the OCT(Phe)-PEG-ss-PTX exhibited much stronger cyotoxicity and apoptosis-inducing ability against NCI-H446 tumor cells (SSTRs overexpression), whereas a comparable cytotoxicity of these prodrugs was obtained against WI-38 normal cells (no SSTRs expression). Finally, the in vivo studies on NCI-H466 tumor-bearing nude mice demonstrated that the OCT(Phe)-PEG-ss-PTX possessed superior tumor-targeting ability and antitumor activity over mPEG-PTX, OCT(Phe)-PEG-PTX and Taxol, as well as minimal collateral damage. This targeted redox-sensitive polymer-PTX prodrug system is promising in tumor therapy.

  14. Monoclonal Antibodies Attached to Carbon Nanotube Transistors for Paclitaxel Detection

    NASA Astrophysics Data System (ADS)

    Lee, Wonbae; Lau, Calvin; Richardson, Mark; Rajapakse, Arith; Weiss, Gregory; Collins, Philip; UCI, Molecular Biology; Biochemistry Collaboration; UCI, Departments of Physics; Astronomy Collaboration

    Paclitaxel is a naturally-occurring pharmaceutical used in numerous cancer treatments, despite its toxic side effects. Partial inhibition of this toxicity has been demonstrated using weakly interacting monoclonal antibodies (3C6 and 8A10), but accurate monitoring of antibody and paclitaxel concentrations remains challenging. Here, single-molecule studies of the kinetics of antibody-paclitaxel interactions have been performed using single-walled carbon nanotube field-effect transistors. The devices were sensitized with single antibody attachments to record the single-molecule binding dynamics of paclitaxel. This label-free technique recorded a range of dynamic interactions between the antibody and paclitaxel, and it provided sensitive paclitaxel detection for pM to nM concentrations. Measurements with two different antibodies suggest ways of extending this working range and uncovering the mechanistic differences among different antibodies.

  15. Complete Regression of Xenograft Tumors upon Targeted Delivery of Paclitaxel via Π-Π 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 π-π 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 μCT-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 π-π 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

  16. 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

  17. Evaluation of magnetic- and carbon-based nano-adsorbents application in pre-purification of paclitaxel from needles of Taxus baccata

    NASA Astrophysics Data System (ADS)

    Naghavi, M. R.; Motamedi, E.; Nasiri, J.; Alizadeh, H.; Fattahi Moghadam, M. R.; Mashouf, A.

    2015-01-01

    In this investigation, the proficiency of a number of magnetic carbon-based nano-adsorbents is evaluated in pre-purification process of the crude paclitaxel extract obtained from fresh needles of yew tree ( Taxus baccata L.). The effectiveness and removal ability of color and impurities from crude extracts, for three novel candidate nano-adsorbents (i.e., Fe3O4 nanoparticles (Fe3O4Nps), graphite oxide (GO), and their hybrids Fe3O4Nps/GO) are compared with commercial graphite in three different solvents. In general, both HPLC and UV-Vis spectroscopy results demonstrate that in less polar solvent (i.e., dichloromethane), the adsorption is greatly affected by the electrostatic attractions, while in more polar solvents (i.e., acetone and ethanol) π-π electron interactions taking place between adsorbent and adsorbate are the most dominant factors in sorption. Considering decolorization efficiency, purity of taxol, recovery and reusability of adsorbents, Fe3O4Nps/GO (50 g/L) in dichloromethane is selected as the best medium for pre-purification of paclitaxel. Additionally, in kinetic studies the sorption equilibrium can be reached within 120 min, and the experimental data are well fitted by the pseudo-second-order model. The Langmuir sorption isotherm model correlates well with the sorption equilibrium data for the crude extract concentration (500-2,000 mg/L). Our findings display promising applications of Fe3O4Nps/GO, as a cost-effective nano-adsorbent, to provide a suitable vehicle toward improvement of paclitaxel pre-purification.

  18. Improving paclitaxel delivery: in vitro and in vivo characterization of PEGylated polyphosphoester-based nanocarriers.

    PubMed

    Zhang, Fuwu; Zhang, Shiyi; Pollack, Stephanie F; Li, Richen; Gonzalez, Amelia M; Fan, Jingwei; Zou, Jiong; Leininger, Sarah E; Pavía-Sanders, Adriana; Johnson, Rachel; Nelson, Laura D; Raymond, Jeffery E; Elsabahy, Mahmoud; Hughes, Dennis M P; Lenox, Mark W; Gustafson, Tiffany P; Wooley, Karen L

    2015-02-11

    Nanomaterials have great potential to offer effective treatment against devastating diseases by providing sustained release of high concentrations of therapeutic agents locally, especially when the route of administration allows for direct access to the diseased tissues. Biodegradable polyphosphoester-based polymeric micelles and shell cross-linked knedel-like nanoparticles (SCKs) have been designed from amphiphilic block-graft terpolymers, PEBP-b-PBYP-g-PEG, which effectively incorporate high concentrations of paclitaxel (PTX). Well-dispersed nanoparticles physically loaded with PTX were prepared, exhibiting desirable physiochemical characteristics. Encapsulation of 10 wt% PTX, into either micelles or SCKs, allowed for aqueous suspension of PTX at concentrations up to 4.8 mg/mL, as compared to <2.0 μg/mL for the aqueous solubility of the drug alone. Drug release studies indicated that PTX released from these nanostructures was defined through a structure-function relationship, whereby the half-life of sustained PTX release was doubled through cross-linking of the micellar structure to form SCKs. In vitro, physically loaded micellar and SCK nanotherapeutics demonstrated IC50 values against osteosarcoma cell lines, known to metastasize to the lungs (CCH-OS-O and SJSA), similar to the pharmaceutical Taxol formulation. Evaluation of these materials in vivo has provided an understanding of the effects of nanoparticle structure-function relationships on intratracheal delivery and related biodistribution and pharmacokinetics. Overall, we have demonstrated the potential of these novel nanotherapeutics toward future sustained release treatments via administration directly to the sites of lung metastases of osteosarcoma.

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

    PubMed

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

    2013-08-15

    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.

  20. Improved anti-glioblastoma efficacy by IL-13Rα2 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 α2 (IL-13Rα2) 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 < 0.001). The in vitro anti-proliferation evaluation showed that the IC50 were 146 ng/ml and 349 ng/ml of Pep-NP-PTX and NP-PTX, respectively. The in vivo fluorescent image results indicated that Pep-NP had higher specificity and efficiency in intracranial tumor accumulation. Following intravenous administration, Pep-NP-PTX could enhance the distribution of PTX in vivo glioma section, 1.98, 1.91 and 1.53-fold over that of NP-PTX group after 0.5, 1 and 4 h, respectively. Pep-NP-PTX could improve the anti-glioma efficacy with a median survival time of 32 days, which was significantly longer than that of PTX-NP (23 days) and Taxol® (22 days). In conclusion, Pep-NP-PTX is a potential targeting drug delivery system for glioma treatment. PMID:26567528

  1. Improved cytotoxicity of paclitaxel loaded in nanosized lipid carriers by intracellular delivery

    NASA Astrophysics Data System (ADS)

    Miao, Jing; Du, Yongzhong; Yuan, Hong; Zhang, Xingguo; Li, Qian; Rao, Yuefeng; Zhao, Mengdan; Hu, Fuqiang

    2015-01-01

    Nanosized lipid carriers (NLC) can improve the limited drug-loading (DL) capacity and drug expulsion during storage, and adjust the drug release profile of solid lipid nanoparticles (SLN). In this study, Paclitaxel (PTX)-loaded NLC were prepared by solvent diffusion method using monostearin as solid lipid and oleic acid (OA) as liquid lipid matrix. The blank NLC with different OA content (the size range was from 89.5 ± 7.4 to 160.2 ± 34.6 nm) showed smaller size than the blank SLN (the size was 272.7 ± 43.6 nm), while the PTX-loaded NLC (the size range was from 481.3 ± 29.8 to 561.7 ± 38.3 nm) showed little bigger size, higher DL capacity, and faster drug in vitro release rate comparing with SLN (the size was 437.3 ± 68.2 nm). The 50 % cellular growth inhibitions (IC50) of PTX-loaded NLC with 0, 5, 10, and 20 wt % OA were 0.92 ± 0.06, 0.69 ± 0.04, 0.25 ± 0.02, and 0.12 ± 0.02 µg mL-1, respectively, while the IC50 of TaxolTM was 1.72 ± 0.09 µg mL-1. For analyzing cellular drug effect, cellular uptakes of fluorescent NLC and intracellular drug concentration were investigated. As the incorporation of OA into solid lipid matrix could accelerate both the cellular uptake and the PTX delivery, loaded by NLC, the cytotoxicity of PTX could be enhanced, and further enhanced by increasing OA content in NLC.

  2. Deoxycholic acid-modified chitooligosaccharide/mPEG-PDLLA mixed micelles loaded with paclitaxel for enhanced antitumor efficacy.

    PubMed

    Jiang, Chengjun; Wang, Hangxiang; Zhang, Xiaomin; Sun, Zhibin; Wang, Feng; Cheng, Jun; Xie, Haiyang; Yu, Bo; Zhou, Lin

    2014-11-20

    Poly(ethylene glycol) (PEG) as a block in polymeric micelles can prolong circulation life and reduce systemic clearance but decrease the cellular uptake. To overcome this limitation, a mixed micelle composed of deoxycholic acid-modified chitooligosaccharide (COS-DOCA) and methoxy poly(ethylene glycol)-polylactide copolymer (mPEG-PDLLA) was designed to load paclitaxel (PTX). The PTX-loaded mixed micelles was prepared by nanoprecipitation method with high drug-loading efficiency of 8.03% and encapsulation efficiency of 97.09% as well as small size (∼40 nm) and narrow size distribution. COS-DOCA/mPEG-PDLLA mixed micelles exhibited the sustained release property. Due to the positive charge and bioadhesive property of COS-DOCA, the cellular uptake of PTX in mixed micelles was higher in cancer cells but lower in macrophage cells compared to the mPEG-PDLLA micelles. The systemic toxicity of PTX in mixed micelles was much lower than Taxol using zebrafish as a toxicological model. Furthermore, the PTX-loaded COS-DOCA/mPEG-PDLLA mixed micelles can prolong the blood circulation time of PTX and enhance the antitumor efficacy in A549 lung xenograft model. Our findings indicate that COS-DOCA/mPEG-PDLLA mixed micelles could be a potential vehicle for enhanced delivery of anticancer drugs.

  3. Enhanced oral absorption of paclitaxel in N-deoxycholic acid-N, O-hydroxyethyl chitosan micellar system.

    PubMed

    Li, Hong; Huo, Meirong; Zhou, Jianping; Dai, Yindi; Deng, Yaping; Shi, Xiangjie; Masoud, Jumah

    2010-11-01

    The overall goal of this study was to develop a micellar system of paclitaxel (PTX) to enhance its oral absorption. An amphiphilic chitosan derivative, N-deoxycholic acid-N, O-hydroxyethyl chitosan (DHC), was synthesized and characterized by FTIR, (1)H NMR, elemental analysis, and X-ray diffraction (XRD) techniques. The degree of substitution (DS) of hydroxyethyl group and deoxycholic acid group ranged from 89.5-114.5% and 1.11-8.17%, respectively. The critical micelle concentration (CMC) values of DHC decreased from 0.26 to 0.16 mg/mL as the DS of deoxycholic acid group increased. PTX was successfully loaded in DHC micelles with a high drug loading (31.68 ± 0.14%) and entrapment efficiency (77.57 ± 0.51%). The particle size of PTX-loaded DHC micelles ranged from 203.35 ± 2.19 to 236.70 ± 3.40 nm as the DS of deoxycholic acid group increased. After orally administration of PTX-loaded DHC micelles, the bioavailability was threefold compared with that of an orally dosed Taxol®. The single-pass intestinal perfusion studies (SPIP) showed that the intestinal absorption of micelles was via endocytosis involving a saturable process and a p-glycoprotein (P-gp)-independent way. All these indicated that the DHC micelles might be a promising tool for oral delivery of poorly water-soluble drugs.

  4. Enhanced antiproliferative and apoptosis effect of paclitaxel-loaded polymeric micelles against non-small cell lung cancers.

    PubMed

    Zhang, Xiao-Ying; Zhang, Yang-De

    2015-07-01

    Amphiphilic copolymer monomethoxy poly(ethylene glycol)-poly(caprolactone)-D-α-tocopheryl polyethylene glycol 1000 succinate (MPEG-PCL-TPGS) was prepared. In the present study, MPEG-PCL-TPGS was used as a novel nanovehicle for the delivery of paclitaxel (PTX) in the treatment of resistant lung cancers. The PTX-loaded MPEG-PCL-TPGS (PTX/MPT) micelles exhibited sustained release profile (168 h) with accelerated drug release at acidic pH conditions. The blank polymeric micelles showed excellent biocompatibility with cell viability of >85 %, making it suitable for all in vivo applications. PTX/MPT micelles displayed superior cytotoxicity in A-549 lung cancer cells than that of free PTX. The selective delivery of PTX to cancer cells resulted in enhanced cancer cell death. The PTX/MPT micelles showed higher cellular uptake via endocytosis pathways. The PTX-bound micelles preferentially arrested the cells at G2/M phase and showed a marked increase in sub G1 cell population (∼ 20 %). The pharmacokinetic study revealed a long blood circulation for PTX/MPT micelles. Finally, micellar formulation showed a remarkable tumor suppression effect in resistant A549/Taxol cells bearing xenograft nude mice along with no toxicity profile. The results indicate that the PTX-loaded biocompatible polymeric nanosystem could act as a potential delivery system for the treatment of lung carcinomas.

  5. Toward an ab initio potential energy surface for paclitaxel: A C-13 isoserine side chain conformational study.

    PubMed

    Janicki, Maciej; Lozynski, Marek

    2017-05-01

    (S)-3-Methyl-3-butenyl-(2R,3S)-N-benzoyl-3-phenylisoserinate is used as a model of the C-13 side chain, an essential subunit for the cytotoxicity of the diterpenoid paclitaxel, a chemotherapeutic drug used in the treatment of cancer. The potential energy surface (PES), calculated using a density functional theory method (DFT) and refined with MP2 single-point energy calculations, based on B3LYP geometries, was evaluated. Twelve intramolecular hydrogen bond patterns were identified for 103 in vacuo conformers. The most stable subset of these structures was found to have cooperative NH ⋯ OH ⋯ OC(O) motifs and six minima of importance that lie within 1.2kcal/mol of each other. The oxygen atoms of the ester groups effectively compete with the 2'-oxygen as a proton acceptor of NH to form stable internal hydrogen bonded structures. Additionally, the conventional OH ⋯ OC(N) hydrogen bond, which is represented by almost one third of the located minima, donates a number of stable conformers. However, the PES of the conformationally flexible model is highly dependent on the polarity of the environment. For example, the OH ⋯ OC(N) feature dominates over the cooperative motif in water. The side chain of the experimental T-taxol shaped structure agrees nicely with the respective theoretical lowest energy minimum. The π-π interactions of the phenyl rings and ethylene moiety of this structure are also discussed.

  6. Synthetic low-density lipoprotein (sLDL) selectively delivers paclitaxel to tumor with low systemic toxicity

    PubMed Central

    Su, Hai-Tao; Li, Xin; Liang, De-Sheng; Qi, Xian-Rong

    2016-01-01

    Low density lipoprotein (LDL), which is a principal carrier for the delivery of cholesterol, has been used as a great candidate for the delivery of drugs to tumor based on the great requirements for cholesterol of many cancer cells. Mimicking the structure and composition of LDL, we designed a synthetic low-density lipoprotein (sLDL) to encapsulate paclitaxel-alpha linolenic acid (PALA) for tumor therapy. The PALA loaded sLDL (PALA-sLDL) and PALA-loaded microemulsion (PALA-ME, without the binding domain for LDLR) displayed uniform sizes with high drug loading efficiency (> 90%). In vitro studies demonstrated PALA-sLDL exhibited enhanced cellular uptake capacity and better cytotoxicity to LDLR over-expressed U87 MG cells as compared to PALA-ME. The uptake mechanisms of PALA-sLDL were involved in a receptor mediated endocytosis and macropinocytosis. Furthermore, the in vivo biodistribution and tumor growth inhibition studies of PALA-sLDL were investigated in xenograft U87 MG tumor-bearing mice. The results showed that PALA-sLDL exhibited higher tumor accumulation than PALA-ME and superior tumor inhibition efficiency (72.1%) compared to Taxol® (51.2%) and PALA-ME (58.8%) but with lower toxicity. These studies suggested that sLDL is potential to be used as a valuable carrier for the selective delivery of anticancer drugs to tumor with low systemic toxicity. PMID:27409176

  7. The Development and Maintenance of Paclitaxel-induced Neuropathic Pain Require Activation of the Sphingosine 1-Phosphate Receptor Subtype 1*

    PubMed Central

    Janes, Kali; Little, Joshua W.; Li, Chao; Bryant, Leesa; Chen, Collin; Chen, Zhoumou; Kamocki, Krzysztof; Doyle, Timothy; Snider, Ashley; Esposito, Emanuela; Cuzzocrea, Salvatore; Bieberich, Erhard; Obeid, Lina; Petrache, Irina; Nicol, Grant; Neumann, William L.; Salvemini, Daniela

    2014-01-01

    The ceramide-sphingosine 1-phosphate (S1P) rheostat is important in regulating cell fate. Several chemotherapeutic agents, including paclitaxel (Taxol), involve pro-apoptotic ceramide in their anticancer effects. The ceramide-to-S1P pathway is also implicated in the development of pain, raising the intriguing possibility that these sphingolipids may contribute to chemotherapy-induced painful peripheral neuropathy, which can be a critical dose-limiting side effect of many widely used chemotherapeutic agents. We demonstrate that the development of paclitaxel-induced neuropathic pain was associated with ceramide and S1P formation in the spinal dorsal horn that corresponded with the engagement of S1P receptor subtype 1 (S1PR1)-dependent neuroinflammatory processes as follows: activation of redox-sensitive transcription factors (NFκB) and MAPKs (ERK and p38) as well as enhanced formation of pro-inflammatory and neuroexcitatory cytokines (TNF-α and IL-1β). Intrathecal delivery of the S1PR1 antagonist W146 reduced these neuroinflammatory processes but increased IL-10 and IL-4, potent anti-inflammatory/neuroprotective cytokines. Additionally, spinal W146 reversed established neuropathic pain. Noteworthy, systemic administration of the S1PR1 modulator FTY720 (Food and Drug Administration-approved for multiple sclerosis) attenuated the activation of these neuroinflammatory processes and abrogated neuropathic pain without altering anticancer properties of paclitaxel and with beneficial effects extended to oxaliplatin. Similar effects were observed with other structurally and chemically unrelated S1PR1 modulators (ponesimod and CYM-5442) and S1PR1 antagonists (NIBR-14/15) but not S1PR1 agonists (SEW2871). Our findings identify for the first time the S1P/S1PR1 axis as a promising molecular and therapeutic target in chemotherapy-induced painful peripheral neuropathy, establish a mechanistic insight into the biomolecular signaling pathways, and provide the rationale for the

  8. Bioreactor engineering as an enabling technology to tap biodiversity. The case of taxol.

    PubMed

    Shuler, M L

    1994-11-30

    One barrier to exploiting the chemical and genetic diversity in nature is the difficulty of cultivating many organisms in a controlled manner. In some cases it is difficult to achieve growth. In many others, good growth is achieved, but the expression of the organism's genetic potential to make a desired product is not realized. The thesis of this paper is that a coupling of an understanding of reactor engineering principles with the basic knowledge of the biology is often necessary to circumvent these barriers. In many cases the construction of appropriate cultivation systems is a necessary step to better understanding of cellular physiology. In some cases the chemical of interest is of high social utility and comes from a natural source that is uncommon and difficult to secure. In these cases a method of controlled cultivation becomes a prerequisite for commercial exploitation. These points were illustrated using a taxol. Taxol is an important new anticancer drug whose development has been greatly impeded by supply problems. Taxol has been derived from the park of the pacific yew tree, a process that kills the tree. The pacific yew is a relatively uncommon tree and very slow growing. One alternative to the natural source is plant cell culture. Such cultures can produce significant levels of taxol with substantial release into the medium. Taxane products not observed in typical extracts from field-grown plants can be found in cell cultures, indicating the potential unmasking of pathways. These cultures are quite responsive to changes in their environments as illustrated by the summary of initial observations. With regard to natural compounds, biochemical engineers can play a major role in the capture and preservation of producing systems, in the discovery of useful compounds, and in providing the basis for commercial production of natural compounds.

  9. Ultrasound-potentiated salicylic acid-induced physiological effects and production of taxol in hazelnut (Corylus avellana L.) cell culture.

    PubMed

    Rezaei, Ayatollah; Ghanati, Faezeh; Behmanesh, Mehrdad; Mokhtari-Dizaji, Manijhe

    2011-11-01

    Effects of ultrasound (US), salicylic acid (SA) and their combined use on the growth and secondary metabolite production of suspension-cultured Corylus avellana cells were investigated. The cultures were treated with US (40 kHz) for short periods of time (2, 3, 5 and 10 min) and SA (25 and 50 mg L(-1)). Results showed that although phenolic content of the cells was significantly increased under exposure to treatments, flavonoids content significantly decreased. Taxol biosynthesis was improved by all treatments. US exposure increased the extracellular, cell-associated and total taxol yield three-, 1.6-, and two-fold compared with that of the control, respectively. SA at all levels was more effective than US in stimulating cell-associated and total taxol production. Combined treatment of US and SA at 50 mg L(-1) resulted in the most improvement in total taxol production, which was about seven times higher than that of the US, three times higher than that of the SA and 14 times higher than that of the control. The results suggest a synergism between US and SA in enhancing taxol production by hazelnut cells.

  10. Anti-proliferative effect of fungal taxol extracted from Cladosporium oxysporum against human pathogenic bacteria and human colon cancer cell line HCT 15

    NASA Astrophysics Data System (ADS)

    Gokul Raj, K.; Manikandan, R.; Arulvasu, C.; Pandi, M.

    2015-03-01

    Cladosporium oxysporum a new taxol producing endophytic fungus was identified and production of taxol were characterized using UV-visible spectroscopy (UV-vis), high-performance liquid chromatography (HPLC), infrared (IR) nuclear magnetic resonance spectroscopy (NMR (13C and 1H)) and liquid chromatography-mass spectrometry (LC-MS). The taxol biosynthetic gene (dbat) was evaluated for new taxol producing fungus. Antibacterial activity against six different human pathogenic bacteria was done by agar well diffusion method. The anticancer efficacy of isolated fungal taxol were also evaluated in human colon cancer cell HCT 15 by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), cytotoxicity and nuclear morphology analysis. The isolated fungal taxol showed positive towards biosynthetic gene (dbat) and effective against both Gram positive as well as Gram negative. The fungal taxol suppress growth of cancer cell line HCT 15 with an IC50 value of 3.5 μM concentration by 24 h treatment. Thus, the result reveals that C. oxysporum could be a potential alternative source for production of taxol and have antibacterial as well as anticancer properties with possible clinical applications.

  11. PEG-PE/phosphatidylcholine mixed immunomicelles specifically deliver encapsulated taxol to tumor cells of different origin and promote their efficient killing.

    PubMed

    Gao, Z; Lukyanov, A N; Chakilam, A R; Torchilin, V P

    2003-02-01

    Mixed micelles were prepared from poly(ethyleneglycol)-distearyl phosphoethanolamine (PEG2000-PE) and egg phosphatidylcholine. The micelles were covalently modified with the nucleosome-specific monoclonal antibody 2C5 known to recognize and bind a variety of tumor cells via their surface-bound nucleosomes. Covalent attachment of 2C5 antibody was performed via a micelle-incorporated PEG-PE with the distal terminus of the PEG block activated with p-nitrophenylcarbonyl group (pNP-PEG-PE). Micelle surface-attached 2C5 antibody maintained its specific activity. 2C5-targeted immunomicelles were able to carry more than 3 wt% of taxol. Taxol-loaded immunomicelles specifically recognized tumor cell lines of several types. The cytotoxicity of 2C5-targeted taxol-loaded immunomicelles in a cell culture model was much higher when compared with free taxol or taxol in non-targeted micelles.

  12. [Level of evidence for therapeutic drug monitoring for paclitaxel].

    PubMed

    Gerritsen-van Schieveen, Pauline; Royer, Bernard

    2010-01-01

    Paclitaxel is an anticancer drug which displays pharmacokinetic properties which can lead to therapeutic drug monitoring requirement. The most effective pharmacokinetic parameter seems to be the time during which the plasma concentration is over 0.05 micromol/L. However, this target needs to be validated with new weekly schedules of administration. These reasons lead to consider the level of evidence of therapeutic drug monitoring of paclitaxel as potentially useful.

  13. Novel thermo-sensitive hydrogel system with paclitaxel nanocrystals: High drug-loading, sustained drug release and extended local retention guaranteeing better efficacy and lower toxicity.

    PubMed

    Lin, Zhiqiang; Gao, Wei; Hu, Hongxiang; Ma, Kun; He, Bing; Dai, Wenbing; Wang, Xueqing; Wang, Jiancheng; Zhang, Xuan; Zhang, Qiang

    2014-01-28

    As a sustained-release drug depot for localized cancer treatment, in situ thermo-sensitive hydrogel has attracted increasing interests. However, it is currently a big challenge to achieve high drug-loading, sustained and stable drug release, as well as long-term local drug retention simultaneously. We hypothesized that this goal could be accomplished by incorporating the nanocrystals (NCs) of a hydrophobic drug, such as paclitaxel (PTX) into the thermo-sensitive hydrogel (Gel). Hence, a PTX-NCs-Gel system has been constructed with thermo-sensitive Pluronic F127, using PTX-NCs and Taxol® as the controls. Besides, near infra-red agent DiR was used to prepare PTX/DiR hybrid NCs and PTX/DiR hybrid NCs-Gel as well. As a result, this hydrogel system could achieve a high drug loading of PTX up to 3 mg/ml while stabilize the particle size of PTX-NCs significantly compared with PTX-NCs alone. There was no obvious interaction between PTX-NCs and F127. Obviously, PTX/DiR hybrid NCs-Gel presented better localized retention capacity and a much longer retention time in murine 4T1 tumor than PTX/DiR hybrid NCs and Cremophor/ethanol solubilized DiR in vivo. With a linear elimination, over 10% of PTX still remained inside of mouse 4T1 tumor 20 days after intratumoral dosing of PTX-NCs-Gel. Importantly, PTX-NCs exhibited comparable cytotoxity against 4T1 and MCF-7 cells in vitro compared with Taxol®, which could ensure the efficacy of PTX-NCs-Gel. After intratumoral injection, PTX-NCs-Gel was found to be the most effective among all PTX formulations in the 4T1 and MCF-7 tumor-bearing mice models, with much lower system toxicity than Taxol®. In general, it is believed that the novel thermo-sensitive hydrogel system prepared in this study with PTX-NCs affords high drug-loading, sustained and stable drug release, as well as extended drug retention inside of tumor, which results in better therapy and lower toxicity.

  14. Cremophor-induced lupus erythematosus-like reaction with taxol administration: a case report and review of the literature.

    PubMed

    Pham, Anthony Q; Berz, David; Karwan, Patricia; Colvin, Gerald A

    2011-09-01

    We report the first case of Cremophor EL-induced cutaneous lupus erythematosus-like reaction in a 40-year-old female undergoing treatment for breast cancer. There have been four reported cases of paclitaxel- and four cases of docetaxel-induced cutaneous lupus reactions in the published literature [Dasanu and Alexandrescu: South Med J 2008;101:1161-1162; Adachi and Horikawa: J Dermatol 2007;34:473-476; Lortholary et al: Presse Med 2007;36:1207-1208; Chen et al: J Rheumatol 2004;31:818-820]. Our patient developed findings of a cutaneous lupus-like reaction with administration of paclitaxel which was subsequently discontinued. She was re-challenged with albumin-bound paclitaxel which has no Cremophor EL compound in its formulation. This administration of albumin-bound paclitaxel did not induce further reaction. She did not develop a cutaneous lupus erythematosus-like reaction with three other subsequent administrations of albumin-bound paclitaxel. The diagnosis of lupus-like reaction in our patient was made based on the development of a malar butterfly rash sparing the nasolabial folds, the appearance of this rash in context of recently receiving treatments with paclitaxel, resolution of the rash after discontinuing the paclitaxel, and the presence of autoimmune antibodies in the patient's serum which resolved with discontinuation of the paclitaxel. This is the first case demonstrating that the cause of the cutaneous lupus erythematosus-like reaction is not likely due to the taxane component of paclitaxel but the chemical composition of Cremophor EL. If the chemotherapeutic agent was causing the reaction then the same reaction should be seen by albumin-bound paclitaxel. We propose that previously reported lupus reactions may actually be due to Cremophor EL, which consists of polyoxyethylated castor oil, and not the chemotherapeutic agent itself.

  15. Phototriggerable 2′,7-Caged Paclitaxel

    PubMed Central

    Gropeanu, Radu A.; Baumann, Hella; Ritz, Sandra; Mailänder, Volker; Surrey, Thomas; del Campo, Aránzazu

    2012-01-01

    Three different variants of photoactivatable caged paclitaxel (PTX) have been synthesized and their bioactivity was characterized in in vitro assays and in living cells. The caged PTXs contain the photoremovable chromophore 4,5-dimethoxy-2-nitrobenzyloxycarbonyl (Nvoc) attached to position C7, C2' and to both of these positions via a carbonate bond. Single caged PTXs remained biologically active even at low dosages. Double caging was necessary in order to fully inhibit its activity and to obtain a phototriggerable PTX that can be applied successfully at commonly used concentrations. Irradiation of solutions containing the double caged PTX allowed dose-dependent delivery of functional PTX. Light-triggered stabilization of microtubule assemblies in vitro and in vivo by controlled light exposure of tubulin solutions or cell cultures containing caged PTX was demonstrated. Short light exposure under a fluorescence microscope allowed controlled delivery of free PTX during imaging. PMID:22970137

  16. Janus nanogels of PEGylated Taxol and PLGA-PEG-PLGA copolymer for cancer therapy

    NASA Astrophysics Data System (ADS)

    Wei, Jun; Wang, Huaimin; Zhu, Meifeng; Ding, Dan; Li, Dongxia; Yin, Zhinan; Wang, Lianyong; Yang, Zhimou

    2013-09-01

    Nanogels are promising carriers for the delivery of anti-cancer drugs for cancer therapy. We report in this study on a Janus nanogel system formed by mixing a prodrug of Taxol (PEGylated Taxol) and a copolymer of PLGA-PEG-PLGA. The Janus nanogels have good stability over months in aqueous solutions and the freeze-dried powder of nanogels can be re-dispersed instantly in aqueous solutions. The Janus nanogels show an enhanced inhibition effect on tumor growth in a mice breast cancer model probably due to the enhanced uptake of the nano-sized materials by the EPR effect. What is more, the nanogels can also serve as physical carriers to co-deliver other anti-cancer drugs such as doxorubicin to further improve the anti-cancer efficacy. The results obtained from H&E staining and TUNEL assay also support the observation of tumor growth inhibition. These results suggest the potential of this novel delivery system for cancer therapy.Nanogels are promising carriers for the delivery of anti-cancer drugs for cancer therapy. We report in this study on a Janus nanogel system formed by mixing a prodrug of Taxol (PEGylated Taxol) and a copolymer of PLGA-PEG-PLGA. The Janus nanogels have good stability over months in aqueous solutions and the freeze-dried powder of nanogels can be re-dispersed instantly in aqueous solutions. The Janus nanogels show an enhanced inhibition effect on tumor growth in a mice breast cancer model probably due to the enhanced uptake of the nano-sized materials by the EPR effect. What is more, the nanogels can also serve as physical carriers to co-deliver other anti-cancer drugs such as doxorubicin to further improve the anti-cancer efficacy. The results obtained from H&E staining and TUNEL assay also support the observation of tumor growth inhibition. These results suggest the potential of this novel delivery system for cancer therapy. Electronic supplementary information (ESI) available: Synthesis and characterization of compounds, dynamic time sweep, H

  17. Determination of paclitaxel in hyaluronic acid polymeric micelles in rat blood by protein precipitation-micelle breaking method: application to a pharmacokinetic study.

    PubMed

    Liu, Yanhua; Sun, Jin; Lian, He; Li, Xin; Cao, Wen; Bai, Liming; Wang, Yongjun; He, Zhonggui

    2013-09-15

    An efficient dissociation of paclitaxel (PTX) from the home-made hyaluronic acid-octadecyl (HA-C18) polymeric micelles formulation in rat blood could not be achieved using previously published PTX analytical methods. So, we intended to develop the micelle-breaking method to determine paclitaxel encapsulated in the HA-C18 polymeric micelles in blood. The pretreatment method of blood samples adopted a simple one-step protein precipitation-micelle breaking process with methanol as micelle-breaking and protein precipitant solvents for complete extraction of PTX from HA-C18 micelles in blood. The micelle breaking efficiency of methanol was as high as 97.7%. Separation was carried out by gradient elution on an Acquity UPLC BEH C18 column with a mobile phase consisting of water (containing 0.1% formic acid) and acetonitrile. A total single run time was as short as 3.0min. Detection was performed by triple-quadrupole mass spectrometry with positive electrospray ionization as source ionization in multiple-reaction monitoring mode at m/z 854.3→286.2 for PTX and m/z 808.5→527.3 for the internal standard, docetaxel. The method demonstrated good linearity at the concentrations ranging from 20 to 10,000ng/mL. The intra- and inter-day relative standard deviations were less than 9.9%. The mean extraction recoveries of PTX and IS were 94.7% and 87.5%, respectively. In summary, the methanol protein precipitation-micelle breaking method could extract PTX completely from the polymeric micelles. Finally, the method was successfully applied to a pharmacokinetic study of the home-made PTX-loaded HA-C18 polymeric micelles and Taxol solution after intravenous administration in rats.

  18. Induction of the sexual stage of Pestalotiopsis microspora, a taxol-producing fungus.

    PubMed

    Metz, A M; Haddad, A; Worapong, J; Long, D M; Ford, E J; Hess, W M; Strobel, G A

    2000-08-01

    Pestalotiopsis microspora, isolate NE-32, is an endophyte of the Himalayan yew (Taxus wallichiana) that produces taxol, an important chemotherapeutic drug used in the treatment of breast and ovarian cancers. Conditions were determined to induce the perfect stage (teleomorph) of this organism in the laboratory as a critical first step to study inheritance of taxol biosynthetic genes. The perfect stage of Pestalotiopsis microspora NE-32 forms in a period of 3-6 weeks on water agarose with dried yew needles at 16-20 degrees C with 12 h of light per day. Morphological analysis of the teleomorph and sequencing of the 18S rDNA indicates that Pestalosphaeria hansenii is the perfect stage of Pestalotiopsis microspora. Only certain plants (e.g. yews, some pines, pecan, oat and some barley cultivars) allow the production of perithecia. Exhaustive methylene chloride extraction of yew (Taxus cuspidata) needles removes their capacity to induce production of perithecia. The methylene chloride extract is able to induce formation of perithecia by strain NE-32 in a bioassay system utilizing the sterilized sheaths of the Cholla cactus (Opuntia bigelovii) spine, indicating that a chemical compound(s) in yew stimulates the formation of the perfect stage. This hydrophobic plant compound(s) has been designated the perithecial-stimulating factor (PSF). The data suggest that plant products may play a role in regulating the biology of endophytic microbes.

  19. Transformation of taxol-stabilized microtubules into inverted tubulin tubules triggered by a tubulin conformation switch

    PubMed Central

    Ginsburg, Avi; Kohl, Phillip A.; Li, Youli; Miller, Herbert P.; Wilson, Leslie; Raviv, Uri; Choi, Myung Chul; Safinya, Cyrus R.

    2014-01-01

    Bundles of taxol-stabilized microtubules (MTs) – hollow tubules comprised of assembled αβ-tubulin heterodimers – spontaneously assemble above a critical concentration of tetravalent spermine and are stable over long times at room temperature. Here we report that at concentrations of spermine several-fold higher the MT bundles (BMT) quickly become unstable and undergo a shape transformation to bundles of inverted tubulin tubules (BITT), the outside surface of which corresponds to the inner surface of the BMT tubules. Using transmission electron microscopy and synchrotron small-angle x-ray scattering, we quantitatively determined both the nature of the BMT to BITT transformation pathway, which results from a spermine-triggered conformation switch from straight to curved in the constituent taxol-stabilized tubulin oligomers, and the structure of the BITT phase, which is formed of tubules of helical tubulin oligomers. Inverted tubulin tubules provide a platform for studies requiring exposure and availability of the inside, luminal surface of MTs to MT-targeted-drugs and MT-associated-proteins. PMID:24441880

  20. Unattached kinetochores rather than intrakinetochore tension arrest mitosis in taxol-treated cells

    PubMed Central

    Magidson, Valentin; He, Jie; Ault, Jeffrey G.; O’Connell, Christopher B.; Yang, Nachen; Tikhonenko, Irina; McEwen, Bruce F.

    2016-01-01

    Kinetochores attach chromosomes to the spindle microtubules and signal the spindle assembly checkpoint to delay mitotic exit until all chromosomes are attached. Light microscopy approaches aimed to indirectly determine distances between various proteins within the kinetochore (termed Delta) suggest that kinetochores become stretched by spindle forces and compact elastically when the force is suppressed. Low Delta is believed to arrest mitotic progression in taxol-treated cells. However, the structural basis of Delta remains unknown. By integrating same-kinetochore light microscopy and electron microscopy, we demonstrate that the value of Delta is affected by the variability in the shape and size of outer kinetochore domains. The outer kinetochore compacts when spindle forces are maximal during metaphase. When the forces are weakened by taxol treatment, the outer kinetochore expands radially and some kinetochores completely lose microtubule attachment, a condition known to arrest mitotic progression. These observations offer an alternative interpretation of intrakinetochore tension and question whether Delta plays a direct role in the control of mitotic progression. PMID:26833787

  1. Paclitaxel-loaded Polymersomes for Enhanced Intraperitoneal Chemotherapy

    PubMed Central

    Simón-Gracia, Lorena; Hunt, Hedi; Scodeller, Pablo D; Gaitzsch, Jens; Braun, Gary B; Willmore, Anne-Mari A; Ruoslahti, Erkki; Battaglia, Giuseppe; Teesalu, Tambet

    2016-01-01

    Peritoneal carcinomatosis is present in more than 60% of gastric cancer, 40% of ovarian cancer, and 35% of colon cancer patients. It is the second most common cause of cancer mortality, with a median survival of 1–3 months. Cytoreductive surgery combined with intraperitoneal chemotherapy is the current clinical treatment, but achieving curative drug accumulation and penetration in peritoneal carcinomatosis lesions remains an unresolved challenge. Here we employed flexible and pH-sensitive polymersomes for payload delivery to peritoneal gastric (MKN-45P) and colon (CT26) carcinoma in mice. Polymersomes were loaded with Paclitaxel® and in vitro drug release was studied as a function of pH and time. Paclitaxel-loaded polymersomes remained stable in aqueous solution at neutral pH for up to four months. In cell viability assay on cultured cancer cell lines (MKN-45P, SKOV3, CT26), Paclitaxel-loaded polymersomes were more toxic than free drug or albumin-bound Paclitaxel (Abraxane®). Intraperitoneally administered fluorescent polymersomes accumulated in malignant lesions, and immunofluorescence revealed intense signal inside tumors with no detectable signal in control organs. A dual targeting of tumors was observed: direct (circulation independent) penetration, and systemic, blood vessel-associated accumulation. Finally, we evaluated preclinical antitumor efficacy of polymersomes-paclitaxel in treatment of MKN-45P disseminated gastric carcinoma using a total dose of 7 mg/kg. Experimental therapy with polymersome-Paclitaxel improved the therapeutic index of drug over Paclitaxel-Cremophor and Abraxane®, as evaluated by intraperitoneal tumor burden and number of metastatic nodules. Our findings underline the potential utility of the polymersome platform for delivery of drugs and imaging agents to peritoneal carcinomatosis lesions. PMID:26880267

  2. Positive effects of Taxol pretreatment on morphology, distribution and ultrastructure of mitochondria and lipid droplets in vitrification of in vitro matured porcine oocytes.

    PubMed

    Fu, Xiang-Wei; Shi, Wen-Qing; Zhang, Qing-Jin; Zhao, Xue-Ming; Yan, Chang Liang; Hou, Yun-Peng; Zhou, Guang-Bin; Fan, Zhi-Qiang; Suo, Lun; Wusiman, Abuliz; Wang, Yan-Ping; Zhu, Shi-En

    2009-10-01

    This study was designed to determine the effects of Taxol pretreatment on the morphology, distribution and ultrastructure of mitochondria and lipid droplets in vitrified porcine oocytes matured in vitro. The result showed that: (1) the rate of normal mitochondria distribution in fresh group (92.85%) was significantly higher (P<0.05) than that in other three groups (toxicity, 72.48%; vitrification, 50.83%; Taxol+vitrification, 69.98%) and Taxol pretreatment significantly (P<0.05) increased the ratio of normal mitochondria distribution in vitrified oocytes; (2) lipid droplets in vitrified oocytes got cracked, resulting in a great number of smaller lipid droplets (diameter <5 microm). The number of lipid droplets (5-10 microm in diameter) in vitrified oocytes pretreated with Taxol was higher (P<0.05) than that in the oocytes without Taxol pretreatment (81.87+/-13.63 vs. 64.27+/-13.72); (3) both toxicity and vitrification cause the difference in the ultrastructure of mitochondria and lipid droplets. Mitochondria were well maintained in the form of typical round and ellipse shape with smooth surface and clear outline and lipid droplets existed in the form of integrity in Taxol pretreatment group. In conclusion, Taxol pretreatment has positive effects on vitrified porcine oocytes matured in vitro in terms of morphology, distribution and ultrastructure of mitochondria and lipid droplets.

  3. Idiotypic mimicry and the assembly of a supramolecular structure: an anti-idiotypic antibody that mimics taxol in its tubulin-microtubule interactions.

    PubMed Central

    Leu, J G; Chen, B X; Diamanduros, A W; Erlanger, B F

    1994-01-01

    Taxol, originally extracted from the bark of the western yew, Taxus brevifolia, is reportedly the first of a new class of anti-cancer agents. It acts by promoting and irreversibly stabilizing microtubule assembly, thus interfering with the dynamic processes required for cell viability and multiplication. With the aim of using immunological techniques to study the mechanism of action of taxol, a monoclonal anti-idiotypic antibody that mimics taxol was prepared, using an auto-anti-idiotypic strategy. It and its Fab fragment inhibited the binding of [3H]taxol to microtubules. Moreover, like taxol, both promoted the assembly of tubulin into microtubules. These findings provide an example of an anti-idiotypic antibody capable of assembling an organized supramolecular structure from soluble cellular components. In addition, it further establishes the ability of anti-idiotypic antibodies to be functional mimics of ligand molecules bearing no structural similarity to immunoglobulins. The variable regions of the antibody have been sequenced. With the exception of the complementarity-determining region 3, the sequence of the heavy chain variable region is strikingly similar to that of an anti-idiotypic antibody raised to anti-insulin. The finding that a polypeptide can mimic taxol raises the possibility that taxol acts as a peptidomimetic compound that interferes with the function of an endogenous polypeptide. Images PMID:7840821

  4. Albumin-bound paclitaxel in solid tumors: clinical development and future directions.

    PubMed

    Kundranda, Madappa N; Niu, Jiaxin

    2015-01-01

    Albumin-bound paclitaxel (nab-paclitaxel) is a solvent-free formulation of paclitaxel that was initially developed more than a decade ago to overcome toxicities associated with the solvents used in the formulation of standard paclitaxel and to potentially improve efficacy. Nab-paclitaxel has demonstrated an advantage over solvent-based paclitaxel by being able to deliver a higher dose of paclitaxel to tumors and decrease the incidence of serious toxicities, including severe allergic reactions. To date, nab-paclitaxel has been indicated for the treatment of three solid tumors in the USA. It was first approved for the treatment of metastatic breast cancer in 2005, followed by locally advanced or metastatic non-small-cell lung cancer in 2012, and most recently for metastatic pancreatic cancer in 2013. Nab-paclitaxel is also under investigation for the treatment of a number of other solid tumors. This review highlights key clinical efficacy and safety outcomes of nab-paclitaxel in the solid tumors for which it is currently indicated, discusses ongoing trials that may provide new data for the expansion of nab-paclitaxel's indications into other solid tumors, and provides a clinical perspective on the use of nab-paclitaxel in practice.

  5. Targeted delivery of albumin bound paclitaxel in the treatment of advanced breast cancer.

    PubMed

    Di Costanzo, Francesco; Gasperoni, Silvia; Rotella, Virginia; Di Costanzo, Federica

    2009-02-18

    Taxanes are chemotherapeutic agents with a large spectrum of antitumor activity when used as monotherapy or in combination regimens. Paclitaxel and docetaxel have poor solubility and require a complex solvent system for their commercial formulation, Cremophor EL(R) (CrEL) and Tween 80(R) respectively. Both these biological surfactants have recently been implicated as contributing not only to the hypersensitivity reactions, but also to the degree of peripheral neurotoxicity and myelosuppression, and may antagonize the cytotoxicity. Nab-paclitaxel, or nanoparticle albumin-bound paclitaxel (ABI-007; Abraxane(R)), is a novel formulation of paclitaxel that does not employ the CrEL solvent system. Nab-paclitaxel demonstrates greater efficacy and a favorable safety profile compared with standard paclitaxel in patients with advanced disease (breast cancer, non-small cell lung cancer, melanoma, ovarian cancer). Clinical studies in breast cancer have shown that nab-paclitaxel is significantly more effective than standard paclitaxel in terms of overall objective response rate (ORR) and time to progression. Nab-paclitaxel in combination with gemcitabine, capecitabine or bevacizumab has been shown to be very active in patients with advanced breast cancer. An economic analysis showed that nab-paclitaxel would be an economically reasonable alternative to docetaxel or standard paclitaxel in metastatic breast cancer. Favorable tumor ORR and manageable toxicities have been reported for nab-paclitaxel as monotherapy or in combination treatment in advanced breast cancer.

  6. Cyclic RGD conjugated poly(ethylene glycol)-co-poly(lactic acid) micelle enhances paclitaxel anti-glioblastoma effect.

    PubMed

    Zhan, Changyou; Gu, Bing; Xie, Cao; Li, Jin; Liu, Yu; Lu, Weiyue

    2010-04-02

    The use of glioblastoma-targeted drug delivery system facilitates efficient delivery of chemotherapeutic agents to malignant gliomas in the central nervous system while minimizing high systemic doses associated with debilitating toxicities. To employ the high binding affinity of a cyclic RGD peptide (c(RGDyK), cyclic Arginine-Glycine-Aspartic acid-D-Tyrosine-Lysine) with integrin alpha(v)beta(3) over-expressed on tumor neovasculature and U87MG glioblastoma cells, we prepared paclitaxel-loaded c(RGDyK)-Poly(ethylene glycol)-block-poly(lactic acid) micelle (c(RGDyK)-PEG-PLA-PTX). In vitro physicochemical characterization of these novel micelles showed satisfactory encapsulated efficiency, loading capacity and size distribution. In vitro cytotoxicity studies proved that the presence of c(RGDyK) enhanced the anti-glioblastoma cell cytotoxic efficacy by 2.5 folds. The binding affinity of c(RGDyK)-PEG-PLA micelle with U87MG cells was also investigated. The competitive binding IC(50) value of c(RGDyK)-PEG-PLA micelle was 26.30 nM, even lower than that of c(RGDyK) (56.23 nM). In U87MG glioblastoma-bearing nude mice model, biodistribution of (125)I-radiolabeled c(RGDyK)-PEG-PLA or DiR encapsulated micelles and anti-glioblastoma pharmacological effect was investigated after intravenous administration. c(RGDyK)-PEG-PLA micelle accumulated in the subcutaneous and intracranial tumor tissue, and when loaded with PTX (c(RGDyK)-PEG-PLA-PTX), exhibited the strongest tumor growth inhibition among the studied paclitaxel formulations. The anti-glioblastoma effect of c(RGDyK)-PEG-PLA-PTX micelle was also reflected in the median survival time of mice bearing intracranial U87MG tumor xenografts where the median survival time of c(RGDyK)-PEG-PLA-PTX micelle-treated mice (48 days) was significantly longer than that of mice treated with PEG-PLA-PTX micelle (41.5 days), Taxol (38.5 days) or saline (34 days). Therefore, our results suggested that c(RGDyK)-PEG-PLA micelle may be a potential

  7. LC-MS Based Sphingolipidomic Study on A2780 Human Ovarian Cancer Cell Line and its Taxol-resistant Strain

    PubMed Central

    Huang, Hao; Tong, Tian-Tian; Yau, Lee-Fong; Chen, Cheng-Yu; Mi, Jia-Ning; Wang, Jing-Rong; Jiang, Zhi-Hong

    2016-01-01

    Drug resistance elicited by cancer cells continue to cause huge problems world-wide, for example, tens of thousands of patients are suffering from taxol-resistant human ovarian cancer. However, its biochemical mechanisms remain unclear. Sphingolipid metabolic dysregulation has been increasingly regarded as one of the drug-resistant mechanisms for various cancers, which in turn provides potential targets for overcoming the resistance. In the current study, a well-established LC-MS based sphingolipidomic approach was applied to investigate the sphingolipid metabolism of A2780 and taxol-resistant A2780 (A2780T) human ovarian cancer cell lines. 102 sphingolipids (SPLs) were identified based on accurate mass and characteristic fragment ions, among which 12 species have not been reported previously. 89 were further quantitatively analyzed by using multiple reaction monitoring technique. Multivariate analysis revealed that the levels of 52 sphingolipids significantly altered in A2780T cells comparing to those of A2780 cells. These alterations revealed an overall increase of sphingomyelin levels and significant decrease of ceramides, hexosylceramides and lactosylceramides, which concomitantly indicated a deviated SPL metabolism in A2780T. This is the most comprehensive sphingolipidomic analysis of A2780 and A2780T, which investigated significantly changed sphingolipid profile in taxol-resistant cancer cells. The aberrant sphingolipid metabolism in A2780T could be one of the mechanisms of taxol-resistance. PMID:27703266

  8. Potential biomarkers for paclitaxel sensitivity in hypopharynx cancer cell

    PubMed Central

    Xu, Cheng-Zhi; Shi, Run-Jie; Chen, Dong; Sun, Yi-Yuan; Wu, Qing-Wei; Wang, Tao; Wang, Pei-Hua

    2013-01-01

    Paclitaxel has been proved to be active in treatment and larynx preservation of HNSCC, however, the fact that about 20-40% patients do not respond to paclitaxel makes it urgent to figure out the biomarkers for paclitaxel-based treatment in Hypopharynx cancer (HPC) patients to improve the therapy effect. In this work, Fadu cells, treated or untreated with low dose of paclitaxel for 24 h, were applied to DNA microarray chips. The differential expression in mRNAs and miRs was analyzed and the network between expression-altered mRNAs and miRs was constructed. Differentially expressed genes were mainly enriched in superpathway of cholesterol biosynthesis (ACAT2, MSMO1, LSS, FDFT1 and FDPS etc.), complement system (C3, C1R, C1S, CFR and CFB etc.), interferon signaling (IFIT1, IFIT3, IFITM1 and MX1 etc.), mTOR signaling (MRAS, PRKAA2, PLD1, RND3 and EIF4A1 etc.) and IGF1 signaling (MRAS, IGFBP7, JUN and FOS etc.), most of these pathways are implicated in tumorigenesis or chemotherapy resistance. The first three pathways were predicted to be suppressed, while the last two pathways were predicted to be induced by paclitaxel, suggesting the combination therapy with mTOR inhibition and paclitaxel might be better than single one. The dramatically expression-altered miRs were miR-112, miR-7, miR-1304, miR-222*, miR-29b-1* (these five miRs were upregulated) and miR-210 (downregulated). The 26 putative target genes mediated by the 6 miRs were figured out and the miR-gene network was constructed. Furthermore, immunoblotting assay showed that ERK signaling in Fadu cells was active by low dose of paclitaxel but repressed by high dose of paclitaxel. Collectively, our data would provide potential biomarkers and therapeutic targets for paclitaxel-based therapy in HPC patients. PMID:24294361

  9. The effect of height on paclitaxel nerve damage.

    PubMed

    Openshaw, Harry; Beamon, Karen; Longmate, Jeffrey; Synold, Timothy; Slatkin, Neal E; Somlo, George

    2005-09-01

    Dying-back neuropathies result in sensory loss and motor signs in the distal distribution of the longest nerves of the body. It would be expected, therefore, that taller individuals with dying-back neuropathies would tend to have worse nerve damage than shorter individuals. This hypothesis was tested in patients receiving high dose paclitaxel. Nerve conductions and quantitative sensory tests were obtained in 21 breast cancer subjects, prior to and 20-40 days after 725 mg/m(2) paclitaxel administered intravenously over 24 h. Despite the uniform dose of paclitaxel, there was a wide variation in post minus pre-paclitaxel changes. Analysis by linear regression showed that decrease of peroneal nerve compound muscle action potential amplitude was significantly greater in taller subjects (P=0.004), and increase in cold detection threshold was greater in taller subjects (P=0.02). No correlation with height was found for paclitaxel drug clearance, maximum concentration, and area under the curve. Decrease in sural sensory nerve action potential amplitude and increase in vibration detection threshold did not correlate with height. In summary, the wide variation of changes seen in neurophysiological tests suggests that multiple factors are involved in determining the severity of neuropathy. Nerve length is probably one of these factors. To determine whether the effect of height is clinically important would require additional study with a larger number of subjects and longer clinical follow-up.

  10. Enhanced anticancer efficacy of paclitaxel through multistage tumor-targeting liposomes modified with RGD and KLA peptides

    PubMed Central

    Sun, Jiawei; Jiang, Lei; Lin, Yi; Gerhard, Ethan Michael; Jiang, Xuehua; Li, Li; Yang, Jian; Gu, Zhongwei

    2017-01-01

    Mitochondria serve as both “energy factories” and “suicide weapon stores” of cells. Targeted delivery of cytotoxic drugs to the mitochondria of tumor cells and tumor vascular cells is a promising strategy to improve the efficacy of chemotherapy. Here, multistage tumor-targeting liposomes containing two targeted peptide-modified lipids, cRGD-PEG2000-DSPE and KLA-PEG2000-DSPE, were developed for encapsulation of the anticancer drug paclitaxel (PTX, RGD-KLA/PTX-Lips). Compared with Taxol (free PTX), RGD/PTX-Lips and KLA/PTX-Lips, the half-maximal inhibitory concentration (IC50) value of RGD-KLA/PTX-Lips in vitro was 1.9-, 36.7- and 22.7-fold lower with 4T1 cells, respectively, because of higher levels of cellular uptake. Similar results were also observed with human umbilical vascular endothelial cells (HUVECs). An apoptosis assay showed that the total apoptotic ratio of RGD-KLA/PTX-Lips was the highest because of the mitochondria-targeted drug delivery and the activation of mitochondrial apoptosis pathways, as evidenced by visible mitochondrial localization, decreased mitochondrial membrane potential, release of cytochrome c and increased activities of caspase-9 and caspase-3. The strongest tumor growth inhibition (TGI; 80.6%) and antiangiogenesis effects without systemic toxicity were also observed in RGD-KLA/PTX-Lip-treated 4T1 tumor xenograft BALB/c mice. In conclusion, these multistage tumor-targeting liposomes represent a promising anticancer drug delivery system (DDS) capable of maximizing anticancer therapeutic efficacy and minimizing systemic toxicity. PMID:28280323

  11. Design and Characterization of PEG-Derivatized Vitamin E as a Nanomicellar Formulation for Delivery of Paclitaxel

    PubMed Central

    Lu, Jianqin; Huang, Yixian; Zhao, Wenchen; Chen, Yichao; Li, Jiang; Gao, Xiang; Venkataramanan, Raman; Li, Song

    2013-01-01

    Various PEG-Vitamin E conjugates including D-alpha-tocopheryl polyethylene glycol succinate 1000 (TPGS) have been extensively studied as a nonionic surfactant in various drug delivery systems. However, limited information is available about the structure-activity relationship of PEG-Vitamin E conjugates as a micellar formulation for paclitaxel (PTX). In this study, four PEG-Vitamin E conjugates were developed that vary in the molecular weight of PEG (PEG2K vs PEG5K) and the molar ratio of PEG/Vitamin E (1/1 vs 1/2) in the conjugates. These conjugates were systematically characterized with respect to CMC, PTX loading efficiency, stability, and their efficiency in delivery of PTX to tumor cells in vitro and in vivo. Our data show that PEG5K-conjugates have lower CMC values and are more effective in PTX loading with respect to both loading capacity and stability. The conjugates with two Vitamin E molecules also worked better than the conjugates with one molecule of Vitamin E, particularly for PEG2K-system. Furthermore, all of the PEG-Vitamin E conjugates can inhibit P-gp function with their activity being comparable to that of TPGS. More importantly, PTX-loaded PEG5K-VE2 resulted in significantly improved tumor growth inhibitory effect in comparison to PTX formulated in PEG2K-VE or PEG2K-VE2, as well as Cremophor EL (Taxol) in a syngeneic mouse model of breast cancer (4T1.2). Our study suggests that PEG5K-Vitmin E2 may hold promise as an improved micellar formulation for in vivo delivery of anticancer agents such as PTX. PMID:23768151

  12. The long-term cellular response to taxol in peripheral nerve: Schwann cell and endoneurial cell changes.

    PubMed

    Vuorinen, V; Röyttä, M; Raine, C S

    1989-12-01

    Taxol, an agent known to stabilize and increase the assembly of microtubules, causes long-lasting nerve damage when injected into peripheral nerve. In the present study, the cellular response to taxol in rat sciatic nerve was studied for up to 6 months after a single injection. The initial response of Schwann cells to taxol at the lesion site involved the accumulation of cytoplasmic microtubules which persisted up to 4 months after injection. Some novel microtubule-related cytoplasmic structures were also noted; these included microtubule-lined cytoplasmic crypts and channels. Despite these structural abnormalities, Schwann cells were able to produce myelin sheaths around taxol-induced axonal bulbs. This myelination showed some anomalies up to 4 months consisting of the widening of myelin lamellae, variability in sheath thickness, paranodal myelin infoldings and myelin protrusions. With time the diameter of the axonal bulbs decreased and, concomitant with this, more normal-appearing remyelination occurred. By 5 months, the previously noted myelin abnormalities were rare. By 6 months only a few naked axonal segments occurred at the lesion site. In endoneurial fibroblasts and macrophages cytoplasmic lamellar microtubule formations were frequent at 10 weeks. Needle-like cytoplasmic structures appeared within endoneurial cells at the site of the lesion after 10 weeks. By 3 months these inclusions were numerous and were often surrounded by extended cytoplasmic processes. The needles were up to 50 microns long and 3 microns wide and probably represented cholesterol. By 4 months the number of cytoplasmic needles decreased and at 5 months onwards none was observed. The present findings confirm and extend previous findings that taxol has a long-lasting effect upon both Schwann cells and endoneurial cells and that this is related to abnormal tubulin synthesis.

  13. Paclitaxel-loaded poly(glycolide-co-ε-caprolactone)-b-D-α-tocopheryl polyethylene glycol 2000 succinate nanoparticles for lung cancer therapy

    PubMed Central

    Zhao, Tiejun; Chen, Hezhong; Dong, Yuchao; Zhang, Jiajun; Huang, Haidong; Zhu, Ji; Zhang, Wei

    2013-01-01

    In order to improve the therapeutic efficacy and minimize the side effects of lung cancer chemotherapy, the formulation of paclitaxel-loaded poly(glycolide-co-ε-caprolactone)-b-D-α-tocopheryl polyethylene glycol 2000 succinate nanoparticles (PTX-loaded [PGA-co-PCL]-b-TPGS2k NPs) was prepared. The novel amphiphilic copolymer (PGA-co-PCL)-b-TPGS2k was synthesized by ring-opening polymerization and characterized by proton nuclear magnetic resonance spectroscopy and gel permeation chromatography. The PTX-loaded (PGA-co-PCL)-b-TPGS2k NPs were characterized in terms of size, size distribution, zeta potential, drug encapsulation, surface morphology, and drug release. In vitro cellular uptakes of NPs were investigated with confocal laser scanning microscopy, indicating the coumarin 6-loaded (PGA-co-PCL)-b-TPGS2k NPs could be internalized by human lung cancer A-549 cells. The antitumor effect of PTX-loaded NPs was evaluated, both in vitro and in vivo, on an A-549 cell tumor-bearing mouse model via intratumoral injection. The commercial PTX formulation Taxol was chosen as the reference. Experimental results showed that the PTX-loaded NPs possessed higher cytotoxicity and could effectively inhibit the growth of tumor. All the results suggested that amphiphilic copolymer (PGA-co-PCL)-b-TPGS2k could act as a potential biological material for nanoformulation in the treatment of lung cancer. PMID:23696703

  14. A toxic organic solvent-free technology for the preparation of PEGylated paclitaxel nanosuspension based on human serum albumin for effective cancer therapy.

    PubMed

    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.

  15. Paclitaxel Enhances Carboplatin-DNA Adduct Formation and Cytotoxicity

    PubMed Central

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

    2016-01-01

    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 108 nucleotides at 2 h, p = 0.004). Removal of paclitaxel increased the repair of carboplatin-DNA adducts: 39.4 versus 33.1 adducts per 108 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

  16. Transfer of carboplatin and paclitaxel into breast milk.

    PubMed

    Griffin, Stephen J; Milla, Maria; Baker, Teresa E; Liu, Tianjia; Wang, Hongyan; Hale, Thomas W

    2012-11-01

    Carboplatin is an alkylating agent that is FDA approved for the treatment of advanced ovarian cancer. Paclitaxel is a plant taxane mitotic inhibitor approved for primary or salvage treatment of ovarian and breast cancer. This is a case report of a 40-year-old woman who was exclusively breastfeeding prior to being treated for papillary thyroid cancer with intravenous carboplatin (233 mg) and intravenous paclitaxel (30 mg/m(2)) for 6 consecutive weeks. Breast milk samples were collected during the sixth chemotherapy session. Carboplatin had a relative infant dose of 2.0% and remained measurable after 316 hours. Paclitaxel had a relative infant dose of 16.7% but was eliminated before 316 hours. The potential side effects of infant exposure of these medications include myelosuppression, hypersensitivity reactions, nephrotoxicity, and neurotoxicity. It would be inadvisable for a mother to breastfeed while undergoing therapy with these 2 medications.

  17. Paclitaxel Enhances Carboplatin-DNA Adduct Formation and Cytotoxicity

    DOE PAGES

    Jiang, Shuai; Pan, Amy W.; Lin, Tzu-yin; ...

    2015-11-06

    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 108 nucleotides at 2 h, p = 0.004). Removal of paclitaxel increased the repair of carboplatin-DNA adducts: 39.4 versus 33.1 adducts per 108 nucleotides per hour in carboplatin alone (p = 0.021). In conclusion, this rapid report provides themore » first pharmacodynamics data to support the use of carboplatin/paclitaxel combination in the clinic.« less

  18. Paclitaxel Enhances Carboplatin-DNA Adduct Formation and Cytotoxicity

    SciTech Connect

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

    2015-11-06

    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 108 nucleotides at 2 h, p = 0.004). Removal of paclitaxel increased the repair of carboplatin-DNA adducts: 39.4 versus 33.1 adducts per 108 nucleotides per hour in carboplatin alone (p = 0.021). In conclusion, this rapid report provides the first pharmacodynamics data to support the use of carboplatin/paclitaxel combination in the clinic.

  19. Paclitaxel targets VEGF-mediated angiogenesis in ovarian cancer treatment

    PubMed Central

    Ai, Bin; Bie, Zhixin; Zhang, Shuai; Li, Ailing

    2016-01-01

    Ovarian cancer is one of the gynecologic cancers with the highest mortality, wherein vascular endothelial growth factor (VEGF) is involved in regulating tumor vascularization, growth, migration, and invasion. VEGF-mediated angiogenesis in tumors has been targeted in various cancer treatments, and anti-VEGF therapy has been used clinically for treatment of several types of cancer. Paclitaxel is a natural antitumor agent in the standard front-line treatment that has significant efficiency to treat advanced cancers, including ovarian cancer. Although platinum/paclitaxel-based chemotherapy has good response rates, most patients eventually relapse because the disease develops drug resistance. We aim to review the recent advances in paclitaxel treatment of ovarian cancer via antiangiogenesis. Single-agent therapy may be used in selected cases of ovarian cancer. However, to prevent drug resistance, drug combinations should be identified for optimal effectiveness and existing therapies should be improved. PMID:27648354

  20. Covalent linkage of nanodiamond-paclitaxel for drug delivery and cancer therapy

    NASA Astrophysics Data System (ADS)

    Liu, Kuang-Kai; Zheng, Wen-Wei; Wang, Chi-Ching; Chiu, Yu-Chung; Cheng, Chia-Liang; Lo, Yu-Shiu; Chen, Chinpiao; Chao, Jui-I.

    2010-08-01

    A nanoparticle-conjugated cancer drug provides a novel strategy for cancer therapy. In this study, we manipulated nanodiamond (ND), a carbon nanomaterial, to covalently link paclitaxel for cancer drug delivery and therapy. Paclitaxel was bound to the surface of 3-5 nm sized ND through a succession of chemical modifications. The ND-paclitaxel conjugation was measured by atomic force microscope and nuclear magnetic resonance spectroscopy, and confirmed with infrared spectroscopy by the detection of deuterated paclitaxel. Treatment with 0.1-50 µg ml - 1 ND-paclitaxel for 48 h significantly reduced the cell viability in the A549 human lung carcinoma cells. ND-paclitaxel induced both mitotic arrest and apoptosis in A549 cells. However, ND alone or denatured ND-paclitaxel (after treatment with strong alkaline solution, 1 M NaOH) did not induce the damage effects on A549 cells. ND-paclitaxel was taken into lung cancer cells in a concentration-dependent manner using flow cytometer analysis. The ND-paclitaxel particles were located in the microtubules and cytoplasm of A549 cells observed by confocal microscopy. Furthermore, ND-paclitaxel markedly blocked the tumor growth and formation of lung cancer cells in xenograft SCID mice. Together, we provide a functional covalent conjugation of ND-paclitaxel, which can be delivered into lung carcinoma cells and preserves the anticancer activities on the induction of mitotic blockage, apoptosis and anti-tumorigenesis.

  1. Albumin-bound paclitaxel in solid tumors: clinical development and future directions

    PubMed Central

    Kundranda, Madappa N; Niu, Jiaxin

    2015-01-01

    Albumin-bound paclitaxel (nab-paclitaxel) is a solvent-free formulation of paclitaxel that was initially developed more than a decade ago to overcome toxicities associated with the solvents used in the formulation of standard paclitaxel and to potentially improve efficacy. Nab-paclitaxel has demonstrated an advantage over solvent-based paclitaxel by being able to deliver a higher dose of paclitaxel to tumors and decrease the incidence of serious toxicities, including severe allergic reactions. To date, nab-paclitaxel has been indicated for the treatment of three solid tumors in the USA. It was first approved for the treatment of metastatic breast cancer in 2005, followed by locally advanced or metastatic non-small-cell lung cancer in 2012, and most recently for metastatic pancreatic cancer in 2013. Nab-paclitaxel is also under investigation for the treatment of a number of other solid tumors. This review highlights key clinical efficacy and safety outcomes of nab-paclitaxel in the solid tumors for which it is currently indicated, discusses ongoing trials that may provide new data for the expansion of nab-paclitaxel’s indications into other solid tumors, and provides a clinical perspective on the use of nab-paclitaxel in practice. PMID:26244011

  2. Improving the antitumor activity of squalenoyl-paclitaxel conjugate nanoassemblies by manipulating the linker between paclitaxel and squalene.

    PubMed

    Caron, Joachim; Maksimenko, Andrei; Wack, Séverine; Lepeltier, Elise; Bourgaux, Claudie; Morvan, Estelle; Leblanc, Karine; Couvreur, Patrick; Desmaële, Didier

    2013-01-01

    A series of new lipid prodrugs of paclitaxel, which can be formulated as nanoassemblies, are described. These prodrugs which are designed to overcome the limitations due to the systemic toxicity and low water solubility of paclitaxel consist of a squalene chain bound to the 2'-OH of paclitaxel through a 1,4-cis,cis-dienic linker. This design allows the squalene-conjugates to self-assemble as nanoparticular systems while preserving an efficient release of the free drug, thanks to the dienic spacer. The size, steric hindrance, and functional groups of the spacer have been modulated. All these prodrugs self-assemble into nanosized aggregates in aqueous solution as characterized by dynamic light scattering and transmission electron microscopy and appear stable in water for several days as determined by particle size measurement. In vitro biological assessment shows that these squalenoyl-paclitaxel nanoparticles display notable cytotoxicity on several tumor cell lines including A549 lung cell line, colon cell line HT-29, or KB 3.1 nasopharyngeal epidermoid cell line. The cis,cis-squalenyl-deca-5,8-dienoate prodrug show improved activity over simple 2'-squalenoyl-paclitaxel prodrug highlighting the favourable effect of the dienic linker. The antitumor efficacy of the nanoassemblies constructed with the more active prodrugs has been investigated on human lung (A549) carcinoma xenograft model in mice. The prodrug bearing the cis,cis-deca-5,8-dienoyl linker shows comparable antitumor efficacy to the parent drug, but reveals a much lower subacute toxicity as seen in body weight loss. Thus, nanoparticles with the incorporated squalenoyl paclitaxel prodrug may prove useful for replacement of the toxic Cremophor EL.

  3. Differential effects of natural product microtubule stabilizers on microtubule assembly: single agent and combination studies with taxol, epothilone B, and discodermolide.

    PubMed

    Gertsch, Jürg; Meier, Sarah; Müller, Martin; Altmann, Karl-Heinz

    2009-01-05

    A systematic comparison has been performed of the morphology and stability of microtubules (MTs) induced by the potent microtubule-stabilizing agents (MSAs) taxol, epothilone B (Epo B), and discodermolide (DDM) under GTP-free conditions. DDM-induced tubulin polymerization occurred significantly faster than that induced by taxol and Epo B. At the same time, tubulin polymers assembled from soluble tubulin by DDM were morphologically distinct (shorter and less ordered) from those induced by either taxol or Epo B, as demonstrated by electron microscopy. Exposure of MSA-induced tubulin polymers to ultrasound revealed the DDM-based polymers to be less stable to this type of physical stress than those formed with either Epo B or taxol. Interestingly, MT assembly in the presence of both DDM and taxol appeared to produce a distinct new type of MT polymer with a mixed morphology between those of DDM- and taxol-induced structures. The observed differences in MT morphology and stability might be related, at least partly, to differences in intramicrotubular tubulin isotype distribution, as DDM showed a different pattern of beta-tubulin isotype usage in the assembly process.

  4. 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

  5. Clinical benefit of nanoparticle albumin-bound-paclitaxel in recurrent/metastatic head and neck squamous cell carcinoma resistant to cremophor-based paclitaxel or docetaxel.

    PubMed

    Ley, Jessica; Wildes, Tanya M; Daly, Kristin; Oppelt, Peter; Adkins, Douglas

    2017-02-01

    The clinical benefit of nab-paclitaxel monotherapy for recurrent/metastatic head and neck squamous cell carcinoma (RM-HNSCC) that progressed on other taxanes (cremophor-based paclitaxel or docetaxel) is unknown. A retrospective analysis of patients treated at a single institution with nab-paclitaxel for taxane-resistant RM-HNSCC. The exploratory hypothesis was that nab-paclitaxel would result in clinical benefit (tumor response) in patients with taxane-resistant RM-HNSCC. Twelve patients who were treated with nab-paclitaxel monotherapy for taxane-resistant RM-HNSCC and met all eligibility criteria were identified. The majority of patients (n = 9; 75%) received three or more lines of therapy for RM-HNSCC. All patients had platin-resistant, and ten patients (83%) had cetuximab-resistant disease. Patients had RM-HNSCC that progressed on cremophor-based paclitaxel (8), docetaxel (1), or both (3). With prior taxane, the best tumor response was partial (PR) in 4 patients (33%), stable (SD) in 3 (25%), and progression in 5 (42%). The median time-to-progression (TTP) with prior taxane was 1.7 (range 0.7-9.0) months. The median interval from last dose of taxane to first dose of nab-paclitaxel was 3 (0.7-31.3) months. With nab-paclitaxel, tumor response occurred in two patients (17%; PR in both) and disease control (PR and SD) occurred in five (42%). Median TTP with nab-paclitaxel was 2.1 months (range 0.6-6.2), and median overall survival was 4.9 months (range 1.9-13.5). nab-Paclitaxel provided clinical benefit in some patients with taxane-resistant RM-HNSCC. The median TTP with nab-paclitaxel and with prior taxane were similar. This exploratory observation warrants further investigation in prospective studies.

  6. Paclitaxel inhibits the hyper-activation of spleen cells by lipopolysaccharide and induces cell death

    PubMed Central

    Kim, Hyun-Ji

    2016-01-01

    Paclitaxel was isolated from the bark of the Pacific yew, Taxus brevifolia, and used as an anticancer agent. Paclitaxel prevents cancer cell division by inhibiting spindle fiber function, inducing cell death. A recent study demonstrated that paclitaxel binds to myeloid differentiation protein-2 of Toll-like receptor 4 and prevents the signal transduction of lipopolysaccharide (LPS). Paclitaxel converts immune cells hypo-responsive to LPS. In this study, we investigated whether paclitaxel can inhibit the phenotype and function of immune cells. To accomplish this, we used spleen cells, a major type of immune cell, LPS, a representative inflammatory agent and a mitogen for B lymphocytes. LPS profoundly increased the activation and cytokine production of spleen cells. However, paclitaxel significantly inhibited LPS-induced hyper-activation of spleen cells. Furthermore, we found that paclitaxel induced cell death of LPS-treated spleen cells. These results suggest that paclitaxel can inhibit the hyper-immune response of LPS in spleen cells via a variety of mechanisms. These findings suggest that paclitaxel can be used as a modulating agent for diseases induced by hyper-activation of B lymphocytes. Taken together, these results demonstrate that paclitaxel inhibits the function of spleen cells activated by LPS, and further induces cell death. PMID:27030196

  7. Subcutaneous administration of paclitaxel in dogs with cancer: A preliminary study

    PubMed Central

    Silva, Daniella M.; Franciosi, Aline I.; Pezzini, Paula C.F.; Guérios, Simone D.

    2015-01-01

    Intravenous paclitaxel has been underused in dogs due to severe and acute hypersensitivity reactions. Subcutaneous (SC) administration of paclitaxel and its safety are unknown. In this preliminary study, SC administration of paclitaxel was evaluated for hypersensitivity reactions and toxicity in 21 dogs with advanced cancer. Dogs received 1 to 5 paclitaxel doses, ranging from 85 to 170 mg/m2, SC every 14 or 21 days. A total of 40 paclitaxel doses were administered and none of the 21 dogs developed systemic or acute local hypersensitivity reactions. Severe skin lesions at the injection site developed in 2 dogs after the 4th injection at the same location. Grade 4 neutropenia was observed in 50% of the dogs 5 days after the first treatment at 115 mg/m2 (n = 14). Two animals developed Grade 5 diarrhea and died likely due to hemodynamic failure or sepsis. Paclitaxel can be administered SC in dogs with no hypersensitivity reaction. PMID:26246628

  8. Subcutaneous administration of paclitaxel in dogs with cancer: A preliminary study.

    PubMed

    Silva, Daniella M; Franciosi, Aline I; Pezzini, Paula C F; Guérios, Simone D

    2015-08-01

    Intravenous paclitaxel has been underused in dogs due to severe and acute hypersensitivity reactions. Subcutaneous (SC) administration of paclitaxel and its safety are unknown. In this preliminary study, SC administration of paclitaxel was evaluated for hypersensitivity reactions and toxicity in 21 dogs with advanced cancer. Dogs received 1 to 5 paclitaxel doses, ranging from 85 to 170 mg/m(2), SC every 14 or 21 days. A total of 40 paclitaxel doses were administered and none of the 21 dogs developed systemic or acute local hypersensitivity reactions. Severe skin lesions at the injection site developed in 2 dogs after the 4th injection at the same location. Grade 4 neutropenia was observed in 50% of the dogs 5 days after the first treatment at 115 mg/m(2) (n = 14). Two animals developed Grade 5 diarrhea and died likely due to hemodynamic failure or sepsis. Paclitaxel can be administered SC in dogs with no hypersensitivity reaction.

  9. Decreased expression of microRNA-17 and microRNA-20b promotes breast cancer resistance to taxol therapy by upregulation of NCOA3

    PubMed Central

    Ao, Xiang; Nie, Peipei; Wu, Baoyan; Xu, Wei; Zhang, Tao; Wang, Songmao; Chang, Haocai; Zou, Zhengzhi

    2016-01-01

    Chemoresistance is a major obstacle to effective breast cancer chemotherapy. However, the underlying molecular mechanisms remain unclear. In this study, nuclear receptor coactivator 3 (NCOA3) was found to be significantly increased in taxol-resistant breast cancer tissues and cells. Moreover, overexpression of NCOA3 enhanced breast cancer cell resistance to taxol, whereas depletion of NCOA3 decreased taxol resistance. Subsequently, we investigated whether NCOA3 expression was regulated by miRNAs in breast cancer. By bioinformatics prediction in combination with the data of previous report, miR-17 and miR-20b were selected as the potential miRNAs targeting NCOA3. By real-time PCR analysis, we found that miR-17 and miR-20b were significantly reduced in taxol-resistant breast cancer tissues and cells. In addition, we provided some experimental evidences that miR-17 and miR-20b attenuated breast cancer resistance to taxol in vitro and in vivo models. Furthermore, by luciferase reporter assays, we further validated that both miR-17 and miR-20b directly binded the 3′-untranslated region of NCOA3 mRNA and inhibited its expression in breast cancer cells. Finally, both miR-17 and miR-20b levels were found to be significantly negatively correlated with NCOA3 mRNA levels in breast cancer tissues. Together, our results indicated that loss of miR-17 and miR-20b enhanced breast cancer resistance to taxol by upregulating NCOA3 levels. Our study suggested miR-17, miR-20b and NCOA3 may serve as some predictive biomarkers and potential therapeutic targets in taxol-resistant breast cancer treatment. PMID:27831559

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

    PubMed

    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 μg · h · mL(-1) vs 5.196 ± 1.426 μg · 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 AUC(0-∞) in liver, lung, and spleen (all P < 0.01), but not in heart or kidney.

  11. Extraction and RP-HPLC determination of taxol in rat plasma, cell culture and quality control samples

    PubMed Central

    Tekade, Rakesh Kumar; D'Emanuele, Antony; Elhissi, Abdelbary; Agrawal, Ashish; Jain, Anurekha; Arafat, Basel Tawfiq; Jain, Narendra Kumar

    2013-01-01

    A rapid, sensitive, selective and validated reverse phase high-performance liquid chromatography (RP-HPLC) method for the estimation of paclitaxel in micro-sample of rat plasma and in culture of cancer cells was performed in this study. The mobile phase consisted of an optimized mixture of methanol:water: trifluroacetic acid (80: 20: 0.1, v/v/v). Column elution at a flow rate of 1 mL/minute with UV detection at 225 nm at room temperature was used. The RP-HPLC method was successfully applied for the determination of paclitaxel in plasma samples and in culture of cancer cells with nano-quantity of estimation. The validation studies were performed in accordance with the International Conference on Harmonization (ICH) guidelines. The intra- and inter-day precision showed that the coefficients of variation ranged from 1.07% to 4.27% at different levels of concentrations. To the best of our knowledge, this study also reported for the first time the optimization of different solvents for effective extraction of paclitaxel wherein tert.-butyl methyl ether (TBME): diethyl ether (DEE) in 50: 50 v/v composition was found most efficient with extraction efficiency ranging between 77.99% and 91.74% and between 76.14 and 93.66% in the plasma and cell culture, respectively. This proposed method was successfully applied to study the pharmacokinetics of paclitaxel and the influence of verapamil and all-trans retinoic acid (atRA) on paclitaxel pharmacokinetics in rat models. This proposed method might emerge as a valuable aid in the laboratory monitoring of paclitaxel in a variety of in vitro as well as in vivo scenarios. PMID:24086173

  12. ISOLATION AND IDENTIFICATION OF AN ENDOPHYTIC FUNGUS PRODUCING PACLITAXEL FROM TAXUS WALLICHIANA VAR MAIREI.

    PubMed

    Zaiyou, Jian; Hongsheng, Wang; Ning, Wang; Li, Meng; Guifang, Xu

    2015-12-01

    The objective of this study was to isolate endophytic fungi producing paclitaxel from yew for the purpose of paclitaxel manufacture. Surface sterilized bark of Taxus wallichiana var. mairei was used as source material and potato dextrose agar culture medium was used in isolation of endophytic fungi. Fungal cultures were extracted with a mixture of chloroform / methanol (1:1, v/v) and the paclitaxel in the extracts was determined and authenticated with LC-MS. An endophytic fungus that produced paclitaxel was identified by ITS rDNA and 26S D1/D2 rDNA sequencing. The results showed that a total of 435 endophytic fungal strains were isolated from T. wallichiana var. mairei and purified. Only one of these strains produced paclitaxel and it belongs to Fusarium. The paclitaxel productivity in whole PDB culture and that in spent culture medium from this strain is 0.0153 mg/L and 0.0119 mg/L respectively. The paclitaxel content in dry mycelium is 0.27 mg/kg. This isolated endophytic fungus produced paclitaxel at a considerable level and shows potentiality as a producing strain for paclitaxel manufacture after strain improvement.

  13. Prostate cancer cell response to paclitaxel is affected by abnormally expressed securin PTTG1.

    PubMed

    Castilla, Carolina; Flores, M Luz; Medina, Rafael; Pérez-Valderrama, Begoña; Romero, Francisco; Tortolero, María; Japón, Miguel A; Sáez, Carmen

    2014-10-01

    PTTG1 protein, the human securin, has a central role in sister chromatid separation during mitosis, and its altered expression has been reported in many tumor types. Paclitaxel is a widely used chemotherapeutic drug, whose mechanism of action is related to its ability to arrest cells in mitosis and the subsequent induction of the intrinsic apoptotic pathway. By using two prostate cancer cell lines with different responses to paclitaxel treatment, we have identified two situations in which PTTG1 influences cell fate differentially. In slippage-prone PC3 cells, both PTTG1 downregulation and overexpression induce an increase in mitotic cells that is associated with diminished apoptosis after paclitaxel treatment. In LNCaP cells, however, PTTG1 downregulation prevents mitotic entry and, subsequently, inhibits mitosis-associated, paclitaxel-induced apoptosis. In contrast, PTTG1 overexpression induces an increase in mitotic cells and apoptosis after paclitaxel treatment. We have also identified a role for Mcl-1 protein in preventing apoptosis during mitosis in PC3 cells, as simultaneous PTTG1 and Mcl-1 silencing enhances mitosis-associated apoptosis after paclitaxel treatment. The finding that a more efficient mitotic arrest alone in PC3 cells is not enough to increase apoptosis was also confirmed with the observation that a selected paclitaxel-resistant PC3 cell line showed an apoptosis-resistant phenotype associated with increased mitosis upon paclitaxel treatment. These findings could contribute to identify putative responsive and nonresponsive cells and help us to approach incomplete responses to paclitaxel in the clinical setting.

  14. Severe hyponatremia caused by nab-paclitaxel-induced syndrome of inappropriate antidiuretic hormone secretion

    PubMed Central

    Neuzillet, Cindy; Babai, Samy; Kempf, Emmanuelle; Pujol, Géraldine; Rousseau, Benoît; Le-Louët, Hervé; Christophe Tournigand

    2016-01-01

    Abstract Incidence of pancreatic ductal adenocarcinoma (PDAC) is increasing. Most patients have advanced disease at diagnosis and therapeutic options in this setting are limited. Gemcitabine plus nab-paclitaxel regimen was demonstrated to increase survival compared with gemcitabine monotherapy and is therefore indicated as first-line therapy in patients with metastatic PDAC and performance status Eastern Cooperative Oncology Group (ECOG) 0-2. The safety profile of gemcitabine and nab-paclitaxel combination includes neutropenia, fatigue, and neuropathy as most common adverse events of grade 3 or higher. No case of severe hyponatremia associated with the use of nab-paclitaxel for the treatment of PDAC has been reported to date. We report the case of a 72-year-old Caucasian man with a metastatic PDAC treated with gemcitabine and nab-paclitaxel regimen, who presented with a severe hyponatremia (grade 4) caused by a documented syndrome of inappropriate antidiuretic hormone secretion (SIADH). This SIADH was attributed to nab-paclitaxel after a rigorous imputability analysis, including a rechallenge procedure with dose reduction. After dose and schedule adjustment, nab-paclitaxel was pursued without recurrence of severe hyponatremia and with maintained efficacy. Hyponatremia is a rare but potentially severe complication of nab-paclitaxel therapy that medical oncologists and gastroenterologists should be aware of. Nab-paclitaxel-induced hyponatremia is manageable upon dose and schedule adaptation, and should not contraindicate careful nab-paclitaxel reintroduction. This is of particular interest for a disease in which the therapeutic options are limited. PMID:27368013

  15. Effect of paclitaxel on transient receptor potential vanilloid 1 in rat dorsal root ganglion.

    PubMed

    Hara, Tomomi; Chiba, Terumasa; Abe, Kenji; Makabe, Akiko; Ikeno, Souichi; Kawakami, Kazuyoshi; Utsunomiya, Iku; Hama, Toshihiro; Taguchi, Kyoji

    2013-06-01

    Peripheral neuropathy is a common adverse effect of paclitaxel treatment. To analyze the contribution of transient receptor potential vanilloid 1 (TRPV1) in the development of paclitaxel-induced thermal hyperalgesia, TRPV1 expression in the rat dorsal root ganglion (DRG) was analyzed after paclitaxel treatment. Behavioral assessment using the tail-flick test showed that intraperitoneal administration of 2 and 4 mg/kg paclitaxel induced thermal hyperalgesia after days 7, 14, and 21. Paclitaxel-induced thermal hyperalgesia after day 14 was significantly inhibited by the TRP antagonist ruthenium red (3 mg/kg, s.c.) and the TRPV1 antagonist capsazepine (30 mg/kg, s.c.). Paclitaxel (2 and 4 mg/kg) treatment increased the expression of TRPV1 mRNA and protein in DRG neurons. Immunohistochemistry showed that paclitaxel (4 mg/kg) treatment increased TRPV1 protein expression in small and medium DRG neurons 14 days after treatment. Antibody double labeling revealed that isolectin B4-positive small DRG neurons co-expressed TRPV1. TRPV1 immunostaining was up-regulated in paw skin day 14 after paclitaxel treatment. Moreover, in situ hybridization histochemistry revealed that most of the TRPV1 mRNA-labeled neurons in the DRG were small or medium in size. These results suggest that paclitaxel treatment increases TRPV1 expression in DRG neurons and may contribute to functional peripheral neuropathic pain.

  16. Paclitaxel injection concentrate for nanodispersion versus nab-paclitaxel in women with metastatic breast cancer: a multicenter, randomized, comparative phase II/III study.

    PubMed

    Jain, Minish M; Gupte, Smita U; Patil, Shekhar G; Pathak, Anand B; Deshmukh, Chetan D; Bhatt, Niraj; Haritha, Chiramana; Govind Babu, K; Bondarde, Shailesh A; Digumarti, Raghunadharao; Bajpai, Jyoti; Kumar, Ravi; Bakshi, Ashish V; Bhattacharya, Gouri Sankar; Patil, Poonam; Subramanian, Sundaram; Vaid, Ashok K; Desai, Chirag J; Khopade, Ajay; Chimote, Geetanjali; Bapsy, Poonamalle P; Bhowmik, Shravanti

    2016-02-01

    Paclitaxel is widely used in the treatment of patients with metastatic breast cancer (MBC). Formulations of paclitaxel contain surfactants and solvents or albumin derived from human blood. The use of co-solvents such as polyoxyethylated castor oil is thought to contribute to toxicity profile and hypersensitivity reactions as well as leaching of plasticizers from polyvinyl chloride bags and infusion sets. Currently, nab-paclitaxel, an albumin-bound paclitaxel in nanometer range continues to be the preferred taxane formulation used in clinic. This study (CTRI/2010/091/001116) investigated the efficacy and tolerability of a polyoxyethylated castor oil- and albumin-free formulation of paclitaxel [paclitaxel injection concentrate for nanodispersion (PICN)] compared with nab-paclitaxel in women with refractory MBC. The current study was a multicenter, open-label, parallel-group, randomized, comparative phase II/III trial evaluating the efficacy and safety of PICN (260 mg/m(2) [n = 64] and 295 mg/m(2) [n = 58] every 3 weeks) compared with nab-paclitaxel (260 mg/m(2) every 3 weeks [n = 58]) in women 18 and 70 years old with confirmed MBC. Overall response rate (ORR) was assessed with imaging every 2 cycles. An independent analysis of radiologic data was performed for evaluable patients. Progression-free survival (PFS) was a secondary efficacy measure. Independent radiologist-assessed ORRs in the evaluable population of women aged ≥70 years were 35, 49, and 43 % in the PICN 260 mg/m(2), PICN 295 mg/m(2), and nab-paclitaxel 260 mg/m(2) arms, respectively. Median PFS in the evaluable population was 23, 35, and 34 weeks in the PICN 260 mg/m(2), PICN 295 mg/m(2), and nab-paclitaxel 260 mg/m(2) arms, respectively. Adverse events occurred in similar proportions of patients across treatment arms. Hypersensitivity reactions were not frequently observed with the clinical use of PICN across the treatment cohorts. In women with metastatic breast cancer, PICN at 260 and 295 mg/m(2

  17. Pregnane X receptors regulate CYP2C8 and P-glycoprotein to impact on the resistance of NSCLC cells to Taxol.

    PubMed

    Chen, Yan; Huang, Wandan; Chen, Feiyu; Hu, Guoping; Li, Fenglei; Li, Jianhua; Xuan, Aiguo

    2016-12-01

    Cytochrome P450 2C8 (CYP2C8) is one of the enzymes that primarily participate in producing metabolisms of medications and P-glycoprotein (P-gp) has been regarded as one of the important molecules in chemotherapeutically induced multidrug resistance (MDR). In addition, the pregnane X receptor (PXR) is involved in regulating both CYP2C8 and P-gp. We aim to research the effect of PXR on Taxol-resistant non-small-cell lung cancer (NSCLC cells) via regulating CYP2C8 and P-gp. NSCLC cells were treated with SR12813, LY335979, or PXR siRNA. Cell counting kit (CCK-8) assay was used to detect cell vitality. Colony formation assay was used to observe cell proliferation. Western blotting, real-time polymerase chain reaction (RT-PCR), and immunofluorescence staining were conducted to analyze the expressions of PXR, CYP2C8, and P-gp. Taxol and its metabolic products were detected by high-performance liquid chromatography (HPLC). The expression of PXR in A549 cell line was higher than that in other cell lines. The accumulation of PXR was observed in the nucleus after cells were treated with SR12813. Besides, SR12813 induced higher expressions of CYP2C8 and P-gp proteins. We also discovered that pretreatment with SR12813 reversed the inhibition of cell viability and proliferation after the Taxol treatment in comparison to the SR12813 untreated group. Furthermore, the hydroxylation products of Taxol analyzed by HPLC were increased in comparison to the SR12813 untreated group, indicating that high expressions of CYP2C8 and P-gp enhanced the resistance of A549 cells to Taxol. For cells treated with PXR siRNA, cell viability, cell proliferation, and Taxol metabolites were significantly reduced after the Taxol treatment in comparison to the siRNA-negative group. The cell viability, cell proliferation, and Taxol metabolites were regulated by the expressions of PXR, P-gp, and CYP2C8. That is, PXR expression has an important effect on the resistance of NSCLC cells to Taxol via

  18. Overcoming heterologous protein interdependency to optimize P450-mediated Taxol precursor synthesis in Escherichia coli

    PubMed Central

    Biggs, Bradley Walters; Lim, Chin Giaw; Sagliani, Kristen; Shankar, Smriti; Stephanopoulos, Gregory; Ajikumar, Parayil Kumaran

    2016-01-01

    Recent advances in metabolic engineering have demonstrated the potential to exploit biological chemistry for the synthesis of complex molecules. Much of the progress to date has leveraged increasingly precise genetic tools to control the transcription and translation of enzymes for superior biosynthetic pathway performance. However, applying these approaches and principles to the synthesis of more complex natural products will require a new set of tools for enabling various classes of metabolic chemistries (i.e., cyclization, oxygenation, glycosylation, and halogenation) in vivo. Of these diverse chemistries, oxygenation is one of the most challenging and pivotal for the synthesis of complex natural products. Here, using Taxol as a model system, we use nature’s favored oxygenase, the cytochrome P450, to perform high-level oxygenation chemistry in Escherichia coli. An unexpected coupling of P450 expression and the expression of upstream pathway enzymes was discovered and identified as a key obstacle for functional oxidative chemistry. By optimizing P450 expression, reductase partner interactions, and N-terminal modifications, we achieved the highest reported titer of oxygenated taxanes (∼570 ± 45 mg/L) in E. coli. Altogether, this study establishes E. coli as a tractable host for P450 chemistry, highlights the potential magnitude of protein interdependency in the context of synthetic biology and metabolic engineering, and points to a promising future for the microbial synthesis of complex chemical entities. PMID:26951651

  19. Late acute thrombosis after paclitaxel eluting stent implantation

    PubMed Central

    Liistro, F; Colombo, A

    2001-01-01

    Late (more than six months) total occlusion after coronary stenting is a progressive phenomenon occurring in approximately 4% of patients, leading to acute myocardial infarction in less than 0.5%. The process must be related to severe and progressive intimal hyperplasia. In patients receiving coronary stenting with simultaneous brachytherapy, late total occlusion has been reported at a higher rate and to be related to stent thrombosis rather than intimal hyperplasia. Late total occlusion presenting with an acute clinical event seven months after the implantation of a paclitaxel drug eluting stent is reported. The occlusion developed soon after the interruption of ticlopidine treatment, suggesting that the event had a thrombotic genesis and that the risk is not confined to the first six month period.


Keywords: paclitaxel eluting stent; late thrombosis PMID:11514475

  20. Targeting Paclitaxel-Loaded Nanoparticles to Ovarian Cancer

    DTIC Science & Technology

    2011-05-01

    displaced even by very high concentrations of the free ligand. KEY RESEARCH ACCOMPLISHMENTS Background Despite of the improvements in the...scintillation counter. The amount of [3H]-paclitaxel in each tumor was expressed as DPM/g tumor (Figure 6). HEY also has the greatest tritium count... separate Nexil molecules. The next most important step in the validation of Nexil-DTPA as a patient selection tool would be to prove that tumors

  1. Paclitaxel-coated balloons - Survey of preclinical data.

    PubMed

    Schnorr, B; Kelsch, B; Cremers, B; Clever, Y P; Speck, U; Scheller, B

    2010-10-01

    Restenosis following interventions in the coronary or peripheral arteries develops over weeks to months. In coronary arteries the restenosis rate has been markedly reduced since the advent of drug-eluting stents. Non-stent-based methods for local drug delivery enable restenosis inhibition without the need for stent implantation, does not permanently change the structure of the vessel, are repeatable, and seems to be applicable where drug-eluting stents provide insufficient protection. Preclinical data indicate that short exposure of the vessel wall to a lipophilic inhibitor of cell proliferation is sufficient for preventing restenosis. Initial evidence to this effect emerged from an investigation of paclitaxel embedded in a matrix that enhances the solubility and release of the agent from the balloon coating as well as its transfer to the vessel wall. Further corroborating data from preclinical and clinical studies demonstrating a reduction in late lumen loss and lower restenosis rates led to the market introduction of a variety of paclitaxel-coated angioplasty balloons. The effectiveness of restenosis inhibition is not determined by the active agent alone. Other factors that are crucial for the effectiveness and safety of drug-coated angioplasty balloons are the formulation containing the agent and the coating technique. In this review we first outline the development of paclitaxel-coated balloons to then provide an overview of the preclinical results obtained with different paclitaxel-coated balloons and finally compare these with the outcome in patients. The article concludes with a short outlook on initial results with a zotarolimus-coated angioplasty balloon.

  2. ERK activation by thymosin-beta-4 (TB4) overexpression induces paclitaxel-resistance.

    PubMed

    Oh, Su-Young; Song, Ji-Hee; Gil, Jung-Eun; Kim, Jeong-Hee; Yeom, Young-Il; Moon, Eun-Yi

    2006-05-15

    The development of paclitaxel-resistance in tumors is one of the most significant obstacles to successful therapy. Thymosin-beta-4 (TB4) has been known as actin-sequestering protein and functions in tumor metastasis. Here, we overexpressed TB4 in HeLa cells (TB4-HeLa) and examined the effect of TB4 in paclitaxel-induced cell death. TB4-HeLa cells showed a higher growth rate and a lower percentage of basal apoptosis than HeLa cells. TB4-HeLa cells were more resistant to paclitaxel-induced cell death than HeLa cells. TB4 transcript expression with paclitaxel treatment was dose-dependently increased in HeLa cells but that was not in TB4-HeLa cells. Small interfering RNA (siRNA) of TB4 inhibited HeLa cell growth and enhanced paclitaxel-induced cell death. Basal ERK phosphorylation was elevated and basal p38 kinase phosphorylation was reduced in paclitaxel non-treated TB4-HeLa cells. When treated with paclitaxel, cell death and resistance-induction were independent of ERK and p38 kinase activation. Paclitaxel-resistance of TB4-HeLa cells was overcome by the inhibition of basal ERK activity with PD98059 pre-treatment. The inhibition of basal p38 kinase activity with SB203580 pre-treatment attenuated the paclitaxel-induced HeLa cell death. In conclusion, TB4 induced paclitaxel-resistance through the elevation of basal level of ERK phosphorylation. Therefore, TB4 could be a novel target to regulate paclitaxel-resistance.

  3. The co-solvent Cremophor EL limits absorption of orally administered paclitaxel in cancer patients.

    PubMed

    Malingré, M M; Schellens, J H; Van Tellingen, O; Ouwehand, M; Bardelmeijer, H A; Rosing, H; Koopman, F J; Schot, M E; Ten Bokkel Huinink, W W; Beijnen, J H

    2001-11-16

    The purpose of this study was to investigate the effect of the co-solvents Cremophor EL and polysorbate 80 on the absorption of orally administered paclitaxel. 6 patients received in a randomized setting, one week apart oral paclitaxel 60 mg m(-2) dissolved in polysorbate 80 or Cremophor EL. For 3 patients the amount of Cremophor EL was 5 ml m(-2), for the other three 15 ml m(-2). Prior to paclitaxel administration patients received 15 mg kg(-1) oral cyclosporin A to enhance the oral absorption of the drug. Paclitaxel formulated in polysorbate 80 resulted in a significant increase in the maximal concentration (C(max)) and area under the concentration-time curve (AUC) of paclitaxel in comparison with the Cremophor EL formulations (P = 0.046 for both parameters). When formulated in Cremophor EL 15 ml m(-2), paclitaxel C(max) and AUC values were 0.10 +/- 0.06 microM and 1.29 +/- 0.99 microM h(-1), respectively, whereas these values were 0.31 +/- 0.06 microM and 2.61 +/- 1.54 microM h(-1), respectively, when formulated in polysorbate 80. Faecal data revealed a decrease in excretion of unchanged paclitaxel for the polysorbate 80 formulation compared to the Cremophor EL formulations. The amount of paclitaxel excreted in faeces was significantly correlated with the amount of Cremophor EL excreted in faeces (P = 0.019). When formulated in Cremophor EL 15 ml m(-2), paclitaxel excretion in faeces was 38.8 +/- 13.0% of the administered dose, whereas this value was 18.3 +/-15.5% for the polysorbate 80 formulation. The results show that the co-solvent Cremophor EL is an important factor limiting the absorption of orally administered paclitaxel from the intestinal lumen. They highlight the need for designing a better drug formulation in order to increase the usefulness of the oral route of paclitaxel

  4. Effects of Jia-Wei-Xiao-Yao-San on the Peripheral and Lymphatic Pharmacokinetics of Paclitaxel in Rats

    PubMed Central

    Hou, Mei-Ling; Lu, Chia-Ming

    2016-01-01

    Paclitaxel is effective against breast cancer. The herbal medicine, Jia-Wei-Xiao-Yao-San (JWXYS), is the most frequent prescription used to relieve the symptoms of breast cancer treatments. The aim of the study was to investigate the herb-drug interaction effects of a herbal medicine on the distribution of paclitaxel to lymph. A validated ultraperformance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) method was used to determine the paclitaxel levels in rat plasma and lymph after intravenous infusion of paclitaxel alone with or without 7 days of JWXYS pretreatment. The pharmacokinetic results indicate that paclitaxel concentrations in plasma exceeded those in lymph by approximately 3.6-fold. The biodistribution of paclitaxel from plasma to lymph was 39 ± 5%; however, this increased to 45 ± 4% with JWXYS pretreatment. With JWXYS pretreatment, the AUC and Cmax of paclitaxel in plasma were significantly reduced by approximately 1.5-fold, compared to paclitaxel alone. Additionally, JWXYS decreased the AUC and Cmax of paclitaxel in lymph. However, the lymph absorption rate of paclitaxel with or without JWXYS pretreatment was not significantly changed (27 ± 3 and 30 ± 2%, resp.). Our findings demonstrate that when paclitaxel is prescribed concurrently with herbal medicine, monitoring of the blood pharmacokinetics of paclitaxel is recommended. PMID:27057200

  5. TXNDC17 promotes paclitaxel resistance via inducing autophagy in ovarian cancer.

    PubMed

    Zhang, Song-Fa; Wang, Xin-Yu; Fu, Zhi-Qin; Peng, Qiao-Hua; Zhang, Jian-Yang; Ye, Feng; Fu, Yun-Feng; Zhou, Cai-Yun; Lu, Wei-Guo; Cheng, Xiao-Dong; Xie, Xing

    2015-01-01

    Paclitaxel is recommended as a first-line chemotherapeutic agent against ovarian cancer, but drug resistance becomes a major limitation of its success clinically. The key molecule or mechanism associated with paclitaxel resistance in ovarian cancer still remains unclear. Here, we showed that TXNDC17 screened from 356 differentially expressed proteins by LC-MS/MS label-free quantitative proteomics was more highly expressed in paclitaxel-resistant ovarian cancer cells and tissues, and the high expression of TXNDC17 was associated with poorer prognostic factors and exhibited shortened survival in 157 ovarian cancer patients. Moreover, paclitaxel exposure induced upregulation of TXNDC17 and BECN1 expression, increase of autophagosome formation, and autophagic flux that conferred cytoprotection for ovarian cancer cells from paclitaxel. TXNDC17 inhibition by siRNA or enforced overexpression by a pcDNA3.1(+)-TXNDC17 plasmid correspondingly decreased or increased the autophagy response and paclitaxel resistance. Additionally, the downregulation of BECN1 by siRNA attenuated the activation of autophagy and cytoprotection from paclitaxel induced by TXNDC17 overexpression in ovarian cancer cells. Thus, our findings suggest that TXNDC17, through participation of BECN1, induces autophagy and consequently results in paclitaxel resistance in ovarian cancer. TXNDC17 may be a potential predictor or target in ovarian cancer therapeutics.

  6. Atomized paclitaxel liposome inhalation treatment of bleomycin-induced pulmonary fibrosis in rats.

    PubMed

    Zhou, Y; Zhu, W P; Cai, X J; Chen, M

    2016-04-07

    We sought to determine the efficacy of atomized paclitaxel liposome inhalation treatment of pulmonary fibrosis in a bleomycin-induced rat model. Forty male Sprague-Dawley rats were randomly divided into four groups: healthy control, pulmonary fibrosis without treatment, paclitaxel liposome inhalation-treated, and intravenous paclitaxel liposome-treated. Fibrosis was induced by bleomycin injection. A total of 20 mg/kg paclitaxel liposome was administered by inhalation every other day for a total of 10 doses. The intravenous group received 5 mg/kg paclitaxel liposome on days 1, 7, 14, and 21. We observed the general condition, weight change, survival index, and pathological changes in the lung tissue of the rats. Quantitative analysis of collagen types I and III and transforming growth factor (TGF)-β1 expression in the lungs was also performed. The paclitaxel liposome inhalation and intravenous delivery methods improved survival index and pulmonary fibrosis Ashcroft score, and decreased the thickness of the alveolar interval. No obvious difference was found between the two groups. Compared with the untreated group, paclitaxel liposome inhalation and intravenous injection significantly reduced the levels of collagen types I and III and TGF-β1 expression equally. In conclusion, atomized paclitaxel liposome inhalation protects against severe pulmonary fibrosis in a bleomycin-induced rat model. This delivery method has less systemic side effects and increased safety over intravenous injection.

  7. Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish

    PubMed Central

    Lisse, Thomas S.; Middleton, Leah J.; Pellegrini, Adriana D.; Martin, Paige B.; Spaulding, Emily L.; Lopes, Olivia; Brochu, Elizabeth A.; Carter, Erin V.; Waldron, Ashley; Rieger, Sandra

    2016-01-01

    Paclitaxel is a microtubule-stabilizing chemotherapeutic agent that is widely used in cancer treatment and in a number of curative and palliative regimens. Despite its beneficial effects on cancer, paclitaxel also damages healthy tissues, most prominently the peripheral sensory nervous system. The mechanisms leading to paclitaxel-induced peripheral neuropathy remain elusive, and therapies that prevent or alleviate this condition are not available. We established a zebrafish in vivo model to study the underlying mechanisms and to identify pharmacological agents that may be developed into therapeutics. Both adult and larval zebrafish displayed signs of paclitaxel neurotoxicity, including sensory axon degeneration and the loss of touch response in the distal caudal fin. Intriguingly, studies in zebrafish larvae showed that paclitaxel rapidly promotes epithelial damage and decreased mechanical stress resistance of the skin before induction of axon degeneration. Moreover, injured paclitaxel-treated zebrafish skin and scratch-wounded human keratinocytes (HEK001) display reduced healing capacity. Epithelial damage correlated with rapid accumulation of fluorescein-conjugated paclitaxel in epidermal basal keratinocytes, but not axons, and up-regulation of matrix-metalloproteinase 13 (MMP-13, collagenase 3) in the skin. Pharmacological inhibition of MMP-13, in contrast, largely rescued paclitaxel-induced epithelial damage and neurotoxicity, whereas MMP-13 overexpression in zebrafish embryos rendered the skin vulnerable to injury under mechanical stress conditions. Thus, our studies provide evidence that the epidermis plays a critical role in this condition, and we provide a previously unidentified candidate for therapeutic interventions. PMID:27035978

  8. Evaluation of biosafety and intracellular uptake of Cremophor EL free paclitaxel elastic liposomal formulation.

    PubMed

    Utreja, Puneet; Jain, Subheet; Tiwary, A K

    2012-01-01

    The present study examines the acute, sub-acute toxicity, and cytotoxicity of paclitaxel elastic liposomal formulation in comparison to a marketed Cremophor EL (polyoxyethylated castor oil):ethanol (1:1, v/v) based formulation. In the previous study, Cremophor EL free paclitaxel elastic liposomal formulation was developed and characterized. Cytotoxicity of formulation was evaluated by MTT assay using A549 cell lines. Percentage intracellular uptake of paclitaxel elastic liposomal and marketed formulation was determined using a fluorescence activating cell sorting assay (FACS) and fluorescence microscopy techniques. Single and repeated dose toxicity measurement showed no mortality, hematological, biochemical, or histopathological changes up to a dose of 120 mg/kg for paclitaxel elastic liposomal formulation, in comparison the marketed formulation showed toxicity at a dose of 40 mg/kg. Maximum tolerated dose (MTD) for paclitaxel elastic liposomal and marketed formulation was found to be 160 mg/kg and 40 mg/kg, respectively. Results of FACS analysis showed a 94.6 ± 2.5% intracellular uptake of fluorescence marker acridine orange (AO) loaded in elastic liposomes; in comparison the AO solution showed only a 19.8 ± 1.1% uptake. Paclitaxel elastic liposomal formulation seems to be a better alternative for safe and effective delivery of paclitaxel. This study proves the safety and higher intracellular uptake of paclitaxel elastic liposomal formulation.

  9. Autophagy regulates resistance of non-small cell lung cancer cells to paclitaxel.

    PubMed

    Chen, Kan; Shi, Wenjun

    2016-08-01

    Paclitaxel is a chemotherapeutic drug that is effective for treating non-small cell lung cancer (NSCLC). However, some NSCLCs are not sensitive to paclitaxel treatment with undetermined underlying molecular mechanisms. In this study, we found that paclitaxel dose-dependently activated Beclin-1 in 2 NSCLC cell lines, A549 and Calu-3. Inhibition of autophagy significantly increased the paclitaxel-induced NSCLC cell death in a cell counting kit-8 (CCK-8) assay. Moreover, microRNA (miR)-216b levels were significantly downregulated in paclitaxel-treated NSCLC cells. Bioinformatics study showed that miR-216b targeted the 3'-UTR of Beclin-1 mRNA to inhibit its translation, which was confirmed by luciferase reporter assay. Together, these data suggest that paclitaxel may decrease miR-216b levels in NSCLC cells, which subsequently upregulates Beclin-1 to increase NSCLC cell autophagy to antagonize paclitaxel-induced cell death. Strategies that increase miR-216b levels or inhibit cell autophagy may improve the outcome of paclitaxel treatment in NSCLC therapy.

  10. Blocking the GABA transporter GAT-1 ameliorates spinal GABAergic disinhibition and neuropathic pain induced by paclitaxel

    PubMed Central

    Yadav, Ruchi; Yan, Xisheng; Maixner, Dylan W.; Gao, Mei; Weng, Han-Rong

    2015-01-01

    Paclitaxel is a chemotherapeutic agent widely used for treating carcinomas. Patients receiving paclitaxel often develop neuropathic pain and have a reduced quality of life which hinders the use of this life-saving drug. In this study, we determined the role of GABA transporters in the genesis of paclitaxel-induced neuropathic pain using behavioral tests, electrophysiology, and biochemical techniques. We found that tonic GABA receptor activities in the spinal dorsal horn were reduced in rats with neuropathic pain induced by paclitaxel. In normal controls, tonic GABA receptor activities were mainly controlled by the GABA transporter GAT-1 but not GAT-3. In the spinal dorsal horn, GAT-1 was expressed at presynaptic terminals and astrocytes while GAT-3 was only expressed in astrocytes. In rats with paclitaxel-induced neuropathic pain, the protein expression of GAT-1 was increased while GAT-3 was decreased. This was concurrently associated with an increase of global GABA uptake. The paclitaxel-induced attenuation of GABAergic tonic inhibition was ameliorated by blocking GAT-1 but not GAT-3 transporters. Paclitaxel-induced neuropathic pain was significantly attenuated by the intrathecal injection of a GAT-1 inhibitor. These findings suggest that targeting GAT-1 transporters for reversing disinhibition in the spinal dorsal horn may be a useful approach for treating paclitaxel-induced neuropathic pain. PMID:25827582

  11. Pharmacogenetic analysis of paclitaxel transport and metabolism genes in breast cancer.

    PubMed

    Marsh, S; Somlo, G; Li, X; Frankel, P; King, C R; Shannon, W D; McLeod, H L; Synold, T W

    2007-10-01

    Paclitaxel is commonly used in the treatment of breast cancer. Variability in paclitaxel clearance may contribute to the unpredictability of clinical outcomes. We assessed genomic DNA from the plasma of 93 patients with high-risk primary or stage IV breast cancer, who received dose-intense paclitaxel, doxorubicin and cyclophosphamide. Eight polymorphisms in six genes associated with metabolism and transport of paclitaxel were analyzed using Pyrosequencing. We found no association between ABCB1, ABCG2, CYP1B1, CYP3A4, CYP3A5 and CYP2C8 genotypes and paclitaxel clearance. However, patients homozygous for the CYP1B1*3 allele had a significantly longer progression-free survival than patients with at least one Valine allele (P=0.037). This finding could reflect altered paclitaxel metabolism, however, the finding was independent of paclitaxel clearance. Alternatively, the role of CYP1B1 in estrogen metabolism may influence the risk of invasive or paclitaxel resistant breast cancer in patients carrying the CYP1B1*3 allele.

  12. Fmoc-conjugated PEG-vitamin E2 micelles for tumor-targeted delivery of paclitaxel: enhanced drug-carrier interaction and loading capacity.

    PubMed

    Zhang, Yifei; Huang, Yixian; Zhao, Wenchen; Lu, Jianqin; Zhang, Peng; Zhang, Xiaolan; Li, Jiang; Gao, Xiang; Venkataramanan, Raman; Li, Song

    2014-11-01

    The purpose of this study is to develop an improved drug delivery system for enhanced paclitaxel (PTX) loading capacity and formulation stability based on PEG5K-(vitamin E)2 (PEG5K-VE2) system. PEG5K-(fluorenylmethoxycarbonyl)-(vitamin E)2 (PEG5K-FVE2) was synthesized using lysine as the scaffold. PTX-loaded PEG5K-FVE2 micelles were prepared and characterized. Fluorescence intensity of Fmoc in the micelles was measured as an indicator of drug-carrier interaction. Cytotoxicity of the micelle formulations was tested on various tumor cell lines. The therapeutic efficacy and toxicity of PTX-loaded micelles were investigated using a syngeneic mouse model of breast cancer (4T1.2). Our data suggest that the PEG5K-FVE2 micelles have a low CMC value of 4 μg/mL and small sizes (~60 nm). The PTX loading capacity of PEG5K-FVE2 micelles was much higher than that of PEG5K-VE2 micelles. The Fmoc/PTX physical interaction was clearly demonstrated by a fluorescence quenching assay. PTX-loaded PEG5K-FVE2 micelles exerted more potent cytotoxicity than free PTX or Taxol formulation in vitro. Finally, intravenous injection of PTX-loaded PEG5K-FVE2 micelles showed superior anticancer activity compared with PEG5K-VE2 formulation with minimal toxicity in a mouse model of breast cancer. In summary, incorporation of a drug-interactive motif (Fmoc) into PEG5K-VE2 micelles represents an effective strategy to improve the micelle formulation for the delivery of PTX.

  13. Folate-mediated targeted and intracellular delivery of paclitaxel using a novel deoxycholic acid-O-carboxymethylated chitosan–folic acid micelles

    PubMed Central

    Wang, Feihu; Chen, Yuxuan; Zhang, Dianrui; Zhang, Qiang; Zheng, Dandan; Hao, Leilei; Liu, Yue; Duan, Cunxian; Jia, Lejiao; Liu, Guangpu

    2012-01-01

    Background A critical disadvantage for successful chemotherapy with paclitaxel (PTX) is its nontargeting nature to cancer cells. Folic acid has been employed as a targeting ligand of various anticancer agents to increase their cellular uptake within target cells since the folate receptor is overexpressed on the surface of such tumor cells. In this study, a novel biodegradable deoxycholic acid-O-carboxymethylated chitosan–folic acid conjugate (DOMC-FA) was used to form micelles for encapsulating the anticancer drug PTX. Methods and results The drug-loading efficiency, encapsulation efficiency, in vitro drug release and physicochemical properties of PTX-loaded micelles were investigated in detail. In vitro cell culture studies were carried out in MCF-7 cells, a human breast carcinoma cell line, with folate receptor overexpressed on its surface. An increased level of uptake of folate-conjugated micelles compared to plain micelles in MCF-7 cells was observed, and the enhanced uptake of folate-micelles mainly on account of the effective process of folate receptor-mediated endocytosis. The MTT assay, morphological changes, and apoptosis test implied that the folate-conjugated micelles enhanced the cell death by folate-mediated active internalization, and the cytotoxicity of the FA-micellar PTX (DOMC-FA/PTX) to cancer cells was much higher than micelles without folate (DOMC/PTX) or the commercially available injectable preparation of PTX (Taxol). Conclusion Results indicate that the PTX-loaded DOMC-FA micelle is a successful anticancertargeted drug-delivery system for effective cancer chemotherapy. PMID:22287842

  14. Thermoreversible Pluronic® F127-based hydrogel containing liposomes for the controlled delivery of paclitaxel: in vitro drug release, cell cytotoxicity, and uptake studies

    PubMed Central

    Nie, Shufang; Hsiao, WL Wendy; Pan, Weisan; Yang, Zhijun

    2011-01-01

    Purpose To develop an in situ gel system comprising liposome-containing paclitaxel (PTX) dispersed within the thermoreversible gel (Pluronic® F127 gel) for controlled release and improved antitumor drug efficiency. Methods The dialysis membrane and membrane-less diffusion method were used to investigate the in vitro drug release behavior. Differential scanning calorimetry (DSC) thermal analysis was used to investigate the “micellization” and “sol/gel transition” process of in situ gel systems. In vitro cytotoxicity and drug uptake in KB cancer cells were determined by MTT, intercellular drug concentration, and fluorescence intensity assay. Results The in vitro release experiment performed with a dialysis membrane model showed that the liposomal gel exhibited the longest drug-release period compared with liposome, general gel, and commercial formulation Taxol®. This effect is presumably due to the increased viscosity of liposomal gel, which has the effect of creating a drug reservoir. Both drug and gel release from the in situ gel system operated under zero-order kinetics and showed a correlation of release of PTX with gel, indicating a predominating release mechanism of the erosion type. Dispersing liposomes into the gel replaced larger gel itself for achieving the same gel dissolution rate. Both the critical micelle temperature and the sol/gel temperature, detected by DSC thermal analysis, were shifted to lower temperatures by adding liposomes. The extent of the shifts depended on the amount of embedded liposomes. MTT assay and drug uptake studies showed that the treatment with PTX-loaded liposomal 18% Pluronic F127 yielded cytotoxicities, intercellular fluorescence intensity, and drug concentration in KB cells much higher than that of conventional liposome, while blank liposomal 18% Pluronic F127 gel was far less than the Cremophor EL® vehicle and empty liposomes. Conclusions A thermosensitive hydrogel with embedded liposome is a promising carrier for

  15. Development of multifunctional lipid nanocapsules for the co-delivery of paclitaxel and CpG-ODN in the treatment of glioblastoma.

    PubMed

    Lollo, Giovanna; Vincent, Marie; Ullio-Gamboa, Gabriela; Lemaire, Laurent; Franconi, Florence; Couez, Dominique; Benoit, Jean-Pierre

    2015-11-30

    In this work, multifunctional lipid nanocapsules (M-LNC) were designed to combine the activity of the cytotoxic drug paclitaxel (PTX) with the immunostimulant CpG. This nanosystem, consisting of modified lipid nanocapsules coated with a cationic polymeric shell composed of chitosan (CS), was able to allocate the hydrophobic drug PTX in the inner oily core, and to associate onto the surface the genetic material CpG. The CS-coated LNC (CS-LNC), showed a narrow size distribution with an average size of 70 nm and a positive zeta potential (+25 mV). They encapsulated PTX in a high amount (98%), and, due to the cationic surface charge, were able to adsorb CpG without losing stability. As a preliminary in vitro study, the apoptotic effect on GL261 glioma cells was investigated. The drug-loaded CS-LNC exhibited the ability to interact with glioma cells and induce an important apoptotic effect in comparison with blank systems. Finally, the M-LNC made of CS-LNC loaded with both CpG and PTX were tested in vivo, injected via convention enhanced delivery (CED) in GL261-glioma-bearing mice. The results showed that the overall survival of mice treated with the M-LNC was significantly increased in comparison with the control, Taxol(®), or the separated injection of PTX-loaded LNC and CpG. This effect was also confirmed by magnetic resonance imaging (MRI) which revealed the reduction of tumor growth in the animals treated with CpG and PTX-loaded M-LNC. All these findings suggested that the developed M-LNC could potentiate both CpG immunopotency and PTX antitumor activity by enhancing its delivery into the tumor microenvironment.

  16. 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

  17. 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.

  18. Pharmacokinetic drug interactions between apigenin, rutin and paclitaxel mediated by P-glycoprotein in rats.

    PubMed

    Kumar, K Kishore; Priyanka, Leena; Gnananath, K; Babu, P Ravindra; Sujatha, S

    2015-09-01

    The aim of present study was to investigate the effects of apigenin and rutin on the pharmacokinetics of paclitaxel after oral administration of paclitaxel with apigenin and rutin to rats. Paclitaxel (40 mg/kg) was administered orally alone and in combination with apigenin and rutin (10, 20, and 40 mg/kg) for 15 consecutive days. In the single-dose pharmacokinetic study (SDS), blood samples were collected on 1st day whereas on 15th day in the multiple-dose pharmacokinetic study (MDS). The plasma concentrations of paclitaxel were increased dose-dependently in the combination of apigenin and rutin compared to that of paclitaxel control in SDS and MDS (p < 0.01). The areas under the plasma concentration-time curve (AUC) and the plasma peak concentrations (C max) of paclitaxel with apigenin and rutin were significantly higher (p < 0.01) than that of the control. The AUCs and C max of paclitaxel were increased with apigenin and rutin in the dose-dependent manner. The half-life (t 1/2) was significantly longer than that of the control. Non-everted sacs were filled with paclitaxel 100 μM in the presence and absence of verapamil (50 μM), apigenin, and rutin (50, 100 μM) and incubated at 37 ºC for 60 min. The absorption of paclitaxel was increased in the presence of apigenin, rutin, and verapamil, a typical P-glycoprotein and Cyp3A4 inhibitor. If these results are confirmed in humans in a clinical setting, the paclitaxel dose should be adjusted when it is given concomitantly with apigenin and rutin.

  19. Nab-paclitaxel as alternative treatment regimen in advanced cholangiocellular carcinoma

    PubMed Central

    Unseld, Matthias; Scheithauer, Werner; Weigl, Roman; Kornek, Gabriela; Stranzl, Nadja; Bianconi, Daniela; Brunauer, Georg; Steger, Guenther; Zielinski, Christoph C.

    2016-01-01

    Background Advanced cholangiocellular carcinoma has a poor prognosis with limited therapeutic options. Nab-paclitaxel has recently been described to be beneficial in metastatic pancreatic cancer improving overall and progression free survival (PFS). The potential antitumor activity of nab-paclitaxel in cholangiocellular carcinoma is hitherto unknown. Methods We retrospectively analyzed an institutional cholangiocellular carcinoma registry to determine the potential biological activity of nab-paclitaxel in advanced intrahepatic cholangiocellular carcinoma. Disease control rate (DCR), PFS and overall survival (OS) upon nab-paclitaxel based treatment, after failure of platinum-containing first-line combination chemotherapy, was assessed. Results Twelve patients were identified. Five of 12 patients (42%) received nab-paclitaxel as second line, and 7 patients (56%) as third-line treatment. The objective DCR with nab-paclitaxel was 83% (10/12 patients). One patient had a complete remission (CR), two patients had a partial remission (PR) and 7 patients had stable disease (SD). Disease was rated progressive in two patients. In all 12 patients receiving nab-paclitaxel the median time to progression was 6 months (range, 2.1–19.5 months). Median OS after initiation of nab-paclitaxel treatment was 9 months (2.1–28.4 months). The median time of survival after diagnosis of advanced disease was 21.5 months, whereby 3 patients were alive at the date of censoring (04/01/2015). Conclusions This is the first report suggesting substantial antitumor activity of nab-paclitaxel in advanced cholangiocellular carcinoma. In this small series, nab-paclitaxel based salvage chemotherapy appears to have a biological activity by controlling the disease and positively affecting survival. Randomized trials in this disease entity and subgroup of patients are urged. PMID:27563449

  20. Effects of paclitaxel on the development of neuropathy and affective behaviors in the mouse.

    PubMed

    Toma, Wisam; Kyte, S Lauren; Bagdas, Deniz; Alkhlaif, Yasmin; Alsharari, Shakir D; Lichtman, Aron H; Chen, Zhi-Jian; Del Fabbro, Egidio; Bigbee, John W; Gewirtz, David A; Damaj, M Imad

    2017-02-22

    Paclitaxel, one of the most commonly used cancer chemotherapeutic drugs, effectively extends the progression-free survival of breast, lung, and ovarian cancer patients. However, paclitaxel and other chemotherapy drugs elicit peripheral nerve fiber dysfunction or degeneration that leads to peripheral neuropathy in a large proportion of cancer patients. Patients receiving chemotherapy also often experience changes in mood, including anxiety and depression. These somatic and affective disorders represent major dose-limiting side effects of chemotherapy. Consequently, the present study was designed to develop a preclinical model of paclitaxel-induced negative affective symptoms in order to identify treatment strategies and their underlying mechanisms of action. Intraperitoneal injections of paclitaxel (8 mg/kg) resulted in the development and maintenance of mechanical and cold allodynia. Carboplatin, another cancer chemotherapeutic drug that is often used in combination with paclitaxel, sensitized mice to the nociceptive effects of paclitaxel. Paclitaxel also induced anxiety-like behavior, as assessed in the novelty suppressed feeding and light/dark box tests. In addition, paclitaxel-treated mice displayed depression-like behavior during the forced swim test and an anhedonia-like state in the sucrose preference test. In summary, paclitaxel produced altered behaviors in assays modeling affective states in C57BL/6J male mice, while increases in nociceptive responses were longer in duration. The characterization of this preclinical model of chemotherapy-induced allodynia and affective symptoms, possibly related to neuropathic pain, provides the basis for determining the mechanism(s) underlying severe side effects elicited by paclitaxel, as well as for predicting the efficacy of potential therapeutic interventions.

  1. Measurement of paclitaxel in biological matrices: high-throughput liquid chromatographic-tandem mass spectrometric quantification of paclitaxel and metabolites in human and dog plasma.

    PubMed

    Alexander, Michael S; Kiser, Melissa M; Culley, Travis; Kern, John R; Dolan, John W; McChesney, James D; Zygmunt, Jan; Bannister, Steve J

    2003-03-05

    A GLP-validated, sensitive and specific LC-MS-MS method for the quantification of paclitaxel and its 6-alpha- and 3'-p-hydroxy metabolites is presented. A 0.400 ml plasma aliquot is spiked with a (13)C(6)-labeled paclitaxel internal standard and extracted with 1 ml methyl-tert.-butyl ether. The ether is evaporated and the residue is reconstituted in 130 microl of 30% aqueous acetonitrile (ACN) containing 0.1% trifluoroacetic acid. Isocratic HPLC analysis is performed by injecting 50 microl of the reconstituted material onto a 50x2.1 mm C(18) column with an ACN-water-acetic acid (50:50:0.1) mobile phase at 200 microl/min flow. Detection is by positive ion electrospray followed by multiple reaction monitoring of the following transitions: paclitaxel (854>509 u), 6-alpha-hydroxy paclitaxel (870>525 u), 3'-p-hydroxy paclitaxel (870>509 u) and internal standard (860>509 u). Quantification is by peak area ratio against the 13C(6) internal standard. The method range is 0.117-117 nM (0.1-100 ng/ml) for paclitaxel and both metabolites using a 0.400 ml human or dog plasma sample. Analysis time per sample is less than 5 min.

  2. Taxol and tau overexpression induced calpain-dependent degradation of the microtubule-destabilizing protein SCG10.

    PubMed

    Vega, Irving E; Hamano, Tadanori; Propost, Josh A; Grenningloh, Gabriele; Yen, Shu-Hui

    2006-11-01

    Microtubule-stabilizing and -destabilizing proteins play a crucial role in regulating the dynamic instability of microtubules during neuronal development and synaptic transmission. The microtubule-destabilizing protein SCG10 is a neuron-specific protein implicated in neurite outgrowth. The SCG10 protein is significantly reduced in mature neurons, suggesting that its expression is developmentally regulated. In contrast, the microtubule-stabilizing protein tau is expressed in mature neurons and its function is essential for the maintenance of neuronal polarity and neuronal survival. Thus, the establishment and maintenance of neuronal polarity may down-regulate the protein level/function of SCG10. In this report, we show that treatment of PC12 cells and neuroblastoma cells with the microtubule-stabilizing drug Taxol induced a rapid degradation of the SCG10 protein. Consistently, overexpression of tau protein in neuroblastoma cells also induced a reduction in SCG10 protein levels. Calpain inhibitor MDL-28170, but not caspase inhibitors, blocked a significant decrease in SCG10 protein levels. Collectively, these results indicate that tau overexpression and Taxol treatment induced a calpain-dependent degradation of the microtubule-destabilizing protein SCG10. The results provide evidence for the existence of an intracellular mechanism involved in the regulation of SCG10 upon microtubule stabilization.

  3. Loss of functional E-cadherin renders cells more resistant to the apoptotic agent taxol in vitro

    SciTech Connect

    Ferreira, Paulo; Oliveira, Maria Jose; Beraldi, Eliana; Mateus, Ana Rita; Nakajima, Takashi; Gleave, Martin; Yokota, Jun; Carneiro, Fatima; Huntsman, David; Seruca, Raquel; Suriano, Gianpaolo . E-mail: gsuriano@ipatimup.pt

    2005-10-15

    Experimental evidence supports a role for E-cadherin in suppressing invasion, metastasis, and proliferation. Germline mutations of the E-cadherin represent the genetic cause of hereditary diffuse gastric cancer (HDGC). In this type of tumor, isolated cancer cells permeate the basal membrane and paradoxically survive in the gastric wall in the absence of contact with neighbor epithelial cells or with the extracellular matrix. This suggests that upon E-cadherin deregulation, cells acquired resistance to apoptosis. To test this hypothesis, CHO cells stably expressing either wild-type E-cadherin or the HDGC-related germline mutations T340A and V832M were seeded either on a thin layer of collagen type I or on plastic and then subjected to the apoptotic agent taxol. We found that in vitro functional E-cadherin renders cells more sensitive to the effect of taxol. Our results also indicate that this effect is associated to decreased level of the anti-apoptotic bcl-2 protein.

  4. Inhibition of Skp2 sensitizes lung cancer cells to paclitaxel

    PubMed Central

    Huang, Tonghai; Yang, Lin; Wang, Guangsuo; Ding, Guanggui; Peng, Bin; Wen, Yuxin; Wang, Zheng

    2017-01-01

    S-phase kinase-associated protein 2 (Skp2) is an E3 ubiquitin ligase and plays an important role in the control of cell cycle progression. Skp2 is upregulated in several cancers, including lung cancers, but the role of Skp2 in the tumorigenesis and anticancer drug resistance in human lung cancer remains to be determined. We report here that Skp2 positively regulated mitotic arrest deficient 2 (MAD2) expression and that inhibition of Skp2 sensitizes human lung cancer cells to paclitaxel. Knockdown of Skp2 by small interfering RNA (siRNA) decreased Mad2 messenger RNA (mRNA) and protein levels in A549 and NCI-H1975 cells, accompanied with upregulation of p27 but decrease of the phosphorylation of retinoblastoma (Rb). In contrast, ectopic overexpression of Skp2 increased Mad2 mRNA and protein levels and phosphorylation of Rb, while it decreased p27. Pharmacological inhibition of CDK1/2 by flavopiridol or E2F1 with HLM006474 led to downregulation of Mad2 expression and prevented the increase of Mad2 expression by Skp2. Most importantly, pharmacological inhibition of Skp2 sensitized A549 and NCI-H1299 cells to paclitaxel. Our results demonstrated that SKP2 positively regulates the gene expression of MAD2 through p27-CDKs-E2F1 signaling pathway and that inhibition of Skp2 sensitizes A549 and NCI-H1299 cells to paclitaxel, suggesting that small molecule inhibitors of Skp2 are potential agents for the treatment of lung cancer with upregulation of Skp2. PMID:28176922

  5. 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-β 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

  6. Isolation and characterization of Stemphylium sedicola SBU-16 as a new endophytic taxol-producing fungus from Taxus baccata grown in Iran.

    PubMed

    Mirjalili, Mohammad Hossein; Farzaneh, Mohsen; Bonfill, Mercedes; Rezadoost, Hassan; Ghassempour, Alireza

    2012-03-01

    In this study, a total of 25 endophytic fungi were successfully isolated from the inner bark of Taxus baccata grown in Iran by the aseptic technique. Genomic DNA was extracted from isolated endophytic fungi and subjected to polymerase chain reaction (PCR) analysis for the presence of the Taxus taxadiene synthase (ts) gene, which encodes the enzyme catalyzing the first committed step of taxol biosynthesis. Four of 25 isolated endophytic fungi isolates showed PCR positive for the ts gene. Subsequently, taxol and 10-deacetylbaccatin III (10-DAB III) were extracted from culture filtrates and mycelia of the PCR positive isolates and analyzed by high-performance liquid chromatography and mass spectrometry. The analysis showed that one isolate (SBU-16) produced taxol (6.9 ± 0.2 μg L(-1) ) and its intermediate compound, 10-DAB III (2.2 ± 0.1 μg L(-1) ). The isolate SBU-16 was identified as Stemphylium sedicola SBU-16, according to its morphological characteristics as well as the internal transcribed spacer nuclear rDNA gene sequence analysis. Interestingly, this is the first report of the genus Stemphylium as a taxol-producing taxon.

  7. Twelve protofilament taxol-induced microtubules assembled from purified tublin. A synchrotron X-ray scattering study in comparison with glycerol- and map-induced microtubules

    NASA Astrophysics Data System (ADS)

    Andreu, J. M.; Garcia de Ancos, J.; Medrano, F. J.; Gil, R.; Diaz, J. F.; Nogales, E.; Towns-Andrews, E.; Pantos, E.; Bordas, J.

    1991-05-01

    The X-ray solution scattering profiles of taxol microtubules made of purified tubulin and control microtubules, assembled either from purified tubulin in glycerol buffer (a non-specific enhancer of the polymerization of tubulin) or from microtubule protein (a preparation containing tubulin plus microtubule associated proteins), were obtained to 3.3 nm resolution. These profiles show features of the microtubule wall structure which had not been observed in solution before. Comparison of the different profiles indicated that the structure of the microtubule wall is very similar in the three types of microtubules to the resolution of the measurements, however the mean diameter of the taxol microtubules is smaller than that of the control microtubules, by approximately one protofilament less. Actually, only 12 protofilament computer models of microtubules could fit the position of the maxima in the experimental scattering profile of the taxol microtubules. Having only 12 protofilaments implies a discontinuity on the microtubule wall, irrespective of whether the lateral contacts follow the A or B microtubule lattice, and also requires adjustment of the normal lattice to one protofilament axis with respect to the cylinder axis. The fact that the majority of these taxol microtubules assembled from purified tubulin have 12 protofilaments has been visualized by electron micrographs of tannic acid stained microtubule thin sections, and is fully consistent with the microtubule wall projections (fringe patterns) observed in negatively stained and cryo-electron microscopy specimens, which correspond to a 12 protofilament-three start lattice type.

  8. Spatial-temporal distribution of nitric oxide involved in regulation of phenylalanine ammonialyase activation and Taxol production in immobilized Taxus cuspidata cells.

    PubMed

    Xiao, Wen-Hai; Cheng, Jing-sheng; Yuan, Ying-Jin

    2009-02-05

    The generation of nitric oxide (NO) in Taxus cuspidata in immobilized support matrices and the potential role of NO as signal molecular in regulation of Taxol production were investigated. It was found that the immobilization induced a spatial and temporal-dependent NO burst in immobilized supported matrices. NO level reached the maximum in the central zone of immobilized supported matrices on day 20, which was more than twice compared with that in suspended cells. Further investigations showed that the phenylalanine ammonialyase (PAL) activity and Taxol production of the 20-day-old immobilized T. cuspidata cells increased by onefold and 11% after 4h treatment with 20 microM NO donor (sodium nitroprusside), respectively. NO inhibitor N(omega)-nitro-L-arginine and NO scavenger 2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxyde partially blocked PAL activity and Taxol accumulation in immobilized cells. These results suggest that NO plays a signal role in regulation of PAL activity and Taxol production in immobilized T. cuspidata cells.

  9. Evaluation of the effect of the chiral centers of Taxol on binding to β-tubulin: A docking and molecular dynamics simulation study.

    PubMed

    Ghadari, Rahim; Alavi, Fatemeh S; Zahedi, Mansour

    2015-06-01

    Taxol is one of the most important anti-cancer drugs. The interaction between different variants of Taxol, by altering one of its chiral centers at a time, with β-tubulin protein has been investigated. To achieve such goal, docking and molecular dynamics (MD) simulation studies have been performed. In docking studies, the preferred conformers have been selected to further study by MD method based on the binding energies reported by the AutoDock program. The best result of docking study which shows the highest affinity between ligand and protein has been used as the starting point of the MD simulations. All of the complexes have shown acceptable stability during the simulation process, based on the RMSDs of the backbone of the protein structure. Finally, MM-GBSA calculations have been carried out to select the best ligand, considering the binding energy criteria. The results predict that two of the structures have better affinity toward the mentioned protein, in comparison with Taxol. Three of the structures have affinity similar to that of the Taxol toward the β-tubulin.

  10. Chemotherapy Drugs Thiocolchicoside and Taxol Permeabilize Lipid Bilayer Membranes by Forming Ion Pores

    NASA Astrophysics Data System (ADS)

    Ashrafuzzaman, Md; Duszyk, M.; Tuszynski, J. A.

    2011-12-01

    We report ion channel formation by chemotherapy drugs: thiocolchicoside (TCC) and taxol (TXL) which primarily target tubulin but not only. For example, TCC has been shown to interact with GABAA, nuclear envelope and strychnine-sensitive glycine receptors. TXL interferes with the normal breakdown of microtubules inducing mitotic block and apoptosis. It also interacts with mitochondria and found significant chemotherapeutic applications for breast, ovarian and lung cancer. In order to better understand the mechanisms of TCC and TXL actions, we examined their effects on phospholipid bilayer membranes. Our electrophysiological recordings across membranes constructed in NaCl aqueous phases consisting of TCC or TXL under the influence of an applied transmembrane potential (V) indicate that both molecules induce stable ion flowing pores/channels in membranes. Their discrete current versus time plots exhibit triangular shapes which is consistent with a spontaneous time-dependent change of the pore conductance in contrast to rectangular conductance events usually induced by ion channels. These events exhibit conductance (~0.01-0.1 pA/mV) and lifetimes (~5-30 ms) within the ranges observed in e.g., gramicidin A and alamethicin channels. The channel formation probability increases linearly with TCC/TXL concentration and V and is not affected by pH (5.7 - 8.4). A theoretical explanation on the causes of chemotherapy drug induced ion pore formation and the pore stability has also been found using our recently discovered binding energy between lipid bilayer and the bilayer embedded ion channels using gramicidin A channels as tools. This picture of energetics suggests that as the channel forming agents approach to the lipids on bilayer the localized charge properties in the constituents of both channel forming agents (e.g., chemotherapy drugs in this study) and the lipids determine the electrostatic drug-lipid coupling energy through screened Coulomb interactions between the drug

  11. Effect of a thiolated polymer on oral paclitaxel absorption and tumor growth in rats.

    PubMed

    Föger, Florian; Malaivijitnond, Suchinda; Wannaprasert, Thanakul; Huck, Christian; Bernkop-Schnürch, Andreas; Werle, Martin

    2008-02-01

    The anticancer agent paclitaxel is currently commercially available only as an infusion due to its low oral bioavailability. An oral formulation would be highly beneficial for patients. Besides the low solubility, the main reason for the limited oral bioavailability of paclitaxel is that it is a substrate of the efflux pump P-glycoprotein (P-gp). Recently, it has been demonstrated that P-gp can be inhibited by thiolated polymers. In this study, an oral paclitaxel formulation based on thiolated polycarbophil was evaluated in vivo in wild-type rats and in mammary cancer-induced rats. The paclitaxel plasma level after a single administration of paclitaxel was observed for 12 h in healthy rats. Moreover, cancer-induced rats were treated weekly for 5 weeks with the novel formulation. It was demonstrated that (1) co-administration of thiolated polycarbophil significantly improved paclitaxel plasma levels, (2) a more constant pharmacokinetic profile could be achieved and (3) the tumor growth was reduced. These effects can most likely be attributed to P-gp inhibition. According to the achieved results, thiolated polymers are believed to be interesting tools for the delivery of P-gp substrates such as paclitaxel.

  12. Local Release of Paclitaxel from Aligned, Electrospun Microfibers Promotes Axonal Extension.

    PubMed

    Roman, Jose A; Reucroft, Ian; Martin, Russell A; Hurtado, Andres; Mao, Hai-Quan

    2016-10-01

    Traumatic spinal cord injuries ultimately result in an inhibitory environment that prevents axonal regeneration from occurring. A low concentration administration of paclitaxel has been previously shown to promote axonal extension and attenuate the upregulation of inhibitory molecules after a spinal cord injury. In this study, paclitaxel is incorporated into electrospun poly(l-lactic acid) (PLA) microfibers, and it is established that a local release of paclitaxel from aligned, electrospun microfibers promotes neurite extension in a growth-conducive and inhibitory environment. Isolated dorsal root ganglion cells are cultured for 5 d directly on tissue culture polystyrene surface, PLA film, random, or aligned electrospun PLA microfibers (1.44 ± 0.03 μm) with paclitaxel incorporated at various concentrations (0%-5.0% w/w in reference to fiber weight). To determine the effect of a local release of paclitaxel, paclitaxel-loaded microfibers are placed in CellCrown inserts above cultured neurons. Average neurite extension rate is quantified for each sample. A local release of paclitaxel maintains neuronal survival and neurite extension in a concentration-dependent manner when coupled with aligned microfibers when cultured on laminin or an inhibitory surface of aggrecan. The findings provide a targeted approach to improve axonal extension across the inhibitory environment present after a traumatic injury in the spinal cord.

  13. The Effect of Anakinra on Paclitaxel-Induced Peripheral Neuropathic Pain in Rats

    PubMed Central

    Kuyrukluyıldız, Ufuk; Küpeli, İlke; Bedir, Zehra; Özmen, Özgür; Onk, Didem; Süleyman, Bahadır; Mammadov, Renad; Süleyman, Halis

    2016-01-01

    Objective Paclitaxel is used in the treatment of cancer, and it may cause interleukin-1 beta (IL-1β)-related peripheral neuropathic pain. While our primary aim was to investigate the analgesic efficacy of an IL-1β antagonist, a secondary outcome was to assess whether a correlation exists between analgesic effects and antioxidant activity. Methods A total of 24 albino Wistar male rats were divided into the following groups: paclitaxel-control, paclitaxel+50 mg kg−1 anakinra, paclitaxel+100 mg kg−1 anakinra and healthy group (HG). After the normal paw pain threshold in all animal groups was measured using a Basile algesimeter, a single dose of 2 mg kg−1 paclitaxel was intraperitoneally administered on the 1st, 3rd, 5th and 7th days. Anakinra was intraperitoneally administered following the final paclitaxel administration. The paw pain thresholds in the groups were measured before and seven days after paclitaxel administration and at the 1st and 3rd hours after anakinra administration. After the third hour of measurement, the rats were killed with high doses of ketamine, and the paw tissues were removed. Malondialdehyde, myeloperoxidase and total glutathione levels were measured in claw tissues, and IL-1β gene expression was determined. The biochemical results were compared with the results of the HG; in the meanwhile the claw pain threshold results were compared with the results obtained after the last paclitaxel and the results obtained from the 1st and 3rd hours after the anakinra application. Results The claw paw pain threshold of the rats decreased one and three hours after anakinra administration. Further, 100 mg kg−1 anakinra had greater analgesic activity than 50 mg kg−1 anakinra. A correlation was found between the antioxidant and analgesic activities of 100 mg kg−1 anakinra. Conclusion Anakinra may be useful to reduce paclitaxel-induced neuropathic pain; further, 100 mg kg−1 anakinra may have greater analgesic and antioxidant activities

  14. The FOXM1-ABCC5 axis contributes to paclitaxel resistance in nasopharyngeal carcinoma cells.

    PubMed

    Hou, Youxiang; Zhu, Qianling; Li, Zheng; Peng, Yongbo; Yu, Xiaohui; Yuan, Bowen; Liu, Yijun; Liu, Youhong; Yin, Linglong; Peng, Yuchong; Jiang, Zhenghua; Li, Jinping; Xie, Bowen; Duan, Yumei; Tan, Guolin; Gulina, Kurban; Gong, Zhicheng; Sun, Lunquan; Fan, Xuegong; Li, Xiong

    2017-03-09

    Paclitaxel is clinically used as a first-line chemotherapeutic regimen for several cancer types, including head and neck cancers. However, acquired drug resistance results in the failure of therapy, metastasis and relapse. The drug efflux mediated by ATP-binding cassette (ABC) transporters and the survival signals activated by forkhead box (FOX) molecules are critical in the development of paclitaxel drug resistance. Whether FOX molecules promote paclitaxel resistance through drug efflux remains unknown. In this study, we developed several types of paclitaxel-resistant (TR) nasopharyngeal carcinoma (NPC) cells. These TR NPC cells acquired cancer stem cell (CSC) phenotypes and underwent epithelial to mesenchymal transition (EMT), and developed multidrug resistance. TR cells exhibited stronger drug efflux than parental NPC cells, leading to the reduction of intracellular drug concentrations and drug insensitivity. After screening the gene expression of ABC transporters and FOX molecules, we found that FOXM1 and ABCC5 were consistently overexpressed in the TR NPC cells and in patient tumor tissues. Further studies demonstrated that FOXM1 regulated abcc5 gene transcription by binding to the FHK consensus motifs at the promoter. The depletion of FOXM1 or ABCC5 with siRNA significantly blocked drug efflux and increased the intracellular concentrations of paclitaxel, thereby promoting paclitaxel-induced cell death. Siomycin A, a FOXM1 inhibitor, significantly enhanced in vitro cell killing by paclitaxel in drug-resistant NPC cells. This study is the first to identify the roles of FOXM1 in drug efflux and paclitaxel resistance by regulating the gene transcription of abcc5, one of the ABC transporters. Small molecular inhibitors of FOXM1 or ABCC5 have the potential to overcome paclitaxel chemoresistance in NPC patients.

  15. Advanced thymic cancer treated with carboplatin and paclitaxel in a patient undergoing hemodialysis.

    PubMed

    Miura, Satoru; Kagamu, Hiroshi; Sakai, Takehito; Nozaki, Koichiro; Asakawa, Katsuaki; Moro, Hiroshi; Okajima, Masaaki; Watanabe, Satoshi; Yamamoto, Suguru; Iino, Noriaki; Goto, Shin; Kazama, Junichiro James; Yoshizawa, Hirohisa; Narita, Ichiei

    2015-01-01

    A 53-year-old man with an asymptomatic anterior mediastinal tumor undergoing hemodialysis was referred to our institution. He was diagnosed with thymic basaloid carcinoma based on the findings of a chest tomography-guided biopsy and successfully treated with carboplatin (300 mg/m(2)/day) and paclitaxel (200 mg/m(2)/day) on day 1 for six three-week cycles. To our knowledge, this is the first report regarding the efficiency of a carboplatin dose-definition method based on the body surface area with paclitaxel in a hemodialysis patient. This report may therefore be useful for treating hemodialysis patients who are candidates for carboplatin and paclitaxel therapy.

  16. Paclitaxel Induced Acute ST Elevation Myocardial Infarction: A Rare Case Report

    PubMed Central

    Yadav, Sankalp; Kumar, Raj

    2016-01-01

    Paclitaxel, is a frequently used anti-neoplastic agent and is included in various chemotherapy regimens. The life threatening cardio toxicity associated with its use and the still unclear pathophysiology, has limited the use of this drug. Acute myocardial infarction is a rare adverse event associated with this drug. We report a case of acute ST-elevation myocardial infarction induced by paclitaxel infusion in a patient of oesophageal carcinoma who was saved by percutaneous primary intervention. The authors emphasize the awareness of this side effect of Paclitaxel among the clinicians. PMID:27891444

  17. 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

  18. Cytotoxic activity of paclitaxel incorporated into polyelectrolyte nanocapsules

    NASA Astrophysics Data System (ADS)

    Karabasz, Alicja; Bzowska, Monika; Łukasiewicz, Sylwia; Bereta, Joanna; Szczepanowicz, Krzysztof

    2014-04-01

    Nanoencapsulation is a promising solution for the delivery of chemotherapeutics to tumors. A method of preparation of drug-loaded nanocapsules based on the liquid core encapsulation by a sequential adsorption of a polyelectrolyte is described. An easily evaporative solvent, chloroform, was used as an oil phase. An interfacial complex formed with an oil-soluble, Food and Drug Administration-approved surfactant, and polycation poly- l-lysine (PLL) was used as a microemulsion stabilizer. A polyelectrolyte multilayer shell was constructed by a sequential adsorption of polyelectrolytes using biocompatible polyelectrolytes (PLL as a polycation and poly- l-glutamic acid as a polyanion). A hydrophobic anticancer agent, paclitaxel, was successfully encapsulated in the nanocarriers with the average size of 100 nm. In vitro analysis of the effects of nanoformulations was performed using a mouse colon carcinoma cell line CT26-CEA. Biocompatibility of the nanocapsules was evaluated using various biochemical assays. The results indicate that the cell viability was diminished by positively but not by negatively charged nanocarriers. Analysis of the cellular uptake of nanocapsules determined by flow cytometry and confocal microscopy confirmed their accumulation inside the cells. Encapsulated paclitaxel retains its cytotoxic/cytostatic activity; although its effects were weaker than those of the corresponding concentrations of the free drug. The generated nanocapsules seem to be a valuable vehicle for tumor drug delivery; although further work is needed to increase their overall activity.

  19. 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.

  20. Sialoganglioside Micelles for Enhanced Paclitaxel Solubility: In Vitro Characterization.

    PubMed

    Heredia, Valeria; Alasino, Roxana V; Leonhard, Victoria; Garro, Ariel G; Maggio, Bruno; Beltramo, Dante M

    2016-01-01

    Efficiency of mono-sialogangliosides to load Paclitaxel (Ptx) has recently been found to depend on the structure of the polysaccharide chain. In this study, we demonstrated that incorporation of only one more sialic acid into the ganglioside molecule, independently of its position, causes a 4-fold increase in Ptx-loading capacity, the maximum being at a 5:1 molar ratio (di-sialoganglioside/Paclitaxel, GD/Ptx). These complexes are stable in solution for at least 3 months, and over 90% of Ptx remains loaded in the micelles after extreme stress conditions such as high-speed centrifugation, lyophilization, or freeze-thaw cycles. Ganglioside micelles protect 50% of the initially loaded Ptx from alkaline hydrolysis after 24 h at pH 10. Dynamic light scattering studies revealed that GD micelles increase their size from 9 to 12 nm when loaded with Ptx. Transmission electron microscopy shows a homogeneous population of spherical micelles either with or without Ptx. In vitro biological activity was similar to that of the free drug. These results provide further options of self-assembled nanostructures of di- and tri-sialogangliosides with a higher loading capacity.

  1. Korean red ginseng extract enhances paclitaxel distribution to mammary tumors and its oral bioavailability by P-glycoprotein inhibition.

    PubMed

    Bae, Jin Kyung; Kim, You-Jin; Chae, Hee-Sung; Kim, Do Yeun; Choi, Han Seok; Chin, Young-Won; Choi, Young Hee

    2016-05-17

    1. Drug efflux by P-glycoprotein (P-gp) is a common resistance mechanism of breast cancer cells to paclitaxel, the primary chemotherapy in breast cancer. As a means of overcoming the drug resistance-mediated failure of paclitaxel chemotherapy, the potential of Korean red ginseng extract (KRG) as an adjuvant chemotherapy has been reported only in in vitro. Therefore, we assessed whether KRG alters P-gp mediated paclitaxel efflux, and therefore paclitaxel efficacy in in vitro and vivo models. 2. KRG inhibited P-gp protein expression and transcellular efflux of paclitaxel in MDCK-mdr1 cells, but KRG was not a substrate of P-gp ATPase. In female rats with mammary tumor, the combination of paclitaxel with KRG showed the greater reduction of tumor volumes, lower P-gp protein expression and higher paclitaxel distribution in tumors, and greater oral bioavailability of paclitaxel than paclitaxel alone. 3. From these results, KRG increased systemic circulation of oral paclitaxel and its distribution to tumors via P-gp inhibition in rats and under the current study conditions.

  2. Effects of repeated milnacipran and fluvoxamine treatment on mechanical allodynia in a mouse paclitaxel-induced neuropathic pain model.

    PubMed

    Katsuyama, Soh; Sato, Kazuma; Yagi, Tomomi; Kishikawa, Yukinaga; Nakamura, Hitoshi

    2013-04-01

    Paclitaxel is widely used in cancer chemotherapy for the treatment of solid tumors, but it frequently causes peripheral neuropathy. Milnacipran, a serotonin/noradrenaline reuptake inhibitor and fluvoxamine, a selective serotonin reuptake inhibitor, have shown efficacy against several chronic pain syndromes. In this study, we investigated the attenuation of paclitaxel-induced mechanical allodynia in mice by milnacipran and fluvoxamine. Paclitaxel was administered once per day (2 mg/kg, intraperitoneally (i.p.)) for 5 days to mice. Mechanical allodynia was evaluated by measuring the withdrawal response to stimulation with a von Frey filament. In paclitaxel-treated mice, mechanical allodynia was observed on days 3-15 of paclitaxel administration. A single administration of milnacipran (20 mg/kg, i.p.) or fluvoxamine (40 mg/kg, i.p.) had no effect on paclitaxel- induced mechanical allodynia. However, repeated administration of milnacipran (10, 20 mg/kg, once per day, i.p.) for 5 days significantly reduced paclitaxel-induced mechanical allodynia. In contrast, repeated fluvoxamine administration (40 mg/kg, once per day, i.p.) for 5 days resulted in a weak attenuation of paclitaxel-induced mechanical allodynia. These results suggest that chronic paclitaxel administration induces mechanical allodynia, and that repeated milnacipran administration may be an effective therapeutic approach for the treatment of neuropathic pain caused by paclitaxel treatment for cancer.

  3. [Comparative study on pharmacokinetics and tissue distribution of a novel microemulsion based on the paclitaxel/L-OH lipid complex and paclitaxel injection in cremophor].

    PubMed

    Ma, Yan-li; Ye, Jun; Zhang, Peng-xiao; Xia, Xue-jun; Liu, Yu-ling

    2013-11-01

    The pharmacokinetics and tissue distributions of the novel paclitaxel microemulsion based on the L-OH lipid complex made in our laboratory were studied in this article with the commercial paclitaxel injection in cremophor as reference preparation by injected intravenously with single dose of 5 mg x kg(-1) in rats. LC-MS/MS method was used to determine the drug concentration in plasma and calculate the pharmacokinetic parameters. [3H]-paclitaxel was used to reveal the tissue distributions of different organs in 0.5 h, 3 h, 24 h and 120 h. The results indicated that the AUC of the emulsion group descended to 42.55%, with the CLz and Vz increased by 2.27 times and 3.81 times respectively. Tissue distribution results revealed that the emulsion showed a significantly increase in liver and spleen with a peak concentration up to 5 times; a slightly increase was observed in lung with no statistical differences; a significantly decrease in heart, kidney, gastrointestinal tract, bone marrow, aorta, thymus, pancreas, fat, muscle, skin, seminal vesicle, reproductive organs and brain with a drop of 40%-80%. These results indicated that paclitaxel microemulsion based on L-OH lipid complexes can remarkably reduced the blood exposure, accelerate plasma clearance rate and increase distribution volume. The fact that paclitaxel microemulsion tended to be uptake by reticuloendothelial system (RES) contributed to the target in liver, spleen and lung, and help to reduce the toxicity in blood, heart, kidney and gastrointestinal tract.

  4. Identification of novel microtubule-binding proteins by taxol-mediated microtubule stabilization and mass spectrometry analysis

    PubMed Central

    He, Xianfei; Liu, Zhu; He, Qianqian; Qin, Juan; Liu, Ningning; Zhang, Linlin; Li, Dengwen; Zhou, Jun; Shui, Wenqing; Liu, Min

    2015-01-01

    Microtubule-binding proteins (MBPs) are structurally and functionally diverse regulators of microtubule-mediated cellular processes. Alteration of MBPs has been implicated in the pathogenesis of human diseases, including cancer. MBPs can stabilize or destabilize microtubules or move along microtubules to transport various cargoes. In addition, MBPs can control microtubule dynamics through direct interaction with microtubules or coordination with other proteins. To better understand microtubule structure and function, it is necessary to identify additional MBPs. In this study, we isolated microtubules and MBPs from mammalian cells by a taxol-based method and then profiled a panel of MBPs by mass spectrometry. We discovered a number of previously uncharacterized MBPs, including several membrane-associated proteins and proteins involved in post-translational modifications, in addition to several structural components. These results support the notion that microtubules have a wide range of functions and may undergo more exquisite regulation than previously recognized. PMID:26445615

  5. Cost-effectiveness of paclitaxel plus cisplatin in advanced non-small-cell lung cancer

    PubMed Central

    Earle, C C; Evans, W K

    1999-01-01

    The aim of this study was to assess the cost-effectiveness of combination chemotherapy with paclitaxel/cisplatin, compared with standard etoposide/cisplatin in patients with advanced non-small cell lung cancer (NSCLC). We obtained the primary survival and resource utilization data from a large three-arm randomized trial comparing: paclitaxel 135 mg m−2 by 24-h intravenous (i.v.) infusion + cisplatin; paclitaxel 250 mg m−2 by 24-h i.v. infusion + cisplatin + granulocyte colony-stimulating factor (G-CSF); and standard etoposide/cisplatin in patients with stage IIIb or IV NSCLC. We also modelled the regimens with paclitaxel 135 mg m−2 + cisplatin administered as an outpatient by 3-h infusion, as clinical data suggest that this is equivalent to 24-h infusion. We collected costing data from the Ottawa Regional Cancer Centre and applied it to the resources consumed in the randomized trial. We integrated these data into the Statistics Canada POpulation HEalth Model (POHEM), which generated hypothetical cohorts of patients treated with each regimen. The POHEM model assigned diagnostic work-up, treatment, disease progression and survival characteristics to each individual in these cohorts and tabulated the costs associated with each. We did sensitivity analyses around the costs of chemotherapy and its administration, and the survival differences between the two regimens. All costs are in 1997 Canadian dollars ($1.00 Canadian ˜ £0.39 sterling). The perspective is that of the Canadian health care system. In the trial, the two paclitaxel-containing arms had almost identical survival curves with a median survival of 9.7 months compared with 7.4 months for etoposide/cisplatin. As administered in the trial, paclitaxel/cisplatin cost $76 370 per life-year gained (LYG) and paclitaxel/cisplatin/G-CSF $138 578 per LYG relative to etoposide/cisplatin. However, when modelled as an outpatient 3-h infusion, paclitaxel/cisplatin was moderately cost-effective at $30 619 per LYG

  6. MAPK signaling downstream to TLR4 contributes to paclitaxel-induced peripheral neuropathy

    PubMed Central

    Li, Yan; Zhang, Hongmei; Kosturakis, Alyssa K.; Cassidy, Ryan M.; Zhang, Haijun; Kennamer-Chapman, Ross M.; Jawad, Abdul Basit; Colomand, Cecilia M.; Harrison, Daniel S.; Dougherty, Patrick M.

    2015-01-01

    Toll-like receptor 4 (TLR4) has been implicated as a locus for initiation of paclitaxel related chemotherapy induced peripheral neuropathy (CIPN). This project explores the involvement of the immediate down-stream signal molecules in inducing paclitaxel CIPN. Mitogen-activated protein kinases (MAPK) and nuclear factor-κB (NFκB) were measured in dorsal root ganglia (DRG) and the spinal cord over time using Western blot and immunohistochemistry in a rat model of paclitaxel CIPN. The effects of MAPK inhibitors in preventing and reversing behavioral signs of CIPN were also measured (group sizes 4–9). Extracellular signal related kinase (ERK1/2) and p38 but not c-Jun N terminal kinase (JNK) or PI3K-Akt signaling expression was increased in DRG. Phospho-ERK1/2 staining was co-localized to small CGRP-positive DRG neurons in cell profiles surrounding large DRG neurons consistent with satellite glial cells. The expression of phospho-P38 was co-localized to small IB4-positive and CGRP-positive DRG neurons. The TLR4 antagonist LPS derived from R. sphaeroides (LPS-RS) inhibited paclitaxel-induced phosphorylation of ERK1/2 and P38. The MAPK inhibitors PD98059 (MEK1/2), U0126 (MEK1/2) and SB203580 (P38) prevented but did not reverse paclitaxel-induced behavioral hypersensitivity. Paclitaxel treatment resulted in phosphorylation of Inhibitor α of NFκB (IκBα) in DRG resulting in an apparent release of NFκB from the IκBα-NFκB complex as increased expression of nuclear NFκB was also observed. LPS-RS inhibited paclitaxel-induced translocation of NFκB in DRG. No change was observed in spinal NFκB. These results implicate TLR4 signaling via MAP kinases and NFκB in the induction and maintenance of paclitaxel-related CIPN. PMID:26065826

  7. Paeonol reverses paclitaxel resistance in human breast cancer cells by regulating the expression of transgelin 2.

    PubMed

    Cai, Jiangxia; Chen, Siying; Zhang, Weipeng; Hu, Sasa; Lu, Jun; Xing, Jianfeng; Dong, Yalin

    2014-06-15

    Paclitaxel (PTX) is a first-line antineoplastic drug that is commonly used in clinical chemotherapy for breast cancer treatment. However, the occurrence of drug resistance in chemotherapeutic treatment has greatly restricted its use. There is thus an urgent need to find ways of reversing paclitaxel chemotherapy resistance in breast cancer. Plant-derived agents have great potential in preventing the onset of the carcinogenic process and enhancing the efficacy of mainstream antitumor drugs. Paeonol, a main compound derived from the root bark of Paeonia suffruticosa, has various biological activities, and is reported to have reversal drug resistance effects. This study established a paclitaxel-resistant human breast cancer cell line (MCF-7/PTX) and applied the dual-luciferase reporter gene assay, MTT assay, flow cytometry, transfection assay, Western blotting and the quantitative real-time polymerase chain reaction (qRT-PCR) to investigate the reversing effects of paeonol and its underlying mechanisms. It was found that transgelin 2 may mediate the resistance of MCF-7/PTX cells to paclitaxel by up-regulating the expressions of the adenosine-triphosphate binding cassette transporter proteins, including P-glycoprotein (P-gp), multidrug resistance associated protein 1 (MRP1), and breast cancer resistance protein (BCRP). Furthermore, the ability of paeonol to reverse paclitaxel resistance in breast cancer was confirmed, with a superior 8.2-fold reversal index. In addition, this study found that paeonol down-regulated the transgelin 2-mediated paclitaxel resistance by reducing the expressions of P-gp, MRP1, and BCRP in MCF-7/PTX cells. These results not only provide insight into the potential application of paeonol to the reversal of paclitaxel resistance, thus facilitating the sensitivity of breast cancer chemotherapy, but also highlight a potential role of transgelin 2 in the development of paclitaxel resistance in breast cancer.

  8. Prevention of Paclitaxel-Induced Neuropathy Through Activation of the Central Cannabinoid Type 2 Receptor System

    PubMed Central

    Naguib, Mohamed; Xu, Jijun J.; Diaz, Philippe; Brown, David L.; Cogdell, David; Bie, Bihua; Hu, Jianhua; Craig, Suzanne; Hittelman, Walter N.

    2012-01-01

    Background Peripheral neuropathy is a major dose-limiting toxicity of chemotherapy, especially after multiple courses of paclitaxel. The development of paclitaxel-induced neuropathy is associated with the activation of microglia followed by the activation and proliferation of astrocytes, and the expression and release of proinflammatory cytokines in the spinal dorsal horn. Cannabinoid type 2 (CB2) receptors are expressed in the microglia in neurodegenerative disease models. Methods To explore the potential of CB2 agonists for preventing paclitaxel-induced neuropathy, we designed and synthesized a novel CB2-selective agonist, namely MDA7. The effect of MDA7 in preventing paclitaxel-induced allodynia was assessed in rats and in CB2+/+ and CB2–/– mice. We hypothesize that the CB2 receptor functions in a negative-feedback loop and that early MDA7 administration can blunt the neuroinflammatory response to paclitaxel and prevent mechanical allodynia through interference with specific signaling pathways. Results We found that MDA7 prevents paclitaxel-induced mechanical allodynia in rats and mice in a dose- and time-dependent manner without compromising paclitaxel's antineoplastic effect. MDA7's neuroprotective effect was absent in CB2-/- mice and was blocked by CB2 antagonists, suggesting that MDA7's action directly involves CB2 receptor activation. MDA7 treatment was found to interfere with early events in the paclitaxel-induced neuroinflammatory response as evidenced by relatively reduced Toll-like receptor and CB2 expression in the lumbar spinal cord, reduced levels of extracellular signal regulated kinase 1/2 activity, reduced numbers of activated microglia and astrocytes, and reduced secretion of proinflammatory mediators in vivo and in in vitro models. Conclusions Our findings suggest an innovative therapeutic approach to prevent chemotherapy-induced neuropathy and may permit more aggressive use of active chemotherapeutic regimens with reduced long-term sequelae

  9. Diffuse scleroderma occurring after the use of paclitaxel for ovarian cancer.

    PubMed

    De Angelis, R; Bugatti, L; Cerioni, A; Del Medico, P; Filosa, G

    2003-02-01

    Acase of diffuse scleroderma in a 56-year-old woman who received paclitaxel for the treatment of a metastatic ovarian cancer is presented. The clinical cutaneous alterations, as well as the capillaroscopic and histological findings, were indistinguishable from those encountered in definite systemic sclerosis (SSc). In contrast to SSc, Raynaud's phenomenon and cutaneous calcinosis were absent and antinuclear antibodies were negative. The temporal relationship between the onset of skin involvement and administration of the drug may indicate an effect of paclitaxel.

  10. THE INHIBITORY EFFECT OF PACLITAXEL ON (KV2.1) K+ CURRENT IN H9c2 CELLS

    PubMed Central

    KITAMURA, NAOKO; SAKAMOTO, KAZUHO; ONO, TOMOYUKI; KIMURA, JUNKO

    2015-01-01

    ABSTRACT Using the whole-cell voltage clamp technique, we investigated the effect of paclitaxel, an anticancer agent which promotes microtubule formation, on K+ current in H9c2 cells originated from rat embryonic cardiac myocytes. Paclitaxel inhibited Kv2.1 voltage-dependent K+ current (IKur) with ultra-rapidly activating and slowly inactivating kinetics in a concentration-dependent manner. The inhibitory effect of paclitaxel on IKur was time-dependent and more marked at 200 ms after the onset than at the beginning of the depolarizing pulse. The IC50 value of paclitaxel was 1.1 µM at 200 ms. The time-dependent inhibition suggests that paclitaxel might be an open channel blocker of Kv2.1. This inhibition of Kv2.1 may be involved in the adverse effects of paclitaxel on cardiac and neuronal cells. PMID:25994081

  11. Cannabidiol prevents the development of cold and mechanical allodynia in paclitaxel-treated female C57Bl6 mice.

    PubMed

    Ward, Sara Jane; Ramirez, Michael David; Neelakantan, Harshini; Walker, Ellen Ann

    2011-10-01

    The taxane chemotherapeutic paclitaxel frequently produces peripheral neuropathy in humans. Rodent models to investigate mechanisms and treatments are largely restricted to male rats, whereas female mouse studies are lacking. We characterized a range of paclitaxel doses on cold and mechanical allodynia in male and female C57Bl/6 mice. Because the nonpsychoactive phytocannabinoid cannabidiol attenuates other forms of neuropathic pain, we assessed its effect on paclitaxel-induced allodynia. Paclitaxel produced allodynia that was largely dose independent and more robust in female mice, and this effect was prevented by treatment with cannabidiol. Our preliminary findings therefore indicate that cannabidiol may prevent the development of paclitaxel-induced allodynia in mice and therefore be effective at preventing dose-limiting paclitaxel-induced peripheral neuropathy in humans.

  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

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

    NASA Astrophysics Data System (ADS)

    Chiang, Po-Chang; Gould, Stephen; Nannini, Michelle; Qin, Ann; Deng, Yuzhong; Arrazate, Alfonso; Kam, Kimberly R.; Ran, Yingqing; Wong, Harvey

    2014-04-01

    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.

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

    PubMed

    Chiang, Po-Chang; Gould, Stephen; Nannini, Michelle; Qin, Ann; Deng, Yuzhong; Arrazate, Alfonso; Kam, Kimberly R; Ran, Yingqing; Wong, Harvey

    2014-04-01

    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.

  15. Construction of hydroxypropyl-β-cyclodextrin copolymer nanoparticles and targeting delivery of paclitaxel

    NASA Astrophysics Data System (ADS)

    Miao, Qinghua; Li, Suping; Han, Siyuan; Wang, Zhi; Wu, Yan; Nie, Guangjun

    2012-08-01

    A novel amphiphilic copolymer with p-maleimidophenyl isocyanate-hydroxypropyl-β-cyclodextrin-polylactide-1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine to generate copolymer nanoparticles (NPs) has been designed. In order to develop an active targeting system, integrin αvβ3-specific targeting peptide cyclo(Arg-Gly-Asp-D-Phe-Cys), cRGD, was conjugated to the surface of NPs (NPs-RGD). These NPs were used to encapsulate anti-tumor drug, paclitaxel. The resulting NPs exhibited high drug-loading capacity and controlled drug release in vitro at acidic pH. In vitro cytotoxicity assay demonstrates that paclitaxel-loaded NPs-RGD significantly inhibited B16 tumor cell (high αvβ3) proliferation relative to free paclitaxel and paclitaxel-loaded NPs at high concentrations. Paclitaxel-loaded NPs-RGD localized mainly in lysosomes in B16 cells as revealed by confocal microscopy. These results suggest a novel strategy for fabrication—functionalizing hydroxypropyl-β-cyclodextrin copolymer nanoparticles for targeting delivery of paclitaxel to integrin αvβ3-rich tumor cells. These nanocarriers can be readily extended to couple other bioactive molecules for active targeting and delivery of various chemotherapeutic drugs.

  16. 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

  17. Bisphosphorylated PEA-15 sensitizes ovarian cancer cells to paclitaxel by impairing the microtubule-destabilizing effect of SCLIP.

    PubMed

    Xie, Xuemei; Bartholomeusz, Chandra; Ahmed, Ahmed A; Kazansky, Anna; Diao, Lixia; Baggerly, Keith A; Hortobagyi, Gabriel N; Ueno, Naoto T

    2013-06-01

    Paclitaxel is a standard chemotherapeutic agent for ovarian cancer. PEA-15 (phosphoprotein enriched in astrocytes-15 kDa) regulates cell proliferation, autophagy, apoptosis, and glucose metabolism and also mediates AKT-dependent chemoresistance in breast cancer. The functions of PEA-15 are tightly regulated by its phosphorylation status at Ser104 and Ser116. However, the effect of PEA-15 phosphorylation status on chemosensitivity of cancer cells remains unknown. Here, we tested the hypothesis that PEA-15 phosphorylated at both Ser104 and Ser116 (pPEA-15) sensitizes ovarian cancer cells to paclitaxel. We first found that knockdown of PEA-15 in PEA-15-high expressing HEY and OVTOKO ovarian cancer cells resulted in paclitaxel resistance, whereas re-expression of PEA-15 in these cells led to paclitaxel sensitization. We next found that SKOV3.ip1-DD cells (expressing phosphomimetic PEA-15) were more sensitive to paclitaxel than SKOV3.ip1-AA cells (expressing nonphosphorylatable PEA-15). Compared with SKOV3.ip1-vector and SKOV3.ip1-AA cells, SKOV3.ip1-DD cells displayed reduced cell viability, inhibited anchorage-independent growth, and augmented apoptosis when treated with paclitaxel. Furthermore, HEY and OVTOKO cells displayed enhanced paclitaxel sensitivity when transiently overexpressing phosphomimetic PEA-15 and reduced paclitaxel sensitivity when transiently overexpressing nonphosphorylatable PEA-15. These results indicate that pPEA-15 sensitizes ovarian cancer cells to paclitaxel. cDNA microarray analysis suggested that SCLIP (SCG10-like protein), a microtubule-destabilizing protein, is involved in pPEA-15-mediated chemosensitization. We found that reduced expression and possibly posttranslational modification of SCLIP following paclitaxel treatment impaired the microtubule-destabilizing effect of SCLIP, thereby promoting induction of mitotic arrest and apoptosis by paclitaxel. Our findings highlight the importance of pPEA-15 as a promising target for improving

  18. Targeting of apoptotic pathways by SMAC or BH3 mimetics distinctly sensitizes paclitaxel-resistant triple negative breast cancer cells.

    PubMed

    Panayotopoulou, Effrosini G; Müller, Anna-Katharina; Börries, Melanie; Busch, Hauke; Hu, Guohong; Lev, Sima

    2017-02-06

    Standard chemotherapy is the only systemic treatment for triple-negative breast cancer (TNBC), and despite the good initial response, resistance remains a major therapeutic obstacle. Here, we employed a High-Throughput Screen to identify targeted therapies that overcome chemoresistance in TNBC. We applied short-term paclitaxel treatment and screened 320 small-molecule inhibitors of known targets to identify drugs that preferentially and efficiently target paclitaxel-treated TNBC cells. Among these compounds the SMAC mimetics (BV6, Birinapant) and BH3-mimetics (ABT-737/263) were recognized as potent targeted therapy for multiple paclitaxel-residual TNBC cell lines. However, acquired paclitaxel resistance through repeated paclitaxel pulses result in desensitization to BV6, but not to ABT-263, suggesting that short- and long-term paclitaxel resistance are mediated by distinct mechanisms. Gene expression profiling of paclitaxel-residual, -resistant and naïve MDA-MB-231 cells demonstrated that paclitaxel-residual, as opposed to -resistant cells, were characterized by an apoptotic signature, with downregulation of anti-apoptotic genes (BCL2, BIRC5), induction of apoptosis inducers (IL24, PDCD4), and enrichment of TNFα/NF-κB pathway, including upregulation of TNFSF15, coupled with cell-cycle arrest. BIRC5 and FOXM1 downregulation and IL24 induction was also evident in breast cancer patient datasets following taxane treatment. Exposure of naïve or paclitaxel-resistant cells to supernatants of paclitaxel-residual cells sensitized them to BV6, and treatment with TNFα enhanced BV6 potency, suggesting that sensitization to BV6 is mediated, at least partially, by secreted factor(s). Our results suggest that administration of SMAC or BH3 mimetics following short-term paclitaxel treatment could be an effective therapeutic strategy for TNBC, while only BH3-mimetics could effectively overcome long-term paclitaxel resistance.

  19. Fluorescence properties of several chemotherapy drugs: doxorubicin, paclitaxel and bleomycin

    PubMed Central

    Motlagh, Najme Sadat Hosseini; Parvin, Parviz; Ghasemi, Fatemah; Atyabi, Fatemeh

    2016-01-01

    Several chemo-drugs act as the biocompatible fluorophores. Here, the laser induced fluorescence (LIF) properties of doxorubicin, paclitaxel and bleomycin are investigated. The absorption lines mostly lie over UV range according to the UV-VIS spectra. Therefore, a single XeCl laser provokes the desired transitions of the chemo-drugs of interest at 308 nm. It is shown that LIF spectra are strongly dependent on the fluorophore concentration giving rise to the sensible red shift. This happens when large overlapping area appears between absorption and emission spectra accordingly. The red shift is taken into account as a characteristic parameter of a certain chemo-drug. The fluorescence extinction (α) and self-quenching (k) coefficients are determined based on the best fitting of the adopted Lambert-Beer equation over experimental data. The quantum yield of each chemo-drug is also measured using the linearity of the absorption and emission rates. PMID:27375954

  20. The decrease of paclitaxel efflux by pretreatment of interferon-γ and tumor necrosis factor-α after intracerebral microinjection.

    PubMed

    Lee, Na-Young; Kang, Young-Sook

    2013-03-07

    Paclitaxel is highly efficacious in the treatment of patients suffering from a broad spectrum of neoplastic diseases. However, its efficacy against malignant glioma is very moderate. Paclitaxel is known to be a substrate for P-glycoprotein (P-gp), so this transporter may be due to insufficient access of paclitaxel to the brain. First, we investigated the brain-to-blood transport of paclitaxel across the blood-brain barrier (BBB) using the brain efflux index method. [(3)H]Paclitaxel was eliminated from rat brain with an efflux transport rate of 1.87×10(-2)±0.16×10(-2)min(-1). The elimination of [(3)H]paclitaxel was inhibited by unlabeled paclitaxel and verapamil, suggesting a carrier-mediated transport process via P-gp. Furthermore, TNF-α and IFN-γ induced significant decrease of paclitaxel efflux 1 and 24h pre-treatment. These results suggest that P-gp efflux function at the BBB is reduced by TNF-α and IFN-γ. Therefore, the distribution of P-gp dependant drugs including paclitaxel in the central nervous system can be modulated by neurological diseases.

  1. Paclitaxel inhibits cell proliferation and collagen lattice contraction via TGF-β signaling pathway in human tenon's fibroblasts in vitro.

    PubMed

    Chen, Ninghong; Guo, Dadong; Guo, Yuanyuan; Sun, Yuanyuan; Bi, Hongsheng; Ma, Xiaohua

    2016-04-15

    As an anti-microtubule agent, paclitaxel has been widely applied clinically. However, the effects of paclitaxel on human tenon's fibroblast (HTF) proliferation and migration in vitro was still unclear. In the present study, we explored the influences of paclitaxel on HTF cell proliferation, cell viability, cell cycle phase distribution under various concentrations of paclitaxel (i.e., 0, 10(-8), 10(-7), 10(-6)mol/l) via real-time cell electronic system and flow cytometry, further determined the expression of TGF-β1 and connective tissue growth factor (CTGF) after treatment with different concentrations of paclitaxel. Moreover, extra cellular matrix production and collagen lattice contraction assay were also explored. The results indicate that paclitaxel could apparently inhibit the cell viability, induces the elevation of S and G2/M phases of HTFs, and downregulates the expression of both TGF-β1 and CTGF. Meanwhile, the levels of fibronectin extra domain A (EDA), collagen and collagen lattice contraction were apparently reduced after treatment with paclitaxel. Overall, paclitaxel could apparently inhibit the proliferation of HTFs and leads to cell cycle arrest at both S and G2/M phases, attenuates the generation of collagen and collagen lattice contraction, decreases the expressions of TGF-β1, CTGF and fibronectin EDA. The inhibitory mechanism of paclitaxel on HTFs is involved in TGF-β1 signaling pathway.

  2. Extracellular biosynthesis of gadolinium oxide (Gd2O3) nanoparticles, their biodistribution and bioconjugation with the chemically modified anticancer drug taxol.

    PubMed

    Khan, Shadab Ali; Gambhir, Sanjay; Ahmad, Absar

    2014-01-01

    As a part of our programme to develop nanobioconjugates for the treatment of cancer, we first synthesized extracellular, protein-capped, highly stable and well-dispersed gadolinium oxide (Gd2O3) nanoparticles by using thermophilic fungus Humicola sp. The biodistribution of the nanoparticles in rats was checked by radiolabelling with Tc-99m. Finally, these nanoparticles were bioconjugated with the chemically modified anticancer drug taxol with the aim of characterizing the role of this bioconjugate in the treatment of cancer. The biosynthesized Gd2O3 nanoparticles were characterized by UV-vis spectroscopy, transmission electron microscopy (TEM), X-ray diffraction (XRD) and X-ray photoemission spectroscopy (XPS). The Gd2O3-taxol bioconjugate was confirmed by UV-vis spectroscopy and fluorescence microscopy and was purified by using high performance liquid chromatography (HPLC).

  3. Extracellular biosynthesis of gadolinium oxide (Gd2O3) nanoparticles, their biodistribution and bioconjugation with the chemically modified anticancer drug taxol

    PubMed Central

    Khan, Shadab Ali; Gambhir, Sanjay

    2014-01-01

    Summary As a part of our programme to develop nanobioconjugates for the treatment of cancer, we first synthesized extracellular, protein-capped, highly stable and well-dispersed gadolinium oxide (Gd2O3) nanoparticles by using thermophilic fungus Humicola sp. The biodistribution of the nanoparticles in rats was checked by radiolabelling with Tc-99m. Finally, these nanoparticles were bioconjugated with the chemically modified anticancer drug taxol with the aim of characterizing the role of this bioconjugate in the treatment of cancer. The biosynthesized Gd2O3 nanoparticles were characterized by UV–vis spectroscopy, transmission electron microscopy (TEM), X-ray diffraction (XRD) and X-ray photoemission spectroscopy (XPS). The Gd2O3–taxol bioconjugate was confirmed by UV–vis spectroscopy and fluorescence microscopy and was purified by using high performance liquid chromatography (HPLC). PMID:24778946

  4. Treatment of patients with aortic atherosclerotic disease with paclitaxel-associated lipid nanoparticles

    PubMed Central

    Shiozaki, Afonso A.; Senra, Tiago; Morikawa, Aleksandra T.; Deus, Débora F.; Paladino, Antonio T; Pinto, Ibraim M.F.; Maranhão, Raul C.

    2016-01-01

    OBJECTIVE: The toxicity of anti-cancer chemotherapeutic agents can be reduced by associating these compounds, such as the anti-proliferative agent paclitaxel, with a cholesterol-rich nanoemulsion (LDE) that mimics the lipid composition of low-density lipoprotein (LDL). When injected into circulation, the LDE concentrates the carried drugs in neoplastic tissues and atherosclerotic lesions. In rabbits, atherosclerotic lesion size was reduced by 65% following LDE-paclitaxel treatment. The current study aimed to test the effectiveness of LDE-paclitaxel on inpatients with aortic atherosclerosis. METHODS: This study tested a 175 mg/m2 body surface area dose of LDE-paclitaxel (intravenous administration, 3/3 weeks for 6 cycles) in patients with aortic atherosclerosis who were aged between 69 and 86 yrs. A control group of 9 untreated patients with aortic atherosclerosis (72-83 yrs) was also observed. RESULTS: The LDE-paclitaxel treatment elicited no important clinical or laboratory toxicities. Images were acquired via multiple detector computer tomography angiography (64-slice scanner) before treatment and at 1-2 months after treatment. The images showed that the mean plaque volume in the aortic artery wall was reduced in 4 of the 8 patients, while in 3 patients it remained unchanged and in one patient it increased. In the control group, images were acquired twice with an interval of 6-8 months. None of the patients in this group exhibited a reduction in plaque volume; in contrast, the plaque volume increased in three patients and remained stable in four patients. During the study period, one death unrelated to the treatment occurred in the LDE-paclitaxel group and one death occurred in the control group. CONCLUSION: Treatment with LDE-paclitaxel was tolerated by patients with cardiovascular disease and showed the potential to reduce atherosclerotic lesion size. PMID:27626473

  5. Absorption mechanism of DHP107, an oral paclitaxel formulation that forms a hydrated lipidic sponge phase

    PubMed Central

    Jang, Yura; Chung, Hye Jin; Hong, Jung Wan; Yun, Cheol-Won; Chung, Hesson

    2017-01-01

    Paclitaxel is a most widely used anticancer drug with low oral bioavailability, thus it is currently administered via intravenous infusion. DHP107 is a lipid-based paclitaxel formulation that can be administered as an oral solution. In this study, we investigated the mechanism of paclitaxel absorption after oral administration of DHP107 in mice and rats by changing the dosing interval, and evaluated the influence of bile excretion. DHP107 was orally administered to mice at various dosing intervals (2, 4, 8, 12, 24 h) to examine how residual DHP107 affected paclitaxel absorption during subsequent administration. Studies with small-angle X-ray diffraction (SAXS) and cryo-transmission electron microscopy (cryo-TEM) showed that DHP107 formed a lipidic sponge phase after hydration. The AUC values after the second dose were smaller than those after the first dose, which was correlated to the induction of expression of P-gp and CYP in the livers and small intestines from 2 h to 7 d after the first dose. The smaller AUC value observed after the second dose was also attributed to the intestinal adhesion of residual formulation. The adhered DHP107 may have been removed by ingested food, thus resulting in a higher AUC. In ex vivo and in vivo mucoadhesion studies, the formulation adhered to the villi for up to 24 h, and the amount of DHP107 that adhered was approximately half that of monoolein. The paclitaxel absorption after administration of DHP107 was not affected by bile in the cholecystectomy mice. The dosing interval and food intake affect the oral absorption of paclitaxel from DHP107, which forms a mucoadhesive sponge phase after hydration. Bile excretion does not affect the absorption of paclitaxel from DHP107 in vivo. PMID:27867185

  6. Paclitaxel Drug-eluting Tracheal Stent Could Reduce Granulation Tissue Formation in a Canine Model

    PubMed Central

    Wang, Ting; Zhang, Jie; Wang, Juan; Pei, Ying-Hua; Qiu, Xiao-Jian; Wang, Yu-Ling

    2016-01-01

    Background: Currently available silicone and metallic stents for tracheal stenosis are associated with many problems. Granulation proliferation is one of the main complications. The present study aimed to evaluate the efficacy of paclitaxel drug-eluting tracheal stent in reducing granulation tissue formation in a canine model, as well as the pharmacokinetic features and safety profiles of the coated drug. Methods: Eight beagles were randomly divided into a control group (bare-metal stent group, n = 4) and an experimental group (paclitaxel-eluting stent group, n = 4). The observation period was 5 months. One beagle in both groups was sacrificed at the end of the 1st and 3rd months, respectively. The last two beagles in both groups were sacrificed at the end of 5th month. The proliferation of granulation tissue and changes in tracheal mucosa were compared between the two groups. Blood routine and liver and kidney function were monitored to evaluate the safety of the paclitaxel-eluting stent. The elution method and high-performance liquid chromatography were used to characterize the rate of in vivo release of paclitaxel from the stent. Results: Compared with the control group, the proliferation of granulation tissue in the experimental group was significantly reduced. The drug release of paclitaxel-eluting stent was the fastest in the 1st month after implantation (up to 70.9%). Then, the release slowed down gradually. By the 5th month, the release reached up to 98.5%. During the observation period, a high concentration of the drug in the trachea (in the stented and adjacent unstented areas) and lung tissue was not noted, and the blood test showed no side effect. Conclusions: The paclitaxel-eluting stent could safely reduce the granulation tissue formation after stent implantation in vivo, suggesting that the paclitaxel-eluting tracheal stent might be considered for potential use in humans in the future. PMID:27824004

  7. Cremophor EL causes (pseudo-) non-linear pharmacokinetics of paclitaxel in patients.

    PubMed

    van Tellingen, O; Huizing, M T; Panday, V R; Schellens, J H; Nooijen, W J; Beijnen, J H

    1999-09-01

    The non-linear plasma pharmacokinetics of paclitaxel in patients has been well established, however, the exact underlying mechanism remains to be elucidated. We have previously shown that the non-linear plasma pharmacokinetics of paclitaxel in mice results from Cremophor EL. To investigate whether Cremophor EL also plays a role in the non-linear pharmacokinetics of paclitaxel in patients, we have established its pharmacokinetics in patients receiving paclitaxel by 3-, 24- or 96-h intravenous infusion. The pharmacokinetics of Cremophor EL itself was non-linear as the clearance (Cl) in the 3-h schedules was significantly lower than when using the longer 24- or 96-h infusions (Cl175-3 h = 42.8+/-24.9 ml h(-1) m(-2); CI175-24 h = 79.7+/-24.3; P = 0.035 and Cl135-3 h = 44.1+/-21.8 ml h(-1) m(-1); Cl140-96 h = 211.8+/-32.0; P < 0.001). Consequently, the maximum plasma levels were much higher (0.62%) in the 3-h infusions than when using longer infusion durations. By using an in vitro equilibrium assay and determination in plasma ultrafiltrate we have established that the fraction of unbound paclitaxel in plasma is inversely related with the Cremophor EL level. Despite its relatively low molecular weight, no Cremophor EL was found in the ultrafiltrate fraction. Our results strongly suggest that entrapment of paclitaxel in plasma by Cremophor EL, probably by inclusion in micelles, is the cause of the apparent nonlinear plasma pharmacokinetics of paclitaxel. This mechanism of a (pseudo-)non-linearity contrasts previous postulations about saturable distribution and elimination kinetics and means that we must re-evaluate previous assumptions on pharmacokinetics-pharmacodynamics relationships.

  8. Thermosensitive and mucoadhesive sol-gel composites of paclitaxel/dimethyl-β-cyclodextrin for buccal delivery.

    PubMed

    Choi, Soon Gil; Lee, Sang-Eun; Kang, Bong-Seok; Ng, Choon Lian; Davaa, Enkhzaya; Park, Jeong-Sook

    2014-01-01

    The purpose of this study was to develop a buccal paclitaxel delivery system using the thermosensitive polymer Pluronic F127 (PF127) and the mucoadhesive polymer polyethylene oxide (PEO). The anticancer agent paclitaxel is usually used to treat ovarian, breast, and non-small-cell lung cancer. To improve its aqueous solubility, paclitaxel was incorporated into an inclusion complex with (2,6-di-O-methyl)-β-cyclodextrin (DMβCD). The formation of the paclitaxel inclusion complex was evaluated using various techniques, including x-ray diffractometry (XRD), Fourier-transform infrared (FT-IR) spectrophotometry, differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). Hydrogels were prepared using a cold method. Concentrations of 18, 20, and 23% (w/v) PF127 were dissolved in distilled water including paclitaxel and stored overnight in a refrigerator at 4 °C. PEO was added at concentrations of 0.1, 0.2, 0.4, 0.8, and 1% (w/v). Each formulation included paclitaxel (0.5 mg/mL). The sol-gel transition temperature of the hydrogels was measured using the tube-inverting method. Drug release from the hydrogels was measured using a Franz diffusion cell containing pH 7.4 phosphate-buffered solution (PBS) buffer at 37 °C. The cytotoxicity of each formulation was measured using the MTT assay with a human oral cancer cell (KB cell). The sol-gel transition temperature of the hydrogel decreased when PF127 was present and varied according to the presence of mucoadhesive polymers. The in vitro release was sustained and the release rate was slowed by the addition of the mucoadhesive polymer. The cytotoxicity of the blank formulation was low, although the drug-loaded hydrogel showed acceptable cytotoxicity. The results of our study suggest that the combination of a PF 127-based mucoadhesive hydrogel formulation and inclusion complexes improves the in vitro release and cytotoxic effect of paclitaxel.

  9. The Anticonvulsant Enaminone E139 Attenuates Paclitaxel-Induced Neuropathic Pain in Rodents

    PubMed Central

    Thangamani, Dhandapani; Edafiogho, Ivan Ogheneochuko

    2013-01-01

    The enaminone methyl 4-(4′-bromophenyl)aminocyclohex-3-en-6-methyl-2-oxo-1-oate (E139) has anticonvulsant activities. It has been reported to have a better safety profile than some anticonvulsant drugs. Since some anticonvulsant drugs are used in the management of neuropathic pain, we evaluated the effects of E139 in rodent models of acute pain and paclitaxel-induced neuropathic pain. The reaction latency to thermal stimuli (hot-plate test) of BALB/c mice was recorded before and after intraperitoneal treatment with paclitaxel (2 mg/kg, i.p. for 5 consecutive days), and after treatment with E139 (0.1–40 mg/kg), amitriptyline (10 mg/kg), and gabapentin (10 and 30 mg/kg). Mechanical allodynia in paclitaxel-treated Sprague Dawley (SD) rats was measured using a dynamic plantar aesthesiometer before and after treatment with E139 (10 and 20 mg/kg) or its vehicle for four consecutive days from day 7 after first administration of paclitaxel (16 mg/kg on two alternate days). Administration of E139 (10–40 mg/kg) produced antinociceptive activity against thermal nociception in naïve mice. Treatment with E139, amitriptyline, or gabapentin reduced paclitaxel-induced thermal hyperalgesia. E139 reduced paclitaxel-induced mechanical allodynia, with the effects lasting longer (24 h) after repetitive dosing. Our results indicate that E139 has antinociceptive activity and attenuates paclitaxel-induced neuropathic pain in rodents. PMID:24385872

  10. 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

  11. Loss of FBXW7 and accumulation of MCL1 and PLK1 promote paclitaxel resistance in breast cancer.

    PubMed

    Gasca, Jessica; Flores, Maria Luz; Giráldez, Servando; Ruiz-Borrego, Manuel; Tortolero, María; Romero, Francisco; Japón, Miguel A; Sáez, Carmen

    2016-08-16

    FBXW7 is a component of SCF (complex of SKP1, CUL1 and F-box-protein)-type ubiquitin ligases that targets several oncoproteins for ubiquitination and degradation by the proteasome. FBXW7 regulates cellular apoptosis by targeting MCL1 for ubiquitination. Recently, we identified PLK1 as a new substrate of FBXW7 modulating the intra-S-phase DNA-damage checkpoint. Taxanes are frequently used in breast cancer treatments, but the acquisition of resistance makes these treatments ineffective. We investigated the role of FBXW7 and their substrates MCL1 and PLK1 in regulating the apoptotic response to paclitaxel treatment in breast cancer cells and their expression in breast cancer tissues. Paclitaxel-sensitive MDA-MB-468 and a paclitaxel-resistant MDA-MB-468R subclone were used to study the role of FBXW7 and substrates in paclitaxel-induced apoptosis. Forced expression of FBXW7 or downregulation of MCL1 or PLK1 restored sensitivity to paclitaxel in MDA-MB-468R cells. By contrary, FBXW7-silenced MDA-MB-468 cells became resistant to paclitaxel. The expression of FBXW7 and substrates were studied in 296 invasive carcinomas by immunohistochemistry and disease-free survival was analyzed in a subset of patients treated with paclitaxel. In breast cancer tissues, loss of FBXW7 correlated with adverse prognosis markers and loss of FBXW7 and MCL1 or PLK1 accumulation were associated with diminished disease-free survival in paclitaxel-treated patients. We conclude that FBXW7 regulates the response to paclitaxel by targeting MCL1 and PLK1 in breast cancer cells and thus targeting these substrates may be a valuable adjunct for paclitaxel treatment. Also, FBXW7, MCL1 and PLK1 may be relevant predictive markers of tumor progression and response to paclitaxel treatment.

  12. Paclitaxel sensitivity of breast cancer cells requires efficient mitotic arrest and disruption of Bcl-xL/Bak interaction.

    PubMed

    Flores, M Luz; Castilla, Carolina; Ávila, Rainiero; Ruiz-Borrego, Manuel; Sáez, Carmen; Japón, Miguel A

    2012-06-01

    Taxanes are being used for the treatment of breast cancer. However, cancer cells frequently develop resistance to these drugs with the subsequent recurrence of the tumor. MDA-MB-231 and T-47D breast cancer cell lines were used to assess the effect of paclitaxel treatment on apoptosis and cell cycle, the possible mechanisms of paclitaxel resistance as well as the enhancement of paclitaxel-induced apoptosis based on its combination with phenylethyl isothiocyanate (PEITC). T-47D cells undergo apoptosis in response to paclitaxel treatment. The induction of apoptosis was associated with a robust mitotic arrest and the disruption of Bcl-xL/Bak interaction. By contrary, MDA-MB-231 cells were insensitive to paclitaxel-induced apoptosis and this was associated with a high percentage of cells that slip out of paclitaxel-imposed mitotic arrest and also with the maintenance of Bcl-xL/Bak interaction. The sequential treatment of MDA-MB-231 cells with PEITC followed by paclitaxel inhibited the slippage induced by paclitaxel and increased the apoptosis induction achieved with any of the drugs alone. In breast cancer tissues, high Bcl-xL expression was correlated with a shorter time of disease-free survival in patients treated with a chemotherapeutic regimen that contains paclitaxel, in a statistically significant way. Thus, resistance to paclitaxel in MDA-MB-231 cells is related to the inability to disrupt the Bcl-xL/Bak interaction and increased slippage. In this context, the combination of a drug that induces a strong mitotic arrest, such as paclitaxel, with another that inhibits slippage, such as PEITC, translates into increased apoptotic induction.

  13. Loss of FBXW7 and accumulation of MCL1 and PLK1 promote paclitaxel resistance in breast cancer

    PubMed Central

    Gasca, Jessica; Flores, Maria Luz; Giráldez, Servando; Ruiz-Borrego, Manuel; Tortolero, María; Romero, Francisco; Japón, Miguel A.; Sáez, Carmen

    2016-01-01

    FBXW7 is a component of SCF (complex of SKP1, CUL1 and F-box-protein)-type ubiquitin ligases that targets several oncoproteins for ubiquitination and degradation by the proteasome. FBXW7 regulates cellular apoptosis by targeting MCL1 for ubiquitination. Recently, we identified PLK1 as a new substrate of FBXW7 modulating the intra-S-phase DNA-damage checkpoint. Taxanes are frequently used in breast cancer treatments, but the acquisition of resistance makes these treatments ineffective. We investigated the role of FBXW7 and their substrates MCL1 and PLK1 in regulating the apoptotic response to paclitaxel treatment in breast cancer cells and their expression in breast cancer tissues. Paclitaxel-sensitive MDA-MB-468 and a paclitaxel-resistant MDA-MB-468R subclone were used to study the role of FBXW7 and substrates in paclitaxel-induced apoptosis. Forced expression of FBXW7 or downregulation of MCL1 or PLK1 restored sensitivity to paclitaxel in MDA-MB-468R cells. By contrary, FBXW7-silenced MDA-MB-468 cells became resistant to paclitaxel. The expression of FBXW7 and substrates were studied in 296 invasive carcinomas by immunohistochemistry and disease-free survival was analyzed in a subset of patients treated with paclitaxel. In breast cancer tissues, loss of FBXW7 correlated with adverse prognosis markers and loss of FBXW7 and MCL1 or PLK1 accumulation were associated with diminished disease-free survival in paclitaxel-treated patients. We conclude that FBXW7 regulates the response to paclitaxel by targeting MCL1 and PLK1 in breast cancer cells and thus targeting these substrates may be a valuable adjunct for paclitaxel treatment. Also, FBXW7, MCL1 and PLK1 may be relevant predictive markers of tumor progression and response to paclitaxel treatment. PMID:27409838

  14. Similarity between the sequences of taxol-selected peptides and the disordered loop of the anti-apoptotic protein, Bcl-2.

    PubMed

    Rodi, D J; Makowski, L

    1999-01-01

    The anti-cancer drug taxol is known to bind to and induce the polymerization of tubulin and has recently been shown to bind to the anti-apoptotic protein Bcl-2, but not to its homolog, Bcl-XL. Libraries of random peptides displayed on the surface of a bacteriophage were screened to select those exhibiting affinity for taxol. The sequences of these peptides were compared to sequences of proteins involved in mitosis and apoptosis. No significant similarities were detected between the sequences of tubulins and the taxol-selected peptides. However, a high level of similarity exists between the selected peptides and the disordered loop of Bcl-2. Conversely, there was little similarity between the sequences of the selected peptides and Bcl-XL. These results indicate that peptides displayed on the surface of a bacteriophage can mimic the ligand-binding behavior of a disordered protein loop and that comparison of the sequences of affinity-selected peptides with protein sequences can be predictive for ligand binding.

  15. Rikkunshito prevents paclitaxel-induced peripheral neuropathy through the suppression of the nuclear factor kappa B (NFκB) phosphorylation in spinal cord of mice.

    PubMed

    Kamei, Junzo; Hayashi, Shunsuke; Sakai, Akane; Nakanishi, Yuki; Kai, Misa; Ikegami, Megumi; Ikeda, Hiroko

    2017-01-01

    Peripheral neuropathy is the major side effect caused by paclitaxel, a microtubule-binding antineoplastic drug. Paclitaxel-induced peripheral neuropathy causes a long-term negative impact on the patient's quality of life. However, the mechanism underlying paclitaxel-induced peripheral neuropathy is still unknown, and there is no established treatment. Ghrelin is known to attenuate thermal hyperalgesia and mechanical allodynia in chronic constriction injury of the sciatic nerve, and inhibit the activation of nuclear factor kappa B (NFκB) in the spinal dorsal horn. Rikkunshito (RKT), a kampo medicine, increases the secretion of ghrelin in rodents and humans. Thus, RKT may attenuate paclitaxel-induced peripheral neuropathy by inhibiting phosphorylated NFκB (pNFκB) in the spinal cord. We found that paclitaxel dose-dependently induced mechanical hyperalgesia in mice. Paclitaxel increased the protein levels of spinal pNFκB, but not those of spinal NFκB. NFκB inhibitor attenuated paclitaxel-induced mechanical hyperalgesia suggesting that the activation of NFκB mediates paclitaxel-induced hyperalgesia. RKT dose-dependently attenuated paclitaxel-induced mechanical hyperalgesia. Ghrelin receptor antagonist reversed the RKT-induced attenuation of paclitaxel-induced mechanical hyperalgesia. RKT inhibited the paclitaxel-induced increase in the protein levels of spinal pNFκB. Taken together, the present study indicates that RKT exerts an antihyperalgesic effect in paclitaxel-induced neuropathic pain by suppressing the activation of spinal NFκB.

  16. Rikkunshito prevents paclitaxel-induced peripheral neuropathy through the suppression of the nuclear factor kappa B (NFκB) phosphorylation in spinal cord of mice

    PubMed Central

    Kamei, Junzo; Hayashi, Shunsuke; Sakai, Akane; Nakanishi, Yuki; Kai, Misa; Ikegami, Megumi; Ikeda, Hiroko

    2017-01-01

    Peripheral neuropathy is the major side effect caused by paclitaxel, a microtubule-binding antineoplastic drug. Paclitaxel-induced peripheral neuropathy causes a long-term negative impact on the patient's quality of life. However, the mechanism underlying paclitaxel-induced peripheral neuropathy is still unknown, and there is no established treatment. Ghrelin is known to attenuate thermal hyperalgesia and mechanical allodynia in chronic constriction injury of the sciatic nerve, and inhibit the activation of nuclear factor kappa B (NFκB) in the spinal dorsal horn. Rikkunshito (RKT), a kampo medicine, increases the secretion of ghrelin in rodents and humans. Thus, RKT may attenuate paclitaxel-induced peripheral neuropathy by inhibiting phosphorylated NFκB (pNFκB) in the spinal cord. We found that paclitaxel dose-dependently induced mechanical hyperalgesia in mice. Paclitaxel increased the protein levels of spinal pNFκB, but not those of spinal NFκB. NFκB inhibitor attenuated paclitaxel-induced mechanical hyperalgesia suggesting that the activation of NFκB mediates paclitaxel-induced hyperalgesia. RKT dose-dependently attenuated paclitaxel-induced mechanical hyperalgesia. Ghrelin receptor antagonist reversed the RKT-induced attenuation of paclitaxel-induced mechanical hyperalgesia. RKT inhibited the paclitaxel-induced increase in the protein levels of spinal pNFκB. Taken together, the present study indicates that RKT exerts an antihyperalgesic effect in paclitaxel-induced neuropathic pain by suppressing the activation of spinal NFκB. PMID:28182729

  17. Androgen and taxol cause cell type-specific alterations of centrosome and DNA organization in androgen-responsive LNCaP and androgen-independent DU145 prostate cancer cells

    NASA Technical Reports Server (NTRS)

    Schatten, H.; Ripple, M.; Balczon, R.; Weindruch, R.; Chakrabarti, A.; Taylor, M.; Hueser, C. N.

    2000-01-01

    We investigated the effects of androgen and taxol on the androgen-responsive LNCaP and androgen-independent DU145 prostate cancer cell lines. Cells were treated for 48 and 72 h with 0.05-1 nM of the synthetic androgen R1881 and with 100 nM taxol. Treatment of LNCaP cells with 0.05 nM R1881 led to increased cell proliferation, whereas treatment with 1 nM R1881 resulted in inhibited cell division, DNA cycle arrest, and altered centrosome organization. After treatment with 1 nM R1881, chromatin became clustered, nuclear envelopes convoluted, and mitochondria accumulated around the nucleus. Immunofluorescence microscopy with antibodies to centrosomes showed altered centrosome structure. Although centrosomes were closely associated with the nucleus in untreated cells, they dispersed into the cytoplasm after treatment with 1 nM R1881. Microtubules were only faintly detected in 1 nM R1881-treated LNCaP cells. The effects of taxol included microtubule bundling and altered mitochondria morphology, but not DNA organization. As expected, the androgen-independent prostate cancer cell line DU145 was not affected by R1881. Treatment with taxol resulted in bundling of microtubules in both cell lines. Additional taxol effects were seen in DU145 cells with micronucleation of DNA, an indication of apoptosis. Simultaneous treatment with R1881 and taxol had no additional effects on LNCaP or DU145 cells. These results suggest that LNCaP and DU145 prostate cancer cells show differences not only in androgen responsiveness but in sensitivity to taxol as well. Copyright 2000 Wiley-Liss, Inc.

  18. Fluorescence anisotropy, FT-IR spectroscopy and 31-P NMR studies on the interaction of paclitaxel with lipid bilayers.

    PubMed

    Dhanikula, Anand Babu; Panchagnula, Ramesh

    2008-06-01

    To understand the bilayer interaction with paclitaxel, fluorescence polarization, Fourier transform infrared spectroscopy (FT-IR) and 31-phosphorus nuclear magnetic resonance (31P-NMR) studies were performed on paclitaxel bearing liposomes. Fluorescence anisotropy of three probes namely, 1,6-diphenyl-1,3,5-hexatriene (DPH), 12-(9-anthroyloxy) stearic acid (12AS) and 8-anilino-1-naphthalene sulfonate (ANS) were monitored as a function of paclitaxel concentration in the unsaturated bilayers. The incorporation of paclitaxel decreased anisotropy of 12AS and ANS probes, while slightly increased anisotropy of DPH. Paclitaxel has a fluidizing effect in the upper region of the bilayer whereas the hydrophobic core is slightly rigidized. FT-IR spectroscopy showed an increase in the asymmetric and symmetric methylene stretching frequencies, splitting of methylene scissoring band and broadening of carbonyl stretching mode. These studies collectively ascertained that paclitaxel mainly occupies the cooperativity region and interact with the interfacial region of unsaturated bilayers and induces fluidity in the headgroup region of bilayer. At higher loadings (>3 mol%), paclitaxel might gradually tend to accumulate at the interface and eventually partition out of bilayer as a result of solute exclusion phenomenon, resulting in crystallization; seed non-bilayer phases, as revealed by 31P-NMR, thereby destabilizing liposomal formulations. In general, any membrane component which has a rigidization effect will decrease, while that with a fluidizing effect will increase, with a bearing on headgroup interactions, partitioning of paclitaxel into bilayers and stability of the liposomes.

  19. SET protein overexpression contributes to paclitaxel resistance in MCF-7/S cells through PI3K/Akt pathway.

    PubMed

    Zhang, Weipeng; Zheng, Xiaowei; Meng, Ti; You, Haisheng; Dong, Yalin; Xing, Jianfeng; Chen, Siying

    2017-03-01

    Patient SE translation (SET) is a carcinogen in facilitating cellular growth and proliferation, and promoting tumorigenesis and metastasis. The present study was to investigate the resistance mechanisms associated with SET in paclitaxel-induced human breast cancer cells. The different expressions of SET, ATP-binding cassette (ABC) transporters and PI3K/Akt pathway between paclitaxel sensitive MCF-7/S and paclitaxel resistant MCF-7/PTX cells were identified using western blotting. We adopted plasmid transfection to upregulate SET in MCF-7/S cells and a novel SET antagonist COG112 to decrease SET in MCF-7/PTX cells. Subsequently, cell viability to paclitaxel was assessed by MTT assay and cell apoptosis was analyzed by flow cytometry. We found that levels of SET, ABC transporters and PI3K/Akt pathway were elevated in MCF-7/PTX. Upregulation of SET in MCF-7/S cells expressed resistant to paclitaxel and decreased cell apoptosis. Moreover, overexpression of SET promoted the mRNA and protein level of ABC transporters and PI3K/Akt signal pathway in MCF-7/S cells. Conversely, decreased level of SET by COG112 not only significantly sensitized MCF-7/PTX cells to paclitaxel, but also enhanced paclitaxel-induced cell apoptosis. Additionally, the levels of the ABC transporters and PI3K/Akt signal pathway were also reduced in the COG112-treated MCF-7/PTX cells. The above results demonstrated that SET was associated with paclitaxel resistance in MCF-7/PTX cells.

  20. [Role of Transient Receptor Potential Channels in Paclitaxel- and Oxaliplatin-induced Peripheral Neuropathy].

    PubMed

    Taguchi, Kyoji

    2016-01-01

    Peripheral neuropathy is a common adverse effect of paclitaxel and oxaliplatin treatment. The major dose-limiting side effect of these drugs is peripheral sensory neuropathy. The symptoms of paclitaxel-induced neuropathy are mostly sensory and peripheral in nature, consisting of mechanical allodynia/hyperalgesia, tingling, and numbness. Oxaliplatin-induced neurotoxicity manifests as rapid-onset neuropathic symptoms that are exacerbated by cold exposure and as chronic neuropathy that develops after several treatment cycles. Although many basic and clinical researchers have studied anticancer drug-induced peripheral neuropathy, the mechanism is not well understood. In this review, we focus on (1) analysis of transient receptor potential vanilloid 1 (TRPV1) channel expression in the rat dorsal root ganglion (DRG) after paclitaxel treatment and (2) analysis of transient receptor potential ankyrin 1 (TRPA1) channel in the DRG after oxaliplatin treatment. This review describes that (1) paclitaxel-induced neuropathic pain may be the result of up-regulation of TRPV1 in small- and medium-diameter DRG neurons. In addition, paclitaxel treatment increases the release of substance P, but not calcitonin gene-related peptide, in the superficial layers of the spinal dorsal horn. (2) TRPA1 expression via activation of p38 mitogen-activated protein kinase in small-diameter DRG neurons, at least in part, contributes to the development of oxaliplatin-induced acute cold hyperalgesia. We suggest that TRPV1 or TRPA1 antagonists may be potential therapeutic lead compounds for treating anticancer drug-induced peripheral neuropathy.

  1. Conversion therapy for pancreatic cancer with peritoneal metastases using intravenous and intraperitoneal paclitaxel with S-1

    PubMed Central

    Kitayama, Hiromitsu; Tsuji, Yasushi; Kondo, Tomohiro; Sugiyama, Junko; Hirayama, Michiaki; Yamamoto, Kazuyuki; Kawarada, You; Oyamada, Yumiko; Hirano, Satoshi

    2016-01-01

    Combination chemotherapy consisting of systemic and intraperitoneal agents against peritoneal metastases from several types of cancer has shown promising results. We herein report a case in which combination therapy with intravenous and intraperitoneal paclitaxel with S-1 converted an unresectable pancreatic cancer with peritoneal metastases into a resectable one. The patient was a 65-year old woman with recurrent pancreatitis for 5 months. Endoscopic ultrasonography-guided fine-needle aspiration revealed minute epithelial masses composed of cells with irregular nuclei in the pancreatic body. The patient underwent abdominal surgery, but no excision was performed, as two peritoneal metastases in the bursa omentalis were detected. Combination therapy was initiated, consisting of intravenous and intraperitoneal paclitaxel with S-1 as a single-center clinical trial. The regimen consisted with 2-week administration of S-1 (80 mg per day) followed by 1 week of rest, intravenous paclitaxel 50 mg/m2, and intraperitoneal paclitaxel 20 mg/m2 by a peritoneal access device on days 1 and 8. Over the seven cycles of the chemotherapy, the primary lesion did not change in size, and peritoneal lavage cytology remained negative. After confirming the disappearance of the peritoneal lesions by exploratory laparoscopy, the patient underwent distal pancreatectomy combined with resection of the transverse mesocolon and stomach wall. Thus, the 2-way chemotherapy of intravenous and intraperitoneal paclitaxel with S-1 was well-tolerated and was able to convert pancreatic cancer with peritoneal metastases to resectable disease. PMID:28105356

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

    PubMed

    Gao, Bo; Russell, Amanda; Beesley, Jonathan; Chen, Xiao Qing; Healey, Sue; Henderson, Michelle; Wong, Mark; Emmanuel, Catherine; Galletta, Laura; Johnatty, Sharon E; Bowtell, David; Haber, Michelle; Norris, Murray; Harnett, Paul; Chenevix-Trench, Georgia; Balleine, Rosemary L; deFazio, Anna

    2014-05-09

    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.

  3. Preparation and characterization of novel poly(ethylene glycol) paclitaxel derivatives.

    PubMed

    Arpicco, Silvia; Stella, Barbara; Schiavon, Oddone; Milla, Paola; Zonari, Daniele; Cattel, Luigi

    2013-10-01

    Paclitaxel has been found to be very effective against several human cancers; one of the major problems with its use is its poor solubility, which makes necessary its solubilization with excipients that can determine allergic reactions often severe. The aim of this study is to develop highly water-soluble prodrugs of paclitaxel. For this purpose we prepared a series of new paclitaxel-poly(ethylene glycol) (PEG) conjugates that were characterized and evaluated for their in vitro stability and cytotoxicity. In particular, in order to modulate the release of paclitaxel from prodrugs, we prepared different compounds introducing PEG in the drug C2' and/or C7 positions via ester or carbamate linkage. The conjugates were obtained in high purity and good yield. The carbamate prodrugs were highly stable in different media, while the compounds obtained linking PEG at C2' position through an ester bond showed lower stability. Finally, the cytotoxic activity of the conjugates was evaluated on two cancer cell lines and the results showed that all the derivatives had a reduced cytotoxicity compared to that of paclitaxel.

  4. Comparative proteomic analysis of paclitaxel resistance-related proteins in human breast cancer cell lines

    PubMed Central

    Fujioka, Hiroya; Sakai, Akiko; Tanaka, Satoru; Kimura, Kosei; Miyamoto, Akiko; Iwamoto, Mitsuhiko; Uchiyama, Kazuhisa

    2017-01-01

    Paclitaxel is widely used to treat various cancers; however, resistance to this drug is a major obstacle to breast cancer chemotherapy. To identify the proteins involved in paclitaxel resistance, the present study compared the proteomes of MCF-7 human breast cancer cells and its paclitaxel-resistant subclone MCF-7/PTX. Using two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time of flight mass spectrometry, 11 upregulated and 12 downregulated proteins were identified in MCF-7/PTX cells compared with the parental cell line. These 23 proteins were functionally classified as stress-induced chaperones, metabolic enzymes and cytoskeletal proteins. The anti-apoptotic proteins, stress-70 protein, 78-kD glucose-regulated protein, peptidyl-prolyl cis-trans isomerase A (PPIA) and heterogeneous nuclear ribonucleoprotein H3, were also upregulated in MCF-7/PTX cells. Notably, knockdown of the stress-response chaperone PPIA using small interfering RNA in MCF-7/PTX cells restored their sensitivity to paclitaxel. These findings indicated that PPIA may have an important role in paclitaxel resistance in MCF-7/PTX cells. PMID:28123557

  5. MENA Confers Resistance to Paclitaxel in Triple-Negative Breast Cancer.

    PubMed

    Oudin, Madeleine J; Barbier, Lucie; Schäfer, Claudia; Kosciuk, Tatsiana; Miller, Miles A; Han, Sangyoon; Jonas, Oliver; Lauffenburger, Douglas A; Gertler, Frank B

    2017-01-01

    Taxane therapy remains the standard of care for triple-negative breast cancer. However, high frequencies of recurrence and progression in treated patients indicate that metastatic breast cancer cells can acquire resistance to this drug. The actin regulatory protein MENA and particularly its invasive isoform, MENA(INV), are established drivers of metastasis. MENA(INV) expression is significantly correlated with metastasis and poor outcome in human patients with breast cancer. We investigated whether MENA isoforms might play a role in driving resistance to chemotherapeutics. We find that both MENA and MENA(INV) confer resistance to the taxane paclitaxel, but not to the widely used DNA-damaging agents doxorubicin or cisplatin. Furthermore, paclitaxel treatment does not attenuate growth of MENA(INV)-driven metastatic lesions. Mechanistically, MENA isoform expression alters the ratio of dynamic and stable microtubule populations in paclitaxel-treated cells. MENA expression also increases MAPK signaling in response to paclitaxel treatment. Decreasing ERK phosphorylation by co-treatment with MEK inhibitor restored paclitaxel sensitivity by driving microtubule stabilization in MENA isoform-expressing cells. Our results reveal a novel mechanism of taxane resistance in highly metastatic breast cancer cells and identify a combination therapy to overcome such resistance. Mol Cancer Ther; 16(1); 143-55. ©2016 AACR.

  6. The chemotherapeutic agent paclitaxel selectively impairs learning while sparing source memory and spatial memory.

    PubMed

    Smith, Alexandra E; Slivicki, Richard A; Hohmann, Andrea G; Crystal, Jonathon D

    2017-03-01

    Chemotherapeutic agents are widely used to treat patients with systemic cancer. The efficacy of these therapies is undermined by their adverse side-effect profiles such as cognitive deficits that have a negative impact on the quality of life of cancer survivors. Cognitive side effects occur across a variety of domains, including memory, executive function, and processing speed. Such impairments are exacerbated under cognitive challenges and a subgroup of patients experience long-term impairments. Episodic memory in rats can be examined using a source memory task. In the current study, rats received paclitaxel, a taxane-derived chemotherapeutic agent, and learning and memory functioning was examined using the source memory task. Treatment with paclitaxel did not impair spatial and episodic memory, and paclitaxel treated rats were not more susceptible to cognitive challenges. Under conditions in which memory was not impaired, paclitaxel treatment impaired learning of new rules, documenting a decreased sensitivity to changes in experimental contingencies. These findings provide new information on the nature of cancer chemotherapy-induced cognitive impairments, particularly regarding the incongruent vulnerability of episodic memory and new learning following treatment with paclitaxel.

  7. Paclitaxel steady-state plasma concentration as a determinant of disease outcome and toxicity in lung cancer patients treated with paclitaxel and cisplatin.

    PubMed

    Rowinsky, E K; Jiroutek, M; Bonomi, P; Johnson, D; Baker, S D

    1999-04-01

    The principal purpose of this study was to evaluate relationships between paclitaxel plasma steady-state concentration (Css) and both disease outcome and toxicity in patients with non-small cell lung cancer (NSCLC) treated with paclitaxel and cisplatin in an Eastern Cooperative Oncology Group (ECOG) Phase III study E5592. Chemotherapy-naive patients with stage IIIb and IV NSCLC were randomized to treatment with either 75 mg/m2 cisplatin i.v. on day 1 and 100 mg/m2 etoposide i.v. on days 1-3 (EC arm) or 75 mg/m2 cisplatin i.v. combined with either a low dose of paclitaxel (135 mg/m2, 24-h i.v. infusion; PC arm) or a higher dose of paclitaxel (250 mg/m2 i.v., 24-h i.v. infusion) with granulocyte colony-stimulating factor (PCG arm). End-of-24-h-infusion paclitaxel concentrations, which have been demonstrated to be nearly equal to CssS on this schedule, were obtained during the first and second courses in patients on the PC and PCG arms. Relationships between the average paclitaxel Css (Css,avg) and the best response to treatment, time to treatment failure (TTF), survival, and worst grade of leukopenia and neurotoxicity were evaluated by univariate analysis. A multivariate model was used to assess the influence of paclitaxel Css in conjunction with other potentially relevant patient variables that may affect disease outcome, including the paclitaxel treatment arm, age, sex, performance status, weight loss during the previous 6 months, and disease stage. Paclitaxel Css in both courses 1 and 2 were obtained in 71 patients treated with PC and 75 patients treated with PCG. Although Css,avgS in patients treated with PC and PCG were significantly different (median, 0.32 versus 0.81 micromol/liter; P < 0.0001), response rates were not (33.8 versus 26.7%; P = 0.3719). In addition, there were no differences between the PC and PCG arms in TTF (median, 5.1 versus 5.5 months, P = 0.6201) or survival (median, 11.6 versus 11.3 months, P = 0.7173). Combined analysis of paclitaxel

  8. Microtubule Associated Protein (MAP)-Tau: a novel mediator of paclitaxel sensitivity in vitro and in vivo.

    PubMed

    Wagner, P; Wang, B; Clark, E; Lee, H; Rouzier, R; Pusztai, L

    2005-09-01

    Microtubule binding protein Tau was recently identified through gene expression analysis of human breast cancer tissues as a novel marker of response to paclitaxel. This article reviews these recent findings and provides additional information to support the role of Tau as an emerging marker and mediator of paclitaxel sensitivity. Low expression of Tau is associated with increased sensitivity to paclitaxel in human breast cancer as well as in a broad range of cell lines. Down regulation of Tau in cell lines by siRNA increases their sensitivity to paclitaxel but not to anthracycline chemotherapy. We propose that this is due to increased paclitaxel binding to microtubules when microtubules are assembled in the presence of low concentrations (or absence) of Tau compared to microtubules that are formed in the presence of physiological (or higher) levels of Tau.

  9. Paclitaxel isomerisation in polymeric micelles based on hydrophobized hyaluronic acid.

    PubMed

    Smejkalová, Daniela; Nešporová, Kristina; Hermannová, Martina; Huerta-Angeles, Gloria; Cožíková, Dagmar; Vištejnová, Lucie; Safránková, Barbora; Novotný, Jaroslav; Kučerík, Jiří; Velebný, Vladimír

    2014-05-15

    Physical and chemical structure of paclitaxel (PTX) was studied after its incorporation into polymeric micelles made of hyaluronic acid (HA) (Mw=15 kDa) grafted with C6 or C18:1 acyl chains. PTX was physically incorporated into the micellar core by solvent evaporation technique. Maximum loading capacity for HAC6 and HAC18:1 was determined to be 2 and 14 wt.%, respectively. The loading efficiency was higher for HAC18:1 and reached 70%. Independently of the derivative, loaded HA micelles had spherical size of approximately 60-80 nm and demonstrated slow and sustained release of PTX in vitro. PTX largely changed its form from crystalline to amorphous after its incorporation into the micelle's interior. This transformation increased PTX sensitivity towards stressing conditions, mainly to UV light exposure, during which the structure of amorphous PTX isomerized and formed C3C11 bond within its structure. In vitro cytotoxicity assay revealed that polymeric micelles loaded with PTX isomer had higher cytotoxic effect to normal human dermal fibroblasts (NHDF) and human colon carcinoma cells (HCT-116) than the same micelles loaded with non-isomerized PTX. Further observation indicated that PTX isomer influenced in different ways cell morphology and markers of cell cycle. Taken together, PTX isomer loaded in nanocarrier systems may have improved anticancer activity in vivo than pure PTX.

  10. Targeting of albumin-embedded paclitaxel nanoparticles to tumors

    PubMed Central

    Karmali, Priya Prakash; Kotamraju, Venkata Ramana; Kastantin, Mark; Black, Matthew; Missirlis, Dimitris; Tirrell, Matthew; Ruoslahti, Erkki

    2010-01-01

    We have used tumor-homing peptides to target abraxane, a clinically approved paclitaxel-albumin nanoparticle, to tumors in mice. The targeting was accomplished with two peptides, CREKA, and LyP-1 (CGQKRTRGC). Fluorescein (FAM)-labeled CREKA-abraxane, when injected intravenously into mice bearing MDA-MB-435 human cancer xenografts, accumulated in tumor blood vessels, forming aggregates that contained red blood cells and fibrin. FAM-LyP-1-abraxane co-localized with extravascular islands expressing its receptor, p32. Self-assembled mixed micelles carrying the homing peptide and the label on different subunits accumulated in the same areas of tumors as LyP-1-abraxane, showing that Lyp-1 can deliver intact nanoparticles into extravascular sites. Untargeted, FAM-abraxane was detected in the form of a faint meshwork in tumor interstitium. LyP-1-abraxane produced a statistically highly significant inhibition of tumor growth compared to untargeted abraxane. These results show that nanoparticles can be effectively targeted into extravascular tumor tissue and that targeting can enhance the activity of a therapeutic nanoparticle. PMID:18829396

  11. SPARC independent delivery of nab-paclitaxel without depleting tumor stroma in patient-derived pancreatic cancer xenografts

    PubMed Central

    Kim, Harrison; Samuel, Sharon L.; Lopez-Casas, Pedro P.; Grizzle, William E.; Hidalgo, Manuel; Kovar, Joy; Oelschlager, Denise K.; Zinn, Kurt R.; Warram, Jason M.; Buchsbaum, Donald J.

    2016-01-01

    The study goal was to examine the relationship between nab-paclitaxel delivery and SPARC (secreted protein acidic and rich in cysteine) expression in pancreatic tumor xenografts and to determine the anti-stromal effect of nab-paclitaxel, which may affect tumor vascular perfusion. SPARC positive and negative mice bearing Panc02 tumor xenografts (n=5–6/group) were injected with IRDye 800CW (IR800)-labeled nab-paclitaxel. After 24 hours, tumors were collected and stained with DL650-labeled anti-SPARC antibody, and the correlation between nab-paclitaxel and SPARC distributions was examined. Eight groups of mice bearing either Panc039 or Panc198 patient-derived xenografts (PDXs) (4 groups/model, 5 animals/group) were untreated (served as control) or treated with gemcitabine (100 mg/kg BW, i.p., twice per week), nab-paclitaxel (30 mg/kg BW, i.v., for 5 consecutive days), and these agents in combination, respectively, for 3 weeks, and tumor volume and perfusion changes were assessed using T2-weighted magnetic resonance imaging (MRI) and dynamic contrast-enhanced (DCE) MRI, respectively. All tumors were collected and stained with Masson’s Trichrome Stain, followed by a blinded comparative analysis of tumor stroma density. IR800-nab-paclitaxel was mainly distributed in tumor stromal tissue, but nab-paclitaxel and SPARC distributions were minimally correlated in either SPARC positive or negative animals. Nab-paclitaxel treatment did not decrease tumor stroma nor increase tumor vascular perfusion in either PDX model when compared to control groups. These data suggest that the specific tumor delivery of nab-paclitaxel is not directly related to SPARC expression, and nab-paclitaxel does not deplete tumor stroma in general. PMID:26832793

  12. In vitro synergistic efficacy of conjugated linoleic acid, oleic acid, safflower oil and taxol cytotoxicity on PC3 cells.

    PubMed

    Kızılşahin, Sadi; Nalbantsoy, Ayşe; Yavaşoğlu, N Ülkü Karabay

    2015-01-01

    The aim of this study was to determine in vitro synergistic efficacy of conjugated linoleic acid (CLA), oleic acid (OLA), safflower oil and taxol (Tax) cytotoxicity on human prostate cancer (PC3) cell line. To determine synergistic efficacy of oil combinations, PC3 treated with different doses of compounds alone and combined with 10 μg/mL Tax. The MTT results indicated that OLA-Tax combinations exhibited cytotoxicity against PC3 at doses of 30 nM+10 μg-Tax, 15 nM+5 μg-Tax and 7.5 nM+2.5 μg-Tax. The treatment of OLA or Tax did not show significant inhibition on PC3, while OLA-Tax combinations showed effective cytotoxicity at treated doses. CLA-Tax combinations demonstrated the same effect on PC3 as combined form with 45.72% versus the alone form as 74.51% viability. Cytotoxic synergy between Tax, OLA and CLA shows enhanced cytotoxicity on PC3 which might be used in the therapy of prostate cancer.

  13. Taxol-stabilized microtubules promote the formation of filaments from unmodified full-length Tau in vitro.

    PubMed

    Duan, Aranda R; Goodson, Holly V

    2012-12-01

    Tau is a neuronal protein that stabilizes the microtubule (MT) network, but it also forms filaments associated with Alzheimer's disease. Understanding Tau-MT and Tau-Tau interactions would help to establish Tau function in health and disease. For many years, literature reports on Tau-MT binding behavior and affinity have remained surprisingly contradictory (e.g., 10-fold variation in Tau-MT affinity). Tau-Tau interactions have also been investigated, but whether MTs might affect Tau filament formation is unknown. We have addressed these issues through binding assays and microscopy. We assessed Tau-MT interactions via cosedimentation and found that the measured affinity of Tau varies greatly, depending on the experimental design and the protein concentrations used. To investigate this dependence, we used fluorescence microscopy to examine Tau-MT binding. Strikingly, we found that Taxol-stabilized MTs promote Tau filament formation without characterized Tau-filament inducers. We propose that these novel Tau filaments account for the incongruence in Tau-MT affinity measurements. Moreover, electron microscopy reveals that these filaments appear similar to the heparin-induced Alzheimer's model. These observations suggest that the MT-induced Tau filaments provide a new model for Alzheimer's studies and that MTs might play a role in the formation of Alzheimer's-associated neurofibrillary tangles.

  14. [Dose response curve of paclitaxel measured by histoculture drug response assay].

    PubMed

    Yoshimasu, Tatsuya; Oura, Shoji; Hirai, Issei; Kokawa, Yozo; Okamura, Yoshitaka; Furukawa, Tomoko

    2005-04-01

    Dose response curves of paclitaxel were measured by histoculture drug response assay (HDRA) in 11 lung cancer patients. Inhibition rates of paclitaxel at several concentrations were measured and fitted to the sigmoid dose response curve, using non-linear least square analysis, with fitting equation y=A (1-1/(1+exp (b (x-log (ED50)). Parameters A, b, and ED50 were 88.3+/-6.0 (80.0-100.0) %, 9.57+/-4.32 (2.25-15.0), and 26.8+/-8.1 (15.0-41.0) microg/ml, respectively. The parameter b was lower in well-differentiated tumors compared with moderately and poorly-differentiated tumors. Dose response curves of paclitaxel could be measured by HDRA in lung cancer. This method provides us more information for drug sensitivity than the usual HDRA method. This may lead to the improved accuracy of HDRA.

  15. [A Case of Recurrent Breast Cancer with Carcinomatous Pleurisy Successfully Treated with Biweekly Paclitaxel and Bevacizumab].

    PubMed

    Yoshida, Takashi; Goto, Yoshinari; Sakiyama, Kana; Kimura, Morihiko

    2016-11-01

    A 72-year-old woman underwent mastectomy with axillary lymph node dissection for left breast cancer at the age of 43 years, and was diagnosed with breast cancer metastasis to the pleura at the age of 68 years. She had been sequentially treated with hormonal therapies, but complained of a cough and dyspnea after 4 years. Chest radiography showed right pleural effusion, and cytological examination of the pleural effusion revealed adenocarcinoma cells. Biweekly paclitaxel and bevacizumab therapy was administered. Two months later, the pleural effusion had disappeared. Biweekly paclitaxel and bevacizumab therapy was continued without any severe adverse events. After 30 months, the patient has remained free of carcinomatous pleurisy recurrence. Therefore, biweekly paclitaxel and bevacizumab therapy can be safely and effectively administered to elderly patients with carcinomatous pleurisy.

  16. [Results of a drug use investigation of nanoparticle albumin-bound Paclitaxel for breast cancer].

    PubMed

    Nakamura, Seigo; Iwata, Hiroji; Funato, Yuya; Ito, Kunio; Ito, Yoshinori

    2015-04-01

    A drug use investigation of nanoparticle albumin-bound paclitaxel was conducted based on conditions for approval. A total of 963 patients were enrolled in this study from September 24, 2010 to February 14, 2011. Twenty-nine patients were excluded, and a total of 934 patients were evaluated for determining the safety of nanoparticle albumin-bound paclitaxel. Adverse drug reactions were observed in 92.8%of the patients, and major adverse drug reactions included myelosuppression and peripheral sensory neuropathy, both of which are characteristic adverse reactions of paclitaxel treatment. Both adverse drug reactions were observed at a high frequency after the second course of treatment, resulting in these reactions being primary causes for discontinuation. Increase in the rates of continuous drug administration may be accomplished by carrying out laboratory tests and noting the medical history in order to prevent myelosuppression from becoming serious and to perform earlier countermeasures for peripheral sensory neuropathy, leading to improved therapeutic effects.

  17. Low Levels of NDRG1 in Nerve Tissue Are Predictive of Severe Paclitaxel-Induced Neuropathy

    PubMed Central

    Sundar, Raghav; Jeyasekharan, Anand D.; Pang, Brendan; Soong, Richie Chuan Teck; Kumarakulasinghe, Nesaretnam Barr; Ow, Samuel Guan Wei; Ho, Jingshan; Lim, Joline Si Jing; Tan, David Shao Peng; Wilder-Smith, Einar P. V.; Bandla, Aishwarya; Tan, Stacey Sze Hui; Asuncion, Bernadette Reyna; Fazreen, Zul; Hoppe, Michal Marek; Putti, Thomas Choudary; Poh, Lay Mui; Goh, Boon Cher; Lee, Soo-Chin

    2016-01-01

    Introduction Sensory peripheral neuropathy caused by paclitaxel is a common and dose limiting toxicity, for which there are currently no validated predictive biomarkers. We investigated the relationship between the Charcot-Marie-Tooth protein NDRG1 and paclitaxel-induced neuropathy. Methods/Materials Archived mammary tissue specimen blocks of breast cancer patients who received weekly paclitaxel in a single centre were retrieved and NDRG1 immunohistochemistry was performed on normal nerve tissue found within the sample. The mean nerve NDRG1 score was defined by an algorithm based on intensity of staining and percentage of stained nerve bundles. NDRG1 scores were correlated with paclitaxel induced neuropathy Results 111 patients were studied. 17 of 111 (15%) developed severe paclitaxel-induced neuropathy. The mean nerve NDRG1 expression score was 5.4 in patients with severe neuropathy versus 7.7 in those without severe neuropathy (p = 0.0019). A Receiver operating characteristic (ROC) curve analysis of the mean nerve NDRG1 score revealed an area under the curve of 0.74 (p = 0.0013) for the identification of severe neuropathy, with a score of 7 being most discriminative. 13/54 (24%) subjects with an NDRG1 score < = 7 developed severe neuropathy, compared to only 4/57 (7%) in those with a score >7 (p = 0.017). Conclusion Low NDRG1 expression in nerve tissue present within samples of surgical resection may identify subjects at risk for severe paclitaxel-induced neuropathy. Since nerve biopsies are not routinely feasible for patients undergoing chemotherapy for early breast cancer, this promising biomarker strategy is compatible with current clinical workflow. PMID:27716814

  18. Combretastatin-A4 phosphate improves the distribution and antitumor efficacy of albumin-bound paclitaxel in W256 breast carcinoma model

    PubMed Central

    Gao, Meng; Zhang, Dongjian; Jin, Qiaomei; Jiang, Cuihua; Wang, Cong; Li, Jindian; Peng, Fei; Huang, Dejian; Zhang, Jian; Song, Shaoli

    2016-01-01

    Nanomedicine holds great promise for fighting against malignant tumors. However, tumor elevated interstitial fluid pressure (IFP) seriously hinders convective transvascular and interstitial transport of nanomedicines and thus damages its antitumor efficacy. In this study, combretastatin-A4 phosphate (CA4P) was utilized to reduce tumor IFP, and thereby to improve the intratumoral distribution and antitumor efficacy of nanoparticle albumin-bound paclitaxel (nab-paclitaxel). IFP was measured using the wick-in-needle method in tumors growing subcutaneously pretreatment and posttreatment with a single intravenous injection of CA4P. The tracing method of iodine 131 isotope was used for biodistribution analysis of nab-paclitaxel. Liquid chromatography coupled with tandem mass spectrometry was used to detect the intratumoral concentration of paclitaxel. Magnetic resonance imaging was applied to monitor tumor volume and ratios of necrosis. The tumor IFP continued to decline gradually over time following CA4P treatment, reaching approximately 31% of the pretreatment value by 1 h posttreatment. Biodistribution data indicated that both 131I-nab-paclitaxel and paclitaxel exhibited higher tumor uptake in CA4P + 131I-nab-paclitaxel group compared with I131-nab-paclitaxel group. Nab-paclitaxel combined with CA4Pshowed significant tumor growth inhibition and higher tumor necrosis ratio relative to PBS, CA4P and nab-paclitaxel group, respectively. In conclusion, CA4P improved the intratumoral distribution and antitumor efficacy of nab-paclitaxel in W256 tumor-bearing rats. PMID:27531898

  19. Randomized Phase III Trial of Paclitaxel Once Per Week Compared With Nanoparticle Albumin-Bound Nab-Paclitaxel Once Per Week or Ixabepilone With Bevacizumab As First-Line Chemotherapy for Locally Recurrent or Metastatic Breast Cancer: CALGB 40502/NCCTG N063H (Alliance)

    PubMed Central

    Rugo, Hope S.; Barry, William T.; Moreno-Aspitia, Alvaro; Lyss, Alan P.; Cirrincione, Constance; Leung, Eleanor; Mayer, Erica L.; Naughton, Michael; Toppmeyer, Deborah; Carey, Lisa A.; Perez, Edith A.; Hudis, Clifford; Winer, Eric P.

    2015-01-01

    Purpose We compared nab-paclitaxel or ixabepilone once per week to paclitaxel with bevacizumab as first-line therapy for patients with advanced breast cancer (BC) to evaluate progression-free survival (PFS) for nab-paclitaxel or ixabepilone versus paclitaxel. Patients and Methods Eligible patients were age ≥ 18 years with chemotherapy-naive advanced BC. Patients were randomly assigned to bevacizumab with paclitaxel 90 mg/m2 (arm A), nab-paclitaxel 150 mg/m2 (arm B), or ixabepilone 16 mg/m2 (arm C), once per week for 3 of 4 weeks. Planned enrollment was 900 patients, which would give 88% power to detect a hazard ratio of 0.73. Results In all, 799 patients were enrolled, and 783 received treatment (97% received bevacizumab). Arm C was closed for futility at the first interim analysis (n = 241), and arm A (n = 267) and arm B (n = 275) were closed for futility at the second interim analysis. Median PFS for paclitaxel was 11 months, ixabepilone was inferior to paclitaxel (PFS, 7.4 months; hazard ratio, 1.59; 95% CI, 1.31 to 1.93; P < .001), and nab-paclitaxel was not superior to paclitaxel (PFS, 9.3 months; hazard ratio, 1.20; 95% CI, 1.00 to 1.45; P = .054). Results were concordant with overall survival; time to treatment failure was significantly shorter in both experimental arms v paclitaxel. Hematologic and nonhematologic toxicity, including peripheral neuropathy, was increased with nab-paclitaxel, with more frequent and earlier dose reductions. Conclusion In patients with chemotherapy-naive advanced BC, ixabepilone once per week was inferior to paclitaxel, and nab-paclitaxel was not superior with a trend toward inferiority. Toxicity was increased in the experimental arms, particularly for nab-paclitaxel. Paclitaxel once per week remains the preferred palliative chemotherapy in this setting. PMID:26056183

  20. Paclitaxel suppresses collagen-induced arthritis: a reevaluation

    PubMed Central

    Zhao, Yi; Chang, Zhi-Fang; Li, Ru; Li, Zhan-Guo; Li, Xiao-Xia; Li, Lin

    2016-01-01

    Objective: To reevaluate the suppressive effect of paclitaxel (PTX) liposome on collagen-induced arthritis (CIA) in rats and explore its mechanisms. Methods: Female Lewis rats were immunized with bovine type II collagen (CII) to induce arthritis. The rats with CIA were randomly divided into three groups: 5% GS control group, 2.5 mg/kg PTX treatment group and 1 mg/kg methotrexate (MTX) positive control group. The drugs were administered by intraperitoneal injection on the second day after arthritis onset. The body weights, arthritis scores and paw volumes were observed consecutively. The ankle joints of rats were collected for X-ray examination and histological evaluation. Serum samples were collected to test the levels of anti-CII antibodies and cytokines. Results: Body weights were not significantly affected after PTX or MTX treatments (p>0.05). Compared with 5% GS control or MTX treatment groups, PTX group showed significant decrease of arthritis scores and paw volumes (p<0.05). Radiographic and histologic evaluation provided evidence that rats with PTX treatment had less synovial proliferation and bone erosion. In addition, the levels of anti-CII antibodies as well as serum tumor necrosis factor (TNF)-α and vascular endothelial growth factor (VEGF) levels were remarkably lower in PTX group than those in 5% GS controls (p<0.05). Conclusions: PTX inhibits the progression of CIA in rats and prevents the destruction of joints. The mechanism might be related to its inhibition on the levels of serum anti-CII antibodies, TNF-α and VEGF. PMID:27904705

  1. Low-dose paclitaxel ameliorates renal fibrosis in rat UUO model by inhibition of TGF-beta/Smad activity.

    PubMed

    Zhang, Dongshan; Sun, Lin; Xian, Wang; Liu, Fuyou; Ling, Guanghui; Xiao, Li; Liu, Yanhong; Peng, Youmin; Haruna, Yoshisuke; Kanwar, Yashpal S

    2010-03-01

    Transforming growth factor-beta (TGF-beta) has a pivotal function in the progression of renal fibrosis in a wide variety of renal diseases. Smad proteins have been identified to have an important function in regulating the expression of extracellular matrix (ECM) proteins through TGF-beta signaling pathway. Aberrant TGF-beta/Smad signaling can be modulated by stabilization of microtubules with paclitaxel. In this study, we investigated if paclitaxel can attenuate tubulointerstitial fibrosis in a rat model of unilateral ureteral obstruction (UUO). Rats in groups of six were subjected to UUO and received low-dose intraperitoneal injection of paclitaxel (0.3 mg/kg) twice a week. They were killed at day 7 and 14 after UUO or Sham operation. TGF-beta signaling cascade and status of various ECM proteins were evaluated by RT-PCR, western blotting and immunohistochemical or immunofluorescence staining. The paclitaxel treatment markedly suppressed Smad2 and Smad3 phosphorylation. This was associated with attenuated expression of integrin-linked kinase, collagens I and III, fibronectin (FN) and alpha-smooth muscle actin, and a substantial decrease in renal fibrosis in animals that underwent UUO and received paclitaxel. These data indicate that the low-dose paclitaxel ameliorates renal tubulointerstitial fibrosis by modulating TGF-beta signaling, and thus, the paclitaxel may have some therapeutic value in humans.

  2. Incidence and risk of peripheral neuropathy with nab-paclitaxel in patients with cancer: a meta-analysis.

    PubMed

    Peng, L; Bu, Z; Ye, X; Zhou, Y; Zhao, Q

    2015-11-04

    Nab-paclitaxel, a Cremophor EL-free formulation of paclitaxel, is used to treat various malignancies. Peripheral neuropathy is one of its major toxicities, although the overall incidence remains unclear. We performed a meta-analysis to calculate the incidence of peripheral neuropathy in cancer patients treated with nab-paclitaxel and to compare the relative risk (RR) with conventional taxanes. The electronic databases were searched for relevant clinical trials. Eligible studies included phase II and III prospective clinical trials of cancer patients treated with nab-paclitaxel with toxicity profile on peripheral neuropathy. Statistical analyses were done to calculate summary incidences, RRs and 95% confidence intervals (CI), using fixed-effects or random-effects models based on the heterogeneity of the included studies. Nineteen trials were selected for the meta-analysis, yielding a total of 2878 cancer patients. The overall incidences of peripheral neuropathy (all-grade) was 51.0% (95% CI: 45.1-57.6%), and that of high-grade peripheral neuropathy was 12.4% (9.8-15.7%). The RRs of peripheral neuropathy of nab-paclitaxel compared to taxanes were not increased for all-grade and high-grade peripheral neuropathy. Nab-paclitaxel is associated with an increased risk of developing peripheral neuropathy. Future clinical studies are still needed to investigate the risk reduction and possible use of nab-paclitaxel.

  3. Evidence that spinal astrocytes but not microglia contribute to the pathogenesis of paclitaxel-induced painful neuropathy

    PubMed Central

    Zhang, Haijun; Yoon, Seo-Yeon; Zhang, Hongmei; Dougherty, Patrick M.

    2012-01-01

    Paclitaxel often induces persistent painful neuropathy as its most common treatment limiting side effect. Little is known concerning the underlying mechanisms. Given the prominent role of glial cells in many types of neuropathic pain, we investigated here the morphological and functional changes of spinal astrocytes and microglia in a rat model of paclitaxel-induced neuropathy. Immunohistochemistry, western blotting and real-time polymerase chain reaction (rt-PCR) were performed with samples from 109 rats up to 28 days after paclitaxel treatment. Paclitaxel (2mg/kg, i.p.) induced a rapid and persistent activation of spinal astrocytes assessed using glial fibrillary acidic protein (GFAP), but not apparent activation of microglia assessed using OX42, Iba-1 and phosphorylated p38. In the context of astocyte activation, there was a significant downregulation of glial glutamate transporters GLAST and GLT-1 in spinal dorsal horn. The activation of spinal astrocytes by paclitaxel was not associated with expression of pro-inflammatory cytokines including tumor necrosis factor-α (TNFα), interleukin-1β (IL-1β) or interleukin-6 (IL-6) in spinal dorsal horn. Systemic treatment with minocycline (50mg/kg, i.p.) prevented activation of astrocytes and downregulation of glial glutamate transporters in spinal dorsal horn induced by paclitaxel. These data suggest the involvement of spinal astrocytes but not microglia in the pathogenesis of paclitaxel-induced neuropathy. PMID:22285612

  4. A randomized Phase III trial of weekly or 3-weekly doses of nab-paclitaxel versus weekly doses of Cremophor-based paclitaxel in patients with previously treated advanced gastric cancer (ABSOLUTE Trial).

    PubMed

    Koizumi, Wasaburo; Morita, Satoshi; Sakata, Yuh

    2015-03-01

    Paclitaxel is an agent widely used in second-line chemotherapy for advanced gastric cancer. The aim of this trial is to evaluate the efficacy and safety of 3-weekly or weekly doses of nanoparticle albumin-bound-paclitaxel compared with weekly doses of Cremophor-based paclitaxel in patients with unresectable or recurrent gastric cancer refractory to first-line chemotherapy comprising fluoropyrimidines. A total of 730 patients will be enrolled from 72 institutions. The primary endpoint is the overall survival, and the secondary endpoints are progression-free survival, time to treatment failure, overall response rate, disease control rate, quality of life (by using the EQ-5D system) and safety.

  5. Liposomal cisplatin combined with paclitaxel versus cisplatin and paclitaxel in non-small-cell lung cancer: a randomized phase III multicenter trial

    PubMed Central

    Stathopoulos, G. P.; Antoniou, D.; Dimitroulis, J.; Michalopoulou, P.; Bastas, A.; Marosis, K.; Provata, A.; Yiamboudakis, P.; Veldekis, D.; Lolis, N.; Georgatou, N.; Toubis, M.; Pappas, Ch.; Tsoukalas, G.

    2010-01-01

    Background: Liposomal cisplatin is a new formulation developed to reduce the systemic toxicity of cisplatin while simultaneously improving the targeting of the drug to the primary tumor and to metastases by increasing circulation time in the body fluids and tissues. The primary objectives were to determine nephrotoxicity, gastrointestinal side-effects, peripheral neuropathy and hematological toxicity and secondary objectives were to determine the response rate, time to tumor progression (TTP) and survival. Patients and methods: Two hundred and thirty-six chemotherapy-naive patients with inoperable non-small-cell lung cancer were randomly allocated to receive either 200 mg/m2 of liposomal cisplatin and 135 mg/m2 paclitaxel (arm A) or 75 mg/m2 cisplatin and 135 mg/m2 paclitaxel (arm B), once every 2 weeks on an outpatient basis. Two hundred and twenty-nine patients were assessable for toxicity, response rate and survival. Nine treatment cycles were planned. Results: Arm A patients showed statistically significant lower nephrotoxicity, grade 3 and 4 leucopenia, grade 2 and 3 neuropathy, nausea, vomiting and fatigue. There was no significant difference in median and overall survival and TTP between the two arms; median survival was 9 and 10 months in arms A and B, respectively, and TTP was 6.5 and 6 months in arms A and B, respectively. Conclusions: Liposomal cisplatin in combination with paclitaxel has been shown to be much less toxic than the original cisplatin combined with paclitaxel. Nephrotoxicity in particular was negligible after liposomal cisplatin administration. TTP and survival were similar in both treatment arms. PMID:20439345

  6. Combination use of paclitaxel and avastin enhances treatment effect for the NSCLC patients with malignant pleural effusion

    PubMed Central

    Qi, Nan; Li, Fang; Li, Xiaosong; Kang, Huanrong; Zhao, Hui; Du, Nan

    2016-01-01

    Abstract The current study is conducted to investigate efficacy of the chemotherapy drug paclitaxel in combination with Avastin (Roche Diagnostics GmbH., Mannheim, Germany) (antiangiogenic agent) in treatment of malignant pleural effusions (MPEs). Twenty-four patients with non–small cell lung cancer were randomly assigned for 2 treatment approaches. Ten patients received paclitaxel (175 mg/m2) alone, and 14 patients took a combination therapy of paclitaxel and Avastin (5 mg/kg). Efficacy of the treatment approaches in the patients was validated with the change in the MPE volume. Pharmacokinetic (PK) profile and urinary excretion rate of paclitaxel were analyzed with serum vascular endothelial growth factor (VEGF) level, and adverse events were examined as well. The combination therapy reduced the MPE level with a successful rate of 29% and a survival rate of 25% over the single paclitaxel treatment in the study cohort (both P < 0.05). PKs for the combined treatment displayed a rapid distribution of the anticancer drug paclitaxel with an obvious increase in its elimination half-life in the pleural fluid (both P < 0.01). Mean residence time of paclitaxel increased in the presence of Avastin (P < 0.01). Serum VEGF levels significantly reduced in the Avastin-treated patients as compared to the paclitaxel-treated ones (P < 0.01). The urinary excretion rate was similar in the study cohort. Incidence of adverse events for the 2 treatment approaches was similar in the patients. Intervention of Avastin enhances potency of paclitaxel in treatment of MPEs with the increased survival rate of the patients through inhibiting VEGF production and prolonging time of ongoing interaction between the chemotherapy drug and the tumor tissues. PMID:27893676

  7. Drug-drug Interaction between Losartan and Paclitaxel in Human Liver Microsomes with Different CYP2C8 Genotypes.

    PubMed

    Mukai, Yuji; Senda, Asuna; Toda, Takaki; Hayakawa, Toru; Eliasson, Erik; Rane, Anders; Inotsume, Nobuo

    2015-06-01

    The cytochrome P450 (CYP) 2C8*3 allele is associated with reduced metabolic activity of paclitaxel. This study was aimed to investigate the inhibitory effect of losartan on paclitaxel metabolism in human liver microsomes (HLMs) and to determine the impact of the CYP2C8*3 polymorphism. HLMs that contained the CYP2C8*1 homozygote (HL60) or CYP2C8*3 heterozygote (HL54) genotype were used for the inhibition study. Losartan, at a concentration of 50 μmol/L, significantly inhibited paclitaxel metabolism by 29% and 57% in the HL60 (p < 0.001) and HL54 (p < 0.01), respectively. When using HL60, losartan and the CYP3A4-selective inhibitors, erythromycin and ketoconazole, caused a greater inhibition of the paclitaxel metabolism than quercetin, a CYP2C8-selective inhibitor. This demonstrated that the paclitaxel metabolism was mainly catalysed by CYP3A4 in HL60. There were no significant differences found for the inhibitory effects caused by the four inhibitors of the paclitaxel metabolism in HL54, indicating that both CYP2C8 and CYP3A4 play important roles in paclitaxel metabolism in HL54. These findings suggest that 50 μmol/L of losartan inhibits both CYP2C8 and CYP3A4 in HLMs. In summary, losartan inhibited paclitaxel metabolism, with concentrations over 50 μmol/L in HLMs. The CYP2C8*3 allele carriers are likely susceptible to the interactions of losartan and CYP3A4 inhibitors to paclitaxel metabolism.

  8. The Cancer Chemotherapeutic Paclitaxel Increases Human and Rodent Sensory Neuron Responses to TRPV1 by Activation of TLR4

    PubMed Central

    Li, Yan; Adamek, Pavel; Zhang, Haijun; Tatsui, Claudio Esteves; Rhines, Laurence D.; Mrozkova, Petra; Li, Qin; Kosturakis, Alyssa K.; Cassidy, Ryan M.; Harrison, Daniel S.; Cata, Juan P.; Sapire, Kenneth; Zhang, Hongmei; Kennamer-Chapman, Ross M.; Jawad, Abdul Basit; Ghetti, Andre; Yan, Jiusheng; Palecek, Jiri

    2015-01-01

    Peripheral neuropathy is dose limiting in paclitaxel cancer chemotherapy and can result in both acute pain during treatment and chronic persistent pain in cancer survivors. The hypothesis tested was that paclitaxel produces these adverse effects at least in part by sensitizing transient receptor potential vanilloid subtype 1 (TRPV1) through Toll-like receptor 4 (TLR4) signaling. The data show that paclitaxel-induced behavioral hypersensitivity is prevented and reversed by spinal administration of a TRPV1 antagonist. The number of TRPV1+ neurons is increased in the dorsal root ganglia (DRG) in paclitaxel-treated rats and is colocalized with TLR4 in rat and human DRG neurons. Cotreatment of rats with lipopolysaccharide from the photosynthetic bacterium Rhodobacter sphaeroides (LPS-RS), a TLR4 inhibitor, prevents the increase in numbers of TRPV1+ neurons by paclitaxel treatment. Perfusion of paclitaxel or the archetypal TLR4 agonist LPS activated both rat DRG and spinal neurons directly and produced acute sensitization of TRPV1 in both groups of cells via a TLR4-mediated mechanism. Paclitaxel and LPS sensitize TRPV1 in HEK293 cells stably expressing human TLR4 and transiently expressing human TRPV1. These physiological effects also are prevented by LPS-RS. Finally, paclitaxel activates and sensitizes TRPV1 responses directly in dissociated human DRG neurons. In summary, TLR4 was activated by paclitaxel and led to sensitization of TRPV1. This mechanism could contribute to paclitaxel-induced acute pain and chronic painful neuropathy. SIGNIFICANCE STATEMENT In this original work, it is shown for the first time that paclitaxel activates peripheral sensory and spinal neurons directly and sensitizes these cells to transient receptor potential vanilloid subtype 1 (TRPV1)-mediated capsaicin responses via Toll-like receptor 4 (TLR4) in multiple species. A direct functional interaction between TLR4 and TRPV1 is shown in rat and human dorsal root ganglion neurons, TLR4/TRPV1

  9. The influence of paclitaxel on hydrolytic degradation in matrices obtained from aliphatic polyesters and polyester carbonates.

    PubMed

    Musiał-Kulik, Monika; Kasperczyk, Janusz; Jelonek, Katarzyna; Dobrzyński, Piotr; Gebarowska, Katarzyna; Janeczek, Henryk; Libera, Marcin

    2010-01-01

    Biodegradable polymers have become common materials used in pharmacy and medicine due to their properties such as mechanical strength, biocompatibility and non-toxic degradation products. Different compositions of copolymers and also their chain microstructure may have an effect on matrices degradation and thus on the drug release profile. In our study, we aimed at the influence of paclitaxel content on hydrolytic degradation process of terpolymeric matrices. Hydrolytic degradation of three kinds of matrices (with 5 or 10% of paclitaxel and drug free matrices) prepared from three types of terpolymers was performed in vitro at 37 degrees C in phosphate buffer solution (PBS, pH 7,4). The 1H and 13C NMR spectra of terpolymers were recorded. Thermal properties were monitored by differential scanning calorimetry (DSC). Molecular weight dispersity (D) and molecular weight were determined using gel permeation chromatography (GPC). The surface morphology was studied by means of the scanning electron microscopy (SEM). The most significant degradation was observed in case of poly(L-lactide-co-glycolide-co-epsilon-caprolactone) 44:32:24. Weight loss and water uptake were similar in the event of the same type of matrices obtained from the two poly(L-lactide-co-glycolide-co-TMC). Decelerated paclitaxel release in case of matrices with 51:26:23 molar ratio was noticed and it can be connected with higher content of carbonate units. Knowledge of paclitaxel influence on hydrolytic degradation process may contribute to receive valuable information about its release mechanisms from biodegradable terpolymers.

  10. [Nab-Paclitaxel plus gemcitabine in patients with metastatic pancreatic adenocarcinoma: experience of use].

    PubMed

    Ferris Villanueva, Elena; Martínez Penella, Mónica; Cerezuela Fuentes, Pablo; Guerrero Bautista, Rocío; García Márquez, Andrés; Mira Sirvent, María Del Carmen

    2015-05-01

    Objetivo: Describir los resultados obtenidos en el uso de nab-paclitaxel y gemcitabina en el tratamiento de pacientes con adenocarcinoma de páncreas metastático. Material y métodos: Estudio observacional retrospectivo. Se seleccionaron pacientes en tratamiento con nab-paclitaxel asociado a gemcitabina entre enero 2013 y enero 2014. Se recogieron datos demográficos y clínicos. Resultados: Se incluyeron 15 pacientes (edad media: 59,4 ± 10,3 años). Todos ellos recibieron la combinación de nab-paclitaxel y gemcitabina en primera línea para la enfermedad metastásica. Nueve recibieron tratamiento adyuvante antes de que la enfermedad fuera metastásica, siendo la media de líneas de tratamiento previamente al uso de la combinación de 1,1. La mediana de supervivencia libre de progresión fue de 5,6 meses (IC 95%: 4,44 - 8,03). Sólo dos pacientes suspendieron el tratamiento por toxicidad. Conclusiones: El tratamiento con nab-paclitaxel y gemcitabina en nuestros pacientes ha resultado en una supervivencia libre de progresión similar a la de los ensayos clínicos publicados, presentando además una buena tolerancia.

  11. Angiosarcoma associated with a Kasabach-Merritt syndrome: report of two cases treated with paclitaxel.

    PubMed

    Grellety, Thomas; Italiano, Antoine

    2013-09-01

    Angiosarcomas are rare, aggressive vascular malignancies of endothelial cell differentiation. Kasabach-Merritt syndrome is a rare condition defined by the association of thrombocytopenia and consumption coagulopathy with specific vascular tumors, such as tufted angioma or kaposiform hemangioendothelioma. We report here two cases of angiosarcomas complicated by a Kasabach-Merritt syndrome and their outcome after treatment with paclitaxel.

  12. Tumor Reduction in Primary and Metastatic Pancreatic Cancer Lesions With nab-Paclitaxel and Gemcitabine

    PubMed Central

    Kunzmann, Volker; Ramanathan, Ramesh K.; Goldstein, David; Liu, Helen; Ferrara, Stefano; Lu, Brian; Renschler, Markus F.; Von Hoff, Daniel D.

    2017-01-01

    Objectives Results from the phase 3 Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT) led to approval of nab-paclitaxel plus gemcitabine for first-line treatment of metastatic pancreatic cancer. The current analysis evaluated the effects of nab-paclitaxel plus gemcitabine versus gemcitabine on primary pancreatic and metastatic lesions. Methods In this analysis of the previously described MPACT trial, changes in pancreatic and metastatic tumor burden were assessed using independently measured diameters of lesions on computed tomography or magnetic resonance imaging scans. Changes in the sums of longest tumor diameters were summarized using descriptive statistics and were included in a multivariate analysis of overall survival. Results Primary pancreatic lesion measurement was feasible. Reductions in primary pancreatic tumor burden and metastatic burden from baseline to nadir were significantly greater with nab-paclitaxel plus gemcitabine versus gemcitabine. Baseline pancreatic tumor burden was independently predictive of survival. Both regimens elicited linear reductions in primary pancreatic and metastatic tumor burden through time. There was a high within-patient concordance of tumor changes between primary pancreatic lesions and metastatic lesions. Conclusions This analysis of MPACT demonstrated significant tumor shrinkage benefit for nab-paclitaxel plus gemcitabine in both primary pancreatic and metastatic lesions, supporting ongoing evaluation of this regimen in locally advanced disease. PMID:27841795

  13. Effects of paclitaxel with or without cremophor EL on cellular clonogenic survival and apoptosis.

    PubMed

    Engblom, P; Pulkkinen, J O; Rantanen, V; Hirvonen, H; Kulmala, J; Grènman, R; Grènman, S

    1999-02-01

    Paclitaxel is currently formulated in a vehicle of 50% ethanol and 50% polyethoxylated surfactant cremophor EL. Cremophor EL has been reported to reverse P-glycoprotein-mediated multidrug resistance (MDR) at doses which are clinically achievable. It has also been reported to have a cytotoxic effect per se. In this study we used two different methods to evaluate the survival of cells exposed to paclitaxel with or without cremophor EL and the vehicle alone. Two laryngeal SCC cell lines (UT-SCC-19A and UT-SCC-29) and two ovarian adenocarcinoma cell lines (UT-OC-3 and UT-OC-5) established in our laboratory were investigated. Northern hybridisation was used to study the mdr-1 mRNA expression of the cell lines. With sensitive Northern analyses, these four lines yielded mdr-1 mRNA signals of the expected 4.5 kb size and of variable intensity, generally at higher levels than those in the positive control cell line KB. The 96-well plate clonogenic assay was used to obtain the fraction survival data and apoptosis was recorded by time-lapse video microscopy. Both methods indicate that cremophor EL alone has no effect on cellular survival. Consequently, paclitaxel without cremophor EL is as active as paclitaxel with cremophor EL in vitro.

  14. Muscarinic activation enhances the anti-proliferative effect of paclitaxel in murine breast tumor cells.

    PubMed

    Español, Alejandro Javier; Jacob, Guillermina; Dmytrenko, Ganna; Sales, María Elena

    2013-10-01

    Muscarinic acetylcholine receptors (mAChR) are expressed in cells without nervous origin. mAChR are up-regulated in tumor cells and their stimulation can modulate tumor growth. In this work we investigated the ability of mAChR activation to induce tumor cell death. We studied the action of a combination of low doses of the muscarinic agonist carbachol plus paclitaxel, a chemotherapeutic agent frequently used in breast cancer treatment, in terms of effectiveness. Long term treatment with carbachol exerted anti-proliferative actions on LM2 and LM3 murine mammary adenocarcinoma cells, similarly to paclitaxel. The combination of carbachol with paclitaxel at submaximal concentrations, added during 20 h decreased tumor cell proliferation in a more potent manner than each drug added separately. This effect was reverted by the muscarinic antagonist atropine, and was due to a potentiation of tumor cell apoptosis tested by TUNEL assay. This treatment did not affect the proliferation of the non tumorigenic mammary cell line NMuMG. In conclusion, the combination of a muscarinic agonist plus paclitaxel should be tested as a useful therapeutic tool in breast cancer treatment.

  15. The effects of narrow-band middle infrared radiation in enhancing the antitumor activity of paclitaxel.

    PubMed

    Tsai, Shang-Ru; Sheu, Bor-Ching; Huang, Pei-Shen; Lee, Si-Chen

    2016-01-01

    Paclitaxel is used as an adjuvant to enhance the effectiveness of ionization radiation therapy; however, high-energy radiation often damages the healthy cells surrounding cancer cells. Low-energy, middle-infrared radiation (MIR) has been shown to prevent tissue damage, and recent studies have begun combining MIR with paclitaxel. However, the cytotoxic effects of this treatment combination remain unclear, and the mechanism underlying its effects on HeLa cells has yet to be elucidated. This study investigated the effectiveness of treating HeLa human cervical cancer cells with a combination of paclitaxel for 48 h in conjunction with narrow-band MIR from 3.0 to 5.0 μm. This combined treatment significantly inhibited the growth of HeLa cells. Specifically, results from Annexin V-FITC/PI apoptosis detection and cell mitochondrial membrane potential analyses revealed an increase in apoptotic cell death and a collapse of mitochondrial membrane potential. One possible mechanism underlying cellular apoptosis is an increase in oxidative stress. These preliminary findings provide evidence to support the combination of narrow-band MIR with paclitaxel as an alternative approach in the treatment of human cervical cancer.

  16. Release Kinetics of Paclitaxel and Cisplatin from Two and Three Layered Gold Nanoparticles

    PubMed Central

    England, Christopher G.; Miller, M. Clarke; Kuttan, Ashani; Trent, John O.; Frieboes, Hermann B.

    2015-01-01

    Gold nanoparticles functionalized with biologically-compatible layers may achieve stable drug release while avoiding adverse effects in cancer treatment. We study cisplatin and paclitaxel release from gold cores functionalized with hexadecanethiol (TL) and phosphatidylcholine (PC) to form two-layer nanoparticles, or TL, PC, and high density lipoprotein (HDL) to form three-layer nanoparticles. Drug release was monitored for 14 days to assess long term effects of the core surface modifications on release kinetics. Release profiles were fitted to previously developed kinetic models to differentiate possible release mechanisms. The hydrophilic drug (cisplatin) showed an initial (5-hr.) burst, followed by a steady release over 14 days. The hydrophobic drug (paclitaxel) showed a steady release over the same time period. Two layer nanoparticles released 64.0 ± 2.5% of cisplatin and 22.3 ± 1.5% of paclitaxel, while three layer nanoparticles released the entire encapsulated drug. The Korsmeyer-Peppas model best described each release scenario, while the simplified Higuchi model also adequately described paclitaxel release from the two layer formulation. We conclude that functionalization of gold nanoparticles with a combination of TL and PC may help to modulate both hydrophilic and hydrophobic drug release kinetics, while the addition of HDL may enhance long term release of hydrophobic drug. PMID:25753197

  17. In Vitro Activity of Paclitaxel-Loaded Polymeric Expansile Nanoparticles in Breast Cancer Cells

    PubMed Central

    Zubris, Kimberly Ann V.; Liu, Rong; Colby, Aaron; Schulz, Morgan D.; Colson, Yolonda L.; Grinstaff, Mark W.

    2013-01-01

    Through a series of in vitro studies, the essential steps for intracellular drug delivery of paclitaxel using a pH-responsive nanoparticle system have been investigated in breast cancer cells. We successfully encapsulated paclitaxel within polymeric expansile nanoparticles (Pax-eNPs) at 5% loading via a miniemulsion polymerization procedure. Fluorescently tagged eNPs were readily taken up by MDA-MB-231 breast cancer cells grown in culture as confirmed by confocal microscopy and flow cytometry. The ability of the encapsulated paclitaxel to reach the cytoplasm was also observed using confocal microscopy and fluorescently labeled paclitaxel. Pax-eNPs were shown to be efficacious against three in vitro human breast adenocarcinoma cell lines (MDA-MB-231, MCF-7 and SK-BR-3) as well as cells isolated from the pleural effusions of two different breast cancer patients. Lastly, macropinocytosis was identified as the major cellular pathway responsible for eNP uptake, as confirmed using temperature-sensitive metabolic reduction, pharmacologic inhibitors, and fluid-phase marker co-localization. PMID:23617223

  18. Minoxidil is a potential neuroprotective drug for paclitaxel-induced peripheral neuropathy.

    PubMed

    Chen, Yi-Fan; Chen, Li-Hsien; Yeh, Yu-Min; Wu, Pei-Ying; Chen, Yih-Fung; Chang, Lian-Yun; Chang, Jang-Yang; Shen, Meng-Ru

    2017-03-28

    Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of cancer treatment. No medication has been shown to be effective in the treatment of CIPN. This study aims to integrate the image-based high-content screening, mouse behavior models and mechanistic cell-based assays to discover potential neuroprotective drugs. Among screened compounds, minoxidil showed the most potent neuroprotective effect against paclitaxel, with regard to neurite outgrowth of dorsal root ganglia (DRG). Minoxidil protected mice from thermal insensitivity and alleviated mechanical allodynia in paclitaxel-treated mice. The ultrastructure and quantified G-ratio of myelin integrity of sciatic nerve tissues supported the observations in mouse behavioral tests. The mechanistic study on DRG neurons suggested that minoxidil suppressed neuroinflammation and remodeled the dysregulation of intracellular calcium homeostasis provoked by paclitaxel. Importantly, minoxidil showed a synergistic anti-tumor effect with paclitaxel both in tumor xenograft models of cervical and breast cancer. Interestingly, the quantitative assays on hair length and hair growth both exhibited that minoxidil significantly improved the hair quality after chemotherapy. Since minoxidil is a drug approved by the Food and Drug Administration (FDA), the safety and biocompatibility are well documented. The immediate next step is to launch an early-stage clinical trial intending to prevent CIPN by minoxidil.

  19. Minoxidil is a potential neuroprotective drug for paclitaxel-induced peripheral neuropathy

    PubMed Central

    Chen, Yi-Fan; Chen, Li-Hsien; Yeh, Yu-Min; Wu, Pei-Ying; Chen, Yih-Fung; Chang, Lian-Yun; Chang, Jang-Yang; Shen, Meng-Ru

    2017-01-01

    Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of cancer treatment. No medication has been shown to be effective in the treatment of CIPN. This study aims to integrate the image-based high-content screening, mouse behavior models and mechanistic cell-based assays to discover potential neuroprotective drugs. Among screened compounds, minoxidil showed the most potent neuroprotective effect against paclitaxel, with regard to neurite outgrowth of dorsal root ganglia (DRG). Minoxidil protected mice from thermal insensitivity and alleviated mechanical allodynia in paclitaxel-treated mice. The ultrastructure and quantified G-ratio of myelin integrity of sciatic nerve tissues supported the observations in mouse behavioral tests. The mechanistic study on DRG neurons suggested that minoxidil suppressed neuroinflammation and remodeled the dysregulation of intracellular calcium homeostasis provoked by paclitaxel. Importantly, minoxidil showed a synergistic anti-tumor effect with paclitaxel both in tumor xenograft models of cervical and breast cancer. Interestingly, the quantitative assays on hair length and hair growth both exhibited that minoxidil significantly improved the hair quality after chemotherapy. Since minoxidil is a drug approved by the Food and Drug Administration (FDA), the safety and biocompatibility are well documented. The immediate next step is to launch an early-stage clinical trial intending to prevent CIPN by minoxidil. PMID:28349969

  20. Establishment of opioid-induced rewarding effects under oxaliplatin- and Paclitaxel-induced neuropathy in rats.

    PubMed

    Mori, Tomohisa; Kanbara, Tomoe; Harumiya, Masato; Iwase, Yoshiyuki; Masumoto, Aki; Komiya, Sachiko; Nakamura, Atsushi; Shibasaki, Masahiro; Kanemasa, Toshiyuki; Sakaguchi, Gaku; Suzuki, Tsutomu

    2014-01-01

    The rewarding effects of μ-receptor agonists can be suppressed under several pain conditions. We recently showed that clinically used μ-receptor agonists possess efficacies for relieving the neuropathic pain induced by chemotherapeutic drug in rats; however, it is possible that the use of μ-receptor agonists may trigger the rewarding effects even under chemotherapeutic drug-induced neuropathic pain. Nevertheless, no information is available regarding whether μ-receptor agonists produce psychological dependence under chemotherapeutic drug-induced neuropathic pain. Therefore, we examined the effects of neuropathy induced by chemotherapeutic drugs on the rewarding effects of morphine, oxycodone, and fentanyl in rats. Repeated treatment with oxaliplatin or paclitaxel produced neuropathy as measured by the von Frey test. Rewarding effects produced by antinociceptive doses of μ-receptor agonists were not suppressed under oxaliplatin- or paclitaxel-induced neuropathy. Furthermore, the morphine-induced increase in the release of dopamine from the nucleus accumbens, which is a critical step in the rewarding effects of μ-receptor agonists, was not altered in paclitaxel-treated rats. These results suggest that the rewarding effects of μ-receptor agonists can still be established under oxaliplatin- or paclitaxel-induced neuropathic pain. Therefore, patients should be carefully monitored for psychological dependence on μ-receptor agonists when they are used to control chemotherapeutic drug-induced neuropathic pain.

  1. Paclitaxel is necessary for improved survival in epithelial ovarian cancers with homologous recombination gene mutations

    PubMed Central

    Jean, Stephanie; Li, Jiaqi; Katsaros, Dionyssios; Wubbenhorst, Bradley; Maxwell, Kara N.; Fishbein, Lauren; McLane, Michael W.; Benedetto, Chiara; Canuto, Emilie Marion; Mitra, Nandita; Zhang, Lin; Nathanson, Katherine L.; Tanyi, Janos L.

    2016-01-01

    PURPOSE To investigate the impact of somatic mutations in homologous recombination (HR) genes on the chemotherapeutic response and survival of patients with epithelial ovarian cancer (EOC). EXPERIMENTAL DESIGN We performed targeted massively parallel sequencing of tumor DNA from 158 patients with EOC. We associated adjuvant chemotherapy and clinical outcome with mutations in selected genes, focusing on those encoding HR proteins. RESULTS HR mutations were found in 47 (30%) tumors. We did not detect an overall survival (OS) difference in advanced stage patients whose tumors had HR mutations compared to those without (median OS of 49.6 months (95% CI 29.9-57.7) vs. 43.3 months (95% CI 31.9-75.47), p = 0.87). However, when stratified by chemotherapy regimen, patients whose tumors had TP53 and HR mutations demonstrated a marked survival advantage when treated with platinum and paclitaxel vs. platinum +/− cyclophosphamide (median OS of 90 months (95% CI 50-NA) vs. 29.5 months (95% CI 17.7-50.5), p = 0.0005). CONCLUSIONS Previous studies demonstrating a survival advantage for EOC patients with somatic HR mutations have been conducted with almost universal use of both platinum and paclitaxel. Our study is the first to our knowledge to compare cohorts with somatic HR gene mutations treated with and without paclitaxel containing platinum regimens. The survival benefit attributed to the platinum sensitivity of HR deficient ovarian cancers may depend upon the combined use of paclitaxel. PMID:27191893

  2. Thermosensitive and Mucoadhesive Sol-Gel Composites of Paclitaxel/Dimethyl-β-Cyclodextrin for Buccal Delivery

    PubMed Central

    Kang, Bong-Seok; Ng, Choon Lian; Davaa, Enkhzaya; Park, Jeong-Sook

    2014-01-01

    The purpose of this study was to develop a buccal paclitaxel delivery system using the thermosensitive polymer Pluronic F127 (PF127) and the mucoadhesive polymer polyethylene oxide (PEO). The anticancer agent paclitaxel is usually used to treat ovarian, breast, and non-small-cell lung cancer. To improve its aqueous solubility, paclitaxel was incorporated into an inclusion complex with (2,6-di-O-methyl)-β-cyclodextrin (DMβCD). The formation of the paclitaxel inclusion complex was evaluated using various techniques, including x-ray diffractometry (XRD), Fourier-transform infrared (FT-IR) spectrophotometry, differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). Hydrogels were prepared using a cold method. Concentrations of 18, 20, and 23% (w/v) PF127 were dissolved in distilled water including paclitaxel and stored overnight in a refrigerator at 4°C. PEO was added at concentrations of 0.1, 0.2, 0.4, 0.8, and 1% (w/v). Each formulation included paclitaxel (0.5 mg/mL). The sol-gel transition temperature of the hydrogels was measured using the tube-inverting method. Drug release from the hydrogels was measured using a Franz diffusion cell containing pH 7.4 phosphate-buffered solution (PBS) buffer at 37°C. The cytotoxicity of each formulation was measured using the MTT assay with a human oral cancer cell (KB cell). The sol-gel transition temperature of the hydrogel decreased when PF127 was present and varied according to the presence of mucoadhesive polymers. The in vitro release was sustained and the release rate was slowed by the addition of the mucoadhesive polymer. The cytotoxicity of the blank formulation was low, although the drug-loaded hydrogel showed acceptable cytotoxicity. The results of our study suggest that the combination of a PF 127-based mucoadhesive hydrogel formulation and inclusion complexes improves the in vitro release and cytotoxic effect of paclitaxel. PMID:25275485

  3. 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

  4. Transportan in nanocarriers improves skin localization and antitumor activity of paclitaxel

    PubMed Central

    Pepe, Dominique; Carvalho, Vanessa FM; McCall, Melissa; de Lemos, Débora P; Lopes, Luciana B

    2016-01-01

    In this study, the ability of nanocarriers containing protein transduction domains (PTDs) of various classes to improve cutaneous paclitaxel delivery and efficacy in skin tumor models was evaluated. Microemulsions (MEs) were prepared by mixing a surfactant blend (polyoxyethylene 10 oleoyl ether, ethanol and propylene glycol), monocaprylin, and water. The PTD transportan (ME-T), penetratin (ME-P), or TAT (ME-TAT) was added at a concentration of 1 mM to the plain ME. All MEs displayed nanometric size (32.3–40.7 nm) and slight positive zeta potential (+4.1 mV to +6.8 mV). Skin penetration of paclitaxel from the MEs was assessed for 1–12 hours using porcine skin and Franz diffusion cells. Among the PTD-containing formulations, paclitaxel skin (stratum corneum + epidermis and dermis) penetration at 12 hours was maximized with ME-T, whereas ME-TAT provided the lowest penetration (1.6-fold less). This is consistent with the stronger ability of ME-T to increase transepidermal water loss (2.4-fold compared to water) and tissue permeability. The influence of PTD addition on the ME irritation potential was assessed by measuring interleukin-1α expression and viability of bioengineered skin equivalents. A 1.5- to 1.8-fold increase in interleukin-1α expression was induced by ME-T compared to the other formulations, but this effect was less pronounced (5.8-fold) than that mediated by the moderate irritant Triton. Because ME-T maximized paclitaxel cutaneous localization while being safer than Triton, its efficacy was assessed against basal cell carcinoma cells and a bioengineered three-dimensional melanoma model. Paclitaxel-containing ME-T reduced cells and tissue viability by twofold compared to drug solutions, suggesting the potential clinical usefulness of the formulation for the treatment of cutaneous tumors. PMID:27274232

  5. Research on chemotherapy efficacy of twist gene on cervical cancer cells to paclitaxel.

    PubMed

    Sun, Zhenchang; Zhang, Dan; Cui, Yingying; Cheng, Liangxing; Cao, Jingyu; Wu, Xiaolong

    2014-09-01

    The silent Twist gene may increase the sensitivity of cervical cancer cells chemotherapy to paclitaxel, thus was a new idea to improve the efficacy of cancer chemotherapy. The aim was to explore chemotherapy sensitivity of silent Twist gene increased cervical cancer cells to paclitaxel through study the proliferation and apoptosis of cervical cancer Twist gene after paclitaxel treatment. Cervical carcinoma Caski cells and Hela cells was cultured in vitro, mRNA gene expression was detected by using semi-quantitative, fluorescence quantitative PCR, and transferred to Caski cells transiently, and affected with paclitaxel solution of five kinds of different concentrations of 0.001, 0.01, 0.1, 1, 10 umol/L respectively. Then the results of <0.05). Every 12h after 36 h, the expression inhibition rate in two groups of Caski cells that has transfected this study was Twist gene expression in Caski cells was higher than in Hela cells, which was of significant difference (p siRNA1 and siRNA2 were 20.3%, 38.2%, 33%, 24%, 68.6%, 50.8% respectively. After 48 h in five different concentrations of paclitaxel effect, the cell growth inhibition rate of group siRNA2 with the best transfection efficiency was obviously higher than that of negative control group and blank control group, and the growth inhibition rates showed concentration dependence (p<0.05). It can be concluded that Twist gene in Caski cell was of high expression and the silent Twist gene could inhibit Caski cell proliferation and promote its apoptosis, thus to improve the chemotherapy sensitivity of Caski cells.

  6. Chronic cannabinoid CB2 activation reverses paclitaxel neuropathy without tolerance or CB1-dependent withdrawal

    PubMed Central

    Deng, Liting; Guindon, Josée; Cornett, Benjamin L.; Makriyannis, Alexandros; Mackie, Ken; Hohmann, Andrea G.

    2014-01-01

    Background Mixed cannabinoid CB1/CB2 agonists such as Δ9-tetrahydrocannabinol (Δ9-THC) can produce tolerance, physical withdrawal, and unwanted CB1-mediated central nervous system side effects. Whether repeated systemic administration of a CB2-preferring agonist engages CB1 receptors or produces CB1-mediated side effects is unknown. Methods We evaluated anti-allodynic efficacy, possible tolerance, and cannabimimetic side effects of repeated dosing with a CB2-preferring agonist AM1710 in a model of chemotherapy-induced neuropathy produced by paclitaxel using CB1KO, CB2KO, and WT mice. Comparisons were made with the prototypic classical cannabinoid Δ9-THC. We also explored the site and possible mechanism of action of AM1710. Results Paclitaxel-induced mechanical and cold allodynia developed equivalently in CB1KO, CB2KO, and WT mice. Both AM1710 and Δ9-THC suppressed established paclitaxel-induced allodynia in WT mice. Unlike Δ9-THC, chronic AM1710 did not engage CB1 activity or produce antinociceptive tolerance, CB1-mediated cannabinoid withdrawal, hypothermia, or motor dysfunction. Anti-allodynic efficacy of systemic AM1710 was absent in CB2KO mice or WT mice receiving the CB2 antagonist AM630, administered either systemically or intrathecally. Intrathecal AM1710 also attenuated paclitaxel-induced allodynia in WT but not CB2KO mice, implicating a possible role for spinal CB2 receptors in AM1710 anti-allodynic efficacy. Finally, both acute and chronic treatment with AM1710 decreased mRNA levels of tumor necrosis factor alpha and monocyte chemoattractant protein-1 in lumbar spinal cord of paclitaxel-treated WT mice. Conclusions Our results highlight the potential of prolonged use of CB2 agonists for managing chemotherapy-induced allodynia with a favorable therapeutic ratio marked by sustained efficacy and absence of tolerance, physical withdrawal, or CB1-mediated side effects. PMID:24853387

  7. Transportan in nanocarriers improves skin localization and antitumor activity of paclitaxel.

    PubMed

    Pepe, Dominique; Carvalho, Vanessa Fm; McCall, Melissa; de Lemos, Débora P; Lopes, Luciana B

    2016-01-01

    In this study, the ability of nanocarriers containing protein transduction domains (PTDs) of various classes to improve cutaneous paclitaxel delivery and efficacy in skin tumor models was evaluated. Microemulsions (MEs) were prepared by mixing a surfactant blend (polyoxyethylene 10 oleoyl ether, ethanol and propylene glycol), monocaprylin, and water. The PTD transportan (ME-T), penetratin (ME-P), or TAT (ME-TAT) was added at a concentration of 1 mM to the plain ME. All MEs displayed nanometric size (32.3-40.7 nm) and slight positive zeta potential (+4.1 mV to +6.8 mV). Skin penetration of paclitaxel from the MEs was assessed for 1-12 hours using porcine skin and Franz diffusion cells. Among the PTD-containing formulations, paclitaxel skin (stratum corneum + epidermis and dermis) penetration at 12 hours was maximized with ME-T, whereas ME-TAT provided the lowest penetration (1.6-fold less). This is consistent with the stronger ability of ME-T to increase transepidermal water loss (2.4-fold compared to water) and tissue permeability. The influence of PTD addition on the ME irritation potential was assessed by measuring interleukin-1α expression and viability of bioengineered skin equivalents. A 1.5- to 1.8-fold increase in interleukin-1α expression was induced by ME-T compared to the other formulations, but this effect was less pronounced (5.8-fold) than that mediated by the moderate irritant Triton. Because ME-T maximized paclitaxel cutaneous localization while being safer than Triton, its efficacy was assessed against basal cell carcinoma cells and a bioengineered three-dimensional melanoma model. Paclitaxel-containing ME-T reduced cells and tissue viability by twofold compared to drug solutions, suggesting the potential clinical usefulness of the formulation for the treatment of cutaneous tumors.

  8. Terminal arbor degeneration (TAD): a novel lesion produced by the antineoplastic agent, paclitaxel

    PubMed Central

    Bennett, Gary J.; Liu, Guo Kai; Xiao, Wen Hua; Jin, Hai Wei; Siau, Chiang

    2011-01-01

    The anti-neoplastic agent, paclitaxel, causes a dose-limiting distal, symmetrical, sensory peripheral neuropathy that is often accompanied by a neuropathic pain syndrome. In a low-dose model of paclitaxel-evoked painful peripheral neuropathy in the rat, we have shown that the drug causes degeneration of intraepidermal nerve fibers (IENFs), i.e., the fibers which give rise to the sensory afferent’s terminal receptor arbour. However, we did not find any evidence for axonal degeneration in samples taken at the mid-nerve level. Here we aimed to determine whether the absence of degenerating peripheral nerve axons was due to sampling a level that was too proximal. We used electron microscopy to study the distal-most branches of the nerves innervating the hind paw glabrous skin of normal and paclitaxel-treated rats. We confirmed that we sampled at a time when IENF degeneration was prominent. Because degeneration might be easier to detect with higher paclitaxel doses, we examined a four-fold cumulative dose range (8–32 mg/kg). We found no evidence of degeneration in the superficial subepidermal axon bundles (sSAB) that are located just a few microns below the epidermal basal lamina. Specifically, for all three dose groups there was no change in the number of sSAB per mm of epidermal border, no change in the number of axons per sSAB, and no change in the diameter of sSAB axons. We conclude that paclitaxel produces a novel type of lesion that is restricted to the afferent axon’s terminal arbor; we name this lesion “terminal arbor degeneration (TAD)”. PMID:21395870

  9. nab-Paclitaxel for the treatment of pancreatic cancer

    PubMed Central

    Kim, George

    2017-01-01

    Background Nanoparticle albumin-bound paclitaxel (nab-P) plus gemcitabine (Gem) became a standard treatment option for metastatic pancreatic cancer (MPC) following positive results from a global phase III trial (MPACT). A large number of studies have now published results on the use of nab-P/Gem to treat advanced and early-stage disease, warranting a comprehensive review. The main goal of this systematic review is to summarize the efficacy and safety data of nab-P/Gem for the treatment of pancreatic cancer (PC). Methods This systematic review includes results from studies that either published results in a peer-reviewed journal or presented the results at a major oncology conference. Results Sixty-two studies were included (50 in the advanced/metastatic setting and 12 in the locally advanced setting). Most studies on the treatment of MPC were exclusively first line (33/50). Nevertheless, the studies in this review comprised a broad spectrum of patients, including those <65 and ≥65 years of age and those with a Karnofsky performance status of 70–100. Median overall survival (OS) in studies of nab-P/Gem in the advanced/metastatic setting ranged from 8.7 to 13.5 months. In addition, 15 studies of patients with advanced/metastatic PC examined nab-P/Gem as a backbone on which to add a variety of agents, including cancer stem cell inhibitors, stromal disrupting agents, and immune-modulating agents (median OS, 6.9–17 months). Ongoing trials are investigating nab-P/Gem with or without other agents across disease settings. Discussion Studies conducted after MPACT have demonstrated that nab-P/Gem is an effective regimen for the first-line treatment of MPC for a wide range of patients. Regimens using nab-P/Gem as a backbone on which to combine additional agents are being studied actively, particularly in the advanced disease setting. Ongoing studies will yield valuable insights on the utility of nab-P–containing regimens to improve patient outcomes in PC in both

  10. Development and evaluation of targeting ligands surface modified paclitaxel nanocrystals.

    PubMed

    Sohn, Jeong Sun; Yoon, Doo-Soo; Sohn, Jun Youn; Park, Jeong-Sook; Choi, Jin-Seok

    2017-03-01

    To overcome the toxicity of excipient or blank nanoparticles for drug delivery nano-system, the surface modified paclitaxel nanocrystals (PTX-NC) have been developed. PTX-NCs were prepared by nano-precipitation method. The surface of PTX-NCs were modified by grafting with apo-transferrin (Tf) or hyaluronic acid (HA). The physical properties of PTX-NCs were evaluated by field emission scanning electron microscope (FE-SEM), zeta-sizer, zeta-potential, differential scanning calorimetry (DSC) and Fourier transform infrared (FT-IR) spectrometry. In vitro drug release study was performed in phosphate buffered saline (PBS) with or without 0.5% (w/v) Tween 80 for 24h. Cellular uptake was studied at time intervals of 0.5, 1, and 2h in MCF-7 cells, and cell growth inhibition study was performed for 24h using MCF-7 cells (cancer cells), and HaCaT cells (normal cells). Three different types of PTX-NCs with a mean size of 236.0±100.6nm (PTX-NC), 302.0±152.0nm (Tf-PTX-NC) and 339±180.6nm (HA-PTX-NC) were successfully prepared. The drug release profiles showed 29.1%/6.9% (PTX (pure)), 40.7%/23.9% (PTX-NC), 50.5%/25.1% (Tf-PTX-NC) and 46.8/24.8% (HA-PTX-NC) in PBS with/without 0.5% (w/v) Tween 80 for 24h, respectively. As per the results, the drug release of PTX-NCs showed the faster release as compared to that of PTX (pure). Surface modified PTX-NCs exhibited higher values for cell permeability than unmodified PTX-NC in the cellular uptake study. Surface modified PTX-NCs inhibited the cell growth approximately to 60% in MCF-7 cells, however effect of surface modified PTX-NCs on normal cell line was lower than the PTX-NC and PTX (pure). In conclusion, biological macromolecules (Tf or HA) surface modified PTX-NC enhanced the cellular uptake and the cell growth inhibition.

  11. A Randomized Phase III Trial of IV Carboplatin and Paclitaxel x 3 Courses Followed by Observation Versus Weekly Maintenance Low Dose Paclitaxel in Patients with Early Stage Ovarian Carcinoma: a Gynecologic Oncology Group Study

    PubMed Central

    Mannel, Robert S; Brady, Mark F; Kohn, Elise C.; Hanjani, Parviz; Hiura, Masamichi; Lee, Roger; DeGeest, Koen; Cohn, David E; Monk, Bradley J.; Michael, Helen

    2011-01-01

    Purpose To compare the recurrence-free interval (RFI), and safety profile in patients with completely resected high-risk early-stage ovarian cancer patients treated with intravenous (IV) carboplatin and paclitaxel with or without maintenance low-dose paclitaxel for 24 weeks. Methods Eligibility was limited to patients with Stage I-A/B (Grade 3 or clear cell), all I-C or II epithelial ovarian cancer. All patients were to receive carboplatin AUC 6 and paclitaxel 175 mg/m2 q 3 wks × 3 courses with random assignment to either observation or maintenance paclitaxel 40 mg/m2/wk × 24 wks. Recurrence required clinical or radiological evidence of new tumor. Results There were 571 patients enrolled onto this study, of whom 29 were deemed ineligible due to inappropriate stage or pathology, leaving 542 patients. At least 3 cycles of treatment were administered to 524/542 (97%) of patients, and among those assigned to maintenance paclitaxel, 80% completed the regimen. The incidence of grade 2 or worse peripheral neuropathy (15.5% vs 6%), infection/fever (19.9% vs 8.7%), and dermatologic events (70.8% vs 52.1%) were higher on the maintenance regimen (p<0.001). The cumulative probability of recurring within 5 years for the maintenance paclitaxel regimen is 20% vs. 23% for surveillance (hazard ratio 0.807; 95% CI: 0.565–1.15). The probability of surviving 5 years was 85.4% and 86.2%, respectively. Conclusion Maintenance paclitaxel at 40 mg/m2/wk × 24 wks added to standard dose AUC6 and paclitaxel 175 mg/m2 × 3 doses provides no significant increase in RFI. PMID:21529904

  12. In vitro and in vivo anticancer activity of surface modified paclitaxel attached hydroxyapatite and titanium dioxide nanoparticles.

    PubMed

    Venkatasubbu, G Devanand; Ramasamy, S; Reddy, G Pramod; Kumar, J

    2013-08-01

    Targeted drug delivery using nanocrystalline materials delivers the drug at the diseased site. This increases the efficacy of the drug in killing the cancer cells. Surface modifications were done to target the drug to a particular receptor on the cell surface. This paper reports synthesis of hydroxyapatite and titanium dioxide nanoparticles and modification of their surface with polyethylene glycol (PEG) followed by folic acid (FA). Paclitaxel, an anticancer drug, is attached to functionalized hydroxyapatite and titanium dioxide nanoparticles. The pure and functionalised nanoparticles are characterised with XRD, TEM and UV spectroscopy. Anticancer analysis was carried out in DEN induced hepatocarcinoma animals. Biochemical, hematological and histopathological analysis show that the surface modified paclitaxel attached nanoparticles have an higher anticancer activity than the pure paclitaxel and surface modified nanoparticles without paclitaxel. This is due to the targeting of the drug to the folate receptor in the cancer cells.

  13. Enhanced oral bioavailability and anti-tumour effect of paclitaxel by 20(s)-ginsenoside Rg3 in vivo.

    PubMed

    Yang, Lei-Qiong; Wang, Bin; Gan, Hui; Fu, Shou-Ting; Zhu, Xiao-Xia; Wu, Zhuo-Na; Zhan, Da-Wei; Gu, Ruo-Lan; Dou, Gui-Fang; Meng, Zhi-Yun

    2012-11-01

    The purpose of this study was to investigate the effect of paclitaxel in combination with 20(s)-ginsenoside Rg3 on its anti-tumour effect in nude mice. In the Caco-2 transport assay, the apparent permeability from the apical side to the basal side (P(app)) (A-B) and P(app) (B-A) of paclitaxel were measured when co-incubated with different concentrations of 20(s)-ginsenoside Rg3. The results indicated that the penetration of paclitaxel through the Caco-2 monolayer from the apical side to the basal side was facilitated by 20(s)-ginsenoside Rg3 in a concentration-dependent manner. Meanwhile, 20(s)-ginsenoside Rg3 inhibited P-glycoprotein (P-gp), and the maximum inhibition was achieved at 80 µM (p < 0.05). The pharmacokinetic parameters of paclitaxel after oral co-administration of paclitaxel (40 mg/kg) with various doses of 20(s)-ginsenoside Rg3 in rats were investigated by an in vivo pharmacokinetic experiment. The results showed that the AUC of paclitaxel co-administered with 20(s)-ginsenoside Rg3 was significantly higher (p < 0.001 at 10 mg/kg) compared with the control. The relative bioavailability (RB) % of paclitaxel with 20(s)-ginsenoside Rg3 was 3.4-fold (10 mg/kg) higher than that of the control. The effect of paclitaxel orally co-administered with 20(s)-ginsenoside Rg3 against human tumour MCF-7 xenografts in nude mice was also evaluated. Paclitaxel (20 mg/kg) co-administered with 20(s)-ginsenoside Rg3 (10 mg/kg) exhibited an effective anti-tumour activity with the relative tumor growth rate (T/C) values of 39.36% (p <0.05). The results showed that 20(s)-ginsenoside Rg3 enhanced the oral bioavailability of paclitaxel in rats and improved the anti-tumour activity in nude mice, indicating that oral co-administration of paclitaxel with 20(s)-ginsenoside Rg3 could provide an effective strategy in addition to the established i.v. route.

  14. SPARC is a possible predictive marker for albumin-bound paclitaxel in non-small-cell lung cancer

    PubMed Central

    Komiya, Kazutoshi; Nakamura, Tomomi; Nakashima, Chiho; Takahashi, Koichiro; Umeguchi, Hitomi; Watanabe, Naomi; Sato, Akemi; Takeda, Yuji; Kimura, Shinya; Sueoka-Aragane, Naoko

    2016-01-01

    Objectives Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) produced good tumor response in cases with lung squamous cell carcinoma, one of the most difficult cancers to treat. Secreted protein acidic and rich in cysteine (SPARC) binds to albumin, suggesting that SPARC plays an important role in tumor uptake of nab-paclitaxel. There is as yet no predictive marker for cytotoxic agents against non-small-cell lung cancer (NSCLC), and hence we believed that SPARC expression might be associated with tumor response to nab-paclitaxel. Patients and methods We studied stromal SPARC reactivity and its association with clinicopathological characteristics in 200 cases of NSCLC using a custom tissue microarray fabricated in our laboratory by immunohistochemical staining. We also investigated the relationship between stromal SPARC reactivity and tumor response to nab-paclitaxel using biopsy or surgical specimens obtained from advanced or recurrent lung cancer patients. Results High SPARC stromal reactivity (>50% of optical fields examined) was detected in 16.5% of cases and intermediate SPARC reactivity (10%–50%) in 56% of cases. High expression in cancer cells was rare (five cases). Stromal SPARC level was correlated with smoking index, squamous cell carcinoma, and vessel invasion. Furthermore, patients with high stromal SPARC reactivity in biopsy specimens such as transbronchial lung biopsy or surgical specimens tended to respond better to nab-paclitaxel. Conclusion Stromal SPARC was detected by immunohistochemical staining in ∼70% of NSCLC cases, and good tumor response to nab-paclitaxel was correlated with high stromal SPARC reactivity. SPARC may be a useful predictive marker for selecting patients likely to respond favorably to nab-paclitaxel treatment. PMID:27822069

  15. Prediction of paclitaxel resistance in breast cancer: is CYP1B1*3 a new factor of influence?

    PubMed

    Gehrmann, Mathias; Schmidt, Markus; Brase, Jan C; Roos, Peter; Hengstler, Jan G

    2008-07-01

    This article focuses on the recent findings by Marsh and colleagues, and also discusses recent findings with regards to breast cancer. Taxanes are amongst the most active agents in the treatment of breast cancer. However, many tumors are intrinsically resistant. Therefore, it would be an enormous progress, if factors could be identified that reliably differentiate between taxane-sensitive and -resistant patients. Marsh and colleagues analyzed the CYP1B1*3 (Val432Leu) polymorphism in patients with high-risk stage III and IV breast cancer, who received dose-intense paclitaxel in combination with doxorubicin and cyclophosphamide. They report for the first time that patients with two leucine alleles in codon 432 of CYP1B1 experience a longer progression-free survival compared with patients with the Val/Leu or Val/Val genotypes. If confirmed in independent cohorts CYP1B1*3 may prove to be an important factor that helps to differentiate between paclitaxel-sensitive and resistant breast cancer patients. However, the mechanism behind the association between CYP1B1*3 and prognosis of paclitaxel-treated patients remains unclear. Several studies provide strong evidence that CYP1B1 does not influence tumor progression independently from paclitaxel chemotherapy, and that CYP1B1 itself does not alter paclitaxel resistance. In addition, CYP1B1 mRNA expression does not correlate with paclitaxel sensitivity of primary tumor cells. Although still speculative, a possible explanation is an association between CYP1B1*3 with still unknown factors that, on their part, influence paclitaxel sensitivity. In the future, studies with SNP chips and studies on the transcriptome, proteome and metabolome level should be performed in order to identify signatures differentiating between paclitaxel-sensitive and -resistant patients.

  16. Mitochondrial abnormality in sensory, but not motor, axons in paclitaxel-evoked painful peripheral neuropathy in the rat.

    PubMed

    Xiao, W H; Zheng, H; Zheng, F Y; Nuydens, R; Meert, T F; Bennett, G J

    2011-12-29

    The dose-limiting side effect of the anti-neoplastic agent, paclitaxel, is a chronic distal symmetrical peripheral neuropathy that produces sensory dysfunction (hypoesthesia and neuropathic pain) but little or no distal motor dysfunction. Similar peripheral neuropathies are seen with chemotherapeutics in the vinca alkaloid, platinum-complex, and proteasome inhibitor classes. Studies in rats suggest that the cause is a mitotoxic effect on axonal mitochondria. If so, then the absence of motor dysfunction may be due to mitotoxicity that affects sensory axons but spares motor axons. To investigate this, paclitaxel exposure levels in the dorsal root, ventral root, dorsal root ganglion, peripheral nerve, and spinal cord were measured, and the ultrastructure and the respiratory function of mitochondria in dorsal roots and ventral roots were compared. Sensory and motor axons in the roots and nerve had comparably low exposure to paclitaxel and exposure in the spinal cord was negligible. However, sensory neurons in the dorsal root ganglion had a very high and remarkably persistent (up to 10 days or more after the last injection) exposure to paclitaxel. Paclitaxel evoked a significant increase in the incidence of swollen and vacuolated mitochondria in the myelinated and unmyelinated sensory axons of the dorsal root (as seen previously in the peripheral nerve) but not in the motor axons of the ventral root. Stimulated mitochondrial respiration in the dorsal root was significantly depressed in paclitaxel-treated animals examined 2-4 weeks after the last injection, whereas respiration in the ventral root was normal. We conclude that the absence of motor dysfunction in paclitaxel-evoked peripheral neuropathy may be due to the absence of a mitotoxic effect in motor neuron axons, whereas the sensory dysfunction may be due to a mitotoxic effect resulting from the primary afferent neuron's cell body being exposed to high and persistent levels of paclitaxel.

  17. Delayed seizure associated with paclitaxel-Cremophor el in a patient with early-stage breast cancer.

    PubMed

    O'Connor, Tracey L; Kossoff, Ellen

    2009-08-01

    Paclitaxel, a microtubule stabilizer, is an effective agent for treating cancer of the breast, ovary, head and neck, and lung. Because paclitaxel is insoluble in water, it is formulated with the micelle-forming Cremophor EL. Neurologic toxicity is well described with both the drug and this carrier, with most toxicities manifesting as peripheral neuropathy, motor neuropathy, autonomic neuropathy, and myopathy. Toxic effects on the central nervous system, such as seizures or encephalopathy, have been rarely reported; however, the seizures reported were closely related to the time of infusion. We describe a 41-year-old woman with no history of seizures who was treated with paclitaxel for breast cancer. Four days after the drug was infused, she developed a generalized tonic-clonic seizure that could not be attributed to other causes. The patient was treated with phenytoin and was able to complete her adjuvant chemotherapy with nab-paclitaxel without further events. Her condition was neurologically stable without phenytoin for the next 6 months. Use of the Naranjo adverse drug reaction probability scale indicated a possible association (score of 3) between the delayed seizure and paclitaxel or its solvent, Cremophor EL. Clinicians should be aware of the potential for seizure activity in patients who receive paclitaxel formulated with Cremophor EL.

  18. [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.

  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

    2009-05-07

    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.

  20. Nociceptor beta II, delta, and epsilon isoforms of PKC differentially mediate paclitaxel-induced spontaneous and evoked pain.

    PubMed

    He, Ying; Wang, Zaijie Jim

    2015-03-18

    As one of the most effective and frequently used chemotherapeutic agents, paclitaxel produces peripheral neuropathy (paclitaxel-induced peripheral neuropathy or PIPN) that negatively affects chemotherapy and persists after cancer therapy. The mechanisms underlying this dose-limiting side effect remain to be fully elucidated. This study aimed to investigate the role of nociceptor protein kinase C (PKC) isoforms in PIPN. Employing multiple complementary approaches, we have identified a subset of PKC isoforms, namely βII, δ, and ϵ, were activated by paclitaxel in the isolated primary afferent sensory neurons. Persistent activation of PKCβII, PKCδ, and PKCϵ was also observed in the dorsal root ganglion neurons after chronic treatment with paclitaxel in a mouse model of PIPN. Isoform-selective inhibitors of PKCβII, PKCδ, and PKCϵ given intrathecally dose-dependently attenuated paclitaxel-induced mechanical allodynia and heat hyperalgesia. Surprisingly, spinal inhibition of PKCβII and PKCδ, but not PKCϵ, blocked the spontaneous pain induced by paclitaxel. These data suggest that a subset of nociceptor PKC isoforms differentially contribute to spontaneous and evoked pain in PIPN, although it is not clear whether PKCϵ in other regions regulates spontaneous pain in PIPN. The findings can potentially offer new selective targets for pharmacological intervention of PIPN.

  1. Development and validation of a reversed-phase HPLC method for the quantification of paclitaxel in different PLGA nanocarriers.

    PubMed

    Furman, Christophe; Carpentier, Rodolphe; Barczyk, Amélie; Chavatte, Philippe; Betbeder, Didier; Lipka, Emmanuelle

    2017-03-31

    A reversed-phase high-performance liquid chromatography (RP-HPLC) method has been developed and validated for the quantification of paclitaxel encapsulated in biodegradable poly(lactic-co-glycolic) (PLGA) copolymer nanoparticles. This simple (isocratic mode, without additive) and rapid (retention time of the paclitaxel under 4 minutes) methodology permits the detection of low quantities of paclitaxel in nanoparticulate formulations and the determination of the encapsulation efficiency (EE). Analysis was achieved on an octadecyl stationary phase. The isocratic mobile phase consisted of acetonitrile:water 80:20 (v/v) (flow rate = 0.8 mL/min). Stability of free paclitaxel was preliminary studied in those chromatographic conditions. The calibration curve was linear in the concentration range of 2 to 10 μg/mL (R(2) = 0.9994). The method was specific with valuable trueness, repeatability (intra-day precision) and intermediate precision (inter-day precision) based on relative standard deviation (RSD) values (less than 2%). The limits of detection (LOD) and quantification (LOQ) were 0.56 and 1.85 ng/mL respectively. This developed method was successfully employed for quantifying paclitaxel in PLGA 50:50 co-polymer nanoparticles. The accurate knowledge of the encapsulated paclitaxel concentration is essential to define the quantities of PLGA nanoparticles necessary to achieve the in vitro cell viability study. This article is protected by copyright. All rights reserved.

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

    PubMed

    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 α-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.

  3. Enhanced apoptotic and anticancer potential of paclitaxel loaded biodegradable nanoparticles based on chitosan.

    PubMed

    Gupta, Umesh; Sharma, Saurabh; Khan, Iliyas; Gothwal, Avinash; Sharma, Ashok K; Singh, Yuvraj; Chourasia, Manish K; Kumar, Vipin

    2017-05-01

    Taxanes have established and proven effectivity against different types of cancers; in particular breast cancers. However, the high hemolytic toxicity and hydrophobic nature of paclitaxel and docetaxel have always posed challenges to achieve safe and effective delivery. Use of bio-degradable materials with an added advantage of nanotechnology could possibly improve the condition so as to achieve better and safe delivery. In the present study paclitaxel loaded chitosan nanoparticles were formulated and optimized using simple w/o nanoemulsion technique. The observed average size, pdi, zeta potential, entrapment efficiency and drug loading for the optimized paclitaxel loaded chitosan nanoparticle formulation (PTX-CS-NP-10) was 226.7±0.70nm, 0.345±0.039, 37.4±0.77mV, 79.24±2.95% and 11.57±0.81%; respectively. Nanoparticles were characterized further for size by Transmission Electron Microscopy (TEM). In vitro release studies exhibited sustained release pattern and more than 60% release was observed within 24h. Enhanced in vitro anticancer activity was observed as a result of MTT assay against triple negative MDA-MB-231 breast cancer cell lines. The observed IC50 values obtained for PTX-CS-NP-10 was 9.36±1.13μM and was almost 1.6 folds (p<0.05) less than the pure drug. Similarly, PTX-CS-NP-10 were extremely biocompatible and safe as observed for haemolytic toxicity which was almost 4 folds less (p<0.05) than the naïve drug. Anticancer activity was further evaluated using flow cytometry for apoptosis. Cell apoptosis study revealed that PTX-CS-NP-10 treatment resulted into enhanced (almost double) late cell apoptosis than naïve paclitaxel. Hence the developed nanoparticulate formulation not only reduced the overall toxicity but also resulted into improved anticancer efficacy of paclitaxel. It can be concluded that a robust, stable and comparatively safe nanoformulation of paclitaxel was developed, characterized and evaluated.

  4. Severe hyponatremia caused by nab-paclitaxel-induced syndrome of inappropriate antidiuretic hormone secretion: A case report in a patient with metastatic pancreatic adenocarcinoma.

    PubMed

    Neuzillet, Cindy; Babai, Samy; Kempf, Emmanuelle; Pujol, Géraldine; Rousseau, Benoît; Le-Louët, Hervé; Christophe Tournigand

    2016-06-01

    Incidence of pancreatic ductal adenocarcinoma (PDAC) is increasing. Most patients have advanced disease at diagnosis and therapeutic options in this setting are limited. Gemcitabine plus nab-paclitaxel regimen was demonstrated to increase survival compared with gemcitabine monotherapy and is therefore indicated as first-line therapy in patients with metastatic PDAC and performance status Eastern Cooperative Oncology Group (ECOG) 0-2. The safety profile of gemcitabine and nab-paclitaxel combination includes neutropenia, fatigue, and neuropathy as most common adverse events of grade 3 or higher. No case of severe hyponatremia associated with the use of nab-paclitaxel for the treatment of PDAC has been reported to date.We report the case of a 72-year-old Caucasian man with a metastatic PDAC treated with gemcitabine and nab-paclitaxel regimen, who presented with a severe hyponatremia (grade 4) caused by a documented syndrome of inappropriate antidiuretic hormone secretion (SIADH). This SIADH was attributed to nab-paclitaxel after a rigorous imputability analysis, including a rechallenge procedure with dose reduction. After dose and schedule adjustment, nab-paclitaxel was pursued without recurrence of severe hyponatremia and with maintained efficacy.Hyponatremia is a rare but potentially severe complication of nab-paclitaxel therapy that medical oncologists and gastroenterologists should be aware of. Nab-paclitaxel-induced hyponatremia is manageable upon dose and schedule adaptation, and should not contraindicate careful nab-paclitaxel reintroduction. This is of particular interest for a disease in which the therapeutic options are limited.

  5. New class of squalene-based releasable nanoassemblies of paclitaxel, podophyllotoxin, camptothecin and epothilone A.

    PubMed

    Borrelli, Stella; Christodoulou, Michael S; Ficarra, Ilaria; Silvani, Alessandra; Cappelletti, Graziella; Cartelli, Daniele; Damia, Giovanna; Ricci, Francesca; Zucchetti, Massimo; Dosio, Franco; Passarella, Daniele

    2014-10-06

    The present study reports the preparation of a novel class of squalene conjugates with paclitaxel, podophyllotoxin, camptothecin and epothilone A. The obtained compounds are characterized by a squalene tail that makes them able to self-assemble in water, and by a drug unit connected via a disulfide-containing linker to secure the release inside the cell. All the obtained compounds were effectively able to self-assemble and to release the parent drug in vitro. Disulfide-containing paclitaxel-squalene derivative showed a similar biological activity when compared to the free drug. Immunofluorescence assay shows that this squalene conjugate enters A549 cells and stain microtubule bundles. The results described herein pave the way for different classes of squalene-based releasable nanoassemblies.

  6. Acute Myocardial Infarction in Patient With Triple Negative Breast Cancer After Paclitaxel Infusion: A Case Report

    PubMed Central

    Esber, Christopher; Breathett, Khadijah; Sachak, Taha; Moore, Stephen; Lilly, Scott M.

    2014-01-01

    A 47-year-old woman with breast cancer suffered progressive chest pain and flushing within 5 minutes of her second exposure to paclitaxel. Her symptoms progressed and she became pulseless. Advanced cardiac life support (ACLS) was initiated, and after a series of chest compressions the cardiac monitor revealed ventricular fibrillation. With ongoing ACLS she was transferred to the emergency department where she regained a pulse. Review of electrocardiogram revealed prominent ST elevation in leads V1, V2 and V3 with reciprocal ST depression. She was transferred urgently to the catheterization laboratory. Angiography revealed a high-grade stenosis in the proximal left anterior descending artery (LAD), and drug-eluting stents were placed without complications. She was then transferred to the floor and shortly thereafter suffered pulseless electrical activity and died despite prolonged attempts at resuscitation. Herein, we describe the development of acute myocardial infarction after paclitaxel administration, discuss potential etiologies and review evidence for an allergic component. PMID:28348706

  7. 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

  8. Effect of the paclitaxel vehicle, Cremophor EL, on the pharmacokinetics of doxorubicin and doxorubicinol in mice.

    PubMed Central

    Webster, L. K.; Cosson, E. J.; Stokes, K. H.; Millward, M. J.

    1996-01-01

    The effect of the paclitaxel vehicle Cremophor on the pharmacokinetics of doxorubicin and doxorubicinol was studied in two groups of mice given intravenously either 2.5 ml kg-1 Cremophor or saline followed 5 min later by 10 mg kg-1 doxorubicin. In each group three mice were sacrificed at ten time points and doxorubicin and doxorubicinol were measured in plasma by high-performance liquid chromatography (HPLC). With Cremophor present, doxorubicin AUC increased from 1420+/-440 to 2770+/-660 ng h ml(-1) (P<0.05) and doxorubicinol AUC increased from 130+/-76 to 320+/-88 ng h ml(-1) (p<0.05). Neither the terminal elimination half-lives nor the doxorubicinol-doxorubicin AUC ratio changed in the presence of Cremophor, suggesting a lack of a direct effect on drug metabolism. The possibility exists the Cremophor may change the pharmacokinetics of both paclitaxel and other drugs given concurrently. PMID:8595168

  9. Reversal effects of Raloxifene on paclitaxel resistance in 2 MDR breast cancer cells.

    PubMed

    Xu, Liang; Lei, Jingyu; Jiang, Donghai; Zhou, Lin; Wang, Shu; Fan, Weimin

    2015-01-01

    Raloxifene hydrochloride (RAL), one of second generation of selective estrogen receptor modulators (SERMs), is usually used in preventing osteoporosis and breast cancer. The present study evaluated whether Raloxifene might sensitize multidrug resistant (MDR) breast cancers to chemotherapies, especially in estrogen receptor negative (ER-) breast cancer. The results showed that RAL could significantly sensitize ER- MDR breast tumors to paclitaxel both in vitro and in vivo. Combination of Raloxifene could significantly enhance paclitaxel-induced cell apoptosis, G2-M arrest as well as inhibition of cell proliferation in MDR tumors. Further studies showed that the combined treatment did not alter P-glycoprotein expression but increased P-gp ATPase activity. These results suggested that raloxifene might be a valuable chemosensitizer agent for breast cancer therapy.

  10. 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.

  11. 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.

  12. nab-Paclitaxel in Combination with Carboplatin for a Previously Treated Thymic Carcinoma

    PubMed Central

    Makimoto, Go; Fujiwara, Keiichi; Watanabe, Hiromi; Kameyama, Nobuhisa; Matsushita, Mizuho; Rai, Kammei; Sato, Ken; Yonei, Toshiro; Sato, Toshio; Shibayama, Takuo

    2014-01-01

    We present the case of a 40-year-old man with previously treated thymic carcinoma, complaining of gradually worsening back pain. Computed tomography scans of the chest showed multiple pleural disseminated nodules with a pleural effusion in the right thorax. The patient was treated with carboplatin on day 1 plus nab-paclitaxel on day 1 and 8 in cycles repeated every 4 weeks. Objective tumor shrinkage was observed after 4 cycles of this regimen. In addition, the elevated serum cytokeratin 19 fragment level decreased, and the patient's back pain was relieved without any analgesics. Although he experienced grade 4 neutropenia and granulocyte colony-stimulating factor (G-CSF) injection, the severity of thrombocytopenia and nonhematological toxicities such as reversible neuropathy did not exceed grade 1 during the treatment. To our knowledge, this is the first report to demonstrate the efficacy of combination chemotherapy consisting of carboplatin and nab-paclitaxel against thymic carcinoma. This case report suggests that nab-paclitaxel in combination with carboplatin can be a favorable chemotherapy regimen for advanced thymic carcinoma. PMID:24575009

  13. Formulation, Characterization and Evaluation of Paclitaxel loaded Solid Lipid Nanoparticles Prepared by Temperature Modulated Solidification Technique

    NASA Astrophysics Data System (ADS)

    Deshpande, Ameya Abhay

    The aim of this research was to formulate, characterize, and evaluate the paclitaxel loaded solid lipid nanoparticles (SLNs) prepared by a temperature modulated solidification technique developed and optimized in our laboratory. The particle size analysis through dynamic light scattering (DLS) and transmission electron microscopy (TEM) revealed and confirmed the spherical shape and nanometer size range of the formulated nanoparticles. Zeta potential measurements confirmed the physical stability of the SLNs with a negative surface charge. Atomic force microscopy (AFM) studies were done to study the surface topography and particle size and shape. AFM data showed minimal aggregation and more or less spherical SLNs. Differential scanning calorimetry (DSC), powder X-ray diffraction (P-XRD) and Fourier transform infrared spectroscopy (ATR-FTIR) confirmed the conversion of bulk lipid into SLNs and high entrapment of paclitaxel into the lipid matrix. The optimized formulation had an entrapment efficiency of approximately 62%. The in-vitro drug release depicted a sustained release of paclitaxel from the SLNs over duration of one week. The drug release data was found to best fit and hence followed the Higuchi drug-release model.

  14. Chemosensitizing activities of cyclotides from Clitoria ternatea in paclitaxel-resistant lung cancer cells

    PubMed Central

    SEN, ZHANG; ZHAN, XIAO KAI; JING, JIN; YI, ZHANG; WANQI, ZHOU

    2013-01-01

    Cyclotides comprise a family of circular mini-peptides that have been isolated from various plants and have a wide range of bioactivities. Previous studies have demonstrated that cyclotides have antitumor effects and cause cell death by membrane permeabilization. The present study aimed to evaluate the cytotoxicity and chemosensitizing activities of cyclotides from Clitoria ternatea in paclitaxel-resistant lung cancer cells. In this study, a total of seven cyclotides were selected for colorimetric cell viability assay (MTT assay) to evaluate their anticancer and chemosensitizing activities in the lung cancer cell line A549 and its sub-line A549/paclitaxel. Results suggested that certain cyclotides had significant anticancer and chemosensitizing abilities; such cyclotides were capable of causing multi-fold decreases in the half maximal inhibitory concentration (IC50) value of cliotides in the presence of paclitaxel. More importantly, their bioactivities were found to be correlated with their net charge status. In conclusion, cyclotides from C. ternatea have potential in chemosensitization application. PMID:23419988

  15. 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.

  16. 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

  17. In vitro and in vivo evaluation of paclitaxel-lapatinib-loaded F127 pluronic micelles.

    PubMed

    Dehghankelishadi, Pouya; Saadat, Ebrahim; Ravar, Fatemeh; Safavi, Maliheh; Pordeli, Mahboobeh; Gholami, Mehdi; Dorkoosh, Farid Abedin

    2017-03-01

    The aim of this study was to evaluate the in vitro and in vivo efficacy of paclitaxel-lapatinib-loaded Pluronic micelles. Lapatinib and pluronic sensitize the cancerous cells to paclitaxel via efflux pump inhibition. In addition, pluronic polymers can trigger intrinsic apoptosis pathways. Furthermore, micellar system can passively target the chemotherapeutic agents by enhanced permeability and retention effect. The paclitaxel-lapatinib-loaded micelles were characterized in means of encapsulation efficacy and size. The in vitro analyses were performed by MTT assay and uptake studies. Real-time imaging and in vivo anti-tumor efficacy studies were also performed. The prepared micelles have acceptable encapsulation ratio and size. Hemolysis assay confirmed that the micelles are hemo-compatible. MTT assay demonstrated that drug-loaded micelles have superior cytotoxicity compared with the naked drugs. The confocal microscopy and flowcytometry analyses showed that micelles are mainly internalized by endocytosis. According to the results of the in vivo imaging, the micelles are accumulated within liver. In vivo anti-tumor efficacy studies confirmed that tumor inhibition of drug-loaded micelles was significant compared to Intaxel(®).

  18. Paclitaxel coated-stent for early-onset thrombosis after liver transplantation.

    PubMed

    Reyes-Corona, Jesus; Gonzalez-Huezo, María S; Zea-Medina, María V; Zamora-Valdés, Daniel; Victoria-Campos, José L; Mondragon-Sanchez, Ricardo J

    2007-01-01

    Hepatic artery thrombosis (HAT) is the most common vascular complication of orthotopic liver transplantation (OLT) and constitutes a potential emergency during the postoperative period. Surgical revascularization and retransplantation are the treatments of choice for this condition. The aim of this report is to present long-term follow-up on survival and graft function of three patients with paclitaxel-coated hepatic artery stents placed percutaneously after earlyonset HAT. Three patients developed early onset HAT after cadaveric-donor OLT in a tertiary care center in Mexico. These patients were treated percutaneously with balloon angioplasty and paclitaxel-coated stents. After 24 months or more of follow-up, 2 patients present total occlusion of the stent and one patient, intra-stent stenosis; interestingly, all patients have normal graft function and excellent quality of life. In conclusion, although balloon angioplasty and stent placement may be a therapeutic option for suitable patients with early-onset HAT after OLT, longterm patency is unlikely even with the use of paclitaxel- coated materials.

  19. Long Circulating Lectin Conjugated Paclitaxel Loaded Magnetic Nanoparticles: A New Theranostic Avenue for Leukemia Therapy

    PubMed Central

    Singh, Abhalaxmi; Dilnawaz, Fahima; Sahoo, Sanjeeb Kumar

    2011-01-01

    Amongst all leukemias, Bcr-Abl positive chronic myelogenous leukemia (CML) confers resistance to native drug due to multi drug resistance and also resistance to p53 and fas ligand pathways. In the present study, we have investigated the efficacy of microtubule stabilizing paclitaxel loaded magnetic nanoparticles (pac-MNPs) to ascertain its cytotoxic effect on Bcr-Abl positive K562 cells. For active targeted therapy, pac-MNPs were functionalized with lectin glycoprotein which resulted in higher cellular uptake and lower IC50 value suggesting the efficacy of targeted delivery of paclitaxel. Both pac-MNPs and lectin conjugated pac-MNPs have a prolonged circulation time in serum suggesting increased bioavailability and therapeutics index of paclitaxel in vivo. Further, the molecular mechanism pertaining to pac-induced cytotoxicity was analyzed by studying the involvement of different apoptotic pathway proteins by immunoblotting and quantitative PCR. Our study revealed simultaneous activation of JNK pathway leading to Bcr-Abl instability and the extrinsic apoptotic pathway after pac-MNPs treatment in two Bcr-Abl positive cell lines. In addition, the MRI data suggested the potential application of MNPs as imaging agent. Thus our in vitro and in vivo results strongly suggested the pac-MNPs as a future prospective theranostic tool for leukemia therapy. PMID:22110595

  20. Chemosensitizing activities of cyclotides from Clitoria ternatea in paclitaxel-resistant lung cancer cells.

    PubMed

    Sen, Zhang; Zhan, Xiao Kai; Jing, Jin; Yi, Zhang; Wanqi, Zhou

    2013-02-01

    Cyclotides comprise a family of circular mini-peptides that have been isolated from various plants and have a wide range of bioactivities. Previous studies have demonstrated that cyclotides have antitumor effects and cause cell death by membrane permeabilization. The present study aimed to evaluate the cytotoxicity and chemosensitizing activities of cyclotides from Clitoria ternatea in paclitaxel-resistant lung cancer cells. In this study, a total of seven cyclotides were selected for colorimetric cell viability assay (MTT assay) to evaluate their anticancer and chemosensitizing activities in the lung cancer cell line A549 and its sub-line A549/paclitaxel. Results suggested that certain cyclotides had significant anticancer and chemosensitizing abilities; such cyclotides were capable of causing multi-fold decreases in the half maximal inhibitory concentration (IC(50)) value of cliotides in the presence of paclitaxel. More importantly, their bioactivities were found to be correlated with their net charge status. In conclusion, cyclotides from C. ternatea have potential in chemosensitization application.

  1. Antinociceptive effect of three common analgesic drugs on peripheral neuropathy induced by paclitaxel in rats.

    PubMed

    Pascual, David; Goicoechea, Carlos; Burgos, Elisa; Martín, María Isabel

    2010-05-01

    Nowadays, there are no validated drugs to control the neuropathic pain induced by paclitaxel, one of the most effective antineoplastic drugs. The aim was to study the involvement of opioid and NMDA receptor on established paclitaxel-induced pain, testing three common analgesics drugs morphine, ketamine and methadone. Animals received four intraperitoneal (i.p.) injections on alternate days of paclitaxel (1mg/kg). Three weeks later, animals showed a mechanical and heat allodynia/hyperalgesia. Morphine (1, 2.5, 5 and 10mg/kg) abolished the reduction in the mechanical and thermal withdrawal thresholds in a dose dependent manner. This effect was blocked by naloxone. Only highest dose of ketamine (50mg/kg) was able to increase the mechanical and thermal threshold and returned to basal values. Subanalgesic doses of morphine (1mg/kg) and ketamine (12.5mg/kg) produced an additive effect on heat hyperalgesia reaching an antinociceptive effect. This combination did not induce any change on tactile allodynia. Methadone (2.5 and 5mg/kg) produced an analgesic effect that was completely antagonized by naloxone in both tests. Our results confirm that: the activation of opioids receptor produced analgesia; the blockade of NMDA receptors produce antinociception but at high doses with motor impairments and low doses of ketamine enhancing the effect of opioids.

  2. Magnetic responsive of paclitaxel delivery system based on SPION and palmitoyl chitosan

    NASA Astrophysics Data System (ADS)

    Mansouri, Mona; Nazarpak, Masoumeh Haghbin; Solouk, Atefeh; Akbari, Somaye; Hasani-Sadrabadi, Mohammad Mahdi

    2017-01-01

    Concerns over cancer treatment have largely focused on chemotherapy and its consequent side effects. Utilizing nanocarriers is thought to be a panacea for mitigating the limitations of chemotherapy, and increasing its safety and efficacy. Magnetically driven Paclitaxel delivery systems are among the commonly investigated types of nanocarriers over the last two decades. In this context, we tried to highlight the application of an AC magnetic field and validate its consequential effects on drug delivery pattern and cell death in such nanodevices. So the aim of this study is to develop an appropriate matrix (Palmitoyl chitosan) co-encapsulated with superparamagnetic iron oxide nanoparticles (SPIONs) and anticancer drug, Paclitaxel (PTX) via the nanoprecipitation process. Synthesized nanoparticles were characterized by Dynamic Light Scattering (DLS) and their magnetic properties were investigated by Vibrating Sample Magnetometer (VSM). At initial loading of 10 wt% Paclitaxel, the maximum loading efficiency of nanoparticles with and without SPIONs was in the range of 69% and 72.3%, respectively. In addition, in vitro release data revealed that by the application of a magnetic field, release kinetic changed to the magnetic responsive pattern. Encapsulating anticancer drug in a synthesized nanosystem not only increased the amount of drug in cancer cells but also enhanced cell death (MCF-7) due to hyperthermic effects of SPIONs in the presence of an external magnetic field. In summary, these findings indicate that the resultant nanoparticles may serve as a biocompatible and biodegradable carrier for the precise delivery of powerful cytotoxic anticancer agents such as PTX.

  3. Development and evaluation of paclitaxel nanoparticles using a quality-by-design approach.

    PubMed

    Yerlikaya, Firat; Ozgen, Aysegul; Vural, Imran; Guven, Olgun; Karaagaoglu, Ergun; Khan, Mansoor A; Capan, Yilmaz

    2013-10-01

    The aims of this study were to develop and characterize paclitaxel nanoparticles, to identify and control critical sources of variability in the process, and to understand the impact of formulation and process parameters on the critical quality attributes (CQAs) using a quality-by-design (QbD) approach. For this, a risk assessment study was performed with various formulation and process parameters to determine their impact on CQAs of nanoparticles, which were determined to be average particle size, zeta potential, and encapsulation efficiency. Potential risk factors were identified using an Ishikawa diagram and screened by Plackett-Burman design and finally nanoparticles were optimized using Box-Behnken design. The optimized formulation was further characterized by Fourier transform infrared spectroscopy, X-ray diffractometry, differential scanning calorimetry, scanning electron microscopy, atomic force microscopy, and gas chromatography. It was observed that paclitaxel transformed from crystalline state to amorphous state while totally encapsulating into the nanoparticles. The nanoparticles were spherical, smooth, and homogenous with no dichloromethane residue. In vitro cytotoxicity test showed that the developed nanoparticles are more efficient than free paclitaxel in terms of antitumor activity (more than 25%). In conclusion, this study demonstrated that understanding formulation and process parameters with the philosophy of QbD is useful for the optimization of complex drug delivery systems.

  4. Response to Paclitaxel in an Adult Patient with Advanced Kaposiform Hemangioendothelioma

    PubMed Central

    Mota, José Maurício; Scaranti, Mariana; Fonseca, Leonardo G.; Tolói, Diego Araújo; de Camargo, Veridiana Pires; Munhoz, Rodrigo Ramella; Feher, Olavo; Hoff, Paulo M.

    2016-01-01

    Background Kaposiform hemangioendothelioma (KHE) is a rare neoplasm of vascular origin that typically arises from the skin or soft tissues as a solitary tumor. The optimal therapy for this disease is still unknown. We report the case of an adult patient presenting with metastatic KHE of the spleen, who had a partial response after treatment with paclitaxel. Case Presentation A 36-year-old man presented in November 2012 with a nontraumatic rupture of the spleen. A splenectomy was performed, and the pathology was consistent with a nonspecific vascular proliferation. Follow-up scans revealed lytic bone lesions and liver metastasis. A biopsy of the liver was performed and confirmed KHE. The decision was made to proceed with treatment with gemcitabine and docetaxel, which was discontinued due to myelotoxicity. The patient was then transferred to our institution, and a pathology review supported the diagnosis of metastatic KHE. His disease remained stable until February 2014, when he developed progression in the liver. Chemotherapy was restarted with paclitaxel, and a partial response was documented after 3 cycles. Unfortunately, disease progression occurred after 24 weeks, and subsequent treatments included prednisone, doxorubicin, interferon-α, gemcitabine, and ifosfamide, without any response. The patient developed Kasabach-Merritt phenomenon and passed away 1 week later due to a major gastrointestinal bleeding. Conclusions This case report suggests that paclitaxel could be considered as a treatment option for advanced KHE, a rare condition for which no standard treatment exists. PMID:27721772

  5. Microtubule-Binding Proteins as Promising Biomarkers of Paclitaxel Sensitivity in Cancer Chemotherapy

    PubMed Central

    Xie, Songbo; Ogden, Angela; Aneja, Ritu; Zhou, Jun

    2016-01-01

    Microtubules, tirelessly animated and highly dynamic structures, are vital for most cellular processes and their intricacies are still being revealed even after a century since their discovery. The importance of microtubules as chemotherapeutic targets cannot be overstated, and their clinical role is unlikely to abate in the near future. Indeed, improved understanding of microtubule biology could herald a new epoch of anticancer drug design by permitting fine-tuning of microtubule-targeting agents, the clinical utility of which is presently often limited by primary or acquired resistance. Paclitaxel, one such agent belonging to the taxane family, has proven a resoundingly successful treatment for many cancer patients; however, for too many others with paclitaxel-refractory tumors, the drug has offered nothing but side effects. Accumulating evidence suggests that microtubule-binding proteins (MBPs) can regulate paclitaxel sensitivity in a wide range of cancer types. Improved understanding of how these proteins can be assayed to predict treatment responses or manipulated pharmacologically to improve clinical outcomes could transform modern chemotherapy and is urgently awaited. PMID:26332739

  6. c(RGDyK)-decorated Pluronic micelles for enhanced doxorubicin and paclitaxel delivery to brain glioma

    PubMed Central

    Huang, YuKun; Liu, Wenchao; Gao, Feng; Fang, Xiaoling; Chen, Yanzuo

    2016-01-01

    Brain glioma therapy is an important challenge in oncology. Here, doxorubicin (DOX) and paclitaxel (PTX)-loaded cyclic arginine-glycine-aspartic acid peptide (c(RGDyK))-decorated Pluronic micelles (cyclic arginine-glycine-aspartic acid peptide-decorated Pluronic micelles loaded with doxorubicin and paclitaxel [RGD-PF-DP]) were designed as a potential targeted delivery system to enhance blood–brain barrier penetration and improve drug accumulation via integrin-mediated transcytosis/endocytosis and based on integrin overexpression in blood–brain barrier and glioma cells. The physicochemical characterization of RGD-PF-DP revealed a satisfactory size of 28.5±0.12 nm with uniform distribution and core-shell structure. The transport rates across the in vitro blood–brain barrier model, cellular uptake, cytotoxicity, and apoptosis of U87 malignant glioblastoma cells of RGD-PF-DP were significantly greater than those of non-c(RGDyK)-decorated Pluronic micelles. In vivo fluorescence imaging demonstrated the specificity and efficacy of intracranial tumor accumulation of RGD-PF-DP. RGD-PF-DP displayed an extended median survival time of 39 days, with no serious body weight loss during the regimen. No acute toxicity to major organs was observed in mice receiving treatment doses via intravenous administration. In conclusion, RGD-PF-DP could be a promising vehicle for enhanced doxorubicin and paclitaxel delivery in patients with brain glioma. PMID:27143884

  7. 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.

  8. 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

  9. Preparation and in vitro evaluation of vaginal formulations including siRNA and paclitaxel-loaded SLNs for cervical cancer.

    PubMed

    Büyükköroğlu, Gülay; Şenel, Behiye; Başaran, Ebru; Yenilmez, Evrim; Yazan, Yasemin

    2016-12-01

    Cervical cancer is one of the most life threatening types of cancer among women and is generally resistant to chemotherapy. The objective of this study was to prepare a vaginal suppository containing a chemotherapeutic agent and a genetic material that can be applied locally for cervical cancer. Paclitaxel was selected as the chemotherapeutic agent and siRNA which inhibits BCL-2 oncogene was selected as the genetic material. Bcl-2 siRNA, paclitaxel and paclitaxel/Bcl-2 siRNA combination were incorporated into solid lipid nanoparticles (SLNs) and were dispersed separately in vaginal suppositories prepared with PEG 6000. Physicochemical properties of SLNs, their cytotoxicities on HeLa cell lines and also the effect of SLNs on the total protein amount of the cells were examined followed by the investigation of release rates of the active materials from the SLNs prepared. Average diameters of all SLNs prepared were below 180nm with a positive zeta potential value between +22.20 and +48.16mV at the pH range of 4.2 and 7.4. The release of Bcl-2 siRNA from SLNs incorporated Bcl-2 siRNA and the release of paclitaxel (PTX) from PTX incorporated SLNs were completed within 12h and 36h. SLNs incorporating Bcl-2 siRNA and paclitaxel/Bcl-2 siRNA were found to be more toxic when compared to paclitaxel incorporated SLN and placebo SLN. The disintegration of the vaginal suppositories as well as the release of the SLNs was completed within 2 h. This study indicates that vaginal suppository containing SLNs can bring the advantages of the simultaneous delivery of paclitaxel and siRNA via vaginal route with no help from professionals.

  10. Co-loaded paclitaxel/rapamycin liposomes: Development, characterization and in vitro and in vivo evaluation for breast cancer therapy.

    PubMed

    Eloy, Josimar O; Petrilli, Raquel; Topan, José Fernando; Antonio, Heriton Marcelo Ribeiro; Barcellos, Juliana Palma Abriata; Chesca, Deise L; Serafini, Luciano Neder; Tiezzi, Daniel G; Lee, Robert J; Marchetti, Juliana Maldonado

    2016-05-01

    Paclitaxel and rapamycin have been reported to act synergistically to treat breast cancer. Albeit paclitaxel is available for breast cancer treatment, the most commonly used formulation in the clinic presents side effects, limiting its use. Furthermore, both drugs present pharmacokinetics drawbacks limiting their in vivo efficacy and clinic combination. As an alternative, drug delivery systems, particularly liposomes, emerge as an option for drug combination, able to simultaneously deliver co-loaded drugs with improved therapeutic index. Therefore, the purpose of this study is to develop and characterize a co-loaded paclitaxel and rapamycin liposome and evaluate it for breast cancer efficacy both in vitro and in vivo. Results showed that a SPC/Chol/DSPE-PEG (2000) liposome was able to co-encapsulate paclitaxel and rapamycin with suitable encapsulation efficiency values, nanometric particle size, low polydispersity and neutral zeta potential. Taken together, FTIR and thermal analysis evidenced drug conversion to the more bioavailable molecular and amorphous forms, respectively, for paclitaxel and rapamycin. The pegylated liposome exhibited excellent colloidal stability and was able to retain drugs encapsulated, which were released in a slow and sustained fashion. Liposomes were more cytotoxic to 4T1 breast cancer cell line than the free drugs and drugs acted synergistically, particularly when co-loaded. Finally, in vivo therapeutic evaluation carried out in 4T1-tumor-bearing mice confirmed the in vitro results. The co-loaded paclitaxel/rapamycin pegylated liposome better controlled tumor growth compared to the solution. Therefore, we expect that the formulation developed herein might be a contribution for future studies focusing on the clinical combination of paclitaxel and rapamycin.

  11. Co-loaded paclitaxel/rapamycin liposomes: Development, characterization and in vitro and in vivo evaluation for breast cancer therapy

    PubMed Central

    Eloy, Josimar O.; Petrilli, Raquel; Topan, José Fernando; Antonio, Heriton Marcelo Ribeiro; Barcellos, Juliana Palma Abriata; Chesca, Deise L.; Serafini, Luciano Neder; Tiezzi, Daniel G.; Lee, Robert J.; Marchetti, Juliana Maldonado

    2016-01-01

    Paclitaxel and rapamycin have been reported to act synergistically to treat breast cancer. Albeit paclitaxel is available for breast cancer treatment, the most commonly used formulation in the clinic presents side effects, limiting its use. Furthermore, both drugs present pharmacokinetics drawbacks limiting their in vivo efficacy and clinic combination. As an alternative, drug delivery systems, particularly liposomes, emerge as an option for drug combination, able to simultaneously deliver co-loaded drugs with improved therapeutic index. Therefore, the purpose of this study is to develop and characterize a co-loaded paclitaxel and rapamycin liposome and evaluate it for breast cancer efficacy both in vitro and in vivo. Results showed that a SPC/Chol/DSPE-PEG (2000) liposome was able to co-encapsulate paclitaxel and rapamycin with suitable encapsulation efficiency values, nanometric particle size, low polydispersity and neutral zeta potential. Taken together, FTIR and thermal analysis evidenced drug conversion to the more bioavailable molecular and amorphous forms, respectively, for paclitaxel and rapamycin. The pegylated liposome exhibited excellent colloidal stability and was able to retain drugs encapsulated, which were released in a slow and sustained fashion. Liposomes were more cytotoxic to 4T1 breast cancer cell line than the free drugs and drugs acted synergistically, particularly when co-loaded. Finally, in vivo therapeutic evaluation carried out in 4T1-tumor-bearing mice confirmed the in vitro results. The co-loaded paclitaxel/rapamycin pegylated liposome better controlled tumor growth compared to the solution. Therefore, we expect that the formulation developed herein might be a contribution for future studies focusing on the clinical combination of paclitaxel and rapamycin. PMID:26836480

  12. 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

  13. Quercetin ameliorates paclitaxel-induced neuropathic pain by stabilizing mast cells, and subsequently blocking PKCε-dependent activation of TRPV1

    PubMed Central

    Gao, Wei; Zan, Yan; Wang, Zai-jie Jim; Hu, Xiao-yu; Huang, Fang

    2016-01-01

    Aim: Severe painful sensory neuropathy often occurs during paclitaxel chemotherapy. Since paclitaxel can activate mast cell and basophils, whereas quercetin, a polyphenolic flavonoid contained in various plants, which can specifically inhibit histamine release as a mast cell stabilizer. In this study we explore whether quercetin could ameliorate paclitaxel-induced neuropathic pain and elucidated the underlying mechanisms. Methods: Quercetin inhibition on histamine release was validated in vitro by detecting histamine release from rat basophilic leukemia (RBL-2H3) cells stimulated with paclitaxel (10 μmol/L). In the in vivo experiments, rats and mice received quercetin (20, 40 mg·kg-1·d-1) for 40 and 12 d, respectively. Meanwhile, the animals were injected with paclitaxel (2 mg/kg, ip) four times on d 1, 3, 5 and 7. Heat hyperalgesia and mechanical allodynia were evaluated at the different time points. The animals were euthanized and spinal cords and dorsal root ganglions were harvested for analyzing PKCε and TRPV1 expression levels. The plasma histamine levels were assessed in rats on d 31. Results: Pretreatment with quercetin (3, 10, 30 μmol/L) dose-dependently inhibited excessive histamine release from paclitaxel-stimulated RBL-2H3 cells in vitro, and quercetin administration significantly suppressed the high plasma histamine levels in paclitaxel-treated rats. Quercetin administration dose-dependently raised the thresholds for heat hyperalgesia and mechanical allodynia in paclitaxel-treated rats and mice. Furthermore, quercetin administration dose-dependently suppressed the increased expression levels of PKCε and TRPV1 in the spinal cords and DRGs of paclitaxel-treated rats and mice. Moreover, quercetin administration may inhibited the translocation of PKCε from the cytoplasm to the membrane in the spinal cord and DRG of paclitaxel-treated rats. Conclusion: Our results reveal the underlying mechanisms of paclitaxel-induced peripheral neuropathy and

  14. miR-17-5p downregulation contributes to paclitaxel resistance of lung cancer cells through altering beclin1 expression.

    PubMed

    Chatterjee, Abhisek; Chattopadhyay, Dhrubajyoti; Chakrabarti, Gopal

    2014-01-01

    Non-small-cell lung cancer (NSCLC) is one of the most leading causes of cancer-related deaths worldwide. Paclitaxel based combination therapies have long been used as a standard treatment in aggressive NSCLCs. But paclitaxel resistance has emerged as a major clinical problem in combating non-small-cell lung cancer and autophagy is one of the important mechanisms involved in this phenomenon. In this study, we used microRNA (miRNA) arrays to screen differentially expressed miRNAs between paclitaxel sensitive lung cancer cells A549 and its paclitaxel-resistant cell variant (A549-T24). We identified miR-17-5p was one of most significantly downregulated miRNAs in paclitaxel-resistant lung cancer cells compared to paclitaxel sensitive parental cells. We found that overexpression of miR-17-5p sensitized paclitaxel resistant lung cancer cells to paclitaxel induced apoptotic cell death. Moreover, in this report we demonstrated that miR-17-5p directly binds to the 3'-UTR of beclin 1 gene, one of the most important autophagy modulator. Overexpression of miR-17-5p into paclitaxel resistant lung cancer cells reduced beclin1 expression and a concordant decease in cellular autophagy. We also observed similar results in another paclitaxel resistant lung adenosquamous carcinoma cells (H596-TxR). Our results indicated that paclitaxel resistance of lung cancer is associated with downregulation of miR-17-5p expression which might cause upregulation of BECN1 expression.

  15. Breast cancer cells evade paclitaxel-induced cell death by developing resistance to dasatinib

    PubMed Central

    Jeong, Yun-Ji; Kang, Jong Soon; Lee, Su In; So, Dong Min; Yun, Jieun; Baek, Ji Young; Kim, Sang Kyum; Lee, Kiho; Park, Song-Kyu

    2016-01-01

    Triple negative breast cancer (TNBC), which does not express the progesterone, estrogen, or HER2/neu receptor, is aggressive and difficult to treat. Paclitaxel, a tubulin stabilizing agent, is one of the most frequently prescribed anticancer agents for breast cancers, including TNBC. Residual disease that occurs due to resistance or partial resistance of cancer cells in a tumor against anticancer agents is the most important issue in oncology. In the present study, when MDA-MB-231 cells, a TNBC cell line, were treated with 30 µM paclitaxel, a slightly higher concentration than its GI50 value, for 6 days, a small number of cells with different morphologies survived. Among the surviving cells, small round cells were isolated, cloned, and named MDA-MB-231-JYJ cells. MDA-MB-231-JYJ cells were observed to be highly proliferative and tumorigenic. In addition, signal transduction molecules involved in proliferation, survival, malignancy, or stemness of cancer cells, such as c-Src, c-Met, Notch 1, c-Myc, Sox2, Oct3/4, Nanog, and E-cadherin were highly expressed or activated. While further study is required, MDA-MB-231-JYJ cells appear to have some of the characteristics of cancer precursor cells. Although MDA-MB-231-JYJ cells were isolated from the cells that survived in the continuous presence of paclitaxel, they were not resistant to paclitaxel but developed resistance to dasatinib, a Bcr-Abl and Src kinase family inhibitor. The activated state of Src and Notch 1, and the expression levels of c-Myc and cyclins in MDA-MB-231-JYJ cells were less affected than MDA-MB-231 cells by the treatment of dasatinib, which may explain the resistance of MDA-MB-231-JYJ cells to dasatinib. These results suggest that cancer cells that become resistant to dasatinib during the process of paclitaxel therapy in patients may appear, and caution is required in the design of clinical trials using these two agents. PMID:27602155

  16. 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.

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

    PubMed Central

    Wen, Jian; Yeo, Syn; Wang, Chenran; Chen, Song; Sun, Shaogang; Haas, Michael A.; Tu, Wei; Jin, Feng

    2016-01-01

    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

  18. Paclitaxel plus cisplatin vs. 5-fluorouracil plus cisplatin as first-line treatment for patients with advanced squamous cell esophageal cancer.

    PubMed

    Liu, Ying; Ren, Zhonghai; Yuan, Long; Xu, Shuning; Yao, Zhihua; Qiao, Lei; Li, Ke

    2016-01-01

    Paclitaxel plus cisplatin and 5-fluorouracil plus cisplatin treatments are effective strategies for patients with advanced esophageal squamous cell carcinoma. This study was to evaluate the safety and efficacy of paclitaxel plus cisplatin and 5-fluorouracil plus cisplatin as first-line chemotherapy for patients with advanced esophageal squamous cell carcinoma. A total of 398 patients with advanced esophageal squamous cell carcinoma who received chemotherapy were included and divided into 2 groups: paclitaxel plus cisplatin group and 5-fluorouracil plus cisplatin group. 195 patients received paclitaxel plus cisplatin and 203 patients received 5-fluorouracil plus cisplatin. The objective response rates were 42.5% and 38.4% for paclitaxel plus cisplatin group and 5-fluorouracil plus cisplatin group, respectively (P=0.948). The median progression-free survival was 7.85 months (95% CI, 6.77-8.94 months) for the paclitaxel plus cisplatin group and 6.53 months (95% CI, 5.63-7.43 months) for the 5-fluorouracil plus cisplatin group with significant difference (P=0.02). The median overall survival was 13.46 months (95% CI, 12.01-14.91 months) for the paclitaxel plus cisplatin group and 12.67 months (95% CI, 11.87-13.47 months) for the 5-fluorouracil plus cisplatin group (P=0.204). The first-line chemotherapy of paclitaxel plus cisplatin had better median progression-free survival than 5-fluorouracil plus cisplatin in patients with advanced esophageal squamous cell carcinoma with tolerable toxicities.

  19. Pluronic-poly (acrylic acid)-cysteine/Pluronic L121 mixed micelles improve the oral bioavailability of paclitaxel.

    PubMed

    Zhao, Yanli; Li, Yanli; Ge, Jianjun; Li, Na; Li, Ling-Bing

    2014-11-01

    The aim of the study is to synthesize a thiolated Pluronic copolymer, Pluronic-poly (acrylic acid)-cysteine copolymer, to construct a mixed micelle system with the Pluronic-poly (acrylic acid)-cysteine copolymer and Pluronic L121 (PL121) and to evaluate the potential of these mixed micelles as an oral drug delivery system for paclitaxel. Compared with Pluronic-poly (acrylic acid)-cysteine micelles, drug-loading capacity of Pluronic-poly (acrylic acid)-cysteine/PL121 mixed micelles was increased from 0.4 to 2.87%. In vitro release test indicated that Pluronic-poly (acrylic acid)-cysteine/PL121 mixed micelles exhibited a pH sensitivity. The permeability of drug-loaded micelles in the intestinal tract was studied with an in situ perfusion method in rats. The presence of verapamil and Pluronic both improved the intestinal permeability of paclitaxel, which further certified the inhibition effect of thiolated Pluronic on P-gp. In pharmacokinetic study, the area under the plasma concentration-time curve (AUC0→∞) of paclitaxel-loaded mixed micelles was four times greater than that of the paclitaxel solution (p < 0.05). In general, Pluronic-poly (acrylic acid)-cysteine/PL121 micelles were proven to be a potential oral drug delivery system for paclitaxel.

  20. Direct comparison of two albumin-based paclitaxel-loaded nanoparticle formulations: is the crosslinked version more advantageous?

    PubMed

    Li, Chunlei; Li, Yanhui; Gao, Yuqing; Wei, Na; Zhao, Xi; Wang, Caixia; Li, Yongfeng; Xiu, Xian; Cui, Jingxia

    2014-07-01

    Nanoparticles using albumin as particle matrix have entered the mainstream of drug delivery. It was reported that non-crosslinked albumin nanoparticles were unstable in circulation and could deliver drugs into tumor through gp60/SPARC pathway; in contrast, the delivery of drugs with stable nanoparticles was dependent on enhanced permeability and retention effect. Thus, it is questionable which kind of nanoparticles was more advantageous. Two versions of albumin-bound paclitaxel nanoparticles were prepared. In vitro, the non-crosslinked particles could rapidly disintegrate and the crosslinked was stable. The pharmacokinetics of both formulations was different especially at early time and the non-crosslinked particles were cleared rapidly. After non-crosslinked particle treatment paclitaxel had a tendency to accumulate into heart and kidney and following therapy with the crosslinked particles, paclitaxel was liable to be delivered into lung, spleen and liver. The delivery efficiency of paclitaxel into tumor following the non-crosslinked particle treatment was greater than that of the crosslinked (p<0.05), thus resulting in a considerably improved antineoplastic activity. Moreover, the non-crosslinked formulation was only slightly more toxic. It was concluded that the non-crosslinked formulation was more advantageous for the delivery of paclitaxel and our conclusion might be generalized to other lipophilic drugs delivered with albumin nanoparticles.

  1. Pharmaceutical development of an oral tablet formulation containing a spray dried amorphous solid dispersion of docetaxel or paclitaxel.

    PubMed

    Sawicki, Emilia; Beijnen, Jos H; Schellens, Jan H M; Nuijen, Bastiaan

    2016-09-25

    Previously, it was shown in Phase I clinical trials that solubility-limited oral absorption of docetaxel and paclitaxel can be drastically improved with a freeze dried solid dispersion (fdSD). These formulations, however, are unfavorable for further clinical research because of limitations in amorphicity of SD and scalability of the production process. To resolve this, a spray drying method for an SD (spSD) containing docetaxel or paclitaxel and subsequently drug products were developed. Highest saturation solubility (Smax), precipitation onset time (Tprecip), amorphicity, purity, residual solvents, yield/efficiency and powder flow of spSDs were studied. Drug products were monitored for purity/content and dissolution during 24 months at +15-25°C. Docetaxel spSD Smax was equal to that of fdSD but Tprecip was 3 times longer. Paclitaxel spSD Smax was 30% increased but Tprecip was equal to fdSD. spSDs were fully amorphous, >99% pure, <5% residual solvents, mean batch yield was 100g and 84%. spSDs had poor powder flow characteristics, which could not be resolved by changing settings, but by using 75% lactose as diluent. The drug product was a tablet with docetaxel or paclitaxel spSD and was stable for at least 24 months. Spray drying is feasible for the production of SD of docetaxel or paclitaxel for upcoming clinical trials.

  2. hGBP-1 Expression Predicts Shorter Progression-Free Survival in Ovarian Cancers, While Contributing to Paclitaxel Resistance

    PubMed Central

    Wadi, Suzan; Tipton, Aaron R.; Trendel, Jill A.; Khuder, Sadik A.; Vestal, Deborah J.

    2017-01-01

    Ovarian cancer is the gynecological cancer with the poorest prognosis. One significant reason is the development of resistance to the chemotherapeutic drugs used in its treatment. The large GTPase, hGBP-1, has been implicated in paclitaxel resistance in ovarian cell lines. Forced expression of hGBP-1 in SKOV3 ovarian cancer cells protects them from paclitaxel-induced cell death. However, prior to this study, nothing was known about whether hGBP-1 was expressed in ovarian tumors and whether its expression correlated with paclitaxel resistance. hGBP-1 is expressed in 17% of ovarian tumors from patients that have not yet received treatment. However, at least 80% of the ovarian tumors that recurred after therapies that included a tax-ane, either paclitaxel or docetaxel, were positive for hGBP-1. In addition, hGBP-1 expression predicts a significantly shorter progression-free survival in ovarian cancers. Based on these studies, hGBP-1 could prove to be a potential biomarker for paclitaxel resistance in ovarian cancer. PMID:28090373

  3. A Phase I dose-escalation study of the VEGFR inhibitor tivozanib hydrochloride with weekly paclitaxel in metastatic breast cancer.

    PubMed

    Mayer, Erica L; Scheulen, M E; Beckman, J; Richly, H; Duarte, A; Cotreau, M M; Strahs, A L; Agarwal, S; Steelman, L; Winer, E P; Dickler, M N

    2013-07-01

    Tivozanib is a potent selective tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. This Phase Ib study investigated the safety/tolerability, pharmacokinetics (PK), and activity of tivozanib with weekly paclitaxel in metastatic breast cancer (MBC). MBC patients with no prior VEGFR TKI treatment received daily oral tivozanib (3 weeks on, 1 week off) with weekly paclitaxel 90 mg/m(2). Standard 3 + 3 dose escalation was used; tivozanib cohorts (C) included C1 0.5 mg, C2 1.0 mg, and C3 1.5 mg. Assessments included Response Evaluation Criteria in Solid Tumors response, PK, and vascular function. Eighteen patients enrolled. Toxicities in >20 % of patients included fatigue, alopecia, nausea, diarrhea, peripheral sensory neuropathy, and hypertension. Grade 3/4 toxicities in >15 % of patients included fatigue and neutropenia. Maximum tolerated dose was tivozanib 1.5 mg with paclitaxel 90 mg/m(2). Four patients withdrew because of toxicity and one due to progressive disease. Thirteen patients were evaluable for response: four (30.8 %) had confirmed partial response; four had stable disease ≥6 months (30.8 %). PK data suggest no influence of paclitaxel on tivozanib concentrations. Tivozanib plus weekly paclitaxel was tolerable at all dose levels, supporting their combination at full dose. Activity in this small population was encouraging.

  4. Paclitaxel promotes differentiation of myeloid-derived suppressor cells into dendritic cells in vitro in a TLR4-independent manner.

    PubMed

    Michels, Tillmann; Shurin, Galina V; Naiditch, Hiam; Sevko, Alexandra; Umansky, Viktor; Shurin, Michael R

    2012-01-01

    Myeloid cells play a key role in the outcome of anti-tumor immunity and response to anti-cancer therapy, since in the tumor microenvironment they may exert both stimulatory and inhibitory pressures on the proliferative, angiogenic, metastatic, and immunomodulating potential of tumor cells. Therefore, understanding the mechanisms of myeloid regulatory cell differentiation is critical for developing strategies for the therapeutic reversal of myeloid derived suppressor cell (MDSC) accumulation in the tumor-bearing hosts. Here, using an in vitro model system, several potential mechanisms of the direct effect of paclitaxel on MDSC were tested, which might be responsible for the anti-tumor potential of low-dose paclitaxel therapy in mice. It was hypothesized that a decreased level of MDSC in vivo after paclitaxel administration might be due to (i) the blockage of MDSC generation, (ii) an induction of MDSC apoptosis, or (iii) the stimulation of MDSC differentiation. The results revealed that paclitaxel in ultra-low concentrations neither increased MDSC apoptosis nor blocked MDSC generation, but stimulated MDSC differentiation towards dendritic cells. This effect of paclitaxel was TLR4-independent since it was not diminished in cell cultures originated from TLR4-/- mice. These results support a new concept that certain chemotherapeutic agents in ultra-low non-cytotoxic doses may suppress tumor progression by targeting several cell populations in the tumor microenvironment, including MDSC.

  5. Better pathologic complete response and relapse-free survival after carboplatin plus paclitaxel compared with epirubicin plus paclitaxel as neoadjuvant chemotherapy for locally advanced triple-negative breast cancer: a randomized phase 2 trial

    PubMed Central

    Yin, Yi; Mo, Hongnan; Zhang, Bailin; Wang, Xiang; Li, Qing; Yuan, Peng; Wang, Jiayu; Zheng, Shan; Cai, Ruigang; Ma, Fei; Fan, Yin

    2016-01-01

    Background: No standard chemotherapy is used as neoadjuvant therapy in triple negative breast cancer (TNBC). This study has compared carboplatin plus paclitaxel with commonly used epirubicin plus paclitaxel as neoadjuvant chemotherapy (NAC) in TNBC. Results: 91 patients with a median age of 47 years (PC 47 patients, EP 44 patients) were enrolled. 65% of the patients were premenopausal. While the objective response rate was similar in the PC and EP arm (89.4% vs. 79.5%, P = 0.195), the pCR rate in the PC arm was significantly higher (38.6% vs. 14.0%, P = 0.014). The median follow-up time was 55.0 months. 5-year RFS were 77.6% and 56.2%, significantly higher in the PC arm, P = 0.043. No significant difference in OS was observed between the two arms (P = 0.350). Adverse events were similar, except for more thrombocytopenia in the PC arm (P = 0.001). Methods: Patients with stage II/III TNBC were randomized to receive either paclitaxel (175 mg/m2, day1) plus carboplatin (Area Under the Curve = 5, day2) (PC) or epirubicin (75mg/m2, day1) plus paclitaxel (175 mg/m2, day2) (EP) as NAC every three weeks for 4-6 cycles. The primary endpoint was rate of pathologic complete response (pCR).The secondary endpoints included relapse-free survival (RFS), overall survival (OS) and safety. Conclusions:This study suggested that the addition of carboplatin to paclitaxel was superior to the regimen of epirubicin plus paclitaxel as NAC for TNBC in terms of improving pCR rate and RFS. Further phase 3 study has already started. PMID:27447966

  6. Paclitaxel therapy potentiates cold hyperalgesia in streptozotocin-induced diabetic rats through enhanced mitochondrial reactive oxygen species production and TRPA1 sensitization.

    PubMed

    Barrière, David André; Rieusset, Jennifer; Chanteranne, Didier; Busserolles, Jérôme; Chauvin, Marie-Agnès; Chapuis, Laëtitia; Salles, Jérôme; Dubray, Claude; Morio, Béatrice

    2012-03-01

    Diabetes comorbidities include disabling peripheral neuropathy (DPN) and an increased risk of developing cancer. Antimitotic drugs, such as paclitaxel, are well known to facilitate the occurrence of peripheral neuropathy. Practitioners frequently observe the development or co-occurrence of enhanced DPN, especially cold sensitivity, in diabetic patients during chemotherapy. Preclinical studies showed that reactive oxygen species (ROS) and cold activate transient receptor potential ankyrin-1 (TRPA1) cation channels, which are involved in cold-evoked pain transduction signaling in DPN. Additionally, paclitaxel treatment has been associated with an accumulation of atypical mitochondria in the sensory nerves of rats. We hypothesized that paclitaxel might potentiate cold hyperalgesia by increasing mitochondrial injuries and TRPA1 activation. Thus, the kinetics of paclitaxel-induced cold hyperalgesia, mitochondrial ROS production, and TRPA1 expression were evaluated in dorsal root ganglia of normoglycemic and streptozotocin-induced diabetic rats. In diabetic rats, paclitaxel significantly enhanced cold hyperalgesia in comparison to normoglycemic paclitaxel-treated control rats. These effects were prevented by N-acetyl-cysteine, a reducing agent, and by HC030031, an antagonist of TRPA1. In diabetic and control rats, paclitaxel treatment was associated with an accumulation of atypical mitochondria and a 2-fold increase in mitochondrial ROS production. Moreover, mRNA levels of glutathione peroxidase 4 and glutathione-S-reductase were significantly lower in diabetic groups treated with paclitaxel. Finally, TRPA1 gene expression was enhanced by 45% in diabetic rats. Paclitaxel potentiation of cold hyperalgesia in diabetes may result from the combination of increased mitochondrial ROS production and poor radical detoxification induced by paclitaxel treatment and diabetes-related overexpression of TRPA1.

  7. Inhibition of the mammalian target of rapamycin (mTOR) by rapamycin increases chemosensitivity of CaSki cells to paclitaxel.

    PubMed

    Faried, L S; Faried, A; Kanuma, T; Nakazato, T; Tamura, T; Kuwano, H; Minegishi, T

    2006-05-01

    Paclitaxel, a potent anti-neoplastic agent, has been found to be effective against several tumours, including cervical cancer. However, the exact mechanism underlying the cytotoxic effects of pacitaxel, especially in the survival-signalling pathway, is poorly understood. The aim of this study was to investigate the molecular pathway of the cytotoxic effect of paclitaxel in human cervical cancer cell lines. Four human cervical cancer cell lines were treated for 24 h with various concentration of paclitaxel, and the sensitivity was analysed by an MTT assay. The cell cycle progression and sub-G1 population were analysed by flow cytometry. Apoptosis was further measured by DNA fragmentation and microscope examination. The protein expression was determined by Western blot analysis. Our results showed that HeLa cells demonstrated the highest sensitivity to paclitaxel, whereas CaSki cells showed the lowest. In cervical cancer cells, paclitaxel induced apoptosis through an intrinsic pathway with prior G2/M arrest. In addition, we showed that paclitaxel downregulated the phosphorylation of Akt in both HeLa and CaSki cells. Interestingly, in CaSki cells, which were more suggestive of a resistant phenotype, paclitaxel induced the activation of mTOR as a downstream target of Akt. Pre-treatment with rapamycin inhibited activation of mTOR signalling and significantly enhanced the sensitivity of CaSki cells to paclitaxel by increasing apoptotic cell death. This effect was mediated, at least partly, through caspase activation. Overall, paclitaxel exerts its anti-tumour effects on cervical cancer cells by inducing apoptosis through intrinsic pathway, and rapamycin targeted to mTOR can sensitise paclitaxel-resistant cervical cancer cells.

  8. Targeted delivery of paclitaxel and doxorubicin to cancer xenografts via the nanoparticle of nano-diamino-tetrac

    PubMed Central

    Sudha, Thangirala; Bharali, Dhruba J; Yalcin, Murat; Darwish, Noureldien HE; Debreli Coskun, Melis; Keating, Kelly A; Lin, Hung-Yun; Davis, Paul J; Mousa, Shaker A

    2017-01-01

    The tetraiodothyroacetic acid (tetrac) component of nano-diamino-tetrac (NDAT) is chemically bonded via a linker to a poly(lactic-co-glycolic acid) nanoparticle that can encapsulate anticancer drugs. Tetrac targets the plasma membrane of cancer cells at a receptor on the extracellular domain of integrin αvβ3. In this study, we evaluate the efficiency of NDAT delivery of paclitaxel and doxorubicin to, respectively, pancreatic and breast cancer orthotopic nude mouse xenografts. Intra-tumoral drug concentrations were 5-fold (paclitaxel; P<0.001) and 2.3-fold (doxorubicin; P<0.01) higher than with conventional systemic drug administration. Tumor volume reductions reflected enhanced xenograft drug uptake. Cell viability was estimated by bioluminescent signaling in pancreatic tumors and confirmed an increased paclitaxel effect with drug delivery by NDAT. NDAT delivery of chemotherapy increases drug delivery to cancers and increases drug efficacy. PMID:28243091

  9. Targeted delivery of paclitaxel and doxorubicin to cancer xenografts via the nanoparticle of nano-diamino-tetrac.

    PubMed

    Sudha, Thangirala; Bharali, Dhruba J; Yalcin, Murat; Darwish, Noureldien He; Debreli Coskun, Melis; Keating, Kelly A; Lin, Hung-Yun; Davis, Paul J; Mousa, Shaker A

    2017-01-01

    The tetraiodothyroacetic acid (tetrac) component of nano-diamino-tetrac (NDAT) is chemically bonded via a linker to a poly(lactic-co-glycolic acid) nanoparticle that can encapsulate anticancer drugs. Tetrac targets the plasma membrane of cancer cells at a receptor on the extracellular domain of integrin αvβ3. In this study, we evaluate the efficiency of NDAT delivery of paclitaxel and doxorubicin to, respectively, pancreatic and breast cancer orthotopic nude mouse xenografts. Intra-tumoral drug concentrations were 5-fold (paclitaxel; P<0.001) and 2.3-fold (doxorubicin; P<0.01) higher than with conventional systemic drug administration. Tumor volume reductions reflected enhanced xenograft drug uptake. Cell viability was estimated by bioluminescent signaling in pancreatic tumors and confirmed an increased paclitaxel effect with drug delivery by NDAT. NDAT delivery of chemotherapy increases drug delivery to cancers and increases drug efficacy.

  10. Rescue of neurons from undergoing hallmark tau-induced Alzheimer's disease cell pathologies by the antimitotic drug paclitaxel.

    PubMed

    Shemesh, Or A; Spira, Micha E

    2011-07-01

    Through the use of live confocal imaging, electron microscopy, and the novel cell biological platform of cultured Aplysia neurons we show that unfolding of the hallmark cell pathologies induced by mutant-human-tau (mt-human-tau) expression is rescued by 10 nM paclitaxel. At this concentration paclitaxel prevents mt-human-tau-induced swelling of axonal segments, translocation of tau and microtubules (MT) to submembrane domains, reduction in the number of MTs along the axon, reversal of the MT polar orientation, impaired organelle transport, accumulation of macro-autophagosomes and lysosomes, compromised neurite morphology and degeneration. Unexpectedly, higher paclitaxel concentrations (100 nM) do not prevent these events from occurring and in fact facilitate them. We conclude that antimitotic MT-stabilizing reagents have the potential to serve as drugs to prevent or slow down the unfolding of tauopathies.

  11. Bevacizumab-Induced Inhibition of Angiogenesis Promotes a More Homogeneous Intratumoral Distribution of Paclitaxel, Improving the Antitumor Response.

    PubMed

    Cesca, Marta; Morosi, Lavinia; Berndt, Alexander; Fuso Nerini, Ilaria; Frapolli, Roberta; Richter, Petra; Decio, Alessandra; Dirsch, Olaf; Micotti, Edoardo; Giordano, Silvia; D'Incalci, Maurizio; Davoli, Enrico; Zucchetti, Massimo; Giavazzi, Raffaella

    2016-01-01

    The antitumor activity of angiogenesis inhibitors is reinforced in combination with chemotherapy. It is debated whether this potentiation is related to a better drug delivery to the tumor due to the antiangiogenic effects on tumor vessel phenotype and functionality. We addressed this question by combining bevacizumab with paclitaxel on A2780-1A9 ovarian carcinoma and HT-29 colon carcinoma transplanted ectopically in the subcutis of nude mice and on A2780-1A9 and IGROV1 ovarian carcinoma transplanted orthotopically in the bursa of the mouse ovary. Paclitaxel concentrations together with its distribution by MALDI mass spectrometry imaging (MALDI MSI) were measured to determine the drug in different areas of the tumor, which was immunostained to depict vessel morphology and tumor proliferation. Bevacizumab modified the vessel bed, assessed by CD31 staining and dynamic contrast enhanced MRI (DCE-MRI), and potentiated the antitumor activity of paclitaxel in all the models. Although tumor paclitaxel concentrations were lower after bevacizumab, the drug distributed more homogeneously, particularly in vascularized, non-necrotic areas, and was cleared more slowly than controls. This happened specifically in tumor tissue, as there was no change in paclitaxel pharmacokinetics or drug distribution in normal tissues. In addition, the drug concentration and distribution were not influenced by the site of tumor growth, as A2780-1A9 and IGROV1 growing in the ovary gave results similar to the tumor growing subcutaneously. We suggest that the changes in the tumor microenvironment architecture induced by bevacizumab, together with the better distribution of paclitaxel, may explain the significant antitumor potentiation by the combination.

  12. 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

  13. High expression of TIMP-1 in human breast cancer tissues is a predictive of resistance to paclitaxel-based chemotherapy.

    PubMed

    Zhu, Dongliang; Zha, Xiaoming; Hu, Meiling; Tao, Aidi; Zhou, Hangbo; Zhou, Xiaojun; Sun, Yujie

    2012-12-01

    For breast cancer patients with lymph node metastasis, paclitaxel is the first-line chemotherapy drug. Clinical studies showed that some patients with breast cancer were insensitive to paclitaxel, which led to chemotherapy failure. Today, no validated markers exist for the prediction of chemotherapy sensitivity in this patient group. Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been shown to protect against apoptosis. Epidemiological studies have also associated elevated tumor tissue TIMP-1 levels with a poor response to cyclophosphamide/methotrexate/5-fluorouracil and anthracycline-based chemotherapy. Additionally, our previous study proved that TIMP-1 significantly decreased the sensitivity of breast cancer cells to paclitaxel-induced apoptosis by enhancing degradation of cyclin B1. These data imply that TIMP-1 may be a useful predictive biomarker for chemotherapy resistance. In this retrospective study, we investigated the association between expression levels of TIMP-1 protein in the primary tumor and objective response to paclitaxel-based chemotherapy in 99 patients with breast cancer. With Kaplan-Meier survival analysis, the patients with high TIMP-1 levels were found to have significantly worse 5-year DFS (71.1 %) than the patients with low levels (88.5 %; P = 0.020). Similarly, the patients with high TIMP-1 levels had significantly worse 5-year OS (78.9 %) than patients with low levels (96.7 %; P = 0.004). In Cox's univariate and multivariate analyses, TIMP-1 was prognostic for both DFS and OS. Our data showed that elevated tumor tissue TIMP-1 levels were significantly associated with a poor response to paclitaxel-based chemotherapy, and TIMP-1 might be a potential biomarker for predicting response of breast cancer patients to paclitaxel-based chemotherapy.

  14. Optimization, in vitro cytotoxicity and penetration capability of deformable nanovesicles of paclitaxel for dermal chemotherapy in Kaposi sarcoma.

    PubMed

    Pathak, Kamla; Sharma, Vijay; Sharma, Meenu

    2016-11-01

    Although much research has been published on ways to overcome the low oral bioavailability of paclitaxel, exploration of novel drug delivery systems that can target paclitaxel deep in to the dermal areas in AIDS-related Kaposi sarcoma (KS) have not yet been reported. Our aim was to develop deformable nanovesicles of paclitaxel capable of being used in dermal chemotherapy, especially deep into the dermal areas of AIDS related KS. Deformable nanovesicular formulations (TS1-TS15) composed of soya lecithin and span80 were prepared by the rotary evaporation sonication method within the constraints of our Box-Behnken design. The formulations were subjected to vesicle characterization and ex vivo permeation. The optimized vesicular suspension was formulated as a gel and assessed for in vitro cytotoxicity and penetration characteristics by confocal laser scanning microscopy (CLSM). TS9 with vesicle size characteristics of 185.76 ± 2.15 nm, zeta potential of -23.2 mV, deformability index = 138.02 and cumulative drug permeation of 89.80 ± 1.84% was identified as the optimized formulation. TEM revealed spherical vesicles with firm boundaries that were stable at 4 °C. TS9 was developed as carbopol 934P gel (TG) and compared with the control gel (CG) made with the pure drug (paclitaxel). TG showed significantly higher (p < 0.05) in vitro drug permeation and flux compared to the CG. In vitro cytotoxicity study on KSY-1 cell lines revealed higher IC50 (≤17) for TS against IC50 ≤19 for TG. CLSM confirmed the penetrating potential of transfersomes via TG to the dermal layers of skin, the proposed target site. Conclusively, deformable nonovesicles of paclitaxel appear as a feasible alternative to the conventional formulations of paclitaxel in the management of AIDS-related KS.

  15. Far-Red Light-Activatable Prodrug of Paclitaxel for the Combined Effects of Photodynamic Therapy and Site-Specific Paclitaxel Chemotherapy.

    PubMed

    Thapa, Pritam; Li, Mengjie; Bio, Moses; Rajaputra, Pallavi; Nkepang, Gregory; Sun, Yajing; Woo, Sukyung; You, Youngjae

    2016-04-14

    Paclitaxel (PTX) is one of the most useful chemotherapeutic agents approved for several cancers, including ovarian, breast, pancreatic, and nonsmall cell lung cancer. However, it causes systemic side effects when administered parenterally. Photodynamic therapy (PDT) is a new strategy for treating local cancers using light and photosensitizer. Unfortunately, PDT is often followed by recurrence due to incomplete ablation of tumors. To overcome these problems, we prepared the far-red light-activatable prodrug of PTX by conjugating photosensitizer via singlet oxygen-cleavable aminoacrylate linker. Tubulin polymerization enhancement and cytotoxicity of prodrugs were dramatically reduced. However, once illuminated with far-red light, the prodrug effectively killed SKOV-3 ovarian cancer cells through the combined effects of PDT and locally released PTX. Ours is the first PTX prodrug that can be activated by singlet oxygen using tissue penetrable and clinically useful far-red light, which kills the cancer cells through the combined effects of PDT and site-specific PTX chemotherapy.

  16. Targeted Sequencing Reveals Low-Frequency Variants in EPHA Genes as Markers of Paclitaxel-Induced Peripheral Neuropathy.

    PubMed

    Apellániz-Ruiz, María; Tejero, Héctor; Inglada-Pérez, Lucía; Sánchez-Barroso, Lara; Gutiérrez-Gutiérrez, Gerardo; Calvo, Isabel; Castelo, Beatriz; Redondo, Andrés; García-Donás, Jesús; Romero-Laorden, Nuria; Sereno, María; Merino, María; Currás-Freixes, María; Montero-Conde, Cristina; Mancikova, Veronika; Åvall-Lundqvist, Elisabeth; Green, Henrik; Al-Shahrour, Fátima; Cascón, Alberto; Robledo, Mercedes; Rodríguez-Antona, Cristina

    2017-03-01

    Purpose: Neuropathy is the dose-limiting toxicity of paclitaxel and a major cause for decreased quality of life. Genetic factors have been shown to contribute to paclitaxel neuropathy susceptibility; however, the major causes for interindividual differences remain unexplained. In this study, we identified genetic markers associated with paclitaxel-induced neuropathy through massive sequencing of candidate genes.Experimental Design: We sequenced the coding region of 4 EPHA genes, 5 genes involved in paclitaxel pharmacokinetics, and 30 Charcot-Marie-Tooth genes, in 228 cancer patients with no/low neuropathy or high-grade neuropathy during paclitaxel treatment. An independent validation series included 202 paclitaxel-treated patients. Variation-/gene-based analyses were used to compare variant frequencies among neuropathy groups, and Cox regression models were used to analyze neuropathy along treatment.Results: Gene-based analysis identified EPHA6 as the gene most significantly associated with paclitaxel-induced neuropathy. Low-frequency nonsynonymous variants in EPHA6 were present exclusively in patients with high neuropathy, and all affected the ligand-binding domain of the protein. Accumulated dose analysis in the discovery series showed a significantly higher neuropathy risk for EPHA5/6/8 low-frequency nonsynonymous variant carriers [HR, 14.60; 95% confidence interval (CI), 2.33-91.62; P = 0.0042], and an independent cohort confirmed an increased neuropathy risk (HR, 2.07; 95% CI, 1.14-3.77; P = 0.017). Combining the series gave an estimated 2.5-fold higher risk of neuropathy (95% CI, 1.46-4.31; P = 9.1 × 10(-4)).Conclusions: This first study sequencing EPHA genes revealed that low-frequency variants in EPHA6, EPHA5, and EPHA8 contribute to the susceptibility to paclitaxel-induced neuropathy. Furthermore, EPHA's neuronal injury repair function suggests that these genes might constitute important neuropathy markers for many neurotoxic drugs. Clin Cancer Res; 23

  17. 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.

  18. Paclitaxel Plus Oxaliplatin for Recurrent or Metastatic Cervical Cancer: A New York Cancer Consortium Study

    PubMed Central

    Kuo, Dennis Yi-Shin; Blank, Stephanie V.; Christo, Paul J.; Kim, Mimi; Caputo, Thomas A.; Pothuri, Bhavana; Hershman, Dawn; Goldman, Noah; Ivy, Percy S.; Runowicz, Carolyn D.; Muggia, Franco; Goldberg, Gary L.; Einstein, Mark H.

    2009-01-01

    Objective Survival in women with recurrent or metastatic cervical cancer remains poor. More effective and less toxic regimens are needed. Cisplatin is an effective radiosensitizer, but its single agent activity in recurrent cervical cancer, especially after prior cisplatin exposure, is disappointing, with a response rate of only 13%. Oxaliplatin has preclinical activity in cisplatin-resistant tumors and may have synergic activity when combined with paclitaxel. Our objective is determine the efficacy and toxicity of paclitaxel and oxaliplatin in patients with recurrent or metastatic cervical cancer. Methods Patients with histologic confirmation of primary metastatic or recurrent cervical cancer not amenable to surgical management were eligible. Treatment consisted of paclitaxel 175 mg/m2 IV and oxaliplatin 130 mg/m2 IV every 21 days. The primary endpoints were toxicity, recorded every cycle, and response, determined by RECIST criteria were assessed every 9 weeks, with subsequent confirmation as required. Sample size determinations were made using a Simon's two-stage design with a projected overall response proportion of 13% with cisplatin alone. Survival rates were calculated with Kaplan-Meier methods. Results Of the 35 patients enrolled, 32 were evaluable. The median age was 56(27-78); 30 had had prior radiation (23 concomitant with cisplatin). Patients completed a mean of 4.2 cycles (1-11). There were 2 complete and 5 partial responses for a total response rate of 7/32 (22%; 95% CI: 9.3%-40.0%). Eight patients had stable disease for an overall clinical benefit rate of 15/32 (47%; 95% CI: 29.1% - 65.3%). The mean time to best response was 13.5 weeks (95% C.I.: 10.6, 16.4). The mean progression-free survival was 21 weeks (95% C.I.: 14.7, 27.2) and mean overall survival was 52.1weeks (95% C.I.: 39.4, 64.8). A total of 135 cycles were administered. There were 28 (20.1%) grade 3/4 hematologic toxicities and 46 (34.1%) grade 3/4 non-hematologic toxicities, which were

  19. The removal of Cremophor EL from paclitaxel for quantitative analysis by HPLC-UV.

    PubMed

    Perdue, James D; Seaton, Pamela J; Tyrell, John A; DeVido, Daniel R

    2006-04-11

    A novel method for analysis of hydrophobic drug molecules in matrices that contain Cremophor EL (CrEL) is presented. The method utilized a precipitation technique involving mercuric chloride in a reaction with CrEL to form an insoluble complex in an ethanol matrix. The hydrophobic drug molecule was then analyzed by HPLC-UV without interference from CrEL. Nuclear magnetic resonance and infrared spectroscopy indicated that the mechanism of precipitation involves the reaction of mercuric chloride with the ether bond of CrEL. Analysis by HPLC with UV detection of paclitaxel and related substances was used to verify that the reaction is specific toward CrEL.

  20. Valproic Acid, a Histone Deacetylase Inhibitor, in Combination with Paclitaxel for Anaplastic Thyroid Cancer: Results of a Multicenter Randomized Controlled Phase II/III Trial

    PubMed Central

    Pugliese, Mariateresa; Gallo, Marco; Brignardello, Enrico; Milla, Paola; Orlandi, Fabio; Limone, Paolo Piero; Arvat, Emanuela; Boccuzzi, Giuseppe; Piovesan, Alessandro

    2016-01-01

    Anaplastic thyroid cancer (ATC) has a median survival less than 5 months and, to date, no effective therapy exists. Taxanes have recently been stated as the main drug treatment for ATC, and the histone deacetylase inhibitor valproic acid efficiently potentiates the effects of paclitaxel in vitro. Based on these data, this trial assessed the efficacy and safety of the combination of paclitaxel and valproic acid for the treatment of ATC. This was a randomized, controlled phase II/III trial, performed on 25 ATC patients across 5 centers in northwest Italy. The experimental arm received the combination of paclitaxel (80 mg/m2/weekly) and valproic acid (1,000 mg/day); the control arm received paclitaxel alone. Overall survival and disease progression, evaluated in terms of progression-free survival, were the primary outcomes. The secondary outcome was the pharmacokinetics of paclitaxel. The coadministration of valproic acid did not influence the pharmacokinetics of paclitaxel. Neither median survival nor median time to progression was statistically different in the two arms. Median survival of operated-on patients was significantly better than that of patients who were not operated on. The present trial demonstrates that the addition of valproic acid to paclitaxel has no effect on overall survival and disease progression of ATC patients. This trial is registered with EudraCT 2008-005221-11. PMID:27766105

  1. Geridonin and paclitaxel act synergistically to inhibit the proliferation of gastric cancer cells through ROS-mediated regulation of the PTEN/PI3K/Akt pathway

    PubMed Central

    Chang, Li-Ming; Zhou, Kai-Rui; Wang, Jun-Wei; Ke, Yu; Yang, Dong-Xiao; Shi, Hong-Ge; Wang, Ran; Shi, Xiao-Li; Ma, Li-Ying; Liu, Hong-Min

    2016-01-01

    Paclitaxel, a taxane, is a cytotoxic chemotherapeutic agent that targets microtubules. It has become a front-line therapy for a broad range of malignancies, including lung, breast, gastric, esophageal, and bladder carcinomas. Although paclitaxel can inhibit tumor development and improve survival, poor solubility, myelotoxicity, allergic reactions, and drug resistance have restricted its clinical application. Paclitaxel is frequently combined with other chemotherapeutics to enhance the antitumor effects and reduce side effects. We synthesized geridonin, a derivative of oridonin, and demonstrate that geridonin and paclitaxel act synergistically to inhibit the growth of gastric cancer cells. Importantly, geridonin enhanced the antitumor effects of paclitaxel without increasing toxicity in vivo. Mechanistic analysis revealed that administration of geridonin in combination with paclitaxel up-regulated the tumor suppressor PTEN and inhibited phosphorylation of Akt and MDM2. This led to the accumulation of p53 and induced apoptosis though the mitochondrial pathway. Thus, geridonin in combination with paclitaxel is a new treatment strategy for gastric cancer. PMID:27659528

  2. 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.

  3. Balancing activity and tolerability of neoadjuvant paclitaxel- and docetaxel-based chemotherapy for HER2-positive early stage breast cancer: sensitivity analysis of randomized trials.

    PubMed

    Carbognin, Luisa; Sperduti, Isabella; Nortilli, Rolando; Brunelli, Matteo; Vicentini, Cecilia; Pellini, Francesca; Pollini, Giovanni Paolo; Giannarelli, Diana; Tortora, Giampaolo; Bria, Emilio

    2015-03-01

    Paclitaxel and docetaxel represent the most adopted taxanes in the neoadjuvant treatment of HER2-positive breast cancer. Questions still remain with regard to their difference in terms of activity and tolerability. Events for pathological complete response (pCR), severe and febrile neutropenia (FN), and severe neurotoxicity were pooled by adopting a fixed- and random-effect model. A sensitivity analysis to test for the interaction between paclitaxel and docetaxel was accomplished. Absolute differences with 95% confidence intervals (CIs) and the number of patients needed to treat/harm (NNT/NNH) were calculated to derive the Likelihood of being Helped or Harmed (LHH). Data from 15 trials (3601 patients) were included. Paclitaxel significantly increases pCR rate by 6.8% in comparison with docetaxel (43.4%, 95% CI 41.1-45.7% versus 36.6%, 95% CI 34.3-39.0%, p=0.0001), regardless of the chemotherapy backbone, with an absolute difference of 9% and 9.2% for anthracycline-based or free-regimens. Paclitaxel significantly improves pCR versus docetaxel with a single HER2-inhibition by 6.7% (p=0.0012), with no difference if combined with a dual HER2-inhibition. Severe neutropenia and FN are significantly lower with paclitaxel, with an absolute difference of 32.4% (p<0.0001) and 2.5% (p=0.0059), respectively. Conversely, severe neurotoxicity is slightly higher with paclitaxel (3%, p=0.0001). The LHH ratio calculated for pCR and severe neutropenia is 2.0 and 0.7 for paclitaxel and docetaxel. Although the activity of neoadjuvant paclitaxel and docetaxel HER2-positive breast cancer is considered similar, the slight advantage in pCR, the significantly lower neutropenia and FN, do favor paclitaxel (in the weekly fashion) over docetaxel, despite the slightly worst neurotoxicity.

  4. 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-β-cyclodextrin, random methyl-β-cyclodextrin and soluble β-cyclodextrin polymer, and the cellular uptake of the fluorescent paclitaxel derivative-random methyl-β-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-β-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.

  5. Precise glioblastoma targeting by AS1411 aptamer-functionalized poly (l-γ-glutamylglutamine)-paclitaxel nanoconjugates.

    PubMed

    Luo, Zimiao; Yan, Zhiqiang; Jin, Kai; Pang, Qiang; Jiang, Ting; Lu, Heng; Liu, Xianping; Pang, Zhiqing; Yu, Lei; Jiang, Xinguo

    2017-03-15

    Chemotherapy is still the main adjuvant strategy after surgery in glioblastoma therapy. As the main obstacles of chemotherapeutic drugs for glioblastoma treatment, the blood brain barrier (BBB) and non-specific delivery to non-tumor tissues greatly limit the accumulation of drugs into tumor tissues and simultaneously cause serious toxicity to nearby normal tissues which altogether compromised the chemotherapeutic effect. In the present study, we established an aptamer AS1411-functionalized poly (l-γ-glutamyl-glutamine)-paclitaxel (PGG-PTX) nanoconjugates drug delivery system (AS1411-PGG-PTX), providing an advantageous solution of combining the precisely active targeting and the optimized solubilization of paclitaxel. The receptor nucleolin, highly expressed in glioblastoma U87 MG cells as well as neo-vascular endothelial cells, mediated the binding and endocytosis of AS1411-PGG-PTX nanoconjugates, leading to significantly enhanced uptake of AS1411-PGG-PTX nanoconjugates by tumor cells and three-dimension tumor spheroids, and intensive pro-apoptosis effect of AS1411-PGG-PTX nanoconjugates. In vivo fluorescence imaging and tissue distribution further demonstrated the higher tumor distribution of AS1411-PGG-PTX as compared with PGG-PTX. As a result, the AS1411-PGG-PTX nanoconjugates presented the best anti-glioblastoma effect with prolonged median survival time and most tumor cell apoptosis in vivo as compared with other groups. In conclusion, the AS1411-PGG-PTX nanoconjugates exhibited a promising targeting delivery strategy for glioblastoma therapy.

  6. The clinical development of paclitaxel: a successful collaboration of academia, industry and the National Cancer Institute.

    PubMed

    Donehower, R C

    1996-01-01

    The successful development of paclitaxel as an important new antineoplastic agent with the potential to have an impact on a number of human cancers was possible as a result of significant contributions from individuals and groups with diverse areas of interest and expertise. The advancement of paclitaxel through the preclinical and clinical evaluation which ultimately led to its approval, as well as surmounting the regulatory hurdles which were faced required the close collaboration of individual investigators at academic institutions, the pharmaceutical industry (Bristol-Myers Squibb) and the National Cancer Institute. The latter stages of this developmental effort can be viewed as a prime example of the potential of the Cooperative Research and Development Agreement (CRADA) mechanism to bring novel therapies to patients with serious illnesses in a timely fashion. It is also tangible evidence of the vision and perseverance of a number of members of the Division of Cancer Treatment (DCT) under the direction of Dr. Bruce Chabner, in whose honor this symposium is given.

  7. 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

    2015-01-01

    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.

  8. Heterogeneity of paclitaxel distribution in different tumor models assessed by MALDI mass spectrometry imaging

    PubMed Central

    Giordano, Silvia; Zucchetti, Massimo; Decio, Alessandra; Cesca, Marta; Fuso Nerini, Ilaria; Maiezza, Marika; Ferrari, Mariella; Licandro, Simonetta Andrea; Frapolli, Roberta; Giavazzi, Raffaella; Maurizio, D’Incalci; Davoli, Enrico; Morosi, Lavinia

    2016-01-01

    The penetration of anticancer drugs in solid tumors is important to ensure the therapeutic effect, so methods are needed to understand drug distribution in different parts of the tumor. Mass spectrometry imaging (MSI) has great potential in this field to visualize drug distribution in organs and tumor tissues with good spatial resolution and superior specificity. We present an accurate and reproducible imaging method to investigate the variation of drug distribution in different parts of solid tumors. The method was applied to study the distribution of paclitaxel in three ovarian cancer models with different histopathological characteristics and in colon cancer (HCT116), breast cancer (MDA-MB-231) and malignant pleural mesothelioma (MPM487). The heterogeneous drug penetration in the tumors is evident from the MALDI imaging results and from the images analysis. The differences between the various models do not always relate to significant changes in drug content in tumor homogenate examined by classical HPLC analysis. The specificity of the method clarifies the heterogeneity of the drug distribution that is analyzed from a quantitative point of view too, highlighting how marked are the variations of paclitaxel amounts in different part of solid tumors. PMID:28000726

  9. Ultrasound triggered image-guided drug delivery to inhibit vascular reconstruction via paclitaxel-loaded microbubbles

    PubMed Central

    Zhu, Xu; Guo, Jun; He, Cancan; Geng, Huaxiao; Yu, Gengsheng; Li, Jinqing; Zheng, Hairong; Ji, Xiaojuan; Yan, Fei

    2016-01-01

    Paclitaxel (PTX) has been recognized as a promising drug for intervention of vascular reconstructions. However, it is still difficult to achieve local drug delivery in a spatio-temporally controllable manner under real-time image guidance. Here, we introduce an ultrasound (US) triggered image-guided drug delivery approach to inhibit vascular reconstruction via paclitaxel (PTX)-loaded microbubbles (PLM) in a rabbit iliac balloon injury model. PLM was prepared through encapsulating PTX in the shell of lipid microbubbles via film hydration and mechanical vibration technique. Our results showed PLM could effectively deliver PTX when exposed to US irradiation and result in significantly lower viability of vascular smooth muscle cells. Ultrasonographic examinations revealed the US signals from PLM in the iliac artery were greatly increased after intravenous administration of PLM, making it possible to identify the restenosis regions of iliac artery. The in vivo anti-restenosis experiments with PLM and US greatly inhibited neointimal hyperplasia at the injured site, showing an increased lumen area and reduced the ratio of intima area and the media area (I/M ratio). No obvious functional damages to liver and kidney were observed for those animals. Our study provided a promising approach to realize US triggered image-guided PTX delivery for therapeutic applications against iliac restenosis. PMID:26899550

  10. Glutaminase inhibitor compound 968 inhibits cell proliferation and sensitizes paclitaxel in ovarian cancer

    PubMed Central

    Yuan, Lingqin; Sheng, Xiugui; Clark, Leslie H; Zhang, Lu; Guo, Hui; Jones, Hannah M; Willson, Adam K; Gehrig, Paola A; Zhou, Chunxiao; Bae-Jump, Victoria L

    2016-01-01

    Objective: Our overall goal was to investigate the anti-tumor activity of the glutaminase 1 (GLS1) Inhibitor compound 968 in ovarian cancer cells. The human ovarian cancer cell lines, HEY, SKOV3 and IGROV-1 were used. Cell proliferation was assessed by MTT assay after treatment with compound 968. Cell cycle progression and Annexin V expression were evaluated using Cellometer. Western blotting was performed to determine changes in GLS1, cellular stress and cell cycle checkpoints. Reactive oxygen species (ROS) and glutamate dehydrogenase (GDH) activity were assessed by ELISA assay. Compound 968 significantly inhibited cell proliferation and the expression of GLS1 in a dose-dependent manner in all three ovarian cancer cell lines. Compound 968 induced G1 phase cell cycle arrest and apoptosis. Treatment with compound 968 increased ROS levels and induced the protein expression of calnexin, binding immunoglobulin protein (BiP) and protein kinase RNA-like endoplasmic reticulum kinase (PERK). Deprivation of glutamine increased the sensitivity of cells to paclitaxel, and compound 968 sensitized cells to the anti-proliferative effects of paclitaxel. Compound 968 inhibited cell growth in ovarian cancer cells through induction of G1 phase cell cycle arrest, apoptosis and cellular stress, suggesting that targeting GLS1 provide a novel therapeutic strategy for ovarian cancer. PMID:27830010

  11. A Paclitaxel-Loaded Recombinant Polypeptide Nanoparticle Outperforms Abraxane in Multiple Murine Cancer Models

    PubMed Central

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

    2015-01-01

    Packaging clinically relevant hydrophobic drugs into a self-assembled nanoparticle can improve their aqueous solubility, plasma half-life, tumor 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 diameter near-monodisperse nanoparticles that increased the systemic exposure of PTX by 7-fold compared to free drug and 2-fold compared to the FDA approved taxane nanoformulation (Abraxane®). The tumor uptake of the CP-PTX nanoparticle was 5-fold greater than free drug and 2-fold greater than Abraxane. In a murine cancer model of human triple negative breast cancer and prostate cancer, CP-PTX induced near complete tumor regression after a single dose in both tumor models, whereas at the same dose, no mice treated with Abraxane survived for more than 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 paclitaxel delivery. PMID:26239362

  12. Ultrasound triggered image-guided drug delivery to inhibit vascular reconstruction via paclitaxel-loaded microbubbles.

    PubMed

    Zhu, Xu; Guo, Jun; He, Cancan; Geng, Huaxiao; Yu, Gengsheng; Li, Jinqing; Zheng, Hairong; Ji, Xiaojuan; Yan, Fei

    2016-02-22

    Paclitaxel (PTX) has been recognized as a promising drug for intervention of vascular reconstructions. However, it is still difficult to achieve local drug delivery in a spatio-temporally controllable manner under real-time image guidance. Here, we introduce an ultrasound (US) triggered image-guided drug delivery approach to inhibit vascular reconstruction via paclitaxel (PTX)-loaded microbubbles (PLM) in a rabbit iliac balloon injury model. PLM was prepared through encapsulating PTX in the shell of lipid microbubbles via film hydration and mechanical vibration technique. Our results showed PLM could effectively deliver PTX when exposed to US irradiation and result in significantly lower viability of vascular smooth muscle cells. Ultrasonographic examinations revealed the US signals from PLM in the iliac artery were greatly increased after intravenous administration of PLM, making it possible to identify the restenosis regions of iliac artery. The in vivo anti-restenosis experiments with PLM and US greatly inhibited neointimal hyperplasia at the injured site, showing an increased lumen area and reduced the ratio of intima area and the media area (I/M ratio). No obvious functional damages to liver and kidney were observed for those animals. Our study provided a promising approach to realize US triggered image-guided PTX delivery for therapeutic applications against iliac restenosis.

  13. Paclitaxel-PHBV nanoparticles and their toxicity to endometrial and primary ovarian cancer cells.

    PubMed

    Vilos, Cristian; Morales, Francisco A; Solar, Paula A; Herrera, Natalia S; Gonzalez-Nilo, Fernando D; Aguayo, Daniel A; Mendoza, Hegaly L; Comer, Jeffrey; Bravo, Maria L; Gonzalez, Pamela A; Kato, Sumie; Cuello, Mauricio A; Alonso, Catalina; Bravo, Erasmo J; Bustamante, Eva I; Owen, Gareth I; Velasquez, Luis A

    2013-05-01

    This report is an integrated study to include the molecular simulation, physicochemical characterization and biological analysis of a paclitaxel-loaded PHBV nanoparticle that demonstrates uptake, release and cytotoxicity in cancer cell lines. Taking this nanoparticle one step closer to its use in a clinical setting, we demonstrate that it causes significant cell death in primary cultures of stage IIIc serous ovarian cancer cells isolated from six patients. Molecular simulations revealed a high affinity of paclitaxel for the water-polymer interface, thus the drug is delivered only when the polymer near it is degraded. The Fourier transform infrared spectroscopy suggests the formation of a short-lived crystalline phase, also observed in the CG simulations, and transmission electron microscopy revealed branched structures on the surface of particles, which disappeared after 4 days. Biological analyses indicated that these particles have a 48-h window of toxicity protection, allowing for the endocytosis of the particle by the cells; this finding was corroborated by confocal microscopy and flow cytometry. The low cost to synthesize PHBV using microorganisms and the potential chemical modifications of the polymer make it attractive for inexpensive, large-scale pharmaceutical production.

  14. Effects of paclitaxel on EGFR endocytic trafficking revealed using quantum dot tracking in single cells.

    PubMed

    Li, Hui; Duan, Zhao-Wen; Xie, Ping; Liu, Yu-Ru; Wang, Wei-Chi; Dou, Shuo-Xing; Wang, Peng-Ye

    2012-01-01

    Paclitaxel (PTX), a chemotherapeutic drug, affects microtubule dynamics and influences endocytic trafficking. However, the mechanism and the dynamics of altered endocytic trafficking by paclitaxel treatment in single living cells still remain elusive. By labeling quantum dots (QDs) to the epidermal growth factor (EGF), we continuously tracked the endocytosis and post-endocytic trafficking of EGF receptors (EGFRs) in A549 cells for a long time interval. A single-cell analysis method was introduced to quantitatively study the dynamics of endocytic trafficking. Compared with the control cells, the velocity of directed motion was reduced by 30% due to the suppression of high speed movements of EGF-QDs along the microtubules in PTX-treated cells. The endocytic trafficking in PTX-treated cells was mainly via super-diffusive mode of motion, whereas in control cells, it was mostly via sub-diffusive mode of motion. Moreover, PTX shortened endosomal trafficking and prevented EGF-QDs from moving to the perinuclear area via the rapid delivery of EGF-QDs into the peripheral lysosomes. The present study may shed light on the mechanism of the effect of PTX on the treatment of lung cancer.

  15. Effect of a paclitaxel-eluting metallic stent on rabbit esophagus

    PubMed Central

    Zhang, Yin; Gao, Ying; Chen, Jianping; Ma, Limei; Liu, Li; Wang, Xiang; Fan, Zhining

    2016-01-01

    The use of self-expanding metallic stents (SEMS) is the current treatment of choice for malignant gastrointestinal obstructions. A paclitaxel-eluting metallic SEMS (PEMS) may have an antitumor effect on esophageal tissue. PEMS with 10% paclitaxel or conventional SEMS were inserted into the lower esophagus of rabbits. Following the insertion of the stents for 1, 2, 4 and 6 weeks, the rabbits were sacrificed and the status of the stent insertion was examined, as well as any macroscopic or microscopic mucosal changes in the esophageal tissue. All the rabbits survived until death without any complications. No migration following stent insertion occurred. The number of cases with proximal obstruction increased in a time-dependent manner, and no significant difference was observed between the two groups. Gross histological examination showed similar tissue reaction to the stents at 1, 2 and 4 weeks, and inflammatory cell infiltrating was higher in the SEMS group at 1 and 2 weeks. However, inflammatory cell infiltration was markedly higher in the PEMS group at 4 and 6 weeks. Food-intake and weight were similar in the two groups. The results of the present study demonstrated that PEMS may serve as a safe alternative treatment strategy for esophageal obstruction. Furthermore, PEMS may inhibit the tumor growth of the esophageal wall through inflammatory infiltration and targeted drug delivery. A tumor model will be required in the future for evaluating the prognosis of patients with advanced esophageal carcinoma. PMID:27882097

  16. Reducing Both Pgp Overexpression and Drug Efflux with Anti-Cancer Gold-Paclitaxel Nanoconjugates

    PubMed Central

    Li, Fei; Zhou, Xiaofei; Zhou, Hongyu; Jia, Jianbo; Li, Liwen; Zhai, Shumei; Yan, Bing

    2016-01-01

    Repeated administrations of anti-cancer drugs to patients often induce drug resistance. P-glycoprotein (Pgp) facilitates an efficient drug efflux, preventing cellular accumulation of drugs and causing multi-drug resistance (MDR). In this study, we developed a gold-paclitaxel nanoconjugate system to overcome MDR. Gold nanoparticles (GNPs) were conjugated with β-cyclodextrin enclosing paclitaxel (PTX) molecules and PEG molecules. GNP conjugates were effectively endocytosed by both drug-sensitive human lung cancer H460 cells and Pgp-overexpressed drug-resistant H460PTX cells. Compared with PTX, PGNPs did not induce the Pgp overexpression in drug-sensitive H460 cells after long-term treatment and also avoided being pumped out of cells by overexpressed Pgp molecules in H460PTX with a 17-fold lower EC50 compared to PTX. Fluorescent microscopy and flow cytometry further confirmed that fluorescent labeled PGNPs (f-PGNPs) maintained a high cellular PTX level in both H460 and H460PTX cells. These results demonstrated that nano-drug conjugates were able to avoid the development of drug resistance in sensitive cells and evade Pgp-mediated drug resistance and to maintain a high cytotoxicity in drug-resistant cancer cells. These findings exemplify a powerful nanotechnological approach to the long-lasting issue of chemotherapy-induced drug resistance. PMID:27467397

  17. Facile preparation of paclitaxel loaded silk fibroin nanoparticles for enhanced antitumor efficacy by locoregional drug delivery.

    PubMed

    Wu, Puyuan; Liu, Qin; Li, Rutian; Wang, Jing; Zhen, Xu; Yue, Guofeng; Wang, Huiyu; Cui, Fangbo; Wu, Fenglei; Yang, Mi; Qian, Xiaoping; Yu, Lixia; Jiang, Xiqun; Liu, Baorui

    2013-12-11

    Non-toxic, safe materials and preparation methods are among the most important factors when designing nanoparticles (NPs) for future clinical application. Here we report a novel and facile method encapsulating anticancer drug paclitaxel (PTX) into silk fibroin (SF), a biocompatible and biodegradable natural polymer, without adding any toxic organic solvents, surfactants or other toxic agents. The paclitaxel loaded silk fibroin nanoparticles (PTX-SF-NPs) with a diameter of 130 nm were formed in an aqueous solution at room temperature by self-assembling of SF protein, which demonstrated mainly silk I conformation in the NPs. In cellular uptake experiments, coumarin-6 loaded SF NPs were taken up efficiently by two human gastric cancer cell lines BGC-823 and SGC-7901. In vitro cytotoxicity studies demonstrated that PTX kept its pharmacological activity when incorporating into PTX-SF-NPs, while SF showed no cytotoxicity to cells. The in vivo antitumor effects of PTX-SF-NPs were evaluated on gastric cancer nude mice exnograft model. We found that locoregional delivery of PTX-SF-NPs demonstrated superior antitumor efficacy by delaying tumor growth and reducing tumor weights compared with systemic administration. Furthermore, the organs of mice in NP treated groups didn't show obvious toxicity, indicating the in vivo safety of SF NPs. These results suggest that SF NPs are promising drug delivery carriers, and locoregional delivery of SF NPs could be a potential future clinical cancer treatment regimen.

  18. Cysteine modified and bile salt based micelles: preparation and application as an oral delivery system for paclitaxel.

    PubMed

    Xu, Wei; Fan, Xiaohui; Zhao, Yanli; Li, Lingbing

    2015-04-01

    The aim of the present study is to construct a cysteine modified polyion complex micelles made of Pluronic F127-chitosan (PF127-CS), Pluronic F127-cysteine (PF127-cysteine) and sodium cholate (NaC) and to evaluate the potential of the micelles as an oral drug delivery system for paclitaxel. Systematic studies on physicochemical properties including size distribution, zeta-potential and morphology were conducted to validate the formation of micelle structure. Compared with Pluronic micelles, drug-loading capacity of PF127-CS/PF127-cysteine/NaC micelles was increased from 3.35% to 12.77%. Both the critical micelle concentration and the stability test confirmed that the PF127-CS/PF127-cysteine/NaC micelles were more stable in aqueous solution than sodium cholate micelles. Pharmacokinetic study demonstrated that when oral administration the area under the plasma concentration-time curve (AUC0-∞) and the absolute bioavailability of paclitaxel-loaded micelles were five times greater than that of the paclitaxel solution. In general, PF127-CS/PF127-cysteine/NaC micelles were proven to be a potential oral drug delivery system for paclitaxel.

  19. Paclitaxel-loaded ethosomes®: potential treatment of squamous cell carcinoma, a malignant transformation of actinic keratoses.

    PubMed

    Paolino, Donatella; Celia, Christian; Trapasso, Elena; Cilurzo, Felisa; Fresta, Massimo

    2012-05-01

    Topical application of anticancer drugs for the treatment of malignancies represents a new challenge in dermatology, potentially being an alternative therapeutic approach for the efficacious treatment of non-melanoma skin cancer, that is, actinic keratoses, and malignant lesions of the skin caused by ultraviolet radiation. Anti-proliferative and antimitotic drugs, including many of the taxanes, are currently under investigation for the treatment of cutaneous malignant transformation of actinic keratoses, particularly the squamous cell carcinoma. Paclitaxel-loaded ethosomes® are proposed as topical drug delivery systems for the treatment of this pathology due to their suitable physicochemical characteristics and enhanced skin penetration ability for deep dermal delivery. Our in vitro data show that the skin application of paclitaxel-loaded ethosomes® improved the permeation of paclitaxel in a stratum corneum-epidermis membrane model and increased its anti-proliferative activity in a squamous cell carcinoma model as compared to the free drug. The results obtained encouraged the use of the paclitaxel-loaded ethosomes® as the formulation for the potential treatment of squamous cell carcinoma, a malignant transformation of actinic keratoses.

  20. 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

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

    PubMed Central

    2013-01-01

    A system of novel nanoparticles of star-shaped cholic acid-core polylactide-d-α-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. PMID:24134303

  2. Weekly administration of paclitaxel attenuated rectal stenosis caused by multiple peritoneal recurrence 8 years after the resection of gastric carcinoma.

    PubMed

    Sakurai, Yoichi; Yoshida, Ikuo; Tonomura, Shuhei; Sakai, Wakana; Nakamura, Yasuko; Imazu, Hiroki; Matsubara, Toshiki; Ochiai, Masahiro

    2003-01-01

    We report a patient with rectal stenosis caused by peritoneal recurrence 8 years after a curative resection of advanced stage gastric carcinoma; the recurrence was effectively treated with the weekly administration of paclitaxel. The patient was a 66-year-old Japanese woman who was admitted to our hospital complaining of abdominal pain and frequent bowel movements. She had undergone total gastrectomy, due to advanced-stage gastric carcinoma with extensive lymph node metastasis, 8 years before, and had taken an oral anticancer agent, fluoropyrimidine, for 4 years after the operation. Colonofiberscopy performed on admission revealed circumferential rectal stenosis located 10 cm from the anal verge. Barium enema study demonstrated extensive poor expansion of the upper and lower rectum and irregularity of the descending colon. Abdominal computed tomography (CT) scanning revealed wall thickening in the rectum and descending colon. These findings were compatible with rectal stenosis caused by the peritoneal recurrence of gastric carcinoma. Weekly administration of paclitaxel was started. The abdominal symptoms soon disappeared when the second cycle of paclitaxel was completed, and they have not appeared since then. The rectal stenosis was attenuated, as confirmed by imaging analyses. Weekly paclitaxel has been effective for more than 13 months, suggesting that the patient is in a state of tumor dormancy of recurrent gastric carcinoma.

  3. Effects of ambroxol hydrochloride on concentrations of paclitaxel and carboplatin in lung cancer patients at different administration times.

    PubMed

    Li, J; Yi, W; Jiang, P; Sun, R; Li, T

    2016-11-30

    Our previous preliminary study revealed a synergistic effect of ambroxol hydrochloride with chemotherapeutic agents such as paclitaxel and carboplatin in lung cancer. However, the optimal conditions such as administration time and drug concentration of ambroxol hydrochloride to achieve the maximum synergistic effect remained unclear. Therefore, concentration changes of the chemotherapy drugs paclitaxel and carboplatin in the sputum were observed after ambroxol hydrochloride administration at different times in order to determine the most effective time frame of ambroxol hydrochloride administration. In this study, 470 cases of non-small cell lung cancer (NSCLC) were divided into different groups with ambroxol hydrochloride administered at different time points prior to chemotherapy, while another 171 cases received no ambroxol hydrochloride prior to chemotherapy. The results showed the concentrations of paclitaxel and carboplatin in sputum of patients treated with ambroxol hydrochloride were significantly higher than those of the control group, suggesting that ambroxol hydrochloride significantly increased the local concentrations of chemotherapeutic agents in lung tissues of NSCLC. Furthermore, the intravenous administration of ambroxol hydrochloride more than 48 hours before chemotherapy showed an optimized schedule and much greater efficacy in increasing drug concentrations than that of the control group. No statistical differences were found in the rates of grade 2 or above myelosuppression between the ambroxol intervention and control groups. Taken together, these results demonstrate that ambroxol hydrochloride administered intravenously more than 48 hours prior to chemotherapy optimally increased the concentrations of paclitaxel and carboplatin in lung tissue without significantly increasing hematologic toxicity.

  4. Bisphosphonates Inhibit Stellate Cell Activity and Enhance Antitumor Effects of Nanoparticle Albumin Bound-Paclitaxel in Pancreatic Ductal Adenocarcinoma

    PubMed Central

    Gonzalez-Villasana, Vianey; Rodriguez-Aguayo, Cristian; Arumugam, Thiruvengadam; Cruz-Monserrate, Zobeida; Fuentes-Mattei, Enrique; Deng, Defeng; Hwang, Rosa F.; Wang, Huamin; Ivan, Cristina; Garza, Raul Joshua; Cohen, Evan; Gao, Hui; Armaiz-Pena, Guillermo N.; Monroig-Bosque, Paloma del C.; Philip, Bincy; Rashed, Mohammed H.; Aslan, Burcu; Erdogan, Mumin Alper; Gutierrez-Puente, Yolanda; Ozpolat, Bulent; Reuben, James M.; Sood, Anil K.; Logsdon, Craig; Lopez-Berestein, Gabriel

    2014-01-01

    Pancreatic stellate cells (PSCs) have been recognized as the principal cells responsible for the production of fibrosis in PDAC. Recently PSCs have been noted to share characteristics with cells of monocyte-macrophage lineage (MML cells). Thus, we tested whether PSCs could be targeted with the nitrogen-containing bisphosphonates (NBPs) [pamidronate (Pam) or zoledronic acid (ZA)], which are potent MML cell inhibitors. In addition, we tested NBPs treatment combination with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) to enhance antitumor activity. In vitro we observed that PSCs possess α-naphthyl butyrate esterase (ANBE) enzyme activity, a specific marker of MML cells. Moreover NBPs inhibited PSCs proliferation, activation, release of macrophage chemoattractant protein-1 (MCP-1) and type I collagen expression. NBPs also induced PSC apoptosis and cell cycle arrest in the G1 phase. In vivo, NBPs inactivated PSCs; reduced fibrosis; inhibited tumor volume, tumor weight, peritoneal dissemination, angiogenesis, and cell proliferation; and increased apoptosis in an orthotopic murine model of PDAC. These in vivo antitumor effects were enhanced when NBPs were combined with nab-paclitaxel but not gemcitabine (Gem). Our study suggests that targeting PSCs and tumor cells with NBPs in combination with nab-paclitaxel may be a novel therapeutic approach to PDAC. PMID:25193509

  5. 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

  6. Increased oral bioavailability of paclitaxel by its encapsulation through complex formation with cyclodextrins in poly(anhydride) nanoparticles.

    PubMed

    Agüeros, M; Zabaleta, V; Espuelas, S; Campanero, M A; Irache, J M

    2010-07-01

    The aim of this work was to study the oral bioavailability in rats of paclitaxel (PTX) when encapsulated as a complex with cyclodextrins in poly(anhydride) nanoparticles (NP). For this purpose three different cyclodextrins were selected: beta-cyclodextrin (CD), 2-hydroxypropyl-beta-cyclodextrin (HPCD) and 6-monodeoxy-6-monoamino-beta-cyclodextrin (NHCD). A single dose of 10mg paclitaxel per kg body weight as PTX-cyclodextrin nanoparticles was used. Plasma curves were characterised by a plateau of paclitaxel concentration close to the C(max) from T(max) till 24h post-administration. For PTX-CD NP and PTX-HPCD NP, these sustained levels of the anticancer drug were found to be between 27 and 33-fold higher than the reported value of drug activity whereas the relative oral bioavailability of paclitaxel was calculated to be higher than 80%. These facts would be directly related with a synergistic effect obtained by the combination of the bioadhesive properties of poly(anhydride) nanoparticles and the inhibitory effect of cyclodextrins on the activity of P-glycoprotein and cythocrome P450.

  7. Functional deficits in peripheral nerve mitochondria in rats with paclitaxel- and oxaliplatin-evoked painful peripheral neuropathy.

    PubMed

    Zheng, Huaien; Xiao, Wen Hua; Bennett, Gary J

    2011-12-01

    Cancer chemotherapeutics like paclitaxel and oxaliplatin produce a dose-limiting chronic sensory peripheral neuropathy that is often accompanied by neuropathic pain. The cause of the neuropathy and pain is unknown. In animal models, paclitaxel-evoked and oxaliplatin-evoked painful peripheral neuropathies are accompanied by an increase in the incidence of swollen and vacuolated mitochondria in peripheral nerve axons. It has been proposed that mitochondrial swelling and vacuolation are indicative of a functional impairment and that this results in a chronic axonal energy deficiency that is the cause of the neuropathy's symptoms. However, the significance of mitochondrial swelling and vacuolation is ambiguous and a test of the hypothesis requires a direct assessment of the effects of chemotherapy on mitochondrial function. The results of such an assessment are reported here. Mitochondrial respiration and ATP production were measured in rat sciatic nerve samples taken 1-2 days after and 3-4 weeks after induction of painful peripheral neuropathy with paclitaxel and oxaliplatin. Significant deficits in Complex I-mediated and Complex II-mediated respiration and significant deficits in ATP production were found for both drugs at both time points. In addition, prophylactic treatment with acetyl-l-carnitine, which inhibited the development of paclitaxel-evoked and oxaliplatin-evoked neuropathy, prevented the deficits in mitochondrial function. These results implicate mitotoxicity as a possible cause of chemotherapy-evoked chronic sensory peripheral neuropathy.

  8. Electrophysiological, behavioral and histological characterization of paclitaxel, cisplatin, vincristine and bortezomib-induced neuropathy in C57Bl/6 mice

    PubMed Central

    Boehmerle, Wolfgang; Huehnchen, Petra; Peruzzaro, Sarah; Balkaya, Mustafa; Endres, Matthias

    2014-01-01

    Polyneuropathy is a frequent and potentially severe side effect of clinical tumor chemotherapy. The goal of this study was to characterize paclitaxel-, cisplatin-, vincristine- and bortezomib-induced neuropathy in C57BL/6 mice with a comparative approach. The phenotype of the animals was evaluated at four time points with behavioral and electrophysiological tests, followed by histology. Treatment protocols used in this study were well tolerated and induced a sensory and predominantly axonal polyneuropathy. Behavioral testing revealed normal motor coordination, whereas all mice receiving verum treatment developed mechanical allodynia and distinct gait alterations. Electrophysiological evaluation showed a significant decrease of the caudal sensory nerve action potential amplitude for all cytostatic agents and a moderate reduction of nerve conduction velocity for cisplatin and paclitaxel. This finding was confirmed by histological analysis of the sciatic nerve which showed predominantly axonal damage: Paclitaxel and vincristine affected mostly large myelinated fibers, bortezomib small myelinated fibers and cisplatin damaged all types of myelinated fibers to a similar degree. Neuropathic symptoms developed faster in paclitaxel and vincristine treated animals compared to cisplatin and bortezomib treatment. The animal models in this study can be used to elucidate pathomechanisms underlying chemotherapy-induced polyneuropathy and for the development of novel therapeutic and preventative strategies. PMID:25231679

  9. Paclitaxel-loaded polymeric microparticles: Quantitative relationships between in vitro drug release rate and in vivo pharmacodynamics

    PubMed Central

    Tsai, Max; Lu, Ze; Wientjes, M. Guillaume; Au, Jessie L.-S.

    2013-01-01

    Intraperitoneal therapy (IP) has demonstrated survival advantages in patients with peritoneal cancers, but has not become a widely practiced standard-of-care in part due to local toxicity and sub-optimal drug delivery. Paclitaxel-loaded, polymeric microparticles were developed to overcome these limitations. The present study evaluated the effects of microparticle properties on paclitaxel release (extent and rate) and in vivo pharmacodynamics. In vitro paclitaxel release from microparticles with varying physical characteristics (i.e., particle size, copolymer viscosity and composition) was evaluated. A method was developed to simulate the dosing rate and cumulative dose released in the peritoneal cavity based on the in vitro release data. The relationship between the simulated drug delivery and treatment outcomes of seven microparticle compositions was studied in mice bearing IP human pancreatic tumors, and compared to that of the intravenous Cremophor micellar paclitaxel solution used off-label in previous IP studies. Paclitaxel release from polymeric microparticles in vitro was multi-phasic; release was greater and more rapid from microparticles with lower polymer viscosities and smaller diameters (e.g., viscosity of 0.17 vs. 0.67 dl/g and diameter of 5–6 vs. 50–60 μm). The simulated drug release in the peritoneal cavity linearly correlated with treatment efficacy in mice (r2>0.8, p<0.001). The smaller microparticles, which distribute more evenly in the peritoneal cavity compared to the large microparticles, showed greater dose efficiency. For single treatment, the microparticles demonstrated up to 2-times longer survival extension and 4-times higher dose efficiency, relative to the paclitaxel/Cremophor micellar solution. Upon repeated dosing, the paclitaxel/Cremophor micellar solution showed cumulative toxicity whereas the microparticle that yielded 2-times longer survival did not display cumulative toxicity. The efficacy of IP therapy depended on both

  10. 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

  11. p27kip1 overexpression promotes paclitaxel-induced apoptosis in pRb-defective SaOs-2 cells.

    PubMed

    Gabellini, Chiara; Pucci, Bruna; Valdivieso, Paola; D'Andrilli, Giuseppina; Tafani, Marco; De Luca, Antonio; Masciullo, Valeria

    2006-08-15

    p27kip1 is a cyclin-dependent kinase (CDK) inhibitor, which controls several cellular processes in strict collaboration with pRb. We evaluated the role of p27kip1 in paclitaxel-induced apoptosis in the pRb-defective SaOs-2 cells. Following 48 h of exposure of SaOs-2 cells to 100 nM paclitaxel, we observed an increase in p27kip1 expression caused by the decrease of the ubiquitin-proteasome activity. Such increase was not observed in SaOs-2 cells treated with the caspase inhibitors Z-VAD-FMK, suggesting that p27kip1 enhancement at 48 h is strictly related to apoptosis. Finally, we demonstrated that SaOs-2 cells transiently overexpressing the p27kip1 protein are more susceptible to paclitaxel-induced apoptosis than SaOs-2 cells transiently transfected with the empty vector. Indeed, after 48 h of paclitaxel treatment, 41.8% of SaOs-2 cells transiently transfected with a pcDNA3-p27kip1 construct were Annexin V-positive compared to 30.6% of SaOs-2 cells transfected with the empty vector (P < 0.05). In conclusion, we demonstrated that transfection of the pRb-defective SaOs-2 cells with the p27kip1 gene via plasmid increases their susceptibility to paclitaxel-induced apoptosis. The promoting effect of p27kip1 overexpression on apoptosis makes p27kip1 and proteasomal inhibitors interesting tools for therapy in patients with pRb-defective cancers.

  12. Hyaluronic acid-coated liposomes for targeted delivery of paclitaxel, in-vitro characterization and in-vivo evaluation.

    PubMed

    Ravar, Fatemeh; Saadat, Ebrahim; Gholami, Mehdi; Dehghankelishadi, Pouya; Mahdavi, Mehdi; Azami, Samira; Dorkoosh, Farid A

    2016-05-10

    Breast cancer is the leading cause of cancer death in women. Chemotherapy is regarded as the most essential strategy in inhibiting the proliferation of tumor cells. Paclitaxel is a widely used taxane; however, the side effects of available Cremophor-based formulations and also the limitations of passive targeting uncovered an essential need to develop tumor-specific targeted nanocarriers. A hyaluronic acid targeted liposomal formulation of paclitaxel was prepared in which, hyaluronic acid was electrostatistically attracted to the surface of liposomes. Liposomes, had a particle size of 106.4±3.2nm, a weakly negative zeta potential of -9.7±0.8mV and an acceptable encapsulation efficiency of 92.1±1.7%. The release profile of liposomes in buffer showed that 95% of PTX was released during 40h. Confocal laser scanning microscopy and flow cytometry analysis showed the greater cellular internalization of coumarin-loaded liposomes compared to free coumarin. MTT assay on 4T1 and T47D cells demonstrated the stronger cytotoxic activity of liposomes in comparison to free paclitaxel. Cell cycle analysis showed that cells were mainly blocked at G2/M phases after 48h treatment with liposomes. In vivo real time imaging on 4T1 tumor-bearing mice revealed that the liposomal formulation mainly accumulated in the tumor area. Liposomes also had better antitumor efficacy against Cremophor-based formulation. In conclusion, hyaluronic acid targeted paclitaxel liposome can serve as a promising targeted formulation of paclitaxel for future cancer chemotherapy.

  13. SU2C Phase Ib Study of Paclitaxel and MK-2206 in Advanced Solid Tumors and Metastatic Breast Cancer

    PubMed Central

    Gonzalez-Angulo, Ana M.; Krop, Ian; Akcakanat, Argun; Chen, Huiqin; Liu, Shuying; Li, Yisheng; Culotta, Kirk S.; Tarco, Emily; Piha-Paul, Sarina; Moulder-Thompson, Stacy; Velez-Bravo, Vivianne; Sahin, Aysegul A.; Doyle, Laurence A.; Do, Kim-Anh; Winer, Eric P.; Mills, Gordon B.; Kurzrock, Razelle

    2015-01-01

    Background: There is preclinical synergism between taxanes and MK-2206. We aim to determine the maximum tolerated dose, safety, and activity of combining MK-2206 and paclitaxel in metastatic cancer. Methods: Patients received weekly doses of paclitaxel at 80mg/m2 on day 1, followed by MK-2206 orally on day 2 escalated at 90mg, 135mg, and 200mg. Treatment continued until progression, excessive toxicity, or patient request. Blood and tissue were collected for pharmacokinetic and pharmacodynamics markers. A cycle consisted of three weeks of therapy. Dose-limiting toxicity (DLT) was defined as unacceptable toxicity during the first cycle. All statistical tests were two-sided. Results: Twenty-two patients were treated, nine in dose escalation and 13 in dose expansion. Median age was 55 years. Median number of cycles was four. Dose escalation was completed with no DLT. CTCAE Grade 3 or higher adverse events were fatigue (n = 2), rash (n = 2), hyperglycemia (n = 1), and neutropenia (n = 7). Four patients in the expansion phase required MK-2206 dose reduction. Phase II recommended dose was established as paclitaxel 80mg/m2 weekly on day 1, and MK-2206 135mg weekly on day 2. Paclitaxel systemic exposure was similar in the presence or absence of MK-2206. Plasma MK-2206 concentrations were similar to data from previous phase I monotherapy. There was a statistically significant decrease in expression of pAKT S473 (P = .01) and pAKT T308 (P = .002) after therapy. PI3K/AKT/mTOR downregulation in tumor tissues and circulating markers did not correlate with tumor response or clinical benefit. There were five objective responses, and nine patients had stable disease. Conclusion: MK-2206 was well tolerated with paclitaxel. Preliminary antitumor activity was documented. PMID:25688104

  14. CYP2C8*3 predicts benefit/risk profile in breast cancer patients receiving neoadjuvant paclitaxel

    PubMed Central

    Motsinger-Reif, Alison A.; Drobish, Amy; Winham, Stacey J.; McLeod, Howard L.; Carey, Lisa A.; Dees, E. Claire

    2013-01-01

    Paclitaxel is one of the most frequently used chemotherapeutic agents for the treatment of breast cancer patients. Using a candidate gene approach, we hypothesized that polymorphisms in genes relevant to the metabolism and transport of paclitaxel are associated with treatment efficacy and toxicity. Patient and tumor characteristics and treatment outcomes were collected prospectively for breast cancer patients treated with paclitaxel-containing regimens in the neoadjuvant setting. Treatment response was measured before and after each phase of treatment by clinical tumor measurement and categorized according to RECIST criteria, while toxicity data were collected from physician notes. The primary endpoint was achievement of clinical complete response (cCR) and secondary endpoints included clinical response rate (complete response + partial response) and grade 3+ peripheral neuropathy. The genotypes and haplotypes assessed were CYP1B1*3, CYP2C8*3, CYP3A4*1B/CYP3A5*3C, and ABCB1*2. A total of 111 patients were included in this study. Overall, cCR was 30.1 % to the paclitaxel component. CYP2C8*3 carriers (23/111, 20.7 %) had higher rates of cCR (55 % vs. 23 %; OR = 3.92 [95 % CI: 1.46–10.48], corrected p = 0.046). In the secondary toxicity analysis, we observed a trend toward greater risk of severe neuropathy (22 % vs. 8 %; OR = 3.13 [95 % CI: 0.89–11.01], uncorrected p = 0.075) in subjects carrying the CYP2C8*3 variant. Other polymorphisms interrogated were not significantly associated with response or toxicity. Patients carrying CYP2C8*3 are more likely to achieve clinical complete response from neoadjuvant paclitaxel treatment, but may also be at increased risk of experiencing severe peripheral neurotoxicity. PMID:22527101

  15. A Genome-Wide Association Study Identifies Novel Loci for Paclitaxel-Induced Sensory Peripheral Neuropathy in CALGB 40101

    PubMed Central

    Baldwin, R. Michael; Owzar, Kouros; Zembutsu, Hitoshi; Chhibber, Aparna; Kubo, Michiaki; Jiang, Chen; Watson, Dorothy; Eclov, Rachel J.; Mefford, Joel; McLeod, Howard L.; Friedman, Paula N.; Hudis, Clifford A.; Winer, Eric P.; Jorgenson, Eric M.; Witte, John S.; Shulman, Lawrence N.; Nakamura, Yusuke; Ratain, Mark J.; Kroetz, Deanna L.

    2012-01-01

    Purpose Sensory peripheral neuropathy is a common and sometimes debilitating toxicity associated with paclitaxel therapy. This study aims to identify genetic risk factors for development of this toxicity. Experimental Design A prospective pharmacogenetic analysis of primary breast cancer patients randomized to the paclitaxel arm of CALGB 40101 was used to identify genetic predictors of the onset and severity of sensory peripheral neuropathy. A genome-wide association study in 855 subjects of European ancestry was performed and findings were replicated in additional European (n = 154) and African American (n = 117) subjects. Results A single nucleotide polymorphism in FGD4 was associated with the onset of sensory peripheral neuropathy in the discovery cohort (rs10771973; HR, 1.57; 95% CI, 1.30–1.91; P = 2.6 × 10−6) and in a European (HR, 1.72; 95% CI, 1.06–2.80; P = 0.013) and African American (HR, 1.93; 95% CI, 1.13-3.28; P = 6.7 × 10−3) replication cohort. There is also evidence that markers in additional genes, including EPHA5 (rs7349683) and FZD3 (rs10771973), were associated with the onset or severity of paclitaxel-induced sensory peripheral neuropathy. Conclusions A genome-wide association study has identified novel genetic markers of paclitaxel-induced sensory peripheral neuropathy, including a common polymorphism in FGD4, a congenital peripheral neuropathy gene. These findings suggest that genetic variation may contribute to variation in development of this toxicity. Validation of these findings may allow for the identification of patients at increased risk of peripheral neuropathy and inform the use of an alternative to paclitaxel and/or the clinical management of this toxicity. PMID:22843789

  16. Application of paclitaxel in low non-cytotoxic doses supports vaccination with melanoma antigens in normal mice.

    PubMed

    Sevko, Alexandra; Kremer, Veronika; Falk, Christine; Umansky, Ludmila; Shurin, Michael R; Shurin, Galina V; Umansky, Viktor

    2012-01-01

    Chemotherapeutic agents such as paclitaxel applied in ultra-low, non-cytotoxic doses were previously shown to stimulate dendritic cell activity and anti-tumor immune responses upon vaccination in mouse transplantable tumor models. However, the mechanisms of these alterations-termed chemoimmunomodulation or chemomodulation-are still not clear. This study investigated the effect of paclitaxel applied in ultra-low, non-cytotoxic doses on the efficiency of immunization of healthy C57BL/6 mice with the peptide derived from tyrosinase related protein (TRP)-2 as a model melanoma antigen. Using an IFNγ ELISPOT assay, it was found that administration of 1 mg paclitaxel/kg in combination with the peptide vaccination strongly increased the frequencies of TRP-2 specific spleen T-cells as compared to levels due to the vaccination alone. This was associated with a significant decrease in the levels of regulatory T-cells (T(reg)) and immature myeloid cells (known as a counterpart of myeloid derived suppressor cells [MDSC] in healthy mice). Such impairments of potential immunosuppressive cells were found to correlate with a strong increase in the amount of effector CD8+ and CD4+ T-cells in the bone marrow and spleen. Furthermore, in paclitaxel-treated mice, a significant augmentation of natural killer (NK) cell numbers in the bone marrow and their ability to produce IFNγ were observed. In addition, the level of NK-T-cells in the lymph nodes was also increased. It is suggested that paclitaxel applied in ultra-low, non-cytotoxic doses may potentially enhance the efficacy of anti-tumor vaccinations by neutralizing immunosuppressive T(reg) and MDSC populations in tumor-bearing hosts.

  17. A translation inhibitor identified in a Drosophila screen enhances the effect of ionizing radiation and taxol in mammalian models of cancer

    PubMed Central

    Gladstone, Mara; Frederick, Barbara; Zheng, Di; Edwards, Anthony; Yoon, Petros; Stickel, Stefanie; DeLaney, Tessie; Chan, Daniel C.; Raben, David; Su, Tin Tin

    2012-01-01

    SUMMARY We described previously a screening protocol in Drosophila melanogaster that allows us to identify small molecules that increase the killing effect of ionizing radiation in vivo in a multicellular context. The ability of this screen to identify agents that enhance the effect of radiation in human cancer models has been validated in published proof-of-concept studies. Here we describe an agent, identified by screening through two National Cancer Institute (NCI) small molecule libraries in Drosophila, that increases the effect of radiation. This agent, Bouvardin (NSC 259968), inhibits the elongation step of protein synthesis. We find that Bouvardin enhances the killing effect of X-rays in both Drosophila larvae and in human cancer cells. More detailed analysis showed that Bouvardin also increases the effect of radiation in clonogenic assays and in human cancer xenografts in mice. Finally, we present data that Bouvardin can also increase the efficacy of taxol. Regulation of translation is important to cancer biology. Current therapies target every aspect of cancer cell proliferation from growth factor signaling to cell division, with the exception of translation elongation. Our identification of Bouvardin as an enhancer of radio- and chemo-therapeutic agents suggests that targeting this niche has the potential to improve existing cancer therapies. PMID:22344740

  18. Involvement of nitric oxide in oxidative burst, phenylalanine ammonia-lyase activation and Taxol production induced by low-energy ultrasound in Taxus yunnanensis cell suspension cultures.

    PubMed

    Wang, Jian Wen; Zheng, Li Ping; Wu, Jian Yong; Tan, Ren Xiang

    2006-12-01

    This work was to characterize the generation of nitric oxide (NO) in Taxus yunnanensis cells exposed to low-energy ultrasound (US) and the signal role of NO in elicitation of plant defense responses and secondary metabolite accumulation. The US sonication (3.5-55.6 mW/cm(3) at 40 kHz fixed frequency) for 2 min induced a rapid and dose-dependent NO production in the Taxus cell culture, which exhibited a biphasic time course, reaching the first plateau within 1.5 h and the second within 7 h after US sonication. The NO donor sodium nitroprusside (SNP) potentiated US-induced H(2)O(2) production and cell death. Inhibition of nitric oxide synthase (NOS) activity by N(omega)-nitro-L-arginine (L-NNA) or scavenging NO by 2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxyde (PTIO) partially blocked the US-induced H(2)O(2) production and cell death. Moreover, the NO inhibitors suppressed US-induced activation of phenylalanine ammonium-lyase (PAL) and accumulation of diterpenoid taxanes (Taxol and baccatin III). These results suggest that NO plays a signal role in the US-induced responses and secondary metabolism activities in the Taxus cells.

  19. Succinyl-proteome profiling of a high taxol containing hybrid Taxus species (Taxus × media) revealed involvement of succinylation in multiple metabolic pathways

    PubMed Central

    Shen, Chenjia; Xue, Jie; Sun, Tao; Guo, Hong; Zhang, Lei; Meng, Yijun; Wang, Huizhong

    2016-01-01

    Protein lysine succinylation, a ubiquitous protein post-translational modification among eukaryotic and prokaryotic cells, represents a vital regulator of various metabolic processes. However, little is known about its functions and cellular distribution in Taxus × media, which is a hybrid Taxus species containing a high content of taxol. In this study, LC-MS/MS was used to identify peptides enriched by immune-purification with high-efficiency succinyl-lysine antibody. A total of 193 succinylated proteins and 325 succinylation sites were identified. The bioinformatics analysis indicated that these succinylated proteins were involved in a wide range of cellular functions from metabolism to protein binding and showed diverse subcellular localizations. Furthermore, our findings suggested that lysine succinylation in Taxus × media involved a diverse array of metabolic processes and protein–protein interactions. Many enzymes involved in multiple metabolic pathways, such as glycolysis, pyruvate metabolism, the tricarboxylic acid cycle and carbon fixation, were identified as substrates for lysine succinylation, suggesting the presence of a common mechanism underlying the participation of succinylation in metabolic regulation. These results provide the first comprehensive view of the succinylome of Taxus × media and may catalyze future biological investigation of succinylation. PMID:26902839

  20. First total synthesis of (5Z,9Z)-(±)-2-methoxy-5,9-octadecadienoic acid, a marine derived methoxylated analog of taxoleic acid

    PubMed Central

    Carballeira, Néstor M.; O’Neill, Rosann; Silva, Diana

    2008-01-01

    The first total synthesis for the sponge derived (5Z,9Z)-(±)-2-methoxy-5,9-octadecadienoic acid, an analog of taxoleic acid, was accomplished in seven steps and in a 10% overall yield. It was again corroborated that the best strategy to prepare these cis,cis dimethylene interrupted double bonds is the double-alkyne bromide coupling reaction of 1,5-hexadiyne, which provides the advantage of achieving a 100% cis stereochemical purity for both double bonds after hydrogenation under Lindlar conditions. The α-methoxy functionality was best prepared via the Mukaiyama reaction of (4Z,8Z)-heptadecadienal with trimethylsilyl cyanide and triethylamine followed by acid hydrolysis. Selective methylation of the hydroxyl group of (5Z,9Z)-(±)-2-hydroxy-5,9-octadecadienoic acid was achieved with sodium hydride/methyl iodide when tetrahydrofuran was used as solvent. Complete spectral data is presented, for the first time, for this unusual marine α-methoxylated fatty acid. PMID:18761005

  1. Paclitaxel plus valproic acid versus paclitaxel alone as second- or third-line therapy for advanced gastric cancer: a randomized Phase II trial

    PubMed Central

    Fushida, Sachio; Kinoshita, Jun; Kaji, Masahide; Oyama, Katsunobu; Hirono, Yasuo; Tsukada, Tomoya; Fujimura, Takashi; Ohta, Tetsuo

    2016-01-01

    Background Weekly paclitaxel (wPTX) is the preferred second-line chemotherapy for gastric cancer in Japan. Histone deacetylase inhibitors have been shown to decrease proliferation through cell-cycle arrest, differentiation, and apoptosis in gastric cancer cells. One histone deacetylase inhibitor, valproic acid (VPA), also inhibits tumor growth by inducing apoptosis and enhances the efficacy of paclitaxel (PTX), shown in a murine gastric cancer model. This Phase II trial was designed to evaluate the benefits of adding VPA to wPTX in patients with gastric cancer refractory to first-line treatment with fluoropyrimidine. Patients and methods The patients were randomly assigned in a 1:1 ratio to receive PTX 80 mg/m2 intravenously on days 1, 8, and 15, every 4 weeks, or a dose of PTX plus VPA taken everyday at 7.5 mg/kg twice daily. Random assignment was carried out at the data center with a minimization method adjusted by the Eastern Cooperative Oncology Group performance status (0–1 vs 2), prior chemotherapy (first-line vs second-line), and measurable lesions (presence vs absence). The primary end point was the overall survival (OS) rate, and the secondary end points were the progression-free survival rate and safety analysis. Results Sixty-six patients were randomly assigned to receive wPTX (n=33) or wPTX plus VPA (n=33). The median OS was 9.8 months in the wPTX group and 8.7 months in the wPTX plus VPA group (hazard ratio 1.19; 95% CI 0.702–2.026; P=0.51). The median progression-free survival was 4.5 months in the wPTX group and 3.0 months in the wPTX plus VPA group (hazard ratio 1.29; 95% CI 0.753–2.211; P=0.35). Grade 3–4 adverse events were neutropenia (3.1%), pneumonia (1.6%), liver injury (1.6%), brain infarction (1.6%), and rupture of aorta (1.6%). Conclusion No statistically significant difference was observed between wPTX and wPTX plus VPA for OS. PMID:27524882

  2. Enzymatic stability of 2'-ethylcarbonate-linked paclitaxel in serum and conversion to paclitaxel by rabbit liver carboxylesterase for use in prodrug/enzyme therapy.

    PubMed

    Tanino, Tadatoshi; Nawa, Akihiro; Miki, Yasuyoshi; Iwaki, Masahiro

    2008-07-01

    In prodrug/enzyme therapy for cancer, information on the sensitivity of hydrolytic enzymes to prodrug is required to reduce adverse effects of the parental drug and to find the activating enzyme. The aim of this study was to characterize the enzymatic stability of 2'-ethylcarbonate-linked paclitaxel (TAX-2'-Et) in the sera of several different species including humans. TAX-2'-Et disposition in serum was kinetically analysed using models with hydrolytic and/or degradation processes. To further evaluate the capability of liver carboxylesterases (CESs) in TAX-2'-Et hydrolysis, a CES isolated from rabbit liver (Ra-CES) was utilized as a model enzyme. Rat serum provided rapid enzymatic hydrolysis of TAX-2'-Et with a half-life of 4 min. The degradation of paclitaxel (TAX) (degradation rate constant, 0.16 h(-1)) was accompanied by the formation of an unknown compound. The conversion to TAX was almost completely inhibited by phenylmethyl sulfonylfluoride (PMSF) and bis(p-nitrophenyl) phosphate (BNPP). In human and rabbit sera, the degradation rate constant of TAX-2'-Et was 5.1 x 10(-2) and 0.15 h(-1), respectively, when excepting hydrolysis. The degradation products had the same molecular weight as TAX-2'-Et. The amount of TAX produced accounted for only 8-11% of the decrease in TAX-2'-Et after a 9 h exposure to rabbit or human serum. PMSF, but not BNPP, inhibited more than 90% of the TAX production in a 1.5 h incubation with human or rabbit serum. Ra-CES enzyme converted TAX-2'-Et to TAX with V(max) and K(m) of 74.7+/-13.8 nmol/min/mg protein and 8.8+/-2.8 microM, respectively. These results indicate that TAX-2'-Et is sensitive to serum CESs, but not cholinesterases. However, serum CESs show species-dependent hydrolysis of TAX-2'-Et. Although human serum allows the slow release of TAX, TAX-2'-Et is expected to reduce the side-effects of TAX. The Ra-CES enzyme is capable of hydrolysing TAX-2'-Et, which may be beneficial for the development of a TAX-2'-Et/enzyme therapy

  3. Is there a role of nab-paclitaxel in the treatment of advanced non-small cell lung cancer? The data suggest yes

    PubMed Central

    Villaruz, Liza C.; Socinski, Mark A.

    2016-01-01

    Nab-paclitaxel is a novel therapeutic agent, which was approved in combination with carboplatin in the first-line treatment of advanced non-small cell lung cancer (NSCLC) regardless of histologic subtype in the United States of America by the Food and Drug Administration in 2012 and by the European Commission in 2015. This approval was based on the results of a phase III clinical trial showing superior response rates compared with solvent-based paclitaxel in combination with carboplatin. This review will focus on the early development and clinical data to date supporting the use of nab-paclitaxel in advanced NSCLC. The clinical question central to this review is whether nab-paclitaxel has a place in the current therapeutic landscape of advanced NSCLC. PMID:26875112

  4. Rationally designed treatment for solid tumors with MAPK pathway activation: a Phase I study of paclitaxel and bortezomib using an adaptive dose-finding approach

    PubMed Central

    Mehnert, Janice M.; Tan, Antoinette R.; Moss, Rebecca; Poplin, Elizabeth; Stein, Mark N.; Sovak, Mika; Levinson, Kelly; Lin, Hongxia; Kane, Michael; Gounder, Murugesan; Lin, Yong; Shih, Weichung Joe; White, Eileen; Rubin, Eric H.; Karantza, Vassiliki

    2011-01-01

    In the preclinical setting, phosphorylation and subsequent proteosomal degradation of the proapoptotic protein BIM confers resistance to paclitaxel in solid tumors with RAS/RAF/MAPK pathway activation. Concurrent administration of the proteasome inhibitor bortezomib enables paclitaxel-induced BIM accumulation, restoring cancer cell apoptosis in vitro and producing tumor regression in mice in vivo. A Phase I study was conducted to determine the MTD of paclitaxel and bortezomib combinatorial treatment. Sixteen patients with refractory solid tumors commonly exhibiting MAPK pathway activation were treated with weekly paclitaxel and bortezomib. Starting doses were 40 mg/m2 for paclitaxel and 0.7 mg/m2 for bortezomib. A modified continual reassessment method (MCRM) adapted for 2-drug escalation was used for MTD determination with 3-patient cohorts treated at each dose level. MTD was reached at 60 mg/m2 paclitaxel and 1.0 mg/m2 bortezomib, the recommended phase II dose. Therapy was overall well tolerated. Most frequently observed toxicities included anemia (in 43.75% of patients, one Grade 3 event), fatigue (in 43.75% of patients, one Grade 3 event beyond cycle 1) and neuropathy (in 31.25% of patients, one Grade 3 event after cycle 1). Of 15 evaluable patients, one NSCLC patient with paclitaxel exposure at the adjuvant setting had a PR and five patients had SD; median disease stabilization was 143.5 days; three NSCLC patients had SD lasting 165 days or longer. Thus, rationally designed weekly treatment with paclitaxel and bortezomib in solid tumors with MAPK pathway activation, including previously taxane-treated malignancies, is a tolerable regimen with preliminary signals of antitumor activity worthy of further investigation. PMID:21680752

  5. Phase II multi-institutional prospective randomised trial comparing S-1+paclitaxel with S-1+cisplatin in patients with unresectable and/or recurrent advanced gastric cancer

    PubMed Central

    Mochiki, E; Ogata, K; Ohno, T; Toyomasu, Y; Haga, N; Fukai, Y; Aihara, R; Ando, H; Uchida, N; Asao, T; Kuwano, H

    2012-01-01

    Background: A combination of S-1 and cisplatin has been shown to be effective with acceptable safety for the first-line treatment of far-advanced gastric cancer in Japan. This is the first randomised phase II trial to compare S-1+paclitaxel with S-1+cisplatin in this setting. Methods: Patients with unresectable and/or recurrent advanced gastric cancer were randomly assigned to receive one of the two regimens: S-1 (40 mg m−2 twice daily) on days 1–14 plus paclitaxel (60 mg m−2) on days 1, 8, and 15 of a 4-week cycle (S-1+paclitaxel) or S-1 (40 mg m−2 twice daily) on days 1–21 plus cisplatin (60 mg m−2) on day 8 of a 5-week cycle (S-1+cisplatin). The primary end point was the response rate (RR). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety. Results: A total of 83 patients were eligible for safety and efficacy analyses. In the S-1+paclitaxel and S-1+cisplatin groups, RRs (52.3% vs 48.7% P=0.74) and median PFS (9 vs 6 months; P=0.50) were similar. The median OS was similar in the S-1+paclitaxel and S-1+cisplatin groups (16 vs 17 months; P=0.84). The incidence of grade 3 or higher haematological toxicity was 19.0% with S-1+paclitaxel and 19.5% with S-1+cisplatin. The incidence of grade 3 or higher non-haematological toxicity was 14.2% with S-1+paclitaxel and 17.1% with S-1+cisplatin. Conclusion: S-1+paclitaxel was suggested to be a feasible and effective non-platinum-based regimen for chemotherapy in patients with advanced gastric cancer. Our results should be confirmed in multicenter, phase III-controlled clinical trials. PMID:22617130

  6. Paclitaxel plus cisplatin vs. 5-fluorouracil plus cisplatin as first-line treatment for patients with advanced squamous cell esophageal cancer

    PubMed Central

    Liu, Ying; Ren, Zhonghai; Yuan, Long; Xu, Shuning; Yao, Zhihua; Qiao, Lei; Li, Ke

    2016-01-01

    Paclitaxel plus cisplatin and 5-fluorouracil plus cisplatin treatments are effective strategies for patients with advanced esophageal squamous cell carcinoma. This study was to evaluate the safety and efficacy of paclitaxel plus cisplatin and 5-fluorouracil plus cisplatin as first-line chemotherapy for patients with advanced esophageal squamous cell carcinoma. A total of 398 patients with advanced esophageal squamous cell carcinoma who received chemotherapy were included and divided into 2 groups: paclitaxel plus cisplatin group and 5-fluorouracil plus cisplatin group. 195 patients received paclitaxel plus cisplatin and 203 patients received 5-fluorouracil plus cisplatin. The objective response rates were 42.5% and 38.4% for paclitaxel plus cisplatin group and 5-fluorouracil plus cisplatin group, respectively (P=0.948). The median progression-free survival was 7.85 months (95% CI, 6.77-8.94 months) for the paclitaxel plus cisplatin group and 6.53 months (95% CI, 5.63-7.43 months) for the 5-fluorouracil plus cisplatin group with significant difference (P=0.02). The median overall survival was 13.46 months (95% CI, 12.01-14.91 months) for the paclitaxel plus cisplatin group and 12.67 months (95% CI, 11.87-13.47 months) for the 5-fluorouracil plus cisplatin group (P=0.204). The first-line chemotherapy of paclitaxel plus cisplatin had better median progression-free survival than 5-fluorouracil plus cisplatin in patients with advanced esophageal squamous cell carcinoma with tolerable toxicities. PMID:27822423

  7. Solid tumor penetration by integrin-mediated pegylated poly(trimethylene carbonate) nanoparticles loaded with paclitaxel.

    PubMed

    Jiang, Xinyi; Xin, Hongliang; Gu, Jijin; Xu, Ximing; Xia, Weiyi; Chen, Shuo; Xie, Yike; Chen, Liangcen; Chen, Yanzuo; Sha, Xianyi; Fang, Xiaoling

    2013-02-01

    Limited penetration of antineoplastic agents is one of the contributing factors for chemotherapy failure of many solid tumors. In order to enhance drug penetration into solid cancer, especially, into the avascular regions inside tumors, we proposed cyclic RGD peptide functionalized PEGylated poly(trimethylene carbonate) nanoparticles (c(RGDyK)-NP). By integrin-mediated transcytosis and enhanced drug permeation, c(RGDyK)-NP could access the neoplastic cells distant from blood vessels, and consequently, avoiding the capability of cancer regeneration from these tumor cells. In the present study, the solid tumor penetration, homing specificity and anticancer efficacy were evaluated both on the ex vivo 3D tumor spheroids and on the subcutaneous xenograft mice model. In comparison with conventional nanoparticles (NP/PTX) and Taxol, c(RGDyK)-NP/PTX showed the strongest penetration and accumulation into 3D tumor spheroids, a marked tumor-homing specificity in vivo and the greatest tumor growth inhibitory effect in vitro and in vivo. Histochemistry analysis revealed that no obvious histopathological abnormalities or lesions were observed in major organs after intravenous administration with the treatment doses. In conclusion, cyclic RGD peptide-conjugated PEG-PTMC nanoparticle could facilitate drug penetration and accumulation in tumor tissues and may be a promising vehicle for enhancing the chemotherapy of solid cancers.

  8. Overexpression of microRNA-24 increases the sensitivity to paclitaxel in drug-resistant breast carcinoma cell lines via targeting ABCB9

    PubMed Central

    Gong, Jian-Ping; Yang, Liu; Tang, Jun-Wei; Sun, Peng; Hu, Qing; Qin, Jian-Wei; Xu, Xiao-Ming; Sun, Bei-Cheng; Tang, Jin-Hai

    2016-01-01

    Paclitaxel has been widely used in the treatment of breast cancer. However, the development of drug resistance often increases the failure of chemotherapy. Growing evidence has reported the significant role of microRNAs (miRs) in drug resistance. The present study identified that miR-24 was significantly downregulated in paclitaxel-resistant (PR) breast cancer patients and in MCF-7/PR human breast carcinoma cells, and that overexpression of miR-24 could increase the effect of paclitaxel on drug-resistant breast carcinoma cells. Furthermore, miR-24 could directly bind to the 3′-untranslated region of ATP binding cassette B9 to downregulate its expression, thereby reducing drug transportation and improving the anti-tumor effect of paclitaxel