Sample records for paclitaxel taxol taxolreg

  1. Changes in radiation survival curve parameters in human tumor and rodent cells exposed to Paclitaxel (TAXOL) (Taxol[reg sign])

    SciTech Connect

    Liebmann, J.; Cook, J.A.; Fisher, J.; Teague, D.; Mitchell, J.B. (National Cancer Institute, Bethesda, MD (United States))

    1994-06-15

    Late G[sub 2] and M are the most radiosensitive phases of the cell cycle. Cells exposed to paclitaxel develop a cell cycle arrest in G[sub 2]/M. These studies were performed to assess the in vitro radiosensitization properties of paclitaxel in human tumor and rodent cell lines. The effect of paclitaxel on the radiation sensitivity of human breast (MCF-7), lung (A549), ovary (OVG-1) adenocarcinoma and Chinese hamster lung fibroblast V79 cells was determined with clonogenic assays. DNA flow cytometry studies were performed to define the cell cycle characteristics of the cells during irradiation. Survival curve parameters for all cell lines were determined with the use of a computer program which represents cell survival after radiation by a linear-quadratic model. All cell lines developed a G[sub 2]/M block after exposure to paclitaxel for 24 h. However, the degree of radiosensitization produced by paclitaxel varied among the cell lines. The maximal sensitizer enhancement ratio (SER) of paclitaxel was 1.8 in MCF-7 cells, 1.6 in OVG-1 cells, and 1.7 in V79 cells. However, no concentration of paclitaxel was able to enhance the radiation sensitivity of A549 cells. Paclitaxel increased the linear ([alpha]) component of the radiation survival curves in all cell lines. The quadratic ([beta]) component was unaffected by paclitaxel in the rodent cells. High concentrations of paclitaxel ([ge] 1000 nM) increased [beta] slightly in the human cell lines but there was considerable variation in the effect of paclitaxel on [beta]. The cells which were sensitized to radiation by paclitaxel had a relatively small baseline [alpha] component, while A549 cells had a large [alpha] component. The authors conclude that paclitaxel is a modest radiosensitizer in some, but not all, human tumor cells. Paclitaxel appears to cause radiosensitization mainly by increasing the [alpha] component of radiation survival curves. 16 refs., 3 figs., 2 tabs.

  2. Proliferation, migration and invasion of human glioma cells exposed to paclitaxel (Taxol) in vitro.

    PubMed Central

    Terzis, A. J.; Thorsen, F.; Heese, O.; Visted, T.; Bjerkvig, R.; Dahl, O.; Arnold, H.; Gundersen, G.

    1997-01-01

    Paclitaxel (Taxol), an anti-cancer drug derived from Taxus species, was tested for its anti-migrational, anti-invasive and anti-proliferative effect on two human glioma cell lines (GaMg and D-54Mg) grown as multicellular tumour spheroids. In addition, the direct effect of paclitaxel on glioma cells was studied using flow cytometry and scanning confocal microscopy. Both cell lines showed a dose-dependent growth and migratory response to paclitaxel. The GaMg cells were found to be 5-10 times more sensitive to paclitaxel than D-54Mg cells. Paclitaxel also proved to be remarkably effective in preventing invasion in a co-culture system in which tumour spheroids were confronted with fetal rat brain cell aggregates. Control experiments with Cremophor EL (the solvent of paclitaxel for clinical use) in this study showed no effect on tumour cell migration, cell proliferation or cell invasion. Scanning confocal microscopy of both cell lines showed an extensive random organization of the microtubules in the cytoplasm. After paclitaxel exposure, the GaMg and the D-54Mg cells exhibited a fragmentation of the nuclear material, indicating a possible induction of apoptosis. In line with this, flow cytometric DNA histograms showed an accumulation of cells in the G2/M phase of the cell cycle after 24 h of paclitaxel exposure. After 48 h, a deterioration of the DNA histograms was observed indicating nuclear fragmentation. Images Figure 3 Figure 6 PMID:9192976

  3. Electrochemical study of taxol (paclitaxel) by cathodic stripping voltammetry: determination in human urine

    Microsoft Academic Search

    T. Molina Holgado; M. C. Quintana; J. M. Pinilla

    2003-01-01

    An analytical method for the determination of taxol (paclitaxel) via cathodic stripping square wave voltammetry has been developed. The method allows to achieve a detection limit of 5.2 ngml?1 and a determination limit of 11.0 ngml?1 working with a mercury drop electrode in 0.05 M boric acid\\/borate buffer pH 9.0, previously accumulated at ?0.1 V (v.s. Ag\\/AgCl\\/KCl 3 M) for

  4. In vitro synergy of paclitaxel (Taxol) and vinorelbine (navelbine) against human melanoma cell lines

    Microsoft Academic Search

    A. Photiou; P. Shah; L. K. Leong; J. Moss; S. Retsas

    1997-01-01

    Paclitaxel (PTXL) (Taxol), a taxane, and vinorelbine (VRB), a semisynthetic vinca alkaloid drug, have tubulin as their common intracellular target, but inhibit growth by binding to different sites. We evaluated in vitro the antiproliferative activity of these two drugs as single agents and in combination, against two human melanoma cell lines, G361 and StM111a. The SRB (sulphorhodamine B) assay was

  5. A novel controlled release formulation for the anticancer drug paclitaxel (Taxol ®): PLGA nanoparticles containing vitamin E TPGS

    Microsoft Academic Search

    L Mu; S. S Feng

    2003-01-01

    Paclitaxel (Taxol®) is one of the best antineoplastic drugs found from nature in the past decades. Like many other anticancer drugs, there are difficulties in its clinical administration due to its poor solubility. Therefore an adjuvant called Cremophor EL has to be employed, but this has been found to cause serious side-effects. However, nanoparticles of biodegradable polymers can provide an

  6. Paclitaxel (Taxol) plus doxorubicin plus filgrastim in advanced sarcoma: a phase II study.

    PubMed

    Sandler, A; Fox, S; Meyers, T; Rougraff, B

    1998-06-01

    The authors evaluated the novel chemotherapeutic regimen of paclitaxel (Taxol, Bristol-Myers Squibb, Princeton, NJ, U.S.A.) plus doxorubicin plus filgrastim--a granulocyte colony-stimulating factor (G-CSF)--in advanced or metastatic sarcoma. Eligible patients must have had histologically confirmed advanced previously untreated soft-tissue sarcoma. All patients must have had bidimensionally measurable metastases. Treatment consisted of doxorubicin, 50 mg/m2 by intravenous push, followed 4 hours later by paclitaxel, 150 mg/m2 by continuous infusion over 24 hours every 3 weeks, plus G-CSF, 5 microg/kg, on days 3 through 12 of each cycle. Cycles were repeated every 21 days. A one-time dose escalation for doxorubicin only (60 mg/m2) was allowed in all patients who experienced no significant toxicity after their first cycle of paclitaxel plus doxorubicin. From November 1993 through May 1996, 29 patients were entered in this study. Grade 3 anemia occurred in three patients. Grade 3--4 neutropenia occurred in 20 patients. Seven patients experienced at least one episode of neutropenic fever, including one death. Grade 3 thrombocytopenia occurred in four patients. There were six partial responses in 27 eligible patients, for a response rate of 22.2% (95% confidence interval, 7%-38%). Median time to progression was 4.5 months, and median overall survival was 10.2 months. The regimen of paclitaxel plus doxorubicin plus filgrastim as used in this study appears to have no more activity than single-agent doxorubicin. PMID:9626789

  7. Induction of survivin expression by taxol (paclitaxel) is an early event, which is independent of taxol-mediated G2/M arrest.

    PubMed

    Ling, Xiang; Bernacki, Ralph J; Brattain, Michael G; Li, Fengzhi

    2004-04-01

    Survivin is a novel anti-apoptotic protein that is highly expressed in cancer but is undetectable in most normal adult tissues. It was reported that taxol-mediated mitotic arrest of cancer cells is associated with survivin induction, which preserves a survival pathway and results in resistance to taxol. In this study, we provide new evidence that induction of survivin by taxol is an early event and is independent of taxol-mediated G(2)/M arrest. Taxol treatment of MCF-7 cells rapidly up-regulated survivin expression (3.5-15-fold) within 4 h without G(2)/M arrest. Lengthening the treatment of cells (48 h) with taxol resulted in decreased survivin expression in comparison with early times following taxol treatment, although G(2)/M cells were significantly increased at later times. Interestingly, 3 nm taxol induces survivin as effectively as 300 nm and more effectively than 3000 nm. As a result, 3 nm taxol is ineffective at inducing cell death. However, inhibition of taxol-mediated survivin induction by small interfering RNA significantly increased taxol-mediated cell death. Taxol rapidly activated the phosphatidylinositol 3-kinase/Akt and MAPK pathways. Inhibition of these pathways diminished survivin induction and sensitized cells to taxol-mediated cell death. A cis-acting DNA element upstream of -1430 in the survivin pLuc-2840 construct is at least partially responsible for taxol-mediated survivin induction. Together, these data show, for the first time, that taxol-mediated induction of survivin is an early event and independent of taxol-mediated G(2)/M arrest. This appears to be a new mechanism for cancer cells to evade taxol-induced apoptosis. Targeting this survival pathway may result in novel approaches for cancer therapeutics. PMID:14722122

  8. Intraperitoneal delivery of a novel liposome-encapsulated paclitaxel redirects metabolic reprogramming and effectively inhibits cancer stem cells in Taxol®-resistant ovarian cancer

    PubMed Central

    Shen, Yao-An; Li, Wai-Hou; Chen, Po-Hung; He, Chun-Lin; Chang, Yen-Hou; Chuang, Chi-Mu

    2015-01-01

    Taxol® remained as the mainstay therapeutic agent in the treatment of ovarian cancer, however recurrence rate is still high. Cancer stem cells (CSCs) represent a subset of cells in the bulk of tumors and play a central role in inducing drug resistance and recurrence. Furthermore, cancer metabolism has been an area under intensive investigation, since accumulating evidence has shown that CSCs and cancer metabolism are closely linked, an effect named as metabolic reprogramming. In this work, we aimed to investigate the impacts of a novel liposome-encapsulated paclitaxel (Nano-Taxol) on the stemness phenotype and metabolic reprogramming. A paclitaxel-resistant cell line (TR) was established at first. Tumor growth was induced in the mice peritoneal cavity by inoculation of TR cells. A 2x2 factorial experiment was designed to test the therapeutic efficacy in which factor 1 represented the comparison of drugs (Taxol® versus Nano-Taxol), while factor 2 represented the delivery route (intravenous versus intraperitoneal delivery). In this work, we found that intraperitoneal delivery of Nano-Taxol redirects metabolic reprogramming, from glycolysis to oxidative phosphorylation, and effectively suppresses cancer stem cells. Also, intraperitoneal delivery of Nano-Taxol led to a significantly better control of tumor growth compared with intravenous delivery of Taxol® (current standard treatment). This translational research may serve as a novel pathway for the drug development of nanomedicine. In the future, this treatment modality may be extended to treat several relevant cancers that have been proved to be suitable for the loco-regional delivery of therapeutic agents, including colon cancer, gastric cancer, and pancreatic cancer. PMID:26175846

  9. Transcript: Taxol

    Cancer.gov

    Michael Grever, M.D., Former Associate Director, DTP: The story of Taxol is probably the National Cancer Institute in its finest hour. It was actually through the National Cancer Institute that this Natural Products work was supported, and Dr. Monroe

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

    Microsoft Academic Search

    L Mu; S. S Feng

    2002-01-01

    The d-?-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

  11. Interaction of Taxol with intravenous immunoglobulin: an inhibition of Taxol from crystallizing in aqueous solution.

    PubMed

    Liu, Yongchun; Yang, Zhengyin; Du, Juan; Yao, Xiaojun; Zheng, Xudong; Lei, Ruixia; Liu, Jianning; Hu, Huaisheng; Li, Hong

    2008-03-01

    The interaction of anti-cancer drug Taxol (paclitaxel) with human intravenous immunoglobulin (IVIG) was studied under simulated physiological conditions in vitro by spectroscopic methods including fluorescence spectra and Fourier transformation infrared (FT-IR) difference spectra. Docking was used to calculate the interaction modes between Taxol with IVIG. Transmission electron microscopy (TEM) experiments were carried out to investigate the formation of aggregate and crystal of Taxol in aqueous solution. The binding parameters were calculated according to the Sips procedure. The Taxol-IVIG complexes showed two types of binding with the average affinity constant of 1.776 x 10(4)+/-1.16 M(-1) (n=2, 296 K) and 0.7386 x 10(4)+/-1.18 M(-1) (n=4, 296 K). The molecules of Taxol were mainly located in CDR of Fab regions and Fc regions of IgG. The interaction of IVIG with Taxol was of non-specific and weak drug-protein binding, and it could inhibit Taxol from crystallizing in aqueous solution when the molar concentration ratio of Taxol to IVIG did not exceed 15:1. The content of secondary structure compositions of free IVIG and its Taxol complexes were calculated by the FT-IR difference spectra with its self-deconvolution, second derivative resolution enhancement and the curve-fitting procedures of amide I band. The observed FT-IR spectral changes indicated a partial unfolding of the protein structure in the presence of Taxol in aqueous solution. IVIG can serve as a transport protein (carrier) for Taxol. PMID:18279793

  12. Stabilized micelles as delivery vehicles for paclitaxel.

    PubMed

    Yoncheva, Krassimira; Calleja, Patricia; Agüeros, Maite; Petrov, Petar; Miladinova, Ivanka; Tsvetanov, Christo; Irache, Juan M

    2012-10-15

    Paclitaxel is an antineoplastic drug used against a variety of tumors, but its low aqueous solubility and active removal caused by P-glycoprotein in the intestinal cells hinder its oral administration. In our study, new type of stabilized Pluronic micelles were developed and evaluated as carriers for paclitaxel delivery via oral or intravenous route. The pre-stabilized micelles were loaded with paclitaxel by simple solvent/evaporation technique achieving high encapsulation efficiency of approximately 70%. Gastrointestinal transit of the developed micelles was evaluated by oral administration of rhodamine-labeled micelles in rats. Our results showed prolonged gastrointestinal residence of the marker encapsulated into micelles, compared to a solution containing free marker. Further, the oral administration of micelles in mice showed high area under curve of micellar paclitaxel (similar to the area of i.v. Taxol(®)), longer mean residence time (9-times longer than i.v. Taxol(®)) and high distribution volume (2-fold higher than i.v. Taxol(®)) indicating an efficient oral absorption of paclitaxel delivered by micelles. Intravenous administration of micelles also showed a significant improvement of pharmacokinetic parameters of micellar paclitaxel vs. Taxol(®), in particular higher area under curve (1.2-fold), 5-times longer mean residence time and lower clearance, indicating longer systemic circulation of the micelles. PMID:22721848

  13. Paclitaxel Arrests Growth of Intracellular Toxoplasma gondii

    Microsoft Academic Search

    RANDEE ESTES; NICOLAS VOGEL; DOUGLAS MACK; RIMA MCLEOD

    1998-01-01

    Addition of paclitaxel (Taxol) at a concentration of 1 m Mt oToxoplasma gondii-infected human foreskin fi- broblasts arrested parasite multiplication. Division of the T. gondii tachyzoite nucleus was inhibited, leading to syncytium-like parasite structures within the fibroblasts by 24 h after infection and treatment of the cultures. By 4 days after infection and treatment of the cultures with paclitaxel, this

  14. Quantitative determination of total and unbound paclitaxel in human plasma following Abraxane treatment

    Microsoft Academic Search

    Erin R. Gardner; William Dahut; William D. Figg

    2008-01-01

    A simple, rapid liquid chromatography\\/tandem mass spectrometric (LC–MS\\/MS) assay was developed and validated for the quantification of both unbound and total paclitaxel in plasma following treatment with Abraxane (ABI-007) or Taxol. Accurate and reproducible analysis of ABI-007, an albumin nanoparticle formulation of paclitaxel could not be achieved using previously published methodology designed for Taxol. The final validated method involved protein

  15. Increased intracellular cAMP renders HL-60 cells resistant to cytotoxicity of taxol.

    PubMed

    Pae, H O; Yoo, J C; Jun, C D; Paik, S G; Choi, B M; Baek, K H; Kim, J M; Chung, H T

    1999-05-01

    The treatment of advanced cancers with paclitaxel (taxol) is hindered by the development of drug resistance. Resistance to taxol is known to be associated with multidrug resistance (MDR) and a mutation affecting either the alpha- or beta-subunit of tubulin. In this study, we demonstrated that an intracellular cAMP level may also play an important role in resistance to taxol in HL-60, acute promyelocytic leukemia cells. Exposure of HL-60 cells to various doses of taxol for 18 hr resulted in cell death. However, pretreatment of the cells with cAMP analogs such as N6:O2-dibutyl cAMP (Db-cAMP), 8-(4-chlorophenylthio) cAMP (CPT-cAMP) and 8-bromo-cAMP (8-Br-cAMP) or an intracellular cAMP elevating agent such as forskolin apparently rendered HL-60 cells more resistant to taxol, but not with dimethyl sulfoxide (DMSO) or retinoic acid (RA), well known differentiating agents. To investigate whether protein kinase A (PKA) activated by an increase in intracellular cAMP level could be involved in increased taxol resistance of the cells, we examined the effects of PKA inhibitors, including H-89 and KT5720, on taxol resistance induced by Db-cAMP. The PKA inhibitors significantly abolished Db-cAMP-induced taxol resistance. These results suggest that cAMP analogs may render tumor cells more resistant to taxol via PKA activation. PMID:10319278

  16. Integrin-targeted paclitaxel nanoliposomes for tumor therapy.

    PubMed

    Meng, Shuyan; Su, Bo; Li, Wei; Ding, Yongmei; Tang, Liang; Zhou, Wei; Song, Yin; Caicun, Zhou

    2011-12-01

    A neovessel-targeted PEGylated liposomal formulation of paclitaxel was prepared with the purpose of improving the solubility of paclitaxel and specific targeting ability of this drug to tumor vasculature. AlphaV integrins overexpressed on the surface of new formed tumor vessels were selected to be the targets and their specific ligand, a 12-mer peptide containing a cyclic RGD sequence was used to achieve the goal. After coupled with a KGG-Palmitic acid conjugate, the RGD containing peptide was successfully integrated to the lipid bilayers. Mean particle size of the liposomes was under 100 nm and the drug entrapment efficiency was greater than 95%. Release study showed a much lower release rate of paclitaxel from liposomal formulation than from Cremophor EL-based formulation which indicated that this drug was stable in an entrapped form in vitro. Plasma distribution study showed that liposomal paclitaxel-treated groups obtained higher paclitaxel concentration than Taxol-treated group after 6 h injection. Greater cellular uptake was also found in the integrin-targeted liposomal paclitaxel-treated group compared with Taxol-treated group. Treatment of mice bearing A549 tumors with the integrin-targeted paclitaxel liposomes resulted in a lower tumor microvessel density than Taxol-treated group. Therefore, RGD-based strategy could be used to enhance tumor-specific recognition of nanocarriers. Neovessel-targeted PEGylated paclitaxel liposomes developed in present study might be a more promising drug for cancer treatment. PMID:20645030

  17. Paclitaxel Nano-Delivery Systems: A Comprehensive Review.

    PubMed

    Ma, Ping; Mumper, Russell J

    2013-02-18

    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

  18. Paclitaxel quantification in mouse plasma and tissues containing liposome-entrapped paclitaxel by liquid chromatography-tandem mass spectrometry: application to a pharmacokinetics study

    Microsoft Academic Search

    Wei Guo; Jenifer L. Johnson; Sumsullah Khan; Ateeq Ahmad; Imran Ahmad

    2005-01-01

    A liquid chromatography-tandem mass spectrometry assay to quantify total paclitaxel in mouse plasma and tissue homogenates containing paclitaxel, Taxol, or liposome-entrapped paclitaxel-easy to use (LEP-ETU) was developed and validated. Docetaxel was used as the internal standard (IS). Liquid–liquid extraction with tert-butyl methyl ether was used for plasma sample preparation, and a one-step protein precipitation with acetonitrile containing 0.1% acetic acid

  19. Paclitaxel-liposomes for intracavitary therapy of intraperitoneal P388 leukemia

    Microsoft Academic Search

    Amarnath Sharma; Uma S. Sharma; Robert M. Straubinger

    1996-01-01

    Paclitaxel, a recently approved antineoplastic agent, is cleared slowly from the peritoneal cavity after IP injection, and therefore appears to be promising for intracavitary therapy of malignancies confined to the peritoneal cavity. However the dose-limiting toxicity of Taxol®, the clinical formulation of paclitaxel, was severe abdominal pain, likely caused by the excipients (Cremophor EL® and ethanol) that are required to

  20. Synthesis of Paclitaxel. 2. Construction of the ABCD Ring and Formal Synthesis.

    PubMed

    Fukaya, Keisuke; Kodama, Keisuke; Tanaka, Yuta; Yamazaki, Hirohisa; Sugai, Tomoya; Yamaguchi, Yu; Watanabe, Ami; Oishi, Takeshi; Sato, Takaaki; Chida, Noritaka

    2015-06-01

    A formal synthesis of the antitumor diterpenoid paclitaxel (Taxol) is described. The ABC ring of paclitaxel, synthesized starting from 1,3-cyclohexanedione and tri-O-acetyl-d-glucal by SmI2-mediated cyclization as the key transformation, was successfully converted to Takahashi's tetracyclic oxetane intermediate. A double Chugaev reaction was employed for introduction of the strained bridgehead olefin, and stereoselective formation of the oxetane ring afforded the known synthetic intermediate, completing the formal synthesis of paclitaxel. PMID:26010999

  1. Paclitaxel effects on the proteome of HL60 promyelocytic leukemic cells: comparison to peloruside A

    Microsoft Academic Search

    Anja Wilmes; Ariane Chan; Pisana Rawson; T. William Jordan; John Holmes Miller

    Summary  Paclitaxel (Taxol®), a drug used to treat solid tumors of the breast, ovary and lung, stabilizes microtubules and arrests\\u000a cells in G2\\/M of the cell cycle. Using two-dimensional differential in-gel electrophoresis (DIGE), we examined the proteomic response\\u000a of a human HL-60 promyeloid leukemic cell line to paclitaxel. Our intention was to compare the effects of paclitaxel to those\\u000a of a

  2. Randomly methylated ?-cyclodextrin derivatives enhance taxol permeability through human intestinal epithelial Caco-2 cell monolayer.

    PubMed

    Fenyvesi, Ferenc; Kiss, Tímea; Fenyvesi, Eva; Szente, Lajos; Veszelka, Szilvia; Deli, Mária A; Váradi, Judit; Fehér, Pálma; Ujhelyi, Zoltán; Tósaki, Arpád; Vecsernyés, Miklós; Bácskay, Ildikó

    2011-11-01

    Intestinal absorption and bioavailability of taxol are limited by its low solubility and P-glycoprotein (Pgp) activity. Methylated ?-cyclodextrins (CDs) effectively form complexes with paclitaxel but randomly methylated ?-cyclodextrin (RAMEB) is cytotoxic in high concentrations. Second-generation derivatives containing monoamino (MaRAMEB) and succinylated (SuRAMEB) ionic substituents with similar inclusion capacity but less toxicity could be promising alternatives of RAMEB. Our aim was to examine and compare the efficacy of MaRAMEB and SuRAMEB with the parental RAMEB on taxol bidirectional permeability using the Caco-2 model. Taxol permeability was not changed by 30-min pretreatment with CDs. In co-treatment with ?-cyclodextrins, the apical to basolateral taxol flux was 4 to 6 times greater than in untreated monolayers and it was also higher than in cells treated with Pgp inhibitor cyclosporin A. No decrease in basolateral to apical taxol flux was observed in pretreatment or co-treatment with CDs, suggesting no Pgp inhibition. All three CDs showed similar effects on taxol permeability but RAMEB altered tight junction protein distribution and significantly decreased transepithelial electrical resistance. None of the CDs modified paracellular permeability to mannitol and polyethylene glycol 4000. In conclusion, second-generation derivatives of methyl-?-cyclodextrin, especially MaRAMEB, enhanced taxol permeability across Caco-2 cells with less toxicity and similar effectiveness as RAMEB. PMID:21660974

  3. MiR-634 sensitizes nasopharyngeal carcinoma cells to paclitaxel and inhibits cell growth both in vitro and in vivo

    PubMed Central

    Peng, Xiaowei; Cao, Peiguo; He, Dong; Han, Shuang; Zhou, Jianda; Tan, Guolin; Li, Wei; Yu, Fenghui; Yu, Jianjun; Li, Zan; Cao, Ke

    2014-01-01

    Resistance to chemotherapy is one of the key causal factors in cancer death and increasing evidence has revealed that microRNAs (miRNAs) are involved in chemoresistance in many kinds of human cancers. Paclitaxel has been used for treatment of advanced nasopharyngeal carcinoma (NPC); however, treatment failure often occurs due to development of acquired paclitaxel resistance. In this study, based on miRNA microarray screening and qRT-PCR validation, we found six differentially expressed miRNAs in our induced paclitaxel-resistant NPC CNE-1/Taxol cells. Furthermore, we clarified the role of miR-634, most significantly downregulated in the paclitaxel-resistant CNE-1/Taxol, in regulating the paclitaxel sensitivity in NPC cells. We restored miR-634 expression in the CNE-1/Taxol cells by lentivirus infection, and found restoration of miR-634 re-sensitized the CNE-1/Taxol cells to paclitaxel in vitro by MTT assay and colony formation assay. In xenograft mouse model, we found that miR-634 inhibited tumor growth and enhanced paclitaxel sensitivity. Thus, our findings provide important information for the development of targeted gene therapy for reversing paclitaxel resistance in NPC. PMID:25400759

  4. Cutaneous manifestations of Taxol therapy.

    PubMed

    Link, C J; Sarosy, G A; Kohn, E C; Christian, M C; Davis, P; Adamo, D O; Reed, E

    1995-01-01

    Taxol is a novel chemotherapeutic agent that has produced substantial responses in early clinical studies [1]. Taxol has excellent activity in a number of malignancies based on recently completed clinical trials, including a 30% response rate in platinum-refractory ovarian cancer patients [2-5]. We are currently conducting trials of dose-intense taxol with granulocyte colony stimulating factor (G-CSF) support in relapsed or refractory ovarian cancer patients. Such dose intensification produces a major response rate in 50% of patients with this disease [6]. Taxol was supplied in 5 ml ampules (6 mg/ml) in polyethoxylated castor oil (Cremophor EL) 50% and dehydrated alcohol and the dose was diluted in either 0.9% sodium chloride or 5% dextrose at concentrations of 0.6 to 1.2 mg/ml. We have noted 3 patients with previously unreported cutaneous manifestations which we believe are taxol related and also report our overall complication rate with the administration of taxol by peripheral intravenous lines. PMID:8729957

  5. Diversity of endophytic fungi and screening of fungal paclitaxel producer from Anglojap yew, Taxus x media

    PubMed Central

    2013-01-01

    Background Endophytic fungi represent underexplored resource of novel lead compounds and have a capacity to produce diverse class of plant secondary metabolites. Here we investigated endophytic fungi diversity and screening of paclitaxel-producing fungi from Taxus x media. Results Eighty-one endophytic fungi isolated from T. media were grouped into 8 genera based on the morphological and molecular identification. Guignardia and Colletotrichum were the dominant genera, whereas the remaining genera were infrequent groups. The genera Glomerella and Gibberella were first reported in Taxus. Three representative species of the distinct genera gave positive hits by molecular marker screening and were capable of producing taxol which were validated by HPLC-MS. Among these 3 taxol-producing fungi, the highest yield of taxol was 720 ng/l by Guignardia mangiferae HAA11 compared with those of Fusarium proliferatum HBA29 (240 ng/l) and Colletotrichum gloeosporioides TA67 (120 ng/l). This is the first report of taxol producer from Guignardia. Moreover, the lower similarities of ts and bapt between microbial and plant origin suggested that fungal taxol biosynthetic cluster might be repeatedly invented during evolution, nor horizontal gene transfer from Taxus species. Conclusions Taxol-producing endophytic fungi could be a fascinating reservoir to generate taxol-related drug lead and to elucidate the remained 5 unknown genes or the potential regulation mechanism in the taxol biosynthesis pathway. PMID:23537181

  6. Investigation of the release behavior of DEHP from infusion sets by paclitaxel-loaded polymeric micelles.

    PubMed

    Kim, Sung Chul; Yoon, Hye Jeong; Lee, Jang Won; Yu, Jaewon; Park, Eun-Seok; Chi, Sang-Cheol

    2005-04-11

    The current clinical formulation of paclitaxel (Taxol) contains 1:1 blend of Cremophor EL (polyethoxylated castor oil) and dehydrated ethanol. Cremophor EL and dehydrated ethanol are well known to leach di-(2-ethylhexyl) phthalate (DEHP) from polyvinyl chloride (PVC) infusion bags and PVC administration sets. DEHP is a possible hepatotoxin, carcinogen, teratogen and mutagen. Long-term exposure to DEHP may cause health risks. As an alternative formulation for paclitaxel, paclitaxel-loaded polymeric micelles (PLPM), made of monomethoxy poly(ethylene glycol)-block-poly(d,l-lactide) (mPEG-PDLLA) diblock copolymer, has demonstrated clear advantages over Taxol in pharmacokinetics and therapeutic index. Paclitaxel in either PLPM or Taxol formulations, diluted in 0.9% sodium chloride injection, was stable in the PVC infusion bags. The PLPM formulation significantly reduced the amount of DEHP extracted from PVC infusion bags and PVC administration sets. For PLPM diluted in 0.9% sodium chloride injection, the total amount of DEHP delivered over the simulated infusion period was 0.7 mg for 3h and 2.0 mg for 24 h, which was less than 2.9% of the DEHP extracted by Taxol. These results confirmed that there is negligible risk of DEHP exposure from diluted PLPM i.v. infusion using PVC infusion bags and PVC administration sets. PMID:15778068

  7. In vivo evaluation of polymeric micellar paclitaxel formulation: toxicity and efficacy.

    PubMed

    Kim, S C; Kim, D W; Shim, Y H; Bang, J S; Oh, H S; Wan Kim, S; Seo, M H

    2001-05-14

    Although the current clinical formulation of paclitaxel (Taxol) has a promising clinical activity against a wide variety of tumors, it has significant toxic side effects, some of which are associated with its formulation in a 1:1 (v/v) mixture of Cremophor EL and dehydrated alcohol. One of the problems associated with the intravenous administration of paclitaxel is its low solubility in water. Our study was designed to evaluate the pharmacokinetics, tissue distribution, toxicity and efficacy of a paclitaxel (Genexol)-containing biodegradable polymeric micellar system (Genexol-PM) in comparison to Taxol. Genexol-PM was newly developed by using a low molecular weight, nontoxic and biodegradable amphiphilic diblock copolymer, monomethoxy poly(ethylene glycol)-block-poly(D,L-lactide) (mPEG-PDLLA) and paclitaxel (Genexol, Samyang Genex Co., Seoul, Korea). In a human cancer cell line model, Genexol-PM and Taxol showed comparable in vitro cytotoxicity against human ovarian cancer cell line OVCAR-3 and human breast cancer cell line MCF7. The maximum tolerated dose (MTD) of Genexol-PM and Taxol in nude mice was determined to be 60 and 20 mg/kg, respectively. The median lethal dose (LD(50)) in Sprague--Dawley rats was 205.4 mg/kg (male) and 221.6 mg/kg (female) for Genexol-PM, while 8.3 mg/kg (male) and 8.8 mg/kg (female) for Taxol. After intravenous administration of Genexol-PM in murine B16 melanoma-induced female SPF C57BL/6 mice at a dose of 50 mg/kg, the area under the plasma concentration-time curve (AUC) was similar to Taxol((R)) at a dose of 20 mg/kg, but biodistribution of paclitaxel after administration of Genexol-PM showed 2 to 3-fold higher levels in tissues including liver, spleen, kidneys, lungs, heart and tumor as compared to Taxol. The in vivo antitumor efficacy of Genexol-PM as measured by reduction in tumor volume of SKOV-3 human ovarian cancer implanted in nude (nu/nu) athymic mice and MX-1 human breast cancer implanted in Tac:Cr:(NCr)-nu athymic mice was significantly greater than that of Taxol. The results of cytotoxicity, MTD, LD(50) and antitumor efficacy suggest that Genexol-PM may have a great advantage over present-day chemotherapy with Taxol. PMID:11389998

  8. Alterations in Ovarian Cancer Cell Adhesion Drive Taxol Resistance by Increasing Microtubule Dynamics in a FAK-dependent Manner.

    PubMed

    McGrail, Daniel J; Khambhati, Niti N; Qi, Mark X; Patel, Krishan S; Ravikumar, Nithin; Brandenburg, Chandler P; Dawson, Michelle R

    2015-01-01

    Chemorefractory ovarian cancer patients show extremely poor prognosis. Microtubule-stabilizing Taxol (paclitaxel) is a first-line treatment against ovarian cancer. Despite the close interplay between microtubules and cell adhesion, it remains unknown if chemoresistance alters the way cells adhere to their extracellular environment, a process critical for cancer metastasis. To investigate this, we isolated Taxol-resistant populations of OVCAR3 and SKOV3 ovarian cancer cell lines. Though Taxol-resistant cells neither effluxed more drug nor gained resistance to other chemotherapeutics, they did display increased microtubule dynamics. These changes in microtubule dynamics coincided with faster attachment rates and decreased adhesion strength, which correlated with increased surface ?1-integrin expression and decreased focal adhesion formation, respectively. Adhesion strength correlated best with Taxol-sensitivity, and was found to be independent of microtubule polymerization but dependent on focal adhesion kinase (FAK), which was up-regulated in Taxol-resistant cells. FAK inhibition also decreased microtubule dynamics to equal levels in both populations, indicating alterations in adhesive signaling are up-stream of microtubule dynamics. Taken together, this work demonstrates that Taxol-resistance dramatically alters how ovarian cancer cells adhere to their extracellular environment causing down-stream increases in microtubule dynamics, providing a therapeutic target that may improve prognosis by not only recovering drug sensitivity, but also decreasing metastasis. PMID:25886093

  9. Inhibition of Paclitaxel-induced Decreases in Calcium Signaling*

    PubMed Central

    Benbow, Jennifer H.; Mann, Taylor; Keeler, Camille; Fan, Chengpeng; Hodsdon, Michael E.; Lolis, Elias; DeGray, Brenda; Ehrlich, Barbara E.

    2012-01-01

    Peripheral neuropathy is one of the most severe and irreversible side effects caused by treatment from several chemotherapeutic drugs, including paclitaxel (Taxol®) and vincristine. Strategies are needed that inhibit this unwanted side effect without altering the chemotherapeutic action of these drugs. We previously identified two proteins in the cellular pathway that lead to Taxol-induced peripheral neuropathy, neuronal calcium sensor-1 (NCS-1) and calpain. Prolonged treatment with Taxol induces activation of calpain, degradation of NCS-1, and loss of intracellular calcium signaling. This paper has focused on understanding the molecular basis for prevention of peripheral neuropathy by testing the effects of addition of two candidate compounds to the existing chemotherapeutic drug regime: lithium and ibudilast. We found that the co-administration of either lithium or ibudilast to neuroblastoma cells that were treated with Taxol or vincristine inhibited activation of calpain and the reductions in NCS-1 levels and calcium signaling associated with these chemotherapeutic drugs. The ability of Taxol to alter microtubule formation was unchanged by the addition of either candidate compound. These results allow us to suggest that it is possible to prevent the unnecessary and irreversible damage caused by chemotherapeutic drugs while still maintaining therapeutic efficacy. Specifically, the addition of either lithium or ibudilast to existing chemotherapy treatment protocols has the potential to prevent chemotherapy-induced peripheral neuropathy. PMID:22988235

  10. Phase II study of paclitaxel (Taxol ®) and ifosfamide (Holoxan ®) in inoperable non-small-cell lung cancer 1 This paper was presented at the 8th World Conference on Lung Cancer, Dublin, Ireland, August 10–15, 1997. Abstract no. 78. 1

    Microsoft Academic Search

    Sumitra Thongprasert

    1998-01-01

    A total of 27 patients with advanced previously untreated non-small-cell lung cancer were treated with paclitaxel and ifosfamide. The starting dose of paclitaxel was 175 mg\\/m2 given for 3 h by intravenous infusion on day 1. Ifosfamide 4 g\\/m2 was given for 4 h by intravenous infusion on day 2. Dosage of the two drugs was modified according to nadir

  11. [Mucopenetrating nanoparticles: vehicles for the oral administration of paclitaxel].

    PubMed

    Zabaleta, V; Calleja, P; Espuelas, S; Corrales, L; Pío, R; Agüeros, M; Irache, J M

    2013-03-01

    Paclitaxel is an anticancer drug used as solution for perfusion for the treatment of certain types of cancers. In the last years, a number of strategies have been proposed for the development of an oral formulation of this drug. However, this task is quite complicated due to the poor aqueous solubility of paclitaxel as well as the fact that this compound is substrate of the intestinal P-glycoprotein and the cytochrome P450 enzymatic complex. In this work, we have developed pegylated nanoparticles with mucopenetrating properties in order to conduct paclitaxel onto the surface of the enterocyte. These nanoparticles displayed a size of about 180 nm and a drug loading close to 15% by weight. The pharmacokinetic study in mice has shown that these nanoparticles were capable to offer therapeutic plasma levels of paclitaxel up to 72 hours. In addition, the oral relative bioavailability of paclitaxel when loaded in nanoparticles pegylated with poly(ethylene glycol) 2000 (PEG) was found to be 85%. In a subcutaneous model of tumour in mice, these pegylated nanoparticles administered orally every 3 days have demonstrated a similar efficacy than Taxol® administered intravenously every day during 9 days. All of these results suggested that these pegylated nanoparticles were capable to cross the mucus layer of the gut and, then, reach the surface of the enterocytes. The PEG molecules would facilitate the adhesion of nanoparticles to this epithelial surface, minimise the pre-systemic metabolism of paclitaxel and, thus, promote its absorption. PMID:23537412

  12. Taxol binds to polymerized tubulin in vitro

    Microsoft Academic Search

    JEROME PARNESS; SUSAN BAND HORWITZ

    1981-01-01

    Taxol, a natural plant product that enhances the rate and extent of microtubule assembly in vitro and stabilizes microtubules in vitro and in cells, was labeled with tritium by catalytic exchange with 3H20. The binding of (3H)taxol to microtubule protein was studied by a sedimentation assay . Microtubules assembled in the presence of (3H)taxol bind drug specif- ically with an

  13. Paclitaxel induces calcium oscillations via an inositol 1,4,5-trisphosphate receptor and neuronal calcium sensor 1-dependent mechanism

    PubMed Central

    Boehmerle, Wolfgang; Splittgerber, Ute; Lazarus, Michael B.; McKenzie, Kathleen M.; Johnston, David G.; Austin, David J.; Ehrlich, Barbara E.

    2006-01-01

    Taxol (Paclitaxel) is an important natural product for the treatment of solid tumors. Despite a well documented tubulin-stabilizing effect, many side effects of taxol therapy cannot be explained by cytoskeletal mechanisms. In the present study submicromolar concentrations of taxol, mimicking concentrations found in patients, induced cytosolic calcium (Ca2+) oscillations in a human neuronal cell line. These oscillations were independent of extracellular and mitochondrial Ca2+ but dependent on intact signaling via the phosphoinositide signaling pathway. We identified a taxol binding protein, neuronal Ca2+ sensor 1 (NCS-1), a Ca2+ binding protein that interacts with the inositol 1,4,5-trisphosphate receptor from a human brain cDNA phage display library. Taxol increased binding of NCS-1 to the inositol 1,4,5-trisphosphate receptor. Short hairpin RNA-mediated knockdown of NCS-1 in the same cell line abrogated the response to taxol but not to other agonists stimulating the phosphoinositide signaling pathway. These findings are important for studies involving taxol as a research tool in cell biology and may help to devise new strategies for the management of side effects induced by taxol therapy. PMID:17114292

  14. Free paclitaxel loaded PEGylated-paclitaxel nanoparticles: preparation and comparison with other paclitaxel systems in vitro and in vivo.

    PubMed

    Lu, Jingkai; Chuan, Xingxing; Zhang, Hua; Dai, Wenbing; Wang, Xinglin; Wang, Xueqing; Zhang, Qiang

    2014-08-25

    Previously, PEGylated paclitaxel (PEG-PTX) was found not favorable as a polymer prodrug because of its poor antitumor efficiency. But surprisingly, it was found in our study that PEG-PTX could form a novel nanoparticle system with free PTX. To address how this system works, we compared PTX loaded PEG-PTX nanoparticles (PEG-PTX/PTX) with PTX loaded PEG-PLA micelles (PEG-PLA/PTX) or PTX injection available (Taxol(®)) in vitro and in vivo. Firstly, it was found that PEG-PTX/PTX was more stable in aqueous solution than PEG-PLA/PTX in terms of PTX crystal formation and drug release. Then it was demonstrated that coumarin loaded PEG-PTX nanoparticles had a much higher uptake in MCF-7 cells compared to coumarin loaded PEG-PLA micelles. The in vivo imaging study revealed that DIR or DID (near infrared fluorescent substances) loaded PEG-PTX nanoparticles distributed more in tumors in MCF-7 tumor bearing mice than DIR or DID loaded PEG-PLA micelles and solvent system of Taxol(®). In the efficacy study with MCF-7 tumor bearing mice, PEG-PTX/PTX showed significantly higher antitumor activity than PEG-PLA/PTX at the same PTX dosage. At the dose of 10mg free PTX per kg, PEG-PTX/PTX displayed similar efficacy as Taxol(®) but less toxicity evaluated by the loss of body weight. With the increase of free PTX to 15 mg/kg, PEG-PTX/PTX showed significantly better efficacy than Taxol(®). In conclusion, with favorable characteristics in stability, cellular uptake, cytotoxicity, biodistribution, safety and efficacy, PEG-PTX/PTX seems highly potential as a nanocarrier for PTX delivery. PMID:24858391

  15. Taxol biosynthesis and molecular genetics

    PubMed Central

    Croteau, Rodney; Ketchum, Raymond E. B.; Long, Robert M.; Kaspera, Rüdiger; Wildung, Mark R.

    2010-01-01

    Biosynthesis of the anticancer drug Taxol in Taxus (yew) species involves 19 steps from the universal diterpenoid progenitor geranylgeranyl diphosphate derived by the plastidial methyl erythritol phosphate pathway for isoprenoid precursor supply. Following the committed cyclization to the taxane skeleton, eight cytochrome P450-mediated oxygenations, three CoA-dependent acyl/aroyl transfers, an oxidation at C9, and oxetane (D-ring) formation yield the intermediate baccatin III, to which the functionally important C13-side chain is appended in five additional steps. To gain further insight about Taxol biosynthesis relevant to the improved production of this drug, and to draw inferences about the organization, regulation, and origins of this complex natural product pathway, Taxus suspension cells (induced for taxoid biosynthesis by methyl jasmonate) were used for feeding studies, as the foundation for cell-free enzymology and as the source of transcripts for cDNA library construction and a variety of cloning strategies. This approach has led to the elucidation of early and late pathway segments, the isolation and characterization of over half of the pathway enzymes and their corresponding genes, and the identification of candidate cDNAs for the remaining pathway steps, and it has provided many promising targets for genetically engineering more efficient biosynthetic production of Taxol and its precursors. PMID:20622989

  16. Effect of Gabapentin and Pregabalin in Rat Model of Taxol Induced Neuropathic Pain

    PubMed Central

    Rameshkannan, S.; Ali, R. Meher

    2015-01-01

    Background Chemotherapy induced neuropathy pain remains as a major dose limiting side effect of many commonly used chemotherapeutic drugs. Presently newer antiepileptic agents have been developed with improved safety and tolerability profiles in alleviating neuropathic pain. Objectives To evaluate the effect of Gabapentin and Pregabalin in Paclitaxel (Taxol) induced neuropathic pain and to compare the effect of these drugs in animal models. Materials and Methods Rats were randomly divided into four groups of six animals each. Group 1- vehicle, Group 2 – Paclitaxel (2mg/kg), Group 3 - Gabapentin (60mg/kg) with Paclitaxel, Group 4 - Pregabalin (30mg/kg) with Paclitaxel. Pain was induced by intraperitoneal injection of Paclitaxel on four alternate days. After taking the baseline values, the drugs treated groups (group 3 and 4) were administered with respective drugs once a day orally for eight consecutive days along with paclitaxel. All the animals were tested for thermal hyperalgesia and cold allodynia on day 0, 7, 14, 21 and 28 with Radiant heat method and Tail immersion test, Acetone drop method respectively. Results In Radiant heat method, gabapentin and pregabalin treated animals found to have significant increase in the tail latency period compared to control and paclitaxel treated groups in all periods of observation. Acetone drop test and tail immersion test also showed significant response similar to Radiant heat method. Pregabalin showed highly significant effect when compared to gabapentin group. Conclusion Both gabapentin and pregabalin produced significant anti-hyperalgesic and anti-allodynic effects in experimental animal models. Pregabalin treated group showed highly significant effect compared to gabapentin treated animals. PMID:26155495

  17. 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. PMID:19762199

  18. Characterization, pharmacokinetics and disposition of novel nanoscale preparations of paclitaxel.

    PubMed

    Wang, Cheng; Wang, Yingjing; Wang, Yujun; Fan, Min; Luo, Feng; Qian, Zhiyong

    2011-07-29

    Polymeric nanoparticles (NPs) have great potential application in achieving targeted delivery of anticancer drugs. Paclitaxel (PTX) loaded NPs were developed using biodegradable methoxy poly (ethylene glycol)-poly (?-caprolactone) (MPEG-PCL) diblock copolymer by solid dispersion technique without toxic organic solvent. The lyophilized powder has been stored at room temperature for more than six months and still unchanged. PTX-loaded MPEG-PCL nanoparticles (PTX-NPs) displayed that the highest drug loading of PTX was about 25.6% and entrapment efficiency was over 98%, and the optimized average diameter and polydispersity index (PDI) were about 27.6 ± 0.1 nm and 0.05, respectively. Moreover, experimental results shown PTX-NPs had sustained-release effects and its curve fitting followed the Higuchi model. The maximum tolerated dose (MTD) of PTX-NPs after single dose in Balb/c mice was above 80 mg PTX/kg body weight (b.w), which was 2.6-fold higher than that of Taxol(®) (30 mg PTX/kg b.w). The levels of PTX administrated PTX-NPs had obvious distinction to Taxol(®) in plasma, liver, spleen, kidneys, lungs, heart and tumor. Especially, the concentration of PTX in tumor administrated PTX-NPs was higher than administration of Taxol(®). All results suggested that we had contrived a simple, biodegradable, effective and controllable drug delivery system for paclitaxel. PMID:21596124

  19. Silencing of glutaminase 1 resensitizes Taxol-resistant breast cancer cells to Taxol.

    PubMed

    Fu, Aiqin; Yu, Ze; Song, Yaobo; Zhang, Enning

    2015-06-01

    Taxol is a front?line chemotherapeutic agent for the treatment of patients with multiple types of tumor. However, resistance to Taxol remains one of the principal causes of cancer?associated mortality. Glutamine, which is metabolized via a glutaminase (GLS)?dependent process, termed glutaminolysis, is important in cell growth and metabolism. The present study reported a novel mechanism underlying Taxol resistance in breast cancer cells. By investigating the glutamine metabolism of breast cancer cells in response to treatment with Taxol in vitro, it was observed that Taxol induced the uptake of glutamine and the expression of GLS1. Notably, Taxol?resistant cancer cells exhibited upregulation in the metabolism of glutamine and expression of GLS1. In addition, overexpression of GLS1 rendered cancer cells resistant to Taxol, indicating that GLS1 may be the therapeutic target for overcoming Taxol resistance in clinical therapeutics. The results also demonstrated that knock?down of GLS1 using small interfering RNA, resensitized the Taxol?resistant breast cancer cells to Taxol. PMID:25625774

  20. In vitro and in vivo studies on vitamin E TPGS-emulsified poly( d, l-lactic- co-glycolic acid) nanoparticles for paclitaxel formulation

    Microsoft Academic Search

    Khin Yin Win; Si-Shen Feng

    2006-01-01

    This work shows a full spectrum of research on Vitamin E TPGS-emulsified Poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) for paclitaxel formulation to improve its therapeutic index and to reduce the adverse effects of adjuvant Cremophor EL in its current clinical formulation of Taxol®. Paclitaxel-loaded PLGA NPs were prepared by a modified solvent extraction\\/evaporation technique with vitamin E TPGS as emulsifier. The

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

    PubMed Central

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

    1998-01-01

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

  2. Tau induces cooperative Taxol binding to microtubules

    PubMed Central

    Ross, Jennifer L.; Santangelo, Christian D.; Makrides, Victoria; Fygenson, D. Kuchnir

    2004-01-01

    Taxol and tau are two ligands that stabilize the microtubule (MT) lattice. Taxol is an anti-mitotic drug that binds ? tubulin in the MT interior. Tau is a MT-associated protein that binds both ? and ? tubulin on the MT exterior. Both Taxol and tau reduce MT dynamics and promote tubulin polymerization. Tau alone also acts to bundle, stiffen, and space MTs. A structural study recently suggested that Taxol and tau may interact by binding to the same site. Using fluorescence recovery after photobleaching, we find that tau induces Taxol to bind MTs cooperatively depending on the tau concentration. We develop a model that correctly fits the data in the absence of tau, yields the equilibrium dissociation constant of ?2 ?M, and determines the escape rate of Taxol through one pore to be 1.7 × 103 (M·s)–1. Extension of the model yields a measure of Taxol cooperativity with a Hill coefficient of at least 15 when tau is present at a 1:1 molar ratio with tubulin. PMID:15326286

  3. Quantitative determination of total and unbound paclitaxel in human plasma following Abraxane treatment.

    PubMed

    Gardner, Erin R; Dahut, William; Figg, William D

    2008-02-01

    A simple, rapid liquid chromatography/tandem mass spectrometric (LC-MS/MS) assay was developed and validated for the quantification of both unbound and total paclitaxel in plasma following treatment with Abraxane (ABI-007) or Taxol. Accurate and reproducible analysis of ABI-007, an albumin nanoparticle formulation of paclitaxel could not be achieved using previously published methodology designed for Taxol. The final validated method involved protein precipitation followed by vacuum filtration, in a 96-well format for rapid processing. The 4min run employed gradient elution on a Waters SymmetryShield C8 (2.1mmx50mm, 3.5microm) column, followed by tandem mass spectrometric detection, in electrospray positive mode. Calibrator samples were prepared daily with paclitaxel and analyzed with both ABI-007 and paclitaxel quality control samples. To measure unbound drug, sample preparation was preceded by ultrafiltration. The assay was linear over the range of 10-2500ng/mL, with dilution providing measurement up to 50,000ng/mL. Within-run and between-run precision for all QC samples was less than 5.0% and 10.4%, respectively. Accuracy was high, with deviation of less than 6.1% for all QCs. Measurement of unbound paclitaxel was precise (BRP and WRP <10%). PMID:18191625

  4. Characterization and detection of cellular and proteomic alterations in stable stathmin-overexpressing, taxol-resistant BT549 breast cancer cells using offgel IEF/PAGE difference gel electrophoresis

    PubMed Central

    Balasubramani, Manimalha; Nakao, Chitose; Uechi, Guy T.; Cardamone, John; Kamath, Kathy; Leslie, Kristen L.; Balachandran, Raghavan; Wilson, Leslie; Day, Billy W.; Jordan, Mary Ann

    2010-01-01

    Stathmin/oncoprotein 18, a protein that regulates microtubule dynamics, is highly expressed in a number of tumors including leukemia, lymphoma, neuroblastoma, breast, ovarian, and prostate cancers. High stathmin levels have been associated with the development of resistance to the widely-used anticancer drug taxolTaxol, paclitaxel). The mechanisms of stathmin-mediated taxol resistance are not well-understood at the molecular level. To better understand the role of stathmin in taxol resistance, we stably overexpressed stathmin two-fold in BT549 human breast cancer cells and characterized several cell processes involved in the mechanism of action of taxol. After stable overexpression of stathmin, neither the cell doubling time nor the mitotic index was altered and the microtubule polymer mass was reduced only modestly (by 18%). Unexpectedly, microtubule dynamicity was reduced by 29% after stathmin overexpression, resulting primarily from reduction in the catastrophe frequency. Sensitivity to taxol was reduced significantly (by 44%) in a clonogenic assay, and stathmin appeared to protect the cells from the spindle-damaging effects of taxol. The results suggest that in the stably-stathmin overexpressing clones, compensatory gene expression occurred that resulted in normal rates of cell proliferation and prevented the increase in catastrophe frequency expected in response to stathmin. Stathmin overexpression protected the cells from taxol-induced abnormal mitoses, and thus induced taxol resistance. Using offgel IEF/PAGE difference gel electrophoresis, we identified a number of proteins whose expression is reduced in the taxol-resistant stathmin-overexpressing cell lines, including proteins involved in the cytoskeleton and cell structure, the stress response, protein folding, glycolysis, and catalysis. PMID:20816848

  5. Carboplatin and paclitaxol (Taxol) as an induction regimen for patients with biopsy-proven stage IIIA N2 non-small cell lung cancer

    Microsoft Academic Search

    M. E. R O'Brien; T Splinter; E. F Smit; B Biesma; M Krzakowski; V. C. G Tjan-Heijnen; A Van Bochove; J Stigt; M. J. A Smid-Geirnaerdt; C Debruyne; C Legrand; G Giaccone

    2003-01-01

    The aim of this study was to document the activity and toxicity of paclitaxel (Taxol)\\/carboplatin when used as induction chemotherapy in patients with stage IIIA N2 non-small cell lung cancer (NSCLC) prior to definitive local treatment within a large, ongoing comparative study (EORTC 08941). 52 eligible, consenting, chemotherapy-na??ve patients with NSCLC, median age of 60 years, stage IIIA N2 disease

  6. Studies on Taxol® Biosynthesis. Preparation and Tritium Labeling of Biosynthetic intermediates by Deoxygenation of a Taxadiene Tetra-acetate Obtained from Japanese Yew

    PubMed Central

    Horiguchi, Tohru; Rithner, Christopher D.; Croteau, Rodney; Williams, Robert M.

    2010-01-01

    SUMMARY Taxa-4(20),11(12)-diene-5?-acetate 5 and Taxa-4(20), 11(12)-diene-5?-acetate, 10?-ol 6, have been identified as early stage intermediates involved in the biosynthesis of Taxol® (paclitaxel). Tritium-labeled 5 and 6 were successfully prepared by Barton deoxygenation using tri-n-butyltintritiide of the C-14-hydroxyl group of a taxoid obtained from Japanese Yew. PMID:20221307

  7. [Nab-paclitaxel].

    PubMed

    Lopez-Trabada Ataz, Daniel; Dumont, Sarah; André, Thierry

    2015-06-01

    Paclitaxel is conventionally used in a wide range of oncology indications. Nab-paclitaxel is synthesized by a process of high pressure homogenization of paclitaxel in the presence of human albumin and it was originally developed to reduce the toxicity usually associated with cremophor in soluble paclitaxel and to increase its penetration in tumor tissues. After the trials that led to its approval in first-line treatment of metastatic pancreatic carcinomas and in second line therapy for metastatic breast cancer, nab-paclitaxel is being tested for many other situations in oncology due to its profile of security and its good tolerance. Different lines of research are being developed about the possible biomarkers that could predict the effect of nab-paclitaxel. This review summarizes the results of trials that led to the approval of the nab-paclitaxel in advanced breast cancer and pancreatic cancer, and also resumes the lines of research to the future development of the drug. PMID:26008630

  8. The Early Stages of Taxol Biosynthesis: An Interim Report on the Synthesis and Identification of Early Pathway Metabolites

    PubMed Central

    Guerra-Bubb, Jennifer; Croteau, Rodney; Williams, Robert M.

    2012-01-01

    The biosynthesis of the anti-cancer drug taxol (paclitaxel) has required the collaborative efforts of several research groups to tackle the synthesis and labeling of putative biosynthetic intermediates, in concert with the identification, cloning and functional expression of the biosynthetic genes responsible for the construction of this complex natural product. Based on a combination of precursor labeling and incorporation experiments, and metabolite isolation from Taxus spp., a picture of the complex matrix of pathway oxygenation reactions following formation of the first committed intermediate, taxa-4(5),11(12)-diene, is beginning to emerge. An overview of the current state of knowledge on the early-stages of taxol biosynthesis is presented. PMID:22547034

  9. A thermosensitive chitosan-based hydrogel for the local delivery of paclitaxel.

    PubMed

    Ruel-Gariépy, Eve; Shive, Matthew; Bichara, Ali; Berrada, Mohammed; Le Garrec, Dorothée; Chenite, Abdellatif; Leroux, Jean-Christophe

    2004-01-01

    A novel injectable thermosensitive in situ gelling hydrogel has been developed. The system, which falls under the BST-Gel platform technology developed at Biosyntech Inc. (Laval, QC, Canada), consists of a chitosan solution (C) neutralized with beta-glycerophosphate (GP) that is liquid at room temperature but gels when heated to body temperature. We propose to use this thermosensitive hydrogel for the sustained release of paclitaxel at tumor resection sites in order to prevent local tumor recurrence. The in vitro release profiles demonstrated controlled delivery over 1 month. The initial drug loading substantially affected the release. Local delivery of paclitaxel from the formulation injected intratumorally was investigated using EMT-6 tumors implanted subcutaneously on Balb/c mice. These experiments showed that one intratumoral injection of the thermosensitive hydrogel containing paclitaxel was as efficacious as four intravenous injections of Taxol in inhibiting the growth of EMT-6 cancer cells in mice, but in a less toxic manner. Further histological analysis revealed that while the proportion of necrotic areas was similar for the C/GP/paclitaxel and the Taxol-treated tumors, a disparity between tumor-associated inflammatory cell populations may suggest differing anti-tumor mechanisms. PMID:14729080

  10. Bioavailability enhancement of paclitaxel via a novel oral drug delivery system: paclitaxel-loaded glycyrrhizic acid micelles.

    PubMed

    Yang, Fu-Heng; Zhang, Qing; Liang, Qian-Ying; Wang, Sheng-Qi; Zhao, Bo-Xin; Wang, Ya-Tian; Cai, Yun; Li, Guo-Feng

    2015-01-01

    Paclitaxel (PTX, taxol), a classical antitumor drug against a wide range of tumors, shows poor oral bioavailability. In order to improve the oral bioavailability of PTX, glycyrrhizic acid (GA) was used as the carrier in this study. This was the first report on the preparation, characterization and the pharmacokinetic study in rats of PTX-loaded GA micelles The PTX-loaded micelles, prepared with ultrasonic dispersion method, displayed small particle sizes and spherical shapes. Differential scanning calorimeter (DSC) thermograms indicated that PTX was entrapped in the GA micelles and existed as an amorphous state. The encapsulation efficiency was about 90%, and the drug loading rate could reach up to 7.90%. PTX-loaded GA micelles displayed a delayed drug release compared to Taxol in the in vitro release experiment. In pharmacokinetic study via oral administration, the area under the plasma concentration-time curve (AUC0?24 h) of PTX-loaded GA micelles was about six times higher than that of Taxol (p < 0.05). The significant oral absorption enhancement of PTX from PTX-loaded GA micelles could be largely due to the increased absorption in jejunum and colon intestine. All these results suggested that GA would be a promising carrier for the oral delivery of PTX. PMID:25756651

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

    PubMed

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

    2015-07-01

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

  12. Differential microRNA expression signatures and cell type-specific association with Taxol resistance in ovarian cancer cells

    PubMed Central

    Kim, Yong-Wan; Kim, Eun Young; Jeon, Doin; Liu, Juinn-Lin; Kim, Helena Suhyun; Choi, Jin Woo; Ahn, Woong Shick

    2014-01-01

    Paclitaxel (Taxol) resistance remains a major obstacle for the successful treatment of ovarian cancer. MicroRNAs (miRNAs) have oncogenic and tumor suppressor activity and are associated with poor prognosis phenotypes. miRNA screenings for this drug resistance are needed to estimate the prognosis of the disease and find better drug targets. miRNAs that were differentially expressed in Taxol-resistant ovarian cancer cells, compared with Taxol-sensitive cells, were screened by Illumina Human MicroRNA Expression BeadChips. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to identify target genes of selected miRNAs. Kaplan–Meier survival analysis was applied to identify dysregulated miRNAs in ovarian cancer patients using data from The Cancer Genome Atlas. A total of 82 miRNAs were identified in ovarian carcinoma cells compared to normal ovarian cells. miR-141, miR-106a, miR-200c, miR-96, and miR-378 were overexpressed, and miR-411, miR-432, miR-494, miR-409-3p, and miR-655 were underexpressed in ovarian cancer cells. Seventeen miRNAs were overexpressed in Taxol-resistant cells, including miR-663, miR-622, and HS_188. Underexpressed miRNAs in Taxol-sensitive cells included miR-497, miR-187, miR-195, and miR-107. We further showed miR-663 and miR-622 as significant prognosis markers of the chemo-resistant patient group. In particular, the downregulation of the two miRNAs was associated with better survival, perhaps increasing the sensitivity of cancer cells to Taxol. In the chemo-sensitive patient group, only miR-647 could be a prognosis marker. These miRNAs inhibit several interacting genes of p53 networks, especially in TUOS-3 and TUOS-4, and showed cell line-specific inhibition effects. Taken together, the data indicate that the three miRNAs are closely associated with Taxol resistance and potentially better prognosis factors. Our results suggest that these miRNAs were successfully and reliably identified and would be used in the development of miRNA therapies in treating ovarian cancer. PMID:24591819

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

    PubMed

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

    2013-07-01

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

  14. Proapoptotic miltefosine nanovesicles show synergism with paclitaxel: Implications for glioblastoma multiforme therapy.

    PubMed

    Thakur, Ankita; Joshi, Nitin; Shanmugam, Thanigaivel; Banerjee, Rinti

    2013-07-01

    Hexadecylphosphocholine (HePC) or miltefosine based proapoptotic lipid nanovesicles encapsulating paclitaxel for synergistic anticancer effect of paclitaxel and miltefosine in chemoresistant human glioblastoma multiforme (U-87 MG) overexpressing multidrug resistance 1 (MDR1) gene product P-glycoprotein (P-gp), were developed in this study. The nanovesicles had 100-200nm size and a negative zeta potential (?-25mV) and optimized for miltefosine content based on their physiochemical properties. With a high encapsulation efficiency of 94%, the nanovesicles showed sustained release of paclitaxel in nasal fluid and triggered release in the cerebrospinal fluid. Synergistic action of paclitaxel and miltefosine was observed with a low IC50 of 162±5nM. The nanovesicle also overcame drug resistance and showed ATP dependent uptake via clathrin mediated pathway in glioblastoma cells. An improved therapeutic efficacy in comparison to Taxol®, the current clinical formulation of paclitaxel was observed. Efficient brain uptake of the nanovesicles upon intranasal administration was observed in vivo and the nanovesicles were also found to be able to cross blood brain barrier. These studies therefore suggest the therapeutic potential of proapoptotic lipid nanovesicles and their feasibility for intranasal administration in the treatment of chemoresistant glioblastoma. PMID:22935677

  15. A phase II study of paclitaxel by weekly 1-h infusion for advanced or recurrent esophageal cancer in patients who had previously received platinum-based chemotherapy

    Microsoft Academic Search

    Ken Kato; Makoto Tahara; Shuichi Hironaka; Kei Muro; Hiroya Takiuchi; Yasuo Hamamoto; Haruhiko Imamoto; Norihito Amano; Taku Seriu

    2011-01-01

    Purpose  To evaluate the efficacy and safety of weekly paclitaxel (Taxol®) in patients with advanced or recurrent esophageal cancer.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  Fifty-three patients with recurrent or advanced esophageal cancer who had previously received platinum-based chemotherapy\\u000a were treated with paclitaxel 100 mg\\/m2 once weekly by 1-h infusion on days 1, 8, 15, 22, 29, and 36 of a 49-day cycle. Fifty-two patients were evaluable for

  16. Increased spinal cord Na?-K?-2Cl? cotransporter-1 (NKCC1) activity contributes to impairment of synaptic inhibition in paclitaxel-induced neuropathic pain.

    PubMed

    Chen, Shao-Rui; Zhu, Lihong; Chen, Hong; Wen, Lei; Laumet, Geoffroy; Pan, Hui-Lin

    2014-11-01

    Microtubule-stabilizing agents, such as paclitaxel (Taxol), are effective chemotherapy drugs for treating many cancers, and painful neuropathy is a major dose-limiting adverse effect. Cation-chloride cotransporters, such as Na(+)-K(+)-2Cl(-) cotransporter-1 (NKCC1) and K(+)-Cl(-) cotransporter-2 (KCC2), critically influence spinal synaptic inhibition by regulating intracellular chloride concentrations. Here we show that paclitaxel treatment in rats significantly reduced GABA-induced membrane hyperpolarization and caused a depolarizing shift in GABA reversal potential of dorsal horn neurons. However, paclitaxel had no significant effect on AMPA or NMDA receptor-mediated glutamatergic input from primary afferents to dorsal horn neurons. Paclitaxel treatment significantly increased protein levels, but not mRNA levels, of NKCC1 in spinal cords. Inhibition of NKCC1 with bumetanide reversed the paclitaxel effect on GABA-mediated hyperpolarization and GABA reversal potentials. Also, intrathecal bumetanide significantly attenuated hyperalgesia and allodynia induced by paclitaxel. Co-immunoprecipitation revealed that NKCC1 interacted with ?-tubulin and ?-actin in spinal cords. Remarkably, paclitaxel increased NKCC1 protein levels at the plasma membrane and reduced NKCC1 levels in the cytosol of spinal cords. In contrast, treatment with an actin-stabilizing agent had no significant effect on NKCC1 protein levels in the plasma membrane or cytosolic fractions of spinal cords. In addition, inhibition of the motor protein dynein blocked paclitaxel-induced subcellular redistribution of NKCC1, whereas inhibition of kinesin-5 mimicked the paclitaxel effect. Our findings suggest that increased NKCC1 activity contributes to diminished spinal synaptic inhibition and neuropathic pain caused by paclitaxel. Paclitaxel disrupts intracellular NKCC1 trafficking by interfering with microtubule dynamics and associated motor proteins. PMID:25253692

  17. Preclinical Evaluation of Genexol-PM, a Nanoparticle Formulation of Paclitaxel, as a Novel Radiosensitizer for the Treatment of Non-Small Cell Lung Cancer

    PubMed Central

    Sethi, Manish; Wang, Edina C.; Sukumar, Rohit; Moore, Dominic T.; Wang, Andrew Z.

    2013-01-01

    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 postad-ministration. 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. PMID:23708084

  18. Taxol from Pestalotiopsis microspora, an endophytic fungus of Taxus wallachiana

    Microsoft Academic Search

    Gary Strobel; Xianshu Yang; Joe Sears; Robert Kramer; Rajinder S. Sidhu; W. M. Hess

    1996-01-01

    weeks in still culture at 23 OC. (I4C)Acetate and (14C)phenylalanine served as precursors for fungal (14C)taxol. These observations on P. micmspora are discussed in relation to the biological importance of taxol production by fungi in general.

  19. Transcriptional Profiling of Targets for Combination Therapy of Lung Carcinoma with Paclitaxel and Mitogen-activated Protein\\/Extracellular Signal-regulated Kinase Kinase Inhibitor1

    Microsoft Academic Search

    Debra J. Taxman; Jeffrey P. MacKeigan; Casey Clements; Daniel T. Bergstralh

    2003-01-01

    A combination of paclitaxel (Taxol) and mitogen-activated protein\\/ extracellular signal-regulated kinase kinase (MEK\\/Erk) inhibitor repre- sents a rational new approach to chemotherapy. We performed Af- fymetrix microarray analysis to understand the global effects of this combination in lung carcinoma. Genes involved in cell cycle control, apoptosis, adhesion, proliferation, invasion, and metastasis were modu- lated. We observed similar patterns of gene

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

    PubMed

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

    2014-12-30

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

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

    PubMed

    Koot, Dwayne; Cromarty, Duncan

    2015-06-01

    Contemporary chemotherapy is limited by disseminated, resistant cancer. Targeting nanoparticulate drug delivery systems that encapsulate synergistic drug combinations are a rational means to increase the therapeutic index of chemotherapeutics. A lipopolymeric micelle co-encapsulating an in vitro optimized, synergistic fixed-ratio combination of paclitaxel (PTX) and clofazimine (B663) has been developed and called Riminocelles™. The present pre-clinical study investigated the acute toxicity, systemic exposure, repeat dose toxicity and efficacy of Riminocelles in parallel to Taxol® at an equivalent PTX dose of 10 mg/kg. Daily and weekly dosing schedules were evaluated against Pgp-expressing human colon adenocarcinoma (HCT-15) xenografts implanted subcutaneously in athymic mice. Riminocelles produced statistically significant (p Taxol delaying growth by 0.5 and 0.6 days. Using the control tumor doubling time of 4.2 days, tumor-cell-kill values of 0.23 for Riminocelles and 0.04 for Taxol following daily schedules were calculated. A significant weight loss of 5.7% after 14 days (p < 0.05) relative to the control group (n = 8) was observed for the daily Taxol group whereas Riminocelles did not incur significant weight loss neither were blood markers of toxicity elevated after acute administration (n = 3). The safety and efficacy of Riminocelles is statistically superior to Taxol. However, passive tumor targeting was not achieved and the tumor burden progressed quickly. Prior to further animal studies, the in vivo thermodynamic instability of the simple lipopolymeric micellular delivery system requires improvement so as to maintain and selectively deliver the fixed-ratio drug combination. PMID:25795051

  2. 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

  3. 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 186.8nm and a zeta potential (ZP) of -6.87mV. The PTX content in PTXNS was approximately 3.42%. Moreover, the residual amount of chloroform was lower than the International Conference on Harmonization limit (60ppm) 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. PMID:26027492

  4. Oral administration of paclitaxel with pegylated poly(anhydride) nanoparticles: permeability and pharmacokinetic study.

    PubMed

    Zabaleta, Virginia; Ponchel, Gilles; Salman, Hesham; Agüeros, Maite; Vauthier, Christine; Irache, Juan M

    2012-08-01

    The aim of this work was to study the potential of pegylated poly(anhydride) nanoparticles as carriers for the oral delivery of paclitaxel (PTX). Paclitaxel is an anticancer drug, ascribed to the class IV of the Biopharmaceutical Classification system, characterised for its low aqueous solubility and to act as a substrate of the P-glycoprotein and cytochrome P450. For the pegylation of nanoparticles, three different poly(ethylene glycol) (PEG) were used: PEG 2000 (PTX-NP2), PEG 6000 (PTX-NP6) and PEG 10,000 (PTX-NP10). The transport and permeability of paclitaxel through the jejunum mucosa of rats was determined in Ussing chambers, whereas its oral bioavailability was studied in rats. The loading of PTX in pegylated nanoparticles increased between 3 and 7 times the intestinal permeability of paclitaxel through the jejunum compared with the commercial formulation Taxol. Interestingly, the permeability of PTX was significantly higher for PTX-NP2 and PTX-NP6 than for PTX-NP10. In the in vivo studies, similar results were obtained. When PTX-NP2 and PTX-NP6 were administered to rats by the oral route, sustained and therapeutic plasma levels of paclitaxel for at least 48 h were observed. The relative oral bioavailability of paclitaxel delivered in nanoparticles was calculated to be 70% for PTX-NP2, 40% for PTX-NP6 and 16% in case of PTX-NP10. All of these observations would be related with both the bioadhesive properties of these carriers and the inhibitory effect of PEG on the activity of both P-gp and P450 cytochrome. PMID:22516136

  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. Silencing of Taxol-Sensitizer Genes in Cancer Cells: Lack of Sensitization Effects

    PubMed Central

    Huang, Shang-Lang; Chao, Chuck C.-K.

    2015-01-01

    A previous genome-wide screening analysis identified a panel of genes that sensitize the human non-small-cell lung carcinoma cell line NCI-H1155 to taxol. However, whether the identified genes sensitize other cancer cells to taxol has not been examined. Here, we silenced the taxol-sensitizer genes identified (acrbp, atp6v0d2, fgd4, hs6st2, psma6, and tubgcp2) in nine other cancer cell types (including lung, cervical, ovarian, and hepatocellular carcinoma cell lines) that showed reduced cell viability in the presence of a sub-lethal concentration of taxol. Surprisingly, none of the genes studied increased sensitivity to taxol in the tested panel of cell lines. As observed in H1155 cells, SKOV3 cells displayed induction of five of the six genes studied in response to a cell killing dose of taxol. The other cell types were much less responsive to taxol. Notably, four of the five inducible taxol-sensitizer genes tested (acrbp, atp6v0d2, psma6, and tubgcp2) were upregulated in a taxol-resistant ovarian cancer cell line. These results indicate that the previously identified taxol-sensitizer loci are not conserved genetic targets involved in inhibiting cell proliferation in response to taxol. Our findings also suggest that regulation of taxol-sensitizer genes by taxol may be critical for acquired cell resistance to the drug. PMID:26086592

  7. Microtubule Changes and Cytotoxicity in Leukemic Cell Lines Treated with Taxol1

    Microsoft Academic Search

    Eric K. Rowinsky; Ross C. Donehower; J Jones; Robert W. Tucker

    1988-01-01

    Taxol, a diterpenoid plant product that enhances the polymerization of tubulin, is currently entering clinical trials in the treatment of human leukemia. In order to develop an in vitro assay to predict tumor sensitivity to taxol, human leukemic cell lines were exposed to clinically achievable concentrations of taxol for relevant exposure periods. Changes in micro- tubules visualized by indirect immunofluorescencewere

  8. 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

  9. 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-?-Gal (senescence-associated ?-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-?-Gal, a senescence testing kit, indicating that the form of taxol-induced cell death is not senescence.

  10. 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 ?g/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. PMID:23801250

  11. Paclitaxel and carboplatin in recurrent or metastatic head and neck cancer: a phase II study.

    PubMed

    Fountzilas, G; Athanassiadis, A; Samantas, E; Skarlos, D; Kalogera-Fountzila, A; Nikolaou, A; Bacoyiannis, H; Stathopoulos, G; Kosmidis, P; Daniilidis, J

    1997-02-01

    Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) appears to be one of the most active drugs in the treatment of advanced head and neck cancer. The maximum tolerated dose of paclitaxel in combination with carboplatin is currently being evaluated in phase I/II studies. We designed a phase II study to evaluate the activity and acute and cumulative toxicity of this combination in patients with recurrent or metastatic cancer of the head and neck. Chemotherapy consisted of paclitaxel 200 mg/m2, given as a 3-hour infusion, and carboplatin dosed to an area under the concentration-time curve of 7 mg x min/mL, administered every 28 days. Granulocyte colony-stimulating factor (5 microg/kg) also was given on days 2 to 12 of each cycle. At the time of this report, 41 patients had entered this study. Primary sites included the nasopharynx (10 patients), larynx (18), oral cavity (three), oropharynx (six), hypopharynx (three), and unknown (one). Among 25 evaluable patients with non-nasopharyngeal cancer, there were two complete responses and three partial responses, for an overall response rate of 20% (95% confidence interval, 4% to 36%). Among eight evaluable patients with nasopharyngeal cancer, four achieved a complete response and two a partial response. Grade 3 to 4 toxicities included anemia (2.5%), leukopenia (7.5%), thrombocytopenia (5%), vomiting (5%), stomatitis (2.5%), and infection (5%). These preliminary data indicate that the combination of paclitaxel and carboplatin is active against advanced head and neck cancer, particularly when used in the treatment of nasopharyngeal cancer. PMID:9045340

  12. A PEG-Fmoc conjugate as a nanocarrier for paclitaxel.

    PubMed

    Zhang, Peng; Huang, Yixian; Liu, Hao; Marquez, Rebecca T; Lu, Jianqin; Zhao, Wenchen; Zhang, Xiaolan; Gao, Xiang; Li, Jiang; Venkataramanan, Raman; Xu, Liang; Li, Song

    2014-08-01

    We report here that a simple, well-defined, and easy-to-scale up nanocarrier, PEG5000-lysyl-(?-Fmoc-?-t-Boc-lysine)2 conjugate (PEG-Fmoc), provides high loading capacity, excellent formulation stability and low systemic toxicity for paclitaxel (PTX), a first-line chemotherapeutic agent for various types of cancers. 9-Fluorenylmethoxycarbonyl (Fmoc) was incorporated into the nanocarrier as a functional building block to interact with drug molecules. PEG-Fmoc was synthesized via a three-step synthetic route, and it readily interacted with PTX to form mixed nanomicelles of small particle size (25-30 nm). The PTX loading capacity was about 36%, which stands well among the reported micellar systems. PTX entrapment in this micellar system is achieved largely via an Fmoc/PTX ?-? stacking interaction, which was demonstrated by fluorescence quenching studies and (13)C NMR. PTX formulated in PEG-Fmoc micelles demonstrated sustained release kinetics, and in vivo distribution study via near infrared fluorescence imaging demonstrated an effective delivery of Cy5.5-labled PTX to tumor sites. The maximal tolerated dose for PTX/PEG-Fmoc (MTD > 120 mg PTX/kg) is higher than those for most reported PTX formulations, and in vivo therapeutic study exhibited a significantly improved antitumor activity than Taxol, a clinically used formulation of PTX. Our system may hold promise as a simple, safe, and effective delivery system for PTX with a potential for rapid translation into clinical study. PMID:24856103

  13. Paclitaxel-induced apoptosis in HeLa cells is serum dependent.

    PubMed

    Maldonado, V; De Anda, J; Meléndez-Zajgla, J

    1996-01-01

    Exposure of HeLa cells to different concentrations of the antineoplastic drug paclitaxel resulted in a loss of cell viability that was dependent on the concentration and time of exposure to the drug. This phenomenon was associated with the appearance of nuclear morphology typical of apoptosis and DNA breakage into a "ladder" pattern of discrete fragments of nucleosomal size. The induction of cell death was dependent on the serum concentration of the culture media, repressed by pretreatment with a cAMP-dependent protein kinase (PKA) inhibitor, and enhanced by increasing the cell proliferation with previous exposure to a cAMP-analog and a protein kinase-C (PKC) inducer. The proliferative index modifies the effect of taxol on HeLa cells, probably by means of a more rapid accumulation of cells in the G2/M cycle blockage point, although a direct participation of PKA and PKC should not be excluded. PMID:9062848

  14. 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 (0.35?M) 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

  15. Polymeric complex micelles with double drug-loading strategies for folate-mediated paclitaxel delivery.

    PubMed

    Li, Min; Liu, Yongjun; Feng, Lixia; Liu, Fengxi; Zhang, Li; Zhang, Na

    2015-07-01

    Drug loading is a key procedure in the preparation of drug-loaded nano-carriers. In this study, the paclitaxel (PTX)-loaded polymeric complex micelles (FA-P123-PTX/PTX micelles) with double drug-loading strategies were designed and prepared to improve the drug loading percentage of carriers and its anti-tumor efficiency. PTX was simultaneously conjugated to pluronic P123 (P123) polymer and encapsulated inside the P123 complex micelle. Folate (FA) was linked to the surface of micelles for the active target delivery of micelles to tumor cells. The FA-P123-PTX/PTX micelles showed spherical shaped with high drug loading of 18.08±0.64%. The results of cellular uptake studies suggested that FA could promote the internalization of micelles into the FR positive cells. FA-P123-PTX/PTX micelles showed significant higher anti-tumor activity against FR positive tumor cells compared to Taxol(®) (p<0.05). Moreover, the FA-P123-PTX/PTX micelles exhibited higher anti-tumor efficacy in B16 bearing mice with better safety property compared with Taxol(®). These results suggested that FA-P123-PTX/PTX micelles with double drug-loading strategies showed great potential for targeted delivery of anti-cancer drugs. PMID:25988283

  16. A dicarboxylic fatty acid derivative of paclitaxel for albumin-assisted drug delivery.

    PubMed

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

    2012-09-01

    Paclitaxel (PTX) 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 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, [(3) H]-PTX in the TAXOL formulation was cleared rapidly with a half-life of 7 h. 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

  17. Role of activating transcription factor 3 on TAp73 stability and apoptosis in paclitaxel-treated cervical cancer cells.

    PubMed

    Oh, Yeo Kyoung; Lee, Hyun Jung; Jeong, Mi-Hee; Rhee, Marie; Mo, Ji-Won; Song, Eun Hyeon; Lim, Joong-Yeon; Choi, Kyung-Hee; Jo, Inho; Park, Sang Ick; Gao, Bin; Kwon, Yongil; Kim, Won-Ho

    2008-07-01

    Taxol (paclitaxel) is a potent anticancer drug that has been found to be effective against several tumor types, including cervical cancer. However, the exact mechanism underlying the antitumor effects of paclitaxel is poorly understood. Here, paclitaxel induced the apoptosis of cervical cancer HeLa cells and correlated with the enhanced activation of caspase-3 and TAp73, which was strongly inhibited by TAp73beta small interfering RNA (siRNA). In wild-type activating transcription factor 3 (ATF3)-overexpressed cells, paclitaxel enhanced apoptosis through increased alpha and beta isoform expression of TAp73; however, these events were attenuated in cells containing inactive COOH-terminal-deleted ATF3 [ATF3(DeltaC)] or ATF3 siRNA. In contrast, paclitaxel-induced ATF3 expression did not change in TAp73beta-overexpressed or TAp73beta siRNA-cotransfected cells. Furthermore, paclitaxel-induced ATF3 translocated into the nucleus where TAp73beta is expressed, but not in ATF3(DeltaC) or TAp73beta siRNA-transfected cells. As confirmed by the GST pull-down assay, ATF3 bound to the DNA-binding domain of p73, resulting in the activation of p21 or Bax transcription, a downstream target of p73. Overexpression of ATF3 prolonged the half-life of TAp73beta by inhibiting its ubiquitination and thereby enhancing its transactivation and proapoptotic activities. Additionally, ATF3 induced by paclitaxel potentiated the stability of TAp73beta, not its transcriptional level. Chromatin immunoprecipitation analyses show that TAp73beta and ATF3 are recruited directly to the p21 and Bax promoter. Collectively, these results reveal that overexpression of ATF3 potentiates paclitaxel-induced apoptosis of HeLa cells, at least in part, by enhancing TAp73beta's stability and its transcriptional activity. The investigation shows that ATF3 may function as a tumor-inhibiting factor through direct regulatory effects on TAp73beta, suggesting a functional link between ATF3 and TAp73beta. PMID:18644986

  18. Taxol from Tubercularia sp. strain TF5, an endophytic fungus of Taxus mairei.

    PubMed

    Wang, J; Li, G; Lu, H; Zheng, Z; Huang, Y; Su, W

    2000-12-15

    The diterpenoid taxol is an important anticancer agent used widely in the clinic. The purpose of this work was to identify a taxol-producing endophytic fungus (strain TF5) isolated from Taxus mairei and study its anticancer activities. Strain TF5 was identified as a Tubercularia sp. according to the morphology of the fungal culture, the mechanism of spore production and the characteristics of the spores. Strain TF5 produced taxol, when grown in potato dextrose liquid medium and analyzed by thin layer chromatography, high performance liquid chromatography, ultraviolet and mass spectrometry. The fungal taxol, which was isolated from the organic extract of the TF5 culture, had strong cytotoxic activity towards KB and P388 cancer cells in vitro, tested by the MTT assay. Observed with immunofluorescence and electron microscopy, the fungal taxol enhanced microtubule stability and bundling in culture cells and induced tubulin polymerization in vitro similar to the authentic taxol. PMID:11111032

  19. Cell kill kinetics and cell cycle effects of taxol on human and hamster ovarian cell lines

    Microsoft Academic Search

    Narima M. Lopes; Earl G. Adams; Thomas W. Pitts; Bijoy K. Bhuyan

    1993-01-01

    Taxol is a clinically active anticancer drug, which exerts its cytotoxicity by the unique mechanism of polymerizing tubulin monomers into microtubules and stabilizing microtubules. Our studies with ovarian (hamster CHO and human A2780) cells showed that taxol is a phase-specific agent that is much more cytotoxic to mitotic cells than interphase cells. First, the dose-survival pattern of taxol resembled that

  20. Taxol Induces Apoptosis in Cortical Neurons by a Mechanism Independent of Bcl2 Phosphorylation

    Microsoft Academic Search

    Xavier A. Figueroa-Masot; Michal Hetman; Matthew J. Higgins; Niels Kokot; Zhengui Xia

    2001-01-01

    Bcl-2, an antiapoptotic protein, protects cells against many but not all forms of apoptosis. For example, Bcl-2 does not protect non-neuronal cells against taxol, a microtubule-stabilizing agent. The underlying mechanism for the ineffectiveness of Bcl-2 against taxol has been the subject of intense interest. Data from non-neuronal cells indicate that taxol-induced apo- ptosis requires activation of N-terminal c-Jun protein kinase

  1. An endophytic taxol-producing fungus from Taxus media, Cladosporium cladosporioides MD2.

    PubMed

    Zhang, Peng; Zhou, Peng-Peng; Yu, Long-Jiang

    2009-09-01

    Fermentation processes using taxol-producing fungi other than Taxus spp. may be an alternative way to produce taxol, which is an important antitumor agent used widely in the clinic setting. In this study, a taxol-producing endophytic fungus strain MD2 was isolated from the inner bark of Taxus media. Strain MD2 produced taxol when grown in potato dextrose liquid medium. The fungal taxol-which was analyzed by ultraviolet, high-performance liquid chromatography and mass spectrometry-was shown to be identical to authentic taxol and 10-deacetylbaccatin III. Further analysis with nuclear magnetic resonance (NMR) spectroscopy to show the chemical structure of the fungal taxol indicated that the fungal taxol produced an NMR spectrum identical to that of authentic taxol. Strain MD2 was identified as Cladosporium cladosporioides according to morphology of the fungal culture, characteristics of the spores, and analysis of 18S rDNA sequence. In addition, 10-deacetylbaccatin III-10-O-acetyl transferase gene of C. cladosporioides MD2 was cloned for the first time and was shown to share 99% identity with that of T. x media and 97% identity with that of T. wallichiana var. mairei. PMID:19484305

  2. Controlled preparation and antitumor efficacy of vitamin E TPGS-functionalized PLGA nanoparticles for delivery of paclitaxel.

    PubMed

    Wang, Guoying; Yu, Bo; Wu, Yuequn; Huang, Baolin; Yuan, Yuan; Liu, Chang Sheng

    2013-03-25

    Vitamin E TPGS-functionalized polymeric nanoparticles have been developed as a promising drug delivery platform in recent years. Obtaining reproducible monodisperse TPGS/polymeric nanoparticles with high encapsulation efficiency (EE%) still remains a big challenge. In this study, an inverse-phase nanoprecipitation method was developed to synthesize TPGS-functionalized PLGA nanoparticles (TPNs) for controlled release of paclitaxel (PTX). To take advantages of lipids, a part of TPGS in the TPNs was replaced by lipids. The results showed that with weight ratio of TPGS-to-PLGA of 2-3 and a molar replacement of lecithin ratio of 30%, the PTX-loaded TPNs (PTPNs) and PTX-loaded lipid-containing TPNs (PLTPNs) exhibited controllable and nearly uniform size of 130-150nm and EE% of over 80%. Compared to Taxol(®), both the PTPNs and PLTPNs significantly increased the intracellular uptake and exerted strong inhibitory effect on human lung cancer A549 model cells. Furthermore, a selective accumulation to tumor site and significant antitumor efficacy of TPNs in the A549 lung cancer xenografted nude mice were observed by intravenous administration, especially for the PTPNs group. Our data suggested that the inverse-phase nanoprecipitation method holds great potential for the fabrication of the paclitaxel-loaded TPNs and the TPNs prepared here is a promising controllable delivery system for paclitaxel. PMID:23402977

  3. Micromolar taxol, with or without hyperthermia, induces mitotic catastrophe and cell necrosis in HeLa cells

    Microsoft Academic Search

    John Michalakis; Spyros D. Georgatos; John Romanos; Helen Koutala; Vassilis Georgoulias; Dimitris Tsiftsis; Panayiotis A. Theodoropoulos

    2005-01-01

    Purpose: Although the mode of action of taxol, when used in nanomolar or micromolar concentrations during long periods, is extensively studied, there are few data available on taxol-mediated cytotoxicity when the drug is applied for a short time alone or in combination with hyperthermia. We studied the effect of taxol and hyperthermia on cell cycle kinetics, proliferation, and mode of

  4. Low radon doses sensitize MCF-7 human breast cancer cells to taxol.

    PubMed

    Soto, J; Sainz, C; Gonzalez-Lamuno, D; Falkenbach, A; Cos, S

    2000-01-01

    We studied whether human breast cancer cells show increased sensitivity to the chemotherapeutic agent taxol when they have been treated with low radiation doses (1.7-3.2 x 10(-3) Gy) from the gas radon. To this end, MCF-7 cells were cultivated in a medium either with or without dissolved radon for 3 days and then exposed to taxol (50 nM). Cells exposed to low doses of radon and then to a concentration of 50 nM of taxol exhibit a lower proliferation rate and a lower viability than cells treated with the same concentration of taxol but not irradiated. These findings indicate an important interaction of radon and taxol in the inhibition of MCF-7 cell growth. PMID:10948318

  5. Antisense oligonucleotides to class III ?-tubulin sensitize drug-resistant cells to Taxol

    PubMed Central

    Kavallaris, M; Burkhart, C A; Horwitz, S B

    1999-01-01

    A major impediment to the successful use of Taxol in the treatment of cancer is the development of drug resistance. The major cellular target of Taxol is the microtubule that is comprised of ?- and ?-tubulin heterodimers. Binding sites for Taxol have been delineated on the ?-tubulin subunit that has six isotypes. We have recently described increased expression of the brain-specific human class III ?-tubulin isotype, encoded by the H?4 gene, in both Taxol-resistant ovarian tumours and non-small-cell lung cancer cell lines. To evaluate directly the role of the class III ?-tubulin isotype in mediating Taxol resistance, antisense phosphorothioate oligodeoxynucleotides (ODN) targeted against various regions of the H?4 gene have been designed and examined for their efficacy in reducing H?4 gene and protein expression. Taxol-resistant lung cancer cells, A549-T24, which are 17-fold resistant to Taxol and display a fourfold increase in H?4 expression compared to the parental A549 cells, were treated with 1 ?M antisense ODNs. Two ODNs, AS1 and AS3, were found to reduce mRNA expression by 40–50%, as determined by reverse transcription polymerase chain reaction. A concentration-dependent reduction in H?4 mRNA expression was demonstrated with AS1 ODN. Immunofluorescence staining of cells treated with AS1 ODN revealed a decrease in class III protein expression which corresponded to a 39% increase in sensitivity to Taxol (P < 0.005). These findings support an important role for H?4 (class III) ?-tubulin expression in Taxol resistance and have potential implications for the treatment of Taxol-resistant tumours. © 1999 Cancer Research Campaign PMID:10362110

  6. Acute transient encephalopathy after weekly paclitaxel infusion.

    PubMed

    Muallao?lu, Sad?k; Koçer, Murat; Güler, Nilüfer

    2012-06-01

    Paclitaxel is highly active against a variety of solid tumors including breast lung, ovarian and head and neck cancer. Although peripheral neurotoxicity is well-known side effect, central nervous system (CNS) toxicity-related standard dose of paclitaxel is extremely uncommon, because paclitaxel dose not cross the blood-brain barrier and is not detectable in the cerebrospinal fluid. We present a patient with advanced stage breast carcinoma who developed acute and spontaneous resolving encephalopathy after weekly dose of paclitaxel. The patient did not have brain metastasis, or prior whole-brain irradiation, or any type of neurosurgery. Radiological imaging studies showed no abnormalities. CNS toxicity of paclitaxel should be kept in mind in patients without a previous history of brain metastasis or brain irradiation and even with low weekly doses. PMID:21618057

  7. D-?-tocopherol polyethylene glycol succinate-based redox-sensitive paclitaxel prodrug for overcoming multidrug resistance in cancer cells.

    PubMed

    Bao, Yuling; Guo, Yuanyuan; Zhuang, Xiangting; Li, Dan; Cheng, Bolin; Tan, Songwei; Zhang, Zhiping

    2014-09-01

    To overcome the multidrug resistance (MDR) of P-glycoprotein (P-gp) substrate anticancer drugs, such as paclitaxel (PTX), a novel dual-functional prodrug, D-?-tocopherol polyethylene glycol succinate (TPGS) based PTX prodrug (TPGS-S-S-PTX), was synthesized here to fulfill the synergistic effect of P-gp inhibiting and intracellular redox-sensitive release. The prodrug could self-assemble into stable micelles in physiological environment with a diameter of ?140 nm, while it disassociated in reductive condition and released PTX and TPGS active derivatives rapidly. High cell cytotoxicity in PTX-resistant human ovarian cell line A2780/T was observed with enhanced PTX accumulation due to the P-gp inhibition by the TPGS moiety. The IC50 of TPGS-S-S-PTX was 55% and 91% more effective than that of Taxol (clinical formulation of PTX) and uncleavable TPGS-C-C-PTX prodrug, respectively. This was found to be related with the increased apoptosis/necrosis and cell arrest in G2/M phase. In vivo evaluation of the TPGS-S-S-PTX prodrug exhibited an extended half-life, increased AUC (area under the concentration-time curve), enhanced tumor distribution and significant tumor growth inhibition with reduced side effects as compared to Taxol and TPGS-C-C-PTX. This prodrug has great potential in improving efficiency in the treatment of MDR tumors. PMID:25102234

  8. Isolation and characterization of endophytic taxol-producing fungi from Taxus chinensis.

    PubMed

    Liu, Kaihui; Ding, Xiaowei; Deng, Baiwan; Chen, Wenqiang

    2009-09-01

    This study investigated the endophytic fungi diversity of Taxus chinensis and screened the taxol-producing fungi in the host. A total of 115 endophytic fungi isolates obtained from bark segments of T. chinensis were grouped into 23 genera based on the morphological traits and sequence analysis of the internal transcribed spacers (ITS1-5.8S-ITS2), indicating endophytic fungi in T. chinensis are diverse and abundant. Diaporthe, Phomopsis (anamorph of Diaporthe), Acremonium, and Pezicula were the dominant genera, whereas the remaining genera were infrequent groups. The 13 representative species of the distinct genera were capable of producing taxol verified by reverse-phase high performance liquid chromatography (HPLC). Among the taxol-producing fungi, the yield of taxol produced by the Metarhizium anisopliae, H-27 was 846.1 microg l(-1) in reformative potato dextrose liquid medium, and the fungal taxol was further validated by mass spectrometry (MS). The taxol-producing fungi (92.3%) were infrequent communities, suggesting that infrequent fungi associated with T. chinensis might be a fascinating reservoir of taxol-generating fungi. PMID:19484278

  9. Limited Oral Bioavailability and Active Epithelial Excretion of Paclitaxel (Taxol) Caused by P-glycoprotein in the Intestine

    Microsoft Academic Search

    Alex Sparreboom; Judith van Asperen; Ulrich Mayer; Alfred H. Schinkel; Johan W. Smit; Dirk K. F. Meijer; Piet Borst; Willem J. Nooijen; Jos H. Beijnen; Olaf van Tellingen

    1997-01-01

    In mice, the mdr1a and mdr1b genes encode drug-transporting proteins that can cause multidrug resistance in tumor cells by lowering intracellular drug levels. These P-glycoproteins are also found in various normal tissues such as the intestine. Because mdr1b P-glycoprotein is not detectable in the intestine, mice with a homozygously disrupted mdr1a gene [mdr1a(-\\/-) mice] do not contain functional P-glycoprotein in

  10. 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 ?M 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

  11. Reduction-sensitive dual functional nanomicelles for improved delivery of paclitaxel.

    PubMed

    Zhang, Xiaolan; Liu, Ke; Huang, Yixian; Xu, Jieni; Li, Jiang; Ma, Xiaochao; Li, Song

    2014-09-17

    We have developed a dual-functional nanocarrier composed of a hydrophilic polyethylene glycol (PEG) and a hydrophobic farnesylthiosalicylate (FTS, a nontoxic Ras antagonist), which is effective in delivery of hydrophobic anticancer drug, paclitaxel (PTX). To facilitate the retention of the therapeutic activity of the carrier, FTS was coupled to PEG via a reduction-sensitive disulfide linkage (PEG5k-S-S-FTS2). PEG5k-S-S-FTS2 conjugate formed uniform micelles with very small size (?30 nm) and the hydrophobic drug PTX could be readily incorporated into the micelles. Interestingly, inclusion of a disulfide linkage into the PEG5k-FTS2 micellar system resulted in a 4-fold decrease in the critical micelle concentration (CMC). In addition, the PTX loading capacity and colloidal stability of PTX-loaded micelles were improved. HPLC-MS showed that parent FTS could be more effectively released from PEG5k-S-S-FTS2 conjugate in tumor cells/tissues compared to PEG5k-FTS2 conjugate in vitro and in vivo. PEG5k-S-S-FTS2 exhibited a higher level of cytotoxicity toward tumor cells than PEG5k-FTS2 without a disulfide linkage. Furthermore, PTX-loaded PEG5k-S-S-FTS2 micelles were more effective in inhibiting the proliferation of cultured tumor cells compared to Taxol and PTX loaded in PEG5k-FTS2 micelles. More importantly, PTX-loaded PEG5k-S-S-FTS2 micelles demonstrated superior antitumor activity compared to Taxol and PTX formulated in PEG5k-FTS2 micelles in an aggressive murine breast cancer model (4T1.2). PMID:25121577

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

    PubMed

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

    2015-01-01

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

  13. Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action.

    PubMed

    Bollag, D M; McQueney, P A; Zhu, J; Hensens, O; Koupal, L; Liesch, J; Goetz, M; Lazarides, E; Woods, C M

    1995-06-01

    Tubulin polymerization into microtubules is a dynamic process, with the equilibrium between growth and shrinkage being essential for many cellular processes. The antineoplastic agent taxol hyperstabilizes polymerized microtubules, leading to mitotic arrest and cytotoxicity in proliferating cells. Using a sensitive filtration-calorimetric assay to detect microtubule nucleating activity, we have identified epothilones A and B as compounds that possess all the biological effects of taxol both in vitro and in cultured cells. The epothilones are equipotent and exhibit kinetics similar to taxol in inducing tubulin polymerization into microtubules in vitro (filtration, light scattering, sedimentation, and electron microscopy) and in producing enhanced microtubule stability and bundling in cultured cells. Furthermore, these 16-membered macrolides are competitive inhibitors of [3H]taxol binding, exhibiting a 50% inhibitory concentration almost identical to that of taxol in displacement competition assays. Epothilones also cause cell cycle arrest at the G2-M transition leading to cytotoxicity, similar to taxol. In contrast to taxol, epothilones retain a much greater toxicity against P-glycoprotein-expressing multiple drug resistant cells. Epothilones, therefore, represent a novel structural class of compounds, the first to be described since the original discovery of taxol, which not only mimic the biological effects of taxol but also appear to bind to the same microtubule-binding site as taxol. PMID:7757983

  14. 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.

  15. Management of paclitaxel-induced neurotoxicity

    Microsoft Academic Search

    Manisha Bhutani; Philomena M. Colucci; Heather Laird-Fick; Barbara A. Conley

    2010-01-01

    Paclitaxel exerts its antitumor activity by promoting microtubule assembly and stabilizing microtubules. Microtubules are\\u000a important for the development and maintenance of neurons. As a consequence, neurotoxicity is one of the drug’s major side\\u000a effects. The risk of neurotoxicity depends on dose, duration and schedule of paclitaxel. Risk increases for patients with\\u000a pre-existing conditions that may cause neuropathy (such as alcohol

  16. Synthesis of paclitaxel-BGL conjugates.

    PubMed

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

    2012-09-15

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

  17. Fate of paclitaxel lipid nanocapsules in intestinal mucus in view of their oral delivery

    PubMed Central

    Groo, Anne-Claire; Saulnier, Patrick; Gimel, Jean-Christophe; Gravier, Julien; Ailhas, Caroline; Benoit, Jean-Pierre; Lagarce, Frederic

    2013-01-01

    The bioavailability of paclitaxel (Ptx) has previously been improved via its encapsulation in lipid nanocapsules (LNCs). In this work, the interactions between LNCs and intestinal mucus are studied because they are viewed as an important barrier to successful oral delivery. The rheological properties of different batches of pig intestinal mucus were studied under different conditions (the effect of hydration and the presence of LNCs). Fluorescence resonance energy transfer (FRET) was used to study the stability of LNCs in mucus at 37°C for at least 3 hours. Diffusion through 223, 446, and 893 ?m mucus layers of 8.4, 16.8, and 42 ?g/mL Ptx formulated as Taxol® (Bristol-Myers Squibb, Rueil-Malmaison, France) or encapsulated in LNCs (Ptx-LNCs) were investigated. The effect of the size of the LNCs on their diffusion was also investigated (range, 25–110 nm in diameter). Mucus behaves as a non-Newtonian gel with rheofluidifying properties and a flow threshold. The viscous (G?) and elastic (G?) moduli and flow threshold of the two mucus batches varied with water content, but G? remained below G?. LNCs had no effect on mucus viscosity and flow threshold. The FRET efficiency remained at 78% after 3 hours. Because the destruction of the LNCs would lead to a FRET efficiency below 25%, these results suggest only a slight modification of LNCs after their contact with mucus. The diffusion of Taxol® and Ptx-LNCs in mucus decreases if the mucus layer is thicker. Interestingly, the apparent permeability across mucus is higher for Ptx-LNCs than for Taxol® for drug concentrations of 16.8 and 42 ?g/mL Ptx (P<0.05). The diffusion of Ptx-LNCs through mucus is not size-dependent. This study shows that LNCs are stable in mucus, do not change mucus rheological properties, and improve Ptx diffusion at low concentrations, thus making these systems good candidates for Ptx oral delivery. The study of the physicochemical interaction between the LNC surface and its diffusion in mucus is now envisioned. PMID:24235827

  18. Src family kinases and paclitaxel sensitivity.

    PubMed

    Le, Xiao-Feng; Bast, Robert C

    2011-08-15

    Src-family Kinases (SFKs) participate in the regulation of proliferation, differentiation, apoptosis, autophagy, adhesion, migration, invasion and angiogenesis in normal and cancer cells. Abnormal expression of SFKs has been documented in cancers that arise in breast, colon, ovary, melanocyte, gastric mucosa, head and neck, pancreas, lung, and brain. Targeting SFKs in cancer cells has been shown to be a promising therapeutic strategy in solid tumors, particularly in ovarian, colon and breast cancers. Paclitaxel is one of most widely used chemotherapeutic agents for the management of ovarian, breast, lung and head/neck cancers. As a microtubule-stabilizing agent, paclitaxel possesses both mitosis-dependent and mitosis-independent activities against cancer cells. A variety of mechanisms such as deregulation of P-glycoprotein, alteration of tubulin isotypes, alteration of microtubule-regulatory proteins, deregulation of apoptotic signaling pathways, mutation of tubulins and overexpression of copper transporters have been implicated in the development of primary or secondary resistance to paclitaxel. By affecting cancer cell survival, proliferation, autophagy, microtubule stability, motility, and/or angiogenesis, SFKs interact with mechanisms that regulate paclitaxel sensitivity. Inhibition of SFKs can potentiate the anti-tumor activity of paclitaxel by enhancing apoptosis, autophagy and microtubule stability. Based on pre-clinical observations, administration of SFK inhibitors in combination with paclitaxel could improve treatment for ovarian, breast, lung and head/neck cancers. Identification and validation of predictive biomarkers could also permit personalization of the therapy. PMID:21646863

  19. Highly Selective Electrochemical Determination of Taxol Based on ds-DNA-Modified Pencil Electrode.

    PubMed

    Taei, M; Hassanpour, F; Salavati, H; Sadeghi, Z; Alvandi, H

    2015-05-01

    In this research, TiO2/ZrO2 nanocomposite has been prepared using sol-gel method. The TiO2/ZrO2 composite was characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), and transmission electron microscopy (TEM). A sensitive electrochemical biosensor is also presented for the determination of Taxol based on ds-DNA decorated multiwall carbon nanotubes-TiO2/ZrO2-chitosan-modified pencil electrode (ds-DNA-MWNTs-TiO2/ZrO2-CHIT-PGE). The UV spectroscopic data and differential pulse voltammetry revealed that there is a strong interaction between ds-DNA and Taxol. The groove binding of Taxol to ds-DNA helix has been characterized by a red shift (less than 8 nm) in wavelength and the decrease in the differential pulse voltammetry oxidation signal intensity of the Taxol at pencil graphite electrode (PGE) after its interaction with ds-DNA. Finally, a pretreated PGE modified with ds-DNA-MWNTs-TiO2/ZrO2-CHIT was tested in order to determine Taxol content in the solution. The dynamic range was from 0.7 to 1874.0 nmol L(-1) with a detection limit of 0.01 nmol L(-1). This sensing platform was successfully applied for the determination of Taxol in pharmaceutical and biological samples. PMID:25825248

  20. Non-anti-mitotic concentrations of taxol reduce breast cancer cell invasiveness

    SciTech Connect

    Tran, Truong-An; Gillet, Ludovic; Roger, Sebastien; Besson, Pierre [Inserm, U921, 37000 Tours (France); Universite Francois-Rabelais, 37000 Tours (France); White, Edward [Institute of Membrane and Systems Biology, University of Leeds, LS2 9JT LEEDS (United Kingdom); Le Guennec, Jean-Yves [Inserm, U921, 37000 Tours (France); Universite Francois-Rabelais, 37000 Tours (France)], E-mail: Jean-Yves.LeGuennec@Univ-Tours.Fr

    2009-02-06

    Taxol is widely used in breast cancer chemotherapy. Its effects are primarily attributed to its anti-mitotic activity. Microtubule perturbators also exert antimetastatic activities which cannot be explained solely by the inhibition of proliferation. Voltage-dependent sodium channels (Na{sub V}) are abnormally expressed in the highly metastatic breast cancer cell line MDA-MB-231 and not in MDA-MB-468 cell line. Inhibiting Na{sub V} activity with tetrodotoxin is responsible for an approximately 0.4-fold reduction of MDA-MB-231 cell invasiveness. In this study, we focused on the effect of a single, 2-h application of 10 nM taxol on the two cell lines MDA-MB-231 and MDA-MB-468. At this concentration, taxol had no effect on proliferation after 7 days and on migration in any cell line. However it led to a 40% reduction of transwell invasion of MDA-MB-231 cells. There was no additive effect when taxol and tetrodotoxin were simultaneously applied. Na{sub V} activity, as assessed by patch-clamp, indicates that it was changed by taxol pre-treatment. We conclude that taxol can exert anti-tumoral activities, in cells expressing Na{sub V}, at low doses that have no effect on cell proliferation. This effect might be due to a modulation of signalling pathways involving sodium channels.

  1. Paclitaxel in combination with carboplatin or gemcitabine for the treatment of advanced head and neck cancer.

    PubMed

    Fountzilas, G; Athanassiades, A; Kalogera-Fountzila, A; Samantas, E; Bacoyiannis, C; Briassoulis, E; Pavlidis, N; Kosmidis, P; Skarlos, D

    1997-12-01

    We performed a phase II study to evaluate the activity and toxicity of the combination of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin as first-line treatment in patients with recurrent or metastatic head and neck cancer. From March 1994 until August 1996, 49 patients were treated with paclitaxel 200 mg/m2 by 3-hour infusion followed by carboplatin at an area under the concentration-time curve of 7 mg/mL x min; treatment was requested every 4 weeks. Granulocyte colony-stimulating factor was administered prophylactically on days 2 to 12 of each cycle. The study included 41 men and eight women, with a median age of 57 years (range, 23 to 73 years). Most of the patients were symptomatic and had locoregional disease. Primary sites included nasopharynx (14 patients), oropharynx (six), oral cavity (four), hypopharynx (three), larynx (20), paranasal sinuses (one), and unknown (one). After the completion of treatment, four patients (8%; 95% confidence interval, 0% to 16%) achieved a complete response and 12 (24%; 95% confidence interval, 12% to 37%) achieved a partial response. Grade 3/4 toxicities included anemia (2%) and leukopenia, thrombocytopenia, nausea/vomiting, diarrhea, and stomatitis (4% each). After a median follow-up of 15.3 months, median time to progression was 5.7 months (range, 0.5 to 29.8+ months) and median survival was 13.3 months (range, 0.5 to 30.2+ months). In our ongoing study in a similar patient population, gemcitabine was substituted for carboplatin. PMID:9427262

  2. The development and maintenance of paclitaxel-induced neuropathic pain require activation of the sphingosine 1-phosphate receptor subtype 1.

    PubMed

    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

    2014-07-25

    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 (S1PR(1))- dependent neuroinflammatory processes as follows: activation of redox-sensitive transcription factors (NF?B) and MAPKs (ERK and p38) as well as enhanced formation of pro-inflammatory and neuroexcitatory cytokines (TNF-? and IL-1?). 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 clinical evaluation of FTY720 in chronic pain patients. PMID:24876379

  3. Thermosensitive and biodegradable polymeric micelles for paclitaxel delivery.

    PubMed

    Soga, Osamu; van Nostrum, Cornelus F; Fens, Marcel; Rijcken, Cristianne J F; Schiffelers, Raymond M; Storm, Gert; Hennink, Wim E

    2005-03-21

    The preparation, release and in vitro cytotoxicity of a novel polymeric micellar formulation of paclitaxel (PTX) were investigated. The micelles consisted of an AB block copolymer of poly(N-(2-hydroxypropyl) methacrylamide lactate) and poly(ethylene glycol) (pHPMAmDL-b-PEG). Taking advantage of the thermosensitivity of pHPMAmDL-b-PEG, the loading was done by simply mixing of a small volume of a concentrated PTX solution in ethanol and an aqueous polymer solution and subsequent heating of the resulting solution above the critical micelle temperature of the polymer. PTX could be almost quantitatively loaded in the micelles up to 2 mg/mL. By dynamic light scattering and cryo-transmission electron microscopy, it was shown that PTX-loaded micelles have a mean size around 60 nm with narrow size distribution. At pH 8.8 and 37 degrees C, PTX-loaded micelles destabilized within 10 h due to the hydrolysis of the lactic acid side group of the pHPMAmDL. Because the hydrolysis of the lactic acid side groups is first order in hydroxyl ion concentration, the micelles were stable for about 200 h at physiological conditions. The presence of serum proteins did not have an adverse effect on the stability of the micelles during at least 15 h. Interestingly, the dissolution kinetics of pHPMAmDL-b-PEG micelles was retarded by incorporation of PTX, indicating a strong interaction between PTX and the pHPMAmDL block. The PTX-loaded micelles showed a release of the incorporated 70% of PTX during 20 h at 37 degrees C and at pH 7.4. PTX-loaded pHPMAmDL-b-PEG micelles showed comparable in vitro cytotoxicity against B16F10 cells compared to the Taxol standard formulation containing Cremophor EL, while pHPMAmDL-b-PEG micelles without PTX were far less toxic than the Cremophor EL vehicle. Confocal laser-scanning microscopy (CLSM) and fluorescence activated cell sorting (FACS) analysis of fluorescently labelled micelles showed that pHPMAmDL-b-PEG micelles were internalized by the B16F10 cells. The present results suggest that pHPMAmDL-b-PEG block copolymer micelles are a promising delivery system for the parenteral administration of PTX. PMID:15763618

  4. Comparison of Epothilone and Taxol Binding in Yeast Tubulin using Molecular Modeling.

    PubMed

    Akbari, Vajihe; Moghim, Sharareh; Reza Mofid, Mohammad

    2011-10-01

    Microtubules are unique cytoskeletal structures that have structural subunits of ?? tubulin. Taxol is a typical microtubule stabilizing drug. The epothilones are other natural products with similar mechanism of action totaxol. Despite the highly conserved nature of ?-tubulin, some organism like Saccharomyces cerevesia (S.cerevesia) is resistance to taxol, but sensitive to epothilones. In order to find differences in sensitivity of yeast tubulin to these molecules, we investigated binding mode of the taxol and epothilone A to yeast tubulin using molecular modeling. The multiple sequence alignment of ?-tubulin of different species was performed using ClustalW2. Protein structure of yeast ?-tubulin was constructed with Swiss Model 8.05 by using 1TVK. Modeled tubulin was superimposed with PyMol on1JFF for comparison of three-dimensional structure of two proteins. Our results showed that one of the most interesting differences in binding mode of these molecules is residue 227. The His227 in bovine makes a hydrogen bond by means of its ?-nitrogen with epothilone A and by means of its ?-nitrogen with taxol. The Asn227 of yeast can play role of the ?-nitrogen of imidazole ring of H227, but not of ?-nitrogen of it. So yeast tubulin in contrast to taxol can interact with epothilone A. Due to conservation of essential residues for binding (T274, R282 and Q292), epothilone A in comparison with taxol can tolerate the interchange in the binding pocket (R276I). Our findings may be of a great aid in the rational design of antitumor agents that bind to the taxol binding region of tubulin. PMID:23407671

  5. Cancer chemotherapy, biodiversity, public and private property: the case of the anti-cancer drug taxol.

    PubMed

    Walsh, V; Goodman, J

    1999-11-01

    The drug taxol has been hailed by many in the cancer community as a major breakthrough in the treatment of cancer. It has already been approved in use against ovarian and advanced breast cancer in many countries worldwide. Taxol has also promoted profound debates in the policy arena not, as one might expect, because of the characteristics or purposes of the drug itself, but because of other far-reaching effects. Taxol is a complex compound found in the bark of the Pacific yew tree, primarily in Oregon and Washington in the USA. The bark was first collected in 1962 and cytotoxicity demonstrated in 1964. Yet it was not until 1989 that the first results of clinical trials were reported. In the US taxol was then rushed through the Food and Drug Administration's regulatory procedures, approval being granted for use in refractory ovarian cancer in 1992. The controversies surrounding taxol surfaced in 1989 and grew substantially over the next few years. In this paper we examine two principal controversies concerning taxol, the first of which focused on apparent conflicts between the needs of environmental protection and those of cancer chemotherapy. Although the media portrayed this as a clash of interests between the environment and people with cancer, we argue that it was an attempt to increase lay participation in biomedical decision making and policy formulation. The second controversy was between health policy and the transfer of public scientific property to the corporate sector. The pharmaceutical company Bristol-Myers Squibb was given exclusive rights to provide taxol from Pacific yew trees under a Co-operative Research and Development Agreement signed in 1991. While this was seen to be in the US Government's (as well as the company's) interest, it provoked a public reaction questioning the terms and consequences of the transfer of publicly generated scientific knowledge to the private sector. PMID:10501642

  6. Superior intratumoral penetration of Paclitaxel nanodots strengthens tumor restriction and metastasis prevention.

    PubMed

    Ni, Dezhi; Ding, Hui; Liu, Shan; Yue, Hua; Bao, Yali; Wang, Zhenhua; Su, Zhiguo; Wei, Wei; Ma, Guanghui

    2015-06-01

    Recently discovered intratumoral diffusion resistance, together with poor solubility and nontargeted distribution of chemotherapeutic drugs, has significantly impaired the performance of cancer treatments. By developing a well-designed droplet-confined/cryodesiccation-driven crystallization approach, we herein report the successful preparation of nanocrystallites of insoluble chemotherapeutic drug paclitaxel (PTX) in forms of nanodots (NDs, ?10 nm) and nanoparticles (NPs, ?70 nm) with considerably high drug loading capacity. Superficially coated Pluronic F127 is demonstrated to endow the both PTX nanocrystallites with excellent water solubility and prevent undesired phagocyte uptake. Further decoration with tumor-penetrating peptide iRGD, as expected, indiscriminatively facilitates tumor cell uptake in traditional monolayer cell culture model. On the contrary, distinctly enhanced performances in inward penetration and ensuing elimination of 3D multicellular tumor spheroids are achieved by iRGD-NDs rather than iRGD-NPs, revealing the significant influence of particle size variation in nanoscale. In vivo experiments verify that, although efficient tumor enrichment is achieved by all nanocrystallites, only the iRGD-grafted nanocrystallites of ultranano size realize thorough intratumoral delivery and reach cancer stem cells, which are concealed inside the tumor core. Consequently, much strengthened restriction on progress and metastasis of orthotopic 4T1 mammary adenocarcinoma is achieved in murine model, in sharp contrast to commercial PTX formulation Taxol. PMID:25678130

  7. PEG-farnesyl thiosalicylic acid telodendrimer micelles as an improved formulation for targeted delivery of paclitaxel.

    PubMed

    Zhang, Xiaolan; Huang, Yixian; Zhao, Wenchen; Chen, Yichao; Zhang, Peng; Li, Jiang; Venkataramanan, Raman; Li, Song

    2014-08-01

    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

  8. 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.

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

    PubMed

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

    2015-06-11

    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. PMID:26038337

  10. Thermosensitive micelles-hydrogel hybrid system based on poloxamer 407 for localized delivery of paclitaxel.

    PubMed

    Ju, Caoyun; Sun, Juan; Zi, Peng; Jin, Xiang; Zhang, Can

    2013-08-01

    A thermosensitive micelles-hydrogel hybrid system based on Poloxamer 407 (P407) was prepared to resolve the fast erosion and low loading capability of lipophilic drug of P407 gels for local chemotherapy. Different amounts of glutaraldehyde (GA) were applied to generate cross-linked networks with carboxymethyl chitosan (CMCS) interpenetrated in P407 gels, in which paclitaxel (PTX)-loaded N-octyl-O-sulfate chitosan micelles (PTX-M) were dispersed uniformly. The in vitro characteristics of CMCS-modified P407 gels (PTX-M-MG) were performed by examining the viscosity, swelling ratio, mechanical property, and drug release, while the in vivo evaluation included tissue distribution and anticancer efficacy through intratumoral administration in hepatoma solidity cell (Heps) tumor-bearing mice. The results showed that PTX-M-MG containing 0.05% (w/v) GA possessed lower viscosity, higher swelling ratio, stronger mechanical property, and longer term drug release, in which the loading efficiency of PTX was enlarged by the introduction of PTX-M. Moreover, PTX-M-MG revealed a prolonged retention at tumor sites, lasting for 20 days, and a superior tumor inhibition rate (64.27%) with reduced toxicity compared with Taxol(®) , PTX-M, and PTX-M loaded unmodified P407 gels (PTX-M-P407). It can be concluded that PTX-M-MG is a promising local delivery system for hydrophobic drug in cancer therapy, providing both improved efficacy and relieved side effects. PMID:23839931

  11. Copolymer micelles and nanospheres with different in vitro stability demonstrate similar paclitaxel pharmacokinetics.

    PubMed

    Letchford, Kevin; Burt, Helen M

    2012-02-01

    Paclitaxel loaded amphiphilic block copolymer nanoparticles have been demonstrated to enhance the aqueous solubility and improve the toxicity profile as compared to the commercially available product Taxol; however, in many cases long circulation of the drug is not achieved due to rapid partitioning of the drug from the carrier and/or carrier instability upon injection. In this work we investigated the effect of increasing the hydrophobic block length of methoxy poly(ethylene glycol)-block-poly(?-caprolactone) (MePEG-b-PCL) copolymers on the physicochemical properties and in vitro stability of the formed nanoparticles as well as the pharmacokinetics and biodistribution of both the copolymer and solubilized drug. We hypothesized that copolymers composed of high molecular weight hydrophobic blocks (MePEG???-b-PCL???) that form nanoparticles with a kinetically "frozen core" (which we term nanospheres) would better retain their PTX payload as compared to micelles composed of shorter hydrophobic blocks (MePEG???-b-PCL??), thus leading to prolonged drug circulation. Nanospheres solubilized PTX more efficiently, released the drug in a more sustained fashion and were characterized by enhanced stability and drug retention in the presence of plasma proteins as compared to micelles. Using radiolabeled copolymers and PTX, it was found that, upon injection, MePEG???-b-PCL??? circulated for longer than MePEG???-b-PCL??; however, the drug was rapidly eliminated from the blood regardless of the formulation. These results suggest that, despite formulation in more stable nanospheres, PTX was still rapidly extracted from these nanoparticles. PMID:22204437

  12. Human ?-galactoside ?-2,3-sialyltransferase (ST3Gal III) attenuated Taxol-induced apoptosis in ovarian cancer cells by downregulating caspase-8 activity

    PubMed Central

    Huang, Su; Day, Travis W.; Choi, Mi-Ran; Safa, Ahmad R.

    2015-01-01

    Taxol triggers apoptosis in a variety of cancer cells, but it also upregulates cytoprotective proteins and/or pathways that compromise its therapeutic efficacy. In this report, we found that Taxol treatment resulted in caspase-8-dependent apoptosis in SKOV3 human ovarian cancer cells. Moreover, Taxol-induced apoptosis was associated with caspase-3 activation. Interestingly, Taxol treatment upregulated ?-2,3-sialyltransferase (ST3Gal III) expression and forced expression of ST3Gal III attenuated Taxol-induced apoptosis. Furthermore, ST3Gal III overexpression inhibited Taxol-ttiggered caspase-8 activation, indicating that ST3Gal III upregulation produces cellular resistance to Taxol and hence reduces the efficacy of Taxol therapy. PMID:19415457

  13. Nonconvulsive status epilepticus secondary to paclitaxel administration?

    PubMed Central

    Illán-Gala, Ignacio; Díaz de Terán, Francisco Javier; Alonso, Pablo; Aguilar-Amat, María-José

    2015-01-01

    Nonconvulsive status epilepticus (NCSE) can be triggered by metabolic disturbances and drugs in adults without previous epilepsy. We present the case of a 51-year-old woman without previous history of epilepsy and recently diagnosed with infiltrating lobular breast carcinoma. Following the administration of paclitaxel–cremophor, she presented a striking disinhibited behavior with episodic spatial disorientation, emotional indifference, and irritability. Urgent EEG was consistent with NCSE. Clinical improvement and resolution of EEG abnormalities were observed following the administration of intravenous levetiracetam and lacosamide. Other causes of NCSE were ruled out, and antiepileptic drugs were slowly tapered off without new episodes of abnormal behavior after three months of follow-up. We have reported the first case of NCSE secondary to paclitaxel–cremophor. Neurologists and oncologists should consider NCSE as an unusual complication of treatment with paclitaxel–cremophor in patients without a history of epilepsy. PMID:26106578

  14. Paclitaxel loaded folic acid targeted nanoparticles of mixed lipid-shell and polymer-core: in vitro and in vivo evaluation.

    PubMed

    Zhao, Peiqi; Wang, Hanjie; Yu, Man; Liao, Zhenyu; Wang, Xianhuo; Zhang, Fei; Ji, Wei; Wu, Bing; Han, Jinghua; Zhang, Haichang; Wang, Huaqing; Chang, Jin; Niu, Ruifang

    2012-06-01

    A functional drug carrier comprised of folic acid modified lipid-shell and polymer-core nanoparticles (FLPNPs) including poly(D,L-lactide-co-glycolide) (PLGA) core, PEGylated octadecyl-quaternized lysine modified chitosan (PEG-OQLCS) as lipid-shell, folic acid as targeting ligand and cholesterol was prepared and evaluated for targeted delivery of paclitaxel (PTX). Confocal microscopy analysis confirmed the coating of the lipid-shell on the polymer-core. Physicochemical characterizations of FLPNPs, such as particle size, zeta potential, morphology, encapsulation efficiency, and in vitro PTX release, were also evaluated. The internalization efficiency and targeting ability of FLPNPs were demonstrated by flow cytometry and confocal microscopy. PTX loaded FLPNPs showed a significantly higher cytotoxicity than the commercial PTX formulation (Taxol®). The intravenous administration of PTX encapsulated FLPNPs led to tumor regression and improvement of animal survival in a murine model, compared with that observed with Taxol® and biodistribution study showed that PTX concentration in tumor for PTX encapsulated FLPNPs was higher than other PTX formulations. Our data indicate that PTX loaded FLPNPs are a promising nano-sized drug formulation for cancer therapy. PMID:22446630

  15. Screening of Taxol-producing fungi based on PCR amplification from Taxus.

    PubMed

    Zhang, Peng; Zhou, Peng-Peng; Jiang, Chen; Yu, Hui; Yu, Long-Jiang

    2008-12-01

    Genes coding for 10-deacetylbaccatin III-10-O-acetyl transferase and C-13 phenylpropanoid side chain-CoA acyltransferase were used as molecular markers for screening of Taxol-producing endophytic fungi. Using PCR, three out of 90 endophytic fungi, isolated from Taxus x media and Taxus yunnanensis, gave positive results. These 3 strains, when grown in 300 ml potato/dextrose liquid medium at 25 degrees C for 10 days, contained 100-160 microg Taxol/g dry wt of mycelium. PMID:18709488

  16. Prevention of paclitaxel-induced peripheral neuropathy by lithium pretreatment

    PubMed Central

    Mo, Michelle; Erdelyi, Ildiko; Szigeti-Buck, Klara; Benbow, Jennifer H.; Ehrlich, Barbara E.

    2012-01-01

    Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect that occurs in many patients undergoing chemotherapy. It is often irreversible and frequently leads to early termination of treatment. In this study, we have identified two compounds, lithium and ibudilast, that when administered as a single prophylactic injection prior to paclitaxel treatment, prevent the development of CIPN in mice at the sensory-motor and cellular level. The prevention of neuropathy was not observed in paclitaxel-treated mice that were only prophylactically treated with a vehicle injection. The coadministration of lithium with paclitaxel also allows for administration of higher doses of paclitaxel (survival increases by 60%), protects against paclitaxel-induced cardiac abnormalities, and, notably, does not interfere with the antitumor effects of paclitaxel. Moreover, we have determined a mechanism by which CIPN develops and have discovered that lithium and ibudilast inhibit development of peripheral neuropathy by disrupting the interaction between paclitaxel, neuronal calcium sensor 1 (NCS-1), and the inositol 1,4,5-trisphosphate receptor (InsP3R) to prevent treatment-induced decreases in intracellular calcium signaling. This study shows that lithium and ibudilast are candidate therapeutics for the prevention of paclitaxel-induced neuropathy and could enable patients to tolerate more aggressive treatment regimens.—Mo, M., Erdelyi, I., Szigeti-Buck, K., Benbow, J. H., Ehrlich, B. E. Prevention of paclitaxel-induced peripheral neuropathy by lithium pretreatment. PMID:22889832

  17. Gemcitabine plus epirubicin plus taxol (GET) in advanced breast cancer: a phase II study

    Microsoft Academic Search

    PierFranco Conte; Alessandra Gennari; Sara Donati; Barbara Salvadori; Editta Baldini; Carmelo Bengala; Ilaria Pazzagli; Cinzia Orlandini; Romano Danesi; Stefano Fogli; MarioDel Tacca

    2001-01-01

    Purpose. To investigate the activity of the combination of gemcitabine (G) plus epirubicin (E) and taxol (T), (GET), in metastatic breast cancer, to evaluate the feasibility of this regimen as induction before high dose chemotherapy and to study the pharmacokinetic interactions of these three drugs.

  18. Taxol, a Microtubule Stabilizer, Improves Cardiac Contractile Function during Ischemia in vitro

    Microsoft Academic Search

    Junjie Xiao; Hong Zhao; Dandan Liang; Ying Liu; Hong Zhang; Yi Liu; Jun Li; Luying Peng; Zhaonian Zhou; Yi-Han Chen

    2010-01-01

    Ischemic heart disease is one of the leading causes of heart failure, and microtubule disruption has been implicated in the response to ischemia in cardiac myocytes. The present study was designed to explore the effects of taxol, a microtubule stabilizer, on cardiac contractile function during ischemia. Heart rate, left ventricular developed pressure, left ventricular end-diastolic pressure, maximal time derivatives of

  19. Expression of paclitaxel-inactivating CYP3A activity in human colorectal cancer: implications for drug therapy

    PubMed Central

    Martínez, C; García-Martín, E; Pizarro, R M; García-Gamito, F J; Agúndez, J A G

    2002-01-01

    Cytochrome P450 3A is a drug-metabolising enzyme activity due to CYP3A4 and CYP3A5 gene products, that is involved in the inactivation of anticancer drugs. This study analyses the potential of cytochrome P450 3A enzyme in human colorectal cancer to impact anticancer therapy with drugs that are cytochrome P450 3A substrates. Enzyme activity, variability and properties, and the ability to inactivate paclitaxel (taxol) were analysed in human colorectal cancer and healthy colorectal epithelium. Cytochrome P450 3A enzyme activity is present in healthy and tumoral samples, with a nearly 10-fold interindividual variability. Nifedipine oxidation activity±s.d. for colorectal cancer microsomes was 67.8±36.6?pmol min?1?mg?1. The Km of the tumoral enzyme (42±8??M) is similar to that in healthy colorectal epithelium (36±8??M) and the human liver enzyme. Colorectal cancer microsomes metabolised the anticancer drug paclitaxel with a mean activity was 3.1±1.2?pmol?min?1?mg?1. The main metabolic pathway is carried out by cytochrome P450 3A, and it is inhibited by the cytochrome P450 3A-specific inhibitor ketoconazole with a KI value of 31?nM. This study demonstrates the occurrence of cytochrome P450 3A-dependent metabolism in colorectal cancer tissue. The metabolic activity confers to cancer cells the ability to inactivate cytochrome P450 3A substrates and may modulate tumour sensitivity to anticancer drugs. British Journal of Cancer (2002) 87, 681–686. doi:10.1038/sj.bjc.6600494 www.bjcancer.com © 2002 Cancer Research UK PMID:12237780

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

    PubMed

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

    2015-08-01

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

  1. 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

  2. Possible Side Effects of Paclitaxel Protein-Bound Particles

    Cancer.gov

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

  3. Delayed expression of apoptosis in human lymphoma cells undergoing low-dose taxol-induced mitotic stress

    Microsoft Academic Search

    R Allman; R J Errington; P J Smith

    2003-01-01

    The links between low-dose range taxol-induced mitotic arrest and the subsequent engagement of apoptosis are important for identifying the routes to therapeutic action. Here we have investigated the timing of cell-cycle perturbation and cell death responses following continuous exposure to clinically relevant drug concentrations (1–20 nM). Following 8 h of exposure to taxol, the cell line DoHH2 (p53 wild type)

  4. Stability, compatibility, and plasticizer extraction of taxol (NSC-125973) injection diluted in infusion solutions and stored in various containers.

    PubMed

    Waugh, W N; Trissel, L A; Stella, V J

    1991-07-01

    The stability of taxol (NSC-125973) in various diluents and containers was determined, and the extent of leaching of di(2-ethylhexyl) phthalate (DEHP) from polyvinyl chloride (PVC) bags caused by the taxol formulation was measured. A taxol formulation consisting of a 6-mg/mL solution of taxol in 50% polyoxyethylated castor oil and 50% dehydrated ethanol was added to 50- and 100-mL glass bottles, PVC infusion bags, and polyolefin containers containing 5% dextrose injection or 0.9% sodium chloride injection to give initial nominal taxol concentrations of 0.3, 0.6, 0.9, and 1.2 mg/mL. The containers were maintained at 20-23 degrees C for 12-24 hours. Samples were assayed by stability-indicating high-performance liquid chromatography, and clarity was determined visually. An experiment was run to ascertain whether DEHP would leach from a PVC administration set during a simulated infusion. There was no substantial loss of taxol over 24 hours. Filtration through a membrane resulted in no loss of taxol. All the solutions initially appeared hazy. Solutions stored in PVC bags became more hazy with time than solutions stored in glass or polyolefin containers. The haze seen in PVC bags was traced to leaching of DEHP. Agitation had no effect on the extent of leaching. Leaching was also seen during simulated delivery through PVC administration sets. No DEHP was detected when solutions were stored in glass or polyolefin containers and infused through polyethylene-lined sets. At the dilutions studied, taxol was visually and chemically stable for up to 24 hours.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1679294

  5. 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. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:2018-2028, 2015. PMID:25820241

  6. 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 ?g/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. PMID:25629952

  7. Management of Paclitaxel-Induced Hand-Foot Syndrome

    PubMed Central

    Assi, Hussein A.; Ayoub, Zeina A.; Jaber, Sara M.; Sibai, Hassan A.; El Saghir, Nagi S.

    2013-01-01

    Summary Background Hand-foot syndrome (HFS), also known as acral erythema or palmoplantar dysesthesia, is a manifestation of painful erythema and dysesthesia mostly occurring in the palms and soles. Although many chemotherapeutic agents have been shown to cause HFS, it remains an uncommon adverse cutaneous manifestation of paclitaxel. Case Report We report a case of paclitaxel-induced grade 3 HFS in a patient with breast cancer. HFS developed after 6 weeks of paclitaxel weekly infusions. The patient was managed by avoidance of sun exposure and extensive use of sunscreen and moisturizers. The skin lesions stabilized and improved gradually. This allowed us to continue the planned necessary course of 12 weeks of paclitaxel under close surveillance. Conclusion Paclitaxel-induced HFS can be managed with topical creams and avoidance of sun exposure without the need to discontinue chemotherapy. However, close monitoring for any increase or change in symptoms is warranted. PMID:24415973

  8. Paclitaxel-loaded poly(glycolide-co-?-caprolactone)-b-D-?-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-?-caprolactone)-b-D-?-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

  9. A Randomized Clinical Trial of Cisplatin\\/Paclitaxel Versus Carboplatin\\/Paclitaxel as First-Line Treatment of Ovarian Cancer

    Microsoft Academic Search

    Hans-Joachim Luck; Werner Meier; Hans-Peter Adams; Volker Mobus; Serban Costa; Thomas Bauknecht; Barbara Richter; Matthias Warm; Willibald Schroder; Sigrid Olbricht; Ulrike Nitz; Christian Jackisch; Gunther Emons; Uwe Wagner; Walther Kuhn; Jacobus Pfisterer

    2003-01-01

    Background: Despite considerable improvement in the treat- ment of advanced ovarian cancer, the optimization of effi- cacy and tolerability remains an important issue. Therefore, we performed a randomized, phase III non-inferiority trial comparing paclitaxel plus cisplatin (PT) with paclitaxel plus carboplatin (TC) in patients with advanced ovarian cancer. Methods: A total of 798 patients with International Federa- tion of Gynecology

  10. Reactive oxygen species, cell growth, and taxol production of Taxus cuspidata cells immobilized on polyurethane foam

    Microsoft Academic Search

    De-Ming Yin; Jin-Chuan Wu; Ying-Jin Yuan

    2005-01-01

    Dynamic changes in reactive oxygen species (ROS) of Taxus cuspidata cells immobilized on polyurethane foam were investigated and the relation between ROS content and taxol production was discussed.\\u000a Immobilization shortened the lag period of cell growth and moderately increased H2O2 and O2\\u000a ?• contents inside the microenvironment within the first 15 d. After 20 d, excessive production of H2O2 and

  11. Non-anti-mitotic concentrations of taxol reduce breast cancer cell invasiveness

    Microsoft Academic Search

    Truong-An Tran; Ludovic Gillet; Sébastien Roger; Pierre Besson; Edward White; Jean-Yves Le Guennec

    2009-01-01

    Taxol is widely used in breast cancer chemotherapy. Its effects are primarily attributed to its anti-mitotic activity. Microtubule perturbators also exert antimetastatic activities which cannot be explained solely by the inhibition of proliferation. Voltage-dependent sodium channels (NaV) are abnormally expressed in the highly metastatic breast cancer cell line MDA-MB-231 and not in MDA-MB-468 cell line. Inhibiting NaV activity with tetrodotoxin

  12. [Antiviral and cytotoxic activities of new derivatives of natural sesquiterpenes and taxol].

    PubMed

    Krawczyk, Ewa; Luczak, Miros?aw; Majewska, Anna

    2005-01-01

    Common occurrences of serious viral infections and a small number of available antiviral chemotherapeutics necessitate research for new, biologically active substances, which might be of use as antiviral drugs. Natural compounds, e.g., derived from plants and fungi, which show significant and various biological activities, may be a source of potential drugs. Sesquiterpenes, as well as taxol, and their derivatives, may serve as an example. The aim of the present study was to investigate the antiviral, antibacterial and cytotoxic properties of 7 new compounds: derivatives of sesquiterpenes of Lactarius mushroom origin and taxol--N-benzoylphenylisoserinates of sesquiterpenoid alcohols. The cytotoxicity of the tested compounds against Vero, RD, LLC-MK2 and A549 cell lines were assessed using the formazan method. All compounds showed a lower cytotoxicity than taxol. Their antiviral activity in vitro was evaluated by assessing the reduction of virus titre in cells subjected to the compounds in comparison to the cells, which were not subjected to them. It was found that out of 7 investigated compounds 3 exhibited antiviral activity. These compounds inhibited replication of HSV-1 virus in Vero cells. It appears therefore that further investigation of these groups of compounds and their derivatives is justified because they may constitute a potential source of chemotherapeutics. PMID:16130299

  13. Inhibitory effect of paclitaxel on endothelial cell adhesion and migration.

    PubMed

    Li, Hua; Zhang, Li-jun; Chen, Bai-hua; Zhou, Xuan; Su, Ke; Shi, Wen-tao; Wu, Jun-zhu; Yu, Hong; Wei, Lei

    2010-01-01

    The long-term success of percutaneous coronary interventions has been limited by restenosis. Therefore, local delivery of paclitaxel, an antiproliferative agent, using drug-eluting stents has been applied to prevent in-stent restenosis. However, paclitaxel not only inhibits smooth muscle cell proliferation, but also delays re-endothelialization of the damaged site, which may cause potentially life-threatening cardiovascular adverse events, especially late and very late stent thrombosis. We investigated the role of paclitaxel in endothelial cell line ECV304 adhesion and migration. Accordingly, changes in vasodilator-stimulated phosphoprotein protein (VASP) phosphorylation and cAMP-dependent protein kinase activity during ECV304 cell detachment and reattachment were investigated as well. The results showed that the decrease in VASP phosphorylation paralleled the inhibition of cAMP-dependent protein kinase (PKA) activity in the presence of paclitaxel (10 microg/l). Cell adhesion assay and two- and three-dimensional cell migration assays were performed to determine the effect of paclitaxel on the adhesion and migration of ECV304 cells. Paclitaxel significantly suppresses the adhesion (p < 0.05) and migration of ECV304 cells (p < 0.05). These data suggest that the inhibitory effect of paclitaxel may be produced by decreasing the phosphorylation of VASP via inhibition of PKA activity during ECV304 cell adhesion and migration. PMID:20145425

  14. Development of paclitaxel-TyroSpheres for topical skin treatment.

    PubMed

    Kilfoyle, Brian E; Sheihet, Larisa; Zhang, Zheng; Laohoo, Marissa; Kohn, Joachim; Michniak-Kohn, Bozena B

    2012-10-10

    A potential topical psoriasis therapy has been developed consisting of tyrosine-derived nanospheres (TyroSpheres) with encapsulated anti-proliferative paclitaxel. TyroSpheres provide enhancement of paclitaxel solubility (almost 4000 times greater than PBS) by effective encapsulation and enable sustained, dose-controlled release over 72 h under conditions mimicking skin permeation. TyroSpheres offer potential in the treatment of psoriasis, a disease resulting from over-proliferation of keratinocytes in the basal layer of the epidermis, by (a) enabling delivery of paclitaxel into the epidermis at concentrations >100 ng/cm(2) of skin surface area and (b) enhancing the cytotoxicity of loaded paclitaxel to human keratinocytes (IC(50) of paclitaxel-TyroSpheres was approximately 45% lower than that of free paclitaxel). TyroSpheres were incorporated into a gel-like viscous formulation to improve their flow characteristics with no impact on homogeneity, release or skin distribution of the payload. The findings reported here confirm that the TyroSpheres provide a platform for paclitaxel topical administration allowing skin drug localization and minimal systemic escape. PMID:22732474

  15. neuronal calcium sensor 1-dependent mechanism Paclitaxel induces calcium oscillations via an inositol 1,4,5-trisphosphate receptor and

    E-print Network

    Ehrlich, Barbara E.

    . Despite a well documented tubulin-stabilizing effect, many side effects of taxol therapy cannot,4,5-trisphosphate receptor from a human brain cDNA phage display library. Taxol increased binding of NCS-1 to devise new strategies for the management of side effects induced by taxol therapy. calcium imaging

  16. Interactions between Co-Habitating fungi Elicit Synthesis of Taxol from an Endophytic Fungus in Host Taxus Plants

    PubMed Central

    Soliman, Sameh S. M.; Raizada, Manish N.

    2012-01-01

    Within a plant, there can exist an ecosystem of pathogens and endophytes, the latter described as bacterial and fungal inhabitants that thrive without causing disease to the host. Interactions between microbial inhabitants represent a novel area of study for natural products research. Here we analyzed the interactions between the fungal endophytes of Taxus (yew) trees. Fungal endophytes of Taxus have been proposed to produce the terpenoid secondary metabolite, Taxol, an anti-cancer drug. It is widely reported that plant extracts stimulate endophytic fungal Taxol production, but the underlying mechanism is not understood. Here, Taxus bark extracts stimulated fungal Taxol production 30-fold compared to a 10-fold induction with wood extracts. However, candidate plant-derived defense compounds (i.e., salicylic acid, benzoic acid) were found to act only as modest elicitors of fungal Taxol production from the endophytic fungus Paraconiothyrium SSM001, consistent with previous studies. We hypothesized the Taxus plant extracts may contain elicitors derived from other microbes inhabiting these tissues. We investigated the effects of co-culturing SSM001 with other fungi observed to inhabit Taxus bark, but not wood. Surprisingly, co-culture of SSM001 with a bark fungus (Alternaria) caused a ?threefold increase in Taxol production. When SSM001 was pyramided with both the Alternaria endophyte along with another fungus (Phomopsis) observed to inhabit Taxus, there was an ?eightfold increase in fungal Taxol production from SSM001. These results suggest that resident fungi within a host plant interact with one another to stimulate Taxol biosynthesis, either directly or through their metabolites. More generally, our results suggest that endophyte secondary metabolism should be studied in the context of its native ecosystem. PMID:23346084

  17. Adverse effects of paclitaxel in patients with alcohol abuse histories.

    PubMed

    Henderson-Martin, B

    2000-01-01

    Paclitaxel is a taxane antineoplastic agent formulated in polyoxyethylated castor oil (Cremophor El) and dehydrated alcohol. This case report describes the development of central nervous system toxicity and threatened sobriety related to the alcohol content in a paclitaxel infusion. Nurses need to be aware of the alcohol contained in paclitaxel and other drugs used in oncology practice and document previous and current alcohol use prior to beginning therapy. Alternative chemotherapy regimens may need to be offered to patients with alcohol abuse histories. PMID:10865578

  18. Paclitaxel-carboplatin induced radiation recall colitis.

    PubMed

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

    2004-01-01

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

  19. Immunotherapeutic vitamin E nanoemulsion synergies the antiproliferative activity of paclitaxel in breast cancer cells via modulating Th1 and Th2 immune response.

    PubMed

    Pawar, Vivek K; Panchal, Samir B; Singh, Yuvraj; Meher, Jaya Gopal; Sharma, Komal; Singh, Pankaj; Bora, Himangshu K; Singh, Akhilesh; Datta, Dipak; Chourasia, Manish K

    2014-12-28

    Paclitaxel (PTX) is used as first line treatment for metastatic breast cancer but the relief comes at a heavy cost in terms of accompanying adverse effects. The pharmaceutical credentials of PTX are further dampened by the intrinsically low aqueous solubility. In order to sideline such insidious tendencies, PTX was incorporated in a vitamin E nanoemulsion using high pressure homogenization. The encapsulation efficiency of PTX in nanoemulsion was 97.81±2.7% and a sustained drug release profile was obtained. PTX loaded nanoemulsion exhibited higher cytotoxicity in breast cancer cell line (MCF-7) when compared to free PTX and marketed formulation (Taxol). Cell cycle arrest study depicted that MCF-7 cells treated with PTX loaded nanoemulsion showed high arrest in G2-M phase. Moreover blank nanoemulsion induced additional apoptosis in breast cancer cells through G1-S arrest by disrupting mitochondrial membrane potential. Cytokine estimation study in macrophages showed that both PTX loaded nanoemulsion and blank nanoemulsion enhanced secretion of IL-12 and downregulated secretion of IL-4 and IL-10. Results suggest that inclusion of vitamin E in nanoemulsion opened multiple complementary molecular effects which not only magnified the principle antiproliferative activity of PTX but also independently showcased potential in restoring the proactive nature of the breast cancer slackened chronic immune response. In-vivo anticancer activity showed significantly improved efficacy of PTX loaded nanoemlsion compare to Taxol and free PTX. The list of plausible advantages of PTX nanoemulsification was further substantiated by acceptable haemolytic potential, reduced in-vivo toxicity and conveniently modified pharmacokinetic profile in which the AUC and MRT were extended considerably. Overall, there were strong evidences that developed formulation can serve as a viable alternative to currently available PTX options. PMID:25459427

  20. nab-Paclitaxel dose and schedule in breast cancer.

    PubMed

    Martín, Miguel

    2015-01-01

    nab-Paclitaxel is approved for the treatment of metastatic breast cancer on an every-3-week schedule based on positive findings from a pivotal phase III trial in which nab-paclitaxel 260 mg/m(2) every 3 weeks was superior to solvent-based paclitaxel 175 mg/m(2) every 3 weeks for the primary endpoint of overall response rate (33 % vs 19 %; P?=?0.001). Subsequently, a number of trials have examined different schedules, doses, and combinations in efforts to optimize nab-paclitaxel-based therapy for metastatic and early-stage breast cancer. The goal of this review is to evaluate the clinical experiences to date with nab-paclitaxel as a single agent or in combination with targeted agents in different treatment settings - with a focus on the feasibility of administration, adverse event profile, and standard efficacy endpoints, such as overall survival, progression-free survival, overall response rate, and pathologic complete response rate. In general, weekly dosing during the first 3 of 4 weeks appears to achieve the best clinical benefit in both the metastatic and early-stage settings. Furthermore, the data suggest that high doses of nab-paclitaxel, such as 150 mg/m(2) during first 3 of 4 weeks or 260 mg/m(2) every 2 weeks, may be more feasible and appropriate for treatment of early-stage disease compared with metastatic disease. Intense regimens of nab-paclitaxel may not be the best treatment approach for unselected patients with metastatic breast cancer, but may suit a subset of patients for whom immediate disease control is required. The growing number of nab-paclitaxel trials in breast cancer will lead to greater refinements in tailoring therapy to patients based on their individual disease and patient characteristics. PMID:26067995

  1. Inhibitory Effect of Paclitaxel on Endothelial Cell Adhesion and Migration

    Microsoft Academic Search

    Hua Li; Li-jun Zhang; Bai-hua Chen; Xuan Zhou; Ke Su; Wen-tao Shi; Jun-zhu Wu; Hong Yu; Lei Wei

    2010-01-01

    The long-term success of percutaneous coronary interventions has been limited by restenosis. Therefore, local delivery of paclitaxel, an antiproliferative agent, using drug-eluting stents has been applied to prevent in-stent restenosis. However, paclitaxel not only inhibits smooth muscle cell proliferation, but also delays re-endothelialization of the damaged site, which may cause potentially life-threatening cardiovascular adverse events, especially late and very late

  2. Therapeutic Angiogenesis Inhibits or Rescues Chemotherapy-induced Peripheral Neuropathy: Taxol and Thalidomide-induced Injury of Vasa Nervorum is Ameliorated by VEGF

    Microsoft Academic Search

    Rudolf Kirchmair; Anne B Tietz; Eleftheria Panagiotou; Dirk H Walter; Marcy Silver; Young-Sup Yoon; Peter Schratzberger; Alberto Weber; Kengo Kusano; David H Weinberg; Allan H Ropper; Jeffrey M Isner; Douglas W Losordo

    2007-01-01

    Toxic neuropathy represents an important clinical problem in the use of the chemotherapeutic substances Taxol and thalidomide. Sensory neuropathy has a high incidence, lacks an effective treatment and is the dose-limiting factor for these drugs. The pathogenic basis of these neuropathies is unknown. We investigated the hypothesis that the experimental toxic neuropathies from Taxol and thalidomide results from destruction of

  3. 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

  4. Upregulation of phosphorylated cofilin 1 correlates with taxol resistance in human ovarian cancer in vitro and in vivo.

    PubMed

    Li, Min; Yin, Jie; Mao, Ning; Pan, Lingya

    2013-01-01

    The acquisition of chemoresistance is a major therapeutic obstacle in the clinical treatment of ovarian cancer. Diagnosing chemoresistance in ovarian cancer patients at an early stage is necessary for prognosis, but at present significant proteins related to chemoresistance that may indicate and reverse chemoresistance in human ovarian cancer have not been discovered. In this study, we demonstrated that the protein, phosphorylated cofilin 1 (p-CFL1) correlates with taxol resistance in human ovarian cancer cells. The total proteins of two sensitive (SKOV3 and A2780) and three taxol-resistant (SKOV3/TR2500, SKOV3/TR30 and A2780/TR) human ovarian cancer cell lines were isolated by 2-dimensional gel electrophoresis (2-DE). Twenty-two protein spots in all samples were revealed to be significantly different in spot intensity by statistical analysis, 16 of which were identified using matrix-assisted laser desorption ionization-time-of-flight-mass spectrometry (MALDI-TOF-MS). Cofilin 1 (CFL1) was selected as a candidate which may play an important role in taxol resistance. Higher expression levels of p-CFL1 in taxol-resistant cells were demonstrated. Furthermore, the levels of p-CFL1 in primary human ovarian cancer tissues were shown to be significantly higher in chemoresistant cases compared to those in chemosensitive ones. These findings suggest that p-CFL1 is upregulated in taxol-resistant ovarian cancer and this upregulation is a chara-cteristic of taxol resistance both in vitro and in vivo. However, the mechanisms need to be further elucidated. PMID:23064469

  5. Enhancement of paclitaxel production by temperature shift in suspension culture of Taxus chinensis.

    PubMed

    Choi; Kim; Son; Hong; Lee; Lee

    2000-11-01

    Effect of temperature shift during culture period on cell growth and paclitaxel was investigated to optimize paclitaxel production in suspension culture of Taxus chinensis. Cell growth showed the optimum at 24 degrees C while paclitaxel synthesis showed the maximum at 29 degrees C. To minimize the inhibitory effect of higher temperature on cell growth, temperature was shifted after a certain period of culture time at 24 degrees C. Paclitaxel synthesis in plant cell culture increased dramatically during day 14 to day 21 regardless of treatment, reaching the maximum production of 137.5 mg paclitaxel/L. When the temperature was maintained at 29 degrees C after day 21, the specific productivity of paclitaxel was sustained for prolonged period of 42 days. The possible relationship between temperature and paclitaxel synthetic pathway was also suggested. PMID:11024522

  6. Paclitaxel chemotherapy: from empiricism to a mechanism-based formulation strategy

    PubMed Central

    Scripture, Charity D; Figg, William D; Sparreboom, Alex

    2005-01-01

    Paclitaxel is an anticancer agent effective for the treatment of breast, ovarian, lung, and head and neck cancer. Because of water insolubility, paclitaxel is formulated with the micelle-forming vehicle Cremophor EL to enhance drug solubility. However, the addition of Cremophor EL results in hypersensitivity reactions, neurotoxicity, and altered pharmacokinetics of paclitaxel. To circumvent these unfavorable effects resulting from the addition of Cremophor EL, efforts have been made to develop new delivery systems for paclitaxel administration. For example, ABI-007 is a Cremophor-free, albumin-stabilized, nanoparticle paclitaxel formulation that was found to have significantly less toxicity than Cremophor-containing paclitaxel in mice. Pharmacokinetic studies indicate that in contrast to Cremophor-containing paclitaxel, ABI-007 displays linear pharmacokinetics over the clinically relevant dose range of 135–300 mg/m2. In a phase III study conducted in patients with metastatic breast cancer, patients treated with ABI-007 achieved a significantly higher objective response rate and time to progression than those treated with Cremophor-containing paclitaxel. Together these findings suggest that nanoparticle albumin-bound paclitaxel may enable clinicians to administer paclitaxel at higher doses with less toxicity than is seen with Cremophor-containing paclitaxel. The role of this novel paclitaxel formulation in combination therapy with other antineoplastic agents needs to be determined. PMID:18360550

  7. Scleroderma-like cutaneous lesions induced by paclitaxel: A case study

    Microsoft Academic Search

    I. Kupfer; X. Balguerie; P. Courville; P. Chinet; P. Joly

    2003-01-01

    Paclitaxel is a recent antineoplastic agent that belongs to the taxane family. Its activity has been demonstrated in advanced and refractory ovarian, breast, lung, and head and neck cancer. Adverse cutaneous reactions to paclitaxel have been reported, namely bullous fixed drug eruption, onycholysis, acral erythema, erythema multiforme, and pustular eruption. We report the first case of scleroderma-like changes after paclitaxel

  8. 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 ??-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

  9. The preparation, characterization, and pharmacokinetic studies of chitosan nanoparticles loaded with paclitaxel/dimethyl-?-cyclodextrin inclusion complexes

    PubMed Central

    Ye, Ya-Jing; Wang, Yun; Lou, Kai-Yan; Chen, Yan-Zuo; Chen, Rongjun; Gao, Feng

    2015-01-01

    A novel biocompatible and biodegradable drug-delivery nanoparticle (NP) has been developed to minimize the severe side effects of the poorly water-soluble anticancer drug paclitaxel (PTX) for clinical use. PTX was loaded into the hydrophobic cavity of a hydrophilic cyclodextrin derivative, heptakis (2,6-di-O-methyl)-?-cyclodextrin (DM-?-CD), using an aqueous solution-stirring method followed by lyophilization. The resulting PTX/DM-?-CD inclusion complex dramatically enhanced the solubility of PTX in water and was directly incorporated into chitosan (CS) to form NPs (with a size of 323.9–407.8 nm in diameter) using an ionic gelation method. The formed NPs had a zeta potential of +15.9–23.3 mV and showed high colloidal stability. With the same weight ratio of PTX to CS of 0.7, the loading efficiency of the PTX/DM-?-CD inclusion complex-loaded CS NPs was 30.3-fold higher than that of the PTX-loaded CS NPs. Moreover, it is notable that PTX was released from the DM-?-CD/CS NPs in a sustained-release manner. The pharmacokinetic studies revealed that, compared with reference formulation (Taxol®), the PTX/DM-?-CD inclusion complex-loaded CS NPs exhibited a significant increase in AUC0?24h (the area under the plasma drug concentration–time curve over the period of 24 hours) and mean residence time by 2.7-fold and 1.4-fold, respectively. Therefore, the novel drug/DM-?-CD inclusion complex-loaded CS NPs have promising applications for the significantly improved delivery and controlled release of the poorly water-soluble drug PTX or its derivatives, thus possibly leading to enhanced therapeutic efficacy and less severe side effects. PMID:26170666

  10. iRGD conjugated TPGS mediates codelivery of paclitaxel and survivin shRNA for the reversal of lung cancer resistance.

    PubMed

    Shen, Jianan; Meng, Qingshuo; Sui, Huiping; Yin, Qi; Zhang, Zhiwen; Yu, Haijun; Li, Yaping

    2014-08-01

    Multidrug resistance (MDR) is one of the major obstacles in tumor treatment. Herein, we reported an active targeting strategy with peptide-mediated nanoparticles deep into tumor parenchyma, which iRGD conjugated d-?-tocopheryl polyethylene glycol 1000 succinate (TPGS) mediated codelivery of paclitaxel (PTX) and survivin shRNA (shSur) for the reversal of lung cancer resistance. Pluronic P85-polyethyleneimine/TPGS complex nanoparticles incorporated with iRGD-TPGS conjugate codelivering PTX and shSur systems (iPTPNs) could induce effective cellular uptake, RNAi effects, and cytotoxicity on A549 and A549/T cells. In particular, iPTPNs showed superiority in biodistribution, survivin expression, tumor apoptosis, and antitumor efficacy by simultaneously exerting an enhanced permeability and retention (EPR) effect and iRGD mediated active targeting effects. iPTPNs significantly enhanced the accumulation of PTX and shSur, down-regulated survivin expression, and induced cell apoptosis in tumor tissue. The in vivo antitumor efficacy showed the tumor volume of iPTPNs group (10 mg/kg) was only 12.7% of the Taxol group. Therefore, the iRGD mediated PTX and shSur codelivery system could be a very powerful approach for the reversal and therapy of lung cancer resistance. PMID:24236909

  11. Doxorubicin and Paclitaxel-loaded Lipid-based Nanoparticles Overcome Multi-Drug Resistance by Inhibiting P-gp and Depleting ATP

    PubMed Central

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

    2009-01-01

    To test the ability of nanoparticle (NP) formulations to overcome P-gp-mediated multidrug resistance (MDR), several different doxorubicin (Dox) and paclitaxel (PX)-loaded solid lipid NPs were prepared. Dox NPs showed 6-8-fold lower IC50 values in Pgp overexpressing human cancer cells than those of free Dox. The IC50 value of PX NPs was over 9-fold lower than that of Taxol® in P-gp-overexpressing cells. A series of in-vitro cell assays were used including quantitative studies on uptake and efflux, inhibition of calcein acetoxymethylester (Calcein AM) efflux, alteration of ATP levels, membrane integrity, mitochondrial membrane potential, apoptosis and cytotoxicity. Enhanced uptake and prolonged retention of Dox were observed with NP-based formulations in P-gp-overexpressing cells. Calcein AM and ATP assays confirmed that blank NPs inhibited P-gp and transiently depleted ATP. Intravenous injection of pegylated PX BTM NPs showed marked anticancer efficacy in nude mice bearing resistant NCI/ADR-RES tumors versus all control groups. NPs may be used to both target drug and biological mechanisms to overcome MDR via P-gp inhibition and ATP depletion. PMID:19383919

  12. Synthesis and characterization of a novel polydepsipeptide contained tri-block copolymer (mPEG-PLLA-PMMD) as self-assembly micelle delivery system for paclitaxel.

    PubMed

    Zhao, Yanlei; Li, Juan; Yu, Hua; Wang, Guangji; Liu, Wen

    2012-07-01

    A series of biodegradable polydepsipeptides based new triblock copolymers, poly (ethylene glycol)-poly(L-lactide)-poly(3(S)-methyl-morpholine-2,5-dione) (mPEG-PLLA-PMMD) have been synthesized and characterized as self-assembly micelle delivery system for paclitaxel (PTX). Compared to the mPEG(2000)-PLLA(2000) diblock copolymers, the triblock copolymers present more benefits such as lower CMC value, positive-shifted zeta potential, better drug loading efficiency and stability. Among the triblock polymers, mPEG(2000)-PLLA(2000)-PMMD(1400) micelles present low cytotoxicity and promote the anti-cancer activity of PTX on A-549 and HCT-116cells. In addition, mPEG(2000)-PLLA(2000)-PMMD(1400) micelles prolongs the circulation time of PTX in rat after i.v. injection (5 mg/kg) than that of mPEG(2000)-PLLA(2000) micelles and Taxol. The half life (t(1/2?)), mean residence time (MRT), AUC(0-?) and clearance (CL) for PTX-loaded mPEG(2000)-PLLA(2000)-PMMD(1400) micelles are determined to be 1.941 h, 2.683 h, 5.220 ?g/m Lh (1.8-fold to mPEG(2000)-PLLA(2000) group), 0.967 L/h kg(-1), respectively. In conclusion, mPEG(2000)-PLLA(2000)-PMMD(1400) copolymer could be developed as one of the promising vectors to anti-cancer agents for chemotherapeutics. PMID:22484705

  13. Protection of p53 wild type cells from taxol by nutlin-3 in the combined lung cancer treatment

    PubMed Central

    2010-01-01

    Background Mutations within the tumor suppressor TP53 gene are one of the most common genetic alterations present at high frequency in human tumors and have been shown to be associated with resistance to radio-chemotherapy. The lack of the wild type TP53 gene in cancer cells could be exploited for therapeutic advantage using a sequence of two antagonistic drugs. The aim of this study was to selectively kill p53 deficient cells (FaDu and H1299) by taxol and to protect p53 wild type cells (A549) by the prior administration of nutlin-3 in comparison to certain known anticancer drugs (5-fluorouracil, camptothecin, roscovitine). Methods Cytotoxic and cytostatic properties of 5-fluorouracil, camptothecin, roscovitine and nutlin-3 administrating alone or in combination with taxol were investigated in vitro by flow cytometry. Results It was found that nutlin-3 induced growth arrest and protected A549 cells from taxol. FaDu and H1299 cells responded to the same treatments with mitotic arrest and massive apoptosis. Other compounds (5-fluorouracil, camptothecin and roscovitine) revealed weaker selectivity and elevated toxicity in comparison to nutlin-3. Conclusions We propose a therapeutic strategy protecting normal cells from taxol while increasing apoptosis selectively in p53-deficient cells using nutlin-3. PMID:20178585

  14. Screening of a Library of Phage-displayed Peptides Identifies Human Bcl-2 as a Taxol-binding Protein

    E-print Network

    Wallace, Bonnie Ann

    III which precludes their incorporation into the assembling phage particles (Makowski & Russel, 1997Screening of a Library of Phage-displayed Peptides Identifies Human Bcl-2 as a Taxol A random library of phage displayed peptides was screened for binding to a biotinylated derivative

  15. Epothilones, a New Class of Microtubule-stabilizing Agents with a Taxol-like Mechanism of Action

    Microsoft Academic Search

    Daniel M. Bollag; Patricia A. McQueney; Jian Zhu; Otto Hensens; Lawrence Koupal; Jerrold Liesch; Michael Goetz; Elias Lazarides; Catherine M. Woods

    1995-01-01

    Tubulin polymerizationinto microtubulesis a dynamic process, with the equilibrium between growth and shrinkage being essential for many cellular processes. The antineoplastic agent taxol hyperstabilizes polymerized microtubules, leading to mitotic arrest and cytotoxicity in proliferating cells. Using a sensitive filtration-calorimetric assay to detect microtubule nucleating activity, we have identified epothilones A and B as compounds that possess all the biological effects

  16. Taxol Metabolism by Human Liver Microsomes: Identification of Cytochrome P450 Isozymes Involved in Its Biotransformation 1

    Microsoft Academic Search

    Thierry Cresteil; Bernard Monsarrat; Paul Alvinerie; Isabel Vieira; Michel Wright

    1994-01-01

    The biotransformation of taxol by human liver was investigated in vitro with microsomes isolated from adult and developing human tissues. In vitro, no metabolism was detected with kidney microsomes, whereas two metabolites were generated by liver microsomes. The most prominent metabolite, termed M5, corresponded to an hydroxylation at the C6 po- sition on the taxane ring, while the other metabolite,

  17. Polymer nanoparticles--a novel strategy for administration of Paclitaxel in cancer chemotherapy.

    PubMed

    Deepa, G; Ashwanikumar, N; Pillai, J J; Kumar, G S V

    2012-01-01

    The main challenge encountered while treating using Paclitaxel (PTX) is its poor solubility in aqueous solutions. The cremophor used in the formulation can cause various side effects such as hypersensitivity, myelosuppression and neurotoxicity and also leads to non-specific distribution in tumor and normal tissues. Since the structure of Paclitaxel does not possess a functional group, it is not easy to manipulate to enhance the solubility. Such limitations can be overcome by delivering Paclitaxel with the aid of drug delivery systems such as polymeric micelles, nanoparticles, hydrogels and liposomes. The review discusses various approaches of Paclitaxel delivery via polymeric nanoparticles. It focuses on the passive and active targeting of Paclitaxel. PMID:22834822

  18. Phase I\\/II study of DHA–paclitaxel in combination with carboplatin in patients with advanced malignant solid tumours

    Microsoft Academic Search

    M Harries; A O'Donnell; M Scurr; S Reade; C Cole; I Judson; A Greystoke; C Twelves; S Kaye

    2004-01-01

    DHA–paclitaxel is a conjugate of paclitaxel and the fatty acid, docosahexaenoic acid. Preclinical studies have demonstrated increased activity, relative to paclitaxel, with the potential for an improved therapeutic ratio. We conducted a phase I study to determine the maximum tolerated doses of DHA–paclitaxel and carboplatin when administered in combination. Two cohorts of patients were treated: carboplatin AUC 5 with DHA–paclitaxel

  19. FoxM1 Mediates Resistance to Herceptin and Paclitaxel

    PubMed Central

    Carr, Janai R.; Park, Hyun Jung; Wang, Zebin; Kiefer, Megan M.; Raychaudhuri, Pradip

    2010-01-01

    Inherent and acquired therapeutic resistance in breast cancer remains a major clinical challenge. In human breast cancer samples, overexpression of the oncogenic transcription factor FoxM1 has been suggested to be a marker of poor prognosis. In this study, we report that FoxM1 overexpression confers resistance to the HER2 monoclonal antibody Herceptin and microtubule-stabilizing drug paclitaxel, both as single agents and in combination. FoxM1 altered microtubule dynamics in order to protect tumor cells from paclitaxel-induced apoptosis. Mechanistic investigations revealed that the tubulin destabilizing protein Stathmin, whose expression also confers resistance to paclitaxel, is a direct transcriptional target of FoxM1. Significantly, attenuating FoxM1 expression by siRNA or an ARF-derived peptide inhibitor increased therapeutic sensitivity. Our findings indicate that targeting FoxM1 could relieve therapeutic resistance in breast cancer. PMID:20530690

  20. Expression of immediate early genes after treatment of human astrocytoma cells with radiation and taxol

    SciTech Connect

    Gubits, R.M.; Geard, C.R.; Schiff, P.B. [Columbia Univ., New York, NY (United States)

    1993-10-20

    The promising chemotherapeutic agent, taxol, has been shown to sensitize the G18 line of human astrocytoma cells to ionizing radiation. The present studies were performed to identify specific changes in gene expression associated with this altered sensitivity. The products of immediate early genes, which are induced transiently in cells in response to a variety of treatments, including growth factors, neurotransmitters, and irradiation with UV light or X rays, are thought to initiate a cascade of genetic responses to alterations in cellular environment. The present results demonstrate a dramatic attenuation in one immediate early gene response in association with a treatment that enhances radiosensitivity in a refractory human brain tumor line. 22 refs., 5 figs., 1 tab.

  1. Concurrent Chemoradiotherapy with Weekly Paclitaxel in Malignant Cerebral Glioma Treatment

    Microsoft Academic Search

    José Paulo Montemor; Fernanda Maris Peria; Carlos Roberto Monti; Luis Salvador Petrilli; Benedicto Oscar Colli; Carlos Gilberto Carlotti Júnior

    2008-01-01

    SummaryBackground: Anaplastic astrocytomas (AA) and glioblastomas (GB) are the most common malignant gliomas, and despite newly developed drugs and combined treatments, they still have an adverse prognosis. Paclitaxel is a cytotoxic agent with radiosensitizing properties and exerts objective growth inhibition in glioma tumor cells. Patients and Methods: From 1998 to 2002, 61 microneurosurgically treated patients were randomized to group I

  2. Spleen Tyrosine Kinase Confers Paclitaxel Resistance in Ovarian Cancer.

    PubMed

    Wei, Wei; Birrer, Michael J

    2015-07-13

    Adaptive chemoresistance and consequent tumor recurrence present major obstacles to the improvement of the prognosis and quality-of-life of patients with advanced-stage ovarian cancer. In this issue of Cancer Cell, Yu and colleagues describe the critical role of spleen tyrosine kinase (SYK) in paclitaxel resistance by modulating the stability of microtubules. PMID:26175410

  3. Prevention of local tumor growth with paclitaxel-loaded microspheres

    E-print Network

    resection margin. Methods: Poly-(D,L-lactic-co-glycolic acid) (PLGA) microspheres loaded unloaded (carrier alone) PLGA microspheres, and Lewis lung carcinoma cells com- bined with 50 3 106 or 100 3 106 paclitaxel-loaded PLGA microspheres. After the coinjection of Lewis lung carcinoma cells

  4. Production of CNT-taxol-embedded PCL microspheres using an ammonium-based room temperature ionic liquid: as a sustained drug delivery system.

    PubMed

    Kim, Seong Yeol; Hwang, Ji-Young; Seo, Jae-Won; Shin, Ueon Sang

    2015-03-15

    We describe a one-pot method for the mass production of polymeric microspheres containing water-soluble carbon-nanotube (w-CNT)-taxol complexes using an ammonium-based room temperature ionic liquid. Polycaprolactone (PCL), trioctylmethylammonium chloride (TOMAC; liquid state from -20 to 240°C), and taxol were used, respectively, as a model polymer, room temperature ionic liquid, and drug. Large quantities of white colored PCL powder without w-CNT-taxol complexes and gray colored PCL powders containing w-CNT-taxol (1:1 or 1:2 wt/wt) complexes were produced by phase separation between the hydrophilic TOMAC and the hydrophobic PCL. Both microsphere types had a uniform, spherical structure of average diameter 3-5?m. The amount of taxol embedded in PCL microspheres was determined by HPLC and (1)H NMR to be 8-12?g per 1.0mg of PCL (loading capacity (LC): 0.8-1.2%; entrapment efficiency (EE): 16-24%). An in vitro HPLC release assay showed sustain release of taxol without an initial burst over 60days at an average rate of 0.003-0.0073mg per day. The viability patterns of human breast cancer cells (MCF-7) for PCTx-1 and -2 showed dose-dependent inhibitory effects. In the presence of PCTx-1 and -2, the MCF-7 cells showed high viability in the concentration level of, respectably, <70 and <5?g/mL. PMID:25527087

  5. Nab-paclitaxel monotherapy in refractory pancreatic adenocarcinoma

    PubMed Central

    Peddi, Parvin F.; Cho, May; Wang, Jian; Gao, Feng

    2013-01-01

    Background The standard of care in patients with metastatic pancreatic adenocarcinoma is undefined beyond second line of treatment. There have been scant reports of benefit from nab-paclitaxel in patients with refractory pancreatic cancer. Materials and methods A retrospective review was carried out in patients with pancreatic adenocarcinoma at Siteman Cancer Center, who had received nab-paclitaxel monotherapy after experiencing disease progression on standard treatments. Nab-paclitaxel was given either two out of every three weeks or three out of every four weeks. Results Twenty patients were identified and included for data analysis. Median age was 63.5 years old. All patients had previously received gemcitabine, while 40% had also received FOLFIRINOX. Median number of prior lines of systemic treatment was 2. Patients were treated for a median of 15 weeks, with a range of 1 to 41.7 weeks. Median dose of nab-paclitaxel was 100 mg/m2 with range of 75-125 mg/m2. Best response imaging was available in 17 patients and 11 out of the 17 patients (64.7%) had stable disease. Median progression-free survival (PFS) was 3.7 months and overall survival (OS) were 5.2 months. Most common treatment related toxicities included grade 1 pneumonitis in five patients (25%), grade 3 or 4 neutropenia in three patients (15%), and dehydration resulting in hospitalization in one patient (5%). Conclusions Nab-paclitaxel monotherapy had acceptable level of toxicity in a heavily pretreated patient population with pancreatic cancer and appeared to provide a clinical benefit. This agent is worthy of further prospective studies to evaluate extent of benefit after standard therapies have failed. PMID:24294508

  6. Ovarian epithelial carcinoma metastatic to the choroid of the eye: prolonged survival with radiation and taxol chemotherapy.

    PubMed

    Patsner, B

    1998-01-01

    A 64-year-old was diagnosed with a stage 1aII clear cell adenocarcinoma of the ovary in 1986. Initial chemotherapy was with Cisplatinum, Cytoxan, and Adriamycin. A pelvic recurrence developed in 1991 which failed to respond to Carboplatin therapy, and progression of disease with retroperitoneal nodal and choroidal metastases was noted in 1992. Debulking of retroperitoneal disease along with radiotherapy and seventeen cycles of Taxol chemotherapy resulted in a sustained clinical remission for three years until December 1995 when a right pelvic recurrence was noted. The patient underwent resection of disease again and was restarted on Taxol which was continued for six cycles until increasing serum CA-125 and recurrent pelvic disease were noted. PMID:9744722

  7. Protection of p53 Wild Type Cells From Taxol by Genistein in the Combined Treatment of Lung Cancer

    Microsoft Academic Search

    Sergey V. Tokalov; Andrij M. Abramyuk; Nasreddin D. Abolmaali

    2010-01-01

    This study specifies the basic principles to selectively kill p53-deficient cells (H1299, FaDu) by taxol and to protect p53 wild type cells (A549) by the prior administration of structurally related flavonoids (apigenin, genistein, and quercetin). Cytotoxic and cytostatic properties of flavonoids were investigated in vitro by flow cytometry and were compared to known anticancer drugs (cisplatin, doxorubicin, etoposide). It was

  8. GS164, a small synthetic compound, stimulates tubulin polymerization by a similar mechanism to that of Taxol

    Microsoft Academic Search

    Yasushi Shintani; Toshimasa Tanaka; Yukimasa Nozaki

    1997-01-01

    Purpose: During our search for new microtubule effectors as anticancer agents, we have found that a small synthetic molecule designated\\u000a GS-164 interferes with the assembly of porcine microtubule proteins and has cytotoxic activity against a wide range of human\\u000a tumor cell lines. In this study, we investigated mode of action of the compound in comparison with Taxol and colcemid. Methods:

  9. Synthesis and Biological Evaluation of a Biotinylated Paclitaxel with an Extra-Long Chain Spacer Arm

    PubMed Central

    2012-01-01

    A biotinylated paclitaxel derivative with an extra-long chain (LC-LC-biotin) spacer arm was synthesized using an improved synthetic reaction sequence. The biotinylated paclitaxel analogue retained excellent microtubule stabilizing activity in vitro. Furthermore, it was shown that this analogue can simultaneously engage streptavidin and the binding site on microtubules, making it suitable for localization studies or for the attachment of paclitaxel to solid substrates via a streptavidin linkage. PMID:23259031

  10. Role of Reoxygenation in Induction of Enhancement of Tumor Radioresponse by Paclitaxel1

    Microsoft Academic Search

    Luka Milus; Nancy R. Hunter; Kathryn A. Mason; Christopher G. Milross; Yoshihiro Saito; Lester J. Peters

    We reported previously(L. Milas et al., Cancer Res., 54: 3506-3510, 1994)that paclitaxel greatly enhances the response of a murine mammary carcinoma to subsequent irradiation and hypothesized that the enhanced radioresponse was mediated by tumor cell reoxygenation caused by treat ment with paclitaxel. Because paclitaxel induced massive tumor cell de struction by apoptosis, it was reasoned that as apoptotic cells were

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

    PubMed Central

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

    2011-01-01

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

  12. Weekly paclitaxel as second-line chemotherapy for advanced or recurrent gastric cancer

    Microsoft Academic Search

    Shuichi Hironaka; Sadamoto Zenda; Narikazu Boku; Akira Fukutomi; Takayuki Yoshino; Yusuke Onozawa

    2006-01-01

    Background  Paclitaxel scheduled every 3 weeks has shown a response rate of ?20% for gastric cancer, with modest hematological toxicity.\\u000a Weekly administration of paclitaxel in patients with breast or ovarian cancer has shown equivalent efficacy and milder toxicity\\u000a compared with an every-3 week schedule. We investigated, retrospectively, the antitumor effects and toxicity profiles of weekly\\u000a paclitaxel for patients with metastatic or

  13. Molecular Mechanism of Cell Apoptosis by Paclitaxel and Pirarubicin in a Human Osteosarcoma Cell Line

    Microsoft Academic Search

    Si-Yuan Liu; Shu-Xia Song; Liang Lin; Xing Liu

    2010-01-01

    Background: Paclitaxel and pirarubicin exhibit cytotoxic and antitumor activities. However, little is known about the apoptosis-inducing effects of paclitaxel and pirarubicin on human osteosarcoma MG-63 cells. Methods: The effects of paclitaxel and pirarubicin on cell cycle arrest and apoptosis were studied in MG-63 cells using flow cytometry. PCNA, Bcl-2, Bax, cyclin D1 and cyclin E expression was assessed by Western

  14. Weekly Low-Dose Carboplatin and Paclitaxel in the Treatment of Recurrent Ovarian and Peritoneal Cancer

    Microsoft Academic Search

    Laura J. Havrilesky; Angeles A. Alvarez; Robyn A. Sayer; Johnathan M. Lancaster; John T. Soper; Andrew Berchuck; Daniel L. Clarke-Pearson; Gustavo C. Rodriguez; Michael E. Carney

    2003-01-01

    Objectives. Weekly paclitaxel alone has moderate activity in the salvage treatment of recurrent ovarian cancer and is associated with a favorable toxicity profile. Combination paclitaxel and carboplatin is a well-established first-line regimen for ovarian cancer. The purpose of this study was to evaluate weekly low-dose paclitaxel and carboplatin in recurrent ovarian or peritoneal cancer.Methods. Patients with recurrent ovarian or peritoneal

  15. Pathological Analysis of Local Delivery of Paclitaxel Via a Polymer-Coated Stent

    Microsoft Academic Search

    Andrew Farb; Phillip F. Heller; Sweta Shroff; Linda Cheng; Frank D. Kolodgie; Andrew J. Carter; Douglas S. Scott; Jeffrey Froehlich; Renu Virmani

    2010-01-01

    Background—Paclitaxel can inhibit vascular smooth muscle proliferation in vitro, and early studies suggest that paclitaxel may be useful in preventing restenosis. Early and late intimal growth and local vascular pathological changes associated with paclitaxel delivered via stents have not been fully explored. Methods and Results—Localized drug delivery was accomplished with balloon-expandable stainless steel stents coated with a cross-linked biodegradable polymer,

  16. Protection of p53 wild type cells from taxol by genistein in the combined treatment of lung cancer.

    PubMed

    Tokalov, Sergey V; Abramyuk, Andrij M; Abolmaali, Nasreddin D

    2010-01-01

    This study specifies the basic principles to selectively kill p53-deficient cells (H1299, FaDu) by taxol and to protect p53 wild type cells (A549) by the prior administration of structurally related flavonoids (apigenin, genistein, and quercetin). Cytotoxic and cytostatic properties of flavonoids were investigated in vitro by flow cytometry and were compared to known anticancer drugs (cisplatin, doxorubicin, etoposide). It was confirmed that doxorubicin induced growth arrest and protected A549 cells from taxol while simultaneously killing or blocking H1299 and FaDu cancer cells. It was found that doxorubicin could be successfully substituted in this way by the isoflavone genistein used at physiologically relevant concentrations. The other compounds analyzed revealed less selectivity (apigenin, cisplatin) or demonstrated higher toxicity (cisplatin, etoposide, and quercetin). We concluded that genistein-based therapy may have antagonistic effects when combined with mitotic poisons. The proposed therapeutic strategy allows protection of p53 wild type cells from taxol and selectively increases apoptosis in p53-deficient cells. This strategy exploits the naturally occurring compound that can be used without significant toxicity in rather high concentrations as present in common diets. PMID:20661829

  17. A TPGS-incorporating nanoemulsion of paclitaxel circumvents drug resistance in breast cancer.

    PubMed

    Bu, Huihui; He, Xinyu; Zhang, Zhiwen; Yin, Qi; Yu, Haijun; Li, Yaping

    2014-08-25

    Paclitaxel resistance is usually developed in clinical chemotherapy, which remains a major obstacle for successful cancer treatment. Herein, we attempted to develop a TPGS incorporating nanoemulsion of paclitaxel (NE-PTX) to circumvent the drug resistance in breast cancer. NE-PTX was prepared by a self-assembly technique and the physicochemical properties were characterized. The efficacy of NE-PTX on overcoming paclitaxel resistance was measured by in vitro and in vivo evaluation. The measured results indicated that NE-PTX was nanometer-sized droplets with the mean diameter of 24.93±3.45 nm. The IC50 value of paclitaxel in resistant MCF-7/ADR cells was greatly reduced from 101.45 ?g/mL to 5.39 ?g/mL, which indicated that the paclitaxel resistance was effectively reduced by NE-PTX. The reversal of paclitaxel resistance could mainly ascribe to the significant inhibition of P-gp activity and enhancement of anti-cancer activity. Moreover, the tumor volume in resistant tumor xenograft model treated with NE-PTX was only 10.06% of that of paclitaxel solution group, and the tumor inhibitory rate of NE-PTX reached 93.84%, which effectively verified the efficacy of NE-PTX on treating paclitaxel resistance. Thereby, NE-PTX could provide an effective strategy for circumventing paclitaxel resistance in breast cancer. PMID:24866272

  18. Effect of osmotic pressure on paclitaxel production in suspension cell cultures of Taxus chinensis.

    PubMed

    Kim, S -I.; Choi, H -K.; Kim, J -H.; Lee, H -S.; Hong, S -S.

    2001-02-01

    The effect of osmotic pressure on paclitaxel production was investigated in the suspension cell cultures of Taxus chinensis. Paclitaxel production was definitely influenced by the initial sucrose concentration and the highest production yield was achieved at the concentration of 60 g.l(-1) sucrose (300 mOsm.kg(-1)). High osmotic pressure conditions generated by non-metabolic sugar (mannitol and sorbitol) also enhanced paclitaxel production by about two-fold. Kinetic studies revealed that high initial osmotic pressure enhanced paclitaxel production and that high concentration of sucrose was effective for sustaining secondary metabolism after induction of paclitaxel biosynthesis. Stoichiometric analysis with different combinations of sucrose and mannitol confirmed that osmotic pressure was the more important factor for enhancing paclitaxel metabolism. The addition of non-sugar osmotic agent, PEG also enhanced paclitaxel production. In this paper, we showed that high osmotic pressure led to increases in paclitaxel production and proposed that regulation of osmotic pressure may be useful in controlling paclitaxel production. PMID:11166813

  19. ING4 enhances paclitaxel’s effect on colorectal cancer growth in vitro and in vivo

    PubMed Central

    Cao, Liyu; Chen, Shunhua; Zhang, Cong; Chen, Cong; Lu, Nana; Jiang, Yan; Cai, Yongping; Yin, Yu; Xu, Jianming

    2015-01-01

    Inhibitor of growth 4 (ING4) is a tumor suppressor that can inhibit cell growth and induce apoptosis. ING4 expression levels show negative correlation with the clinical stage, histological grade, and lymph node metastasis of colorectal cancer. Further insights are needed to analyze the effect of adenovirus-mediated ING4 on colorectal cancer cell growth and the response to paclitaxel treatment. In this study, we found adenovirus-mediated ING4 expression reduced proliferation and enhanced apoptosis in the SW1116 cells. p-Stat3 and Ki-67 expression significantly decreased in the SW1116 cells treated with Ad-ING4, PTX, or Ad-ING4 + PTX compared with those treated with PBS or Ad-GFP both in vitro and in vivo (P < 0.05). In animal experiments, the mice treated with Ad-ING4, PTX, or Ad-ING4 + PTX exhibited significantly inhibited growth of SW1116 xenografts compared with those treated with PBS or Ad-GFP (P < 0.05) and the combination (Ad-ING4 + PTX) treatment exhibited the highest inhibition. Our results highlight that Ad-ING4 significantly inhibits growth and induces apoptosis in SW1116 colorectal cancer cells and suppresses tumor growth in SW1116 xenografts by downregulating p-Stat3 and Ki-67 expression. A combination of Ad-ING4 and PTX exhibits the highest inhibition, indicating that ING4 enhances sensitivity to chemotherapy.

  20. Paclitaxel resistance increases oncolytic adenovirus efficacy via upregulated CAR expression and dysfunctional cell cycle control.

    PubMed

    Ingemarsdotter, Carin K; Tookman, Laura A; Browne, Ashley; Pirlo, Katrina; Cutts, Rosalind; Chelela, Claude; Khurrum, Karisma F; Leung, Elaine Y L; Dowson, Suzanne; Webber, Lee; Khan, Iftekhar; Ennis, Darren; Syed, Nelofer; Crook, Tim R; Brenton, James D; Lockley, Michelle; McNeish, Iain A

    2015-04-01

    Resistance to paclitaxel chemotherapy frequently develops in ovarian cancer. Oncolytic adenoviruses are a novel therapy for human malignancies that are being evaluated in early phase trials. However, there are no reliable predictive biomarkers for oncolytic adenovirus activity in ovarian cancer. We investigated the link between paclitaxel resistance and oncolytic adenovirus activity using established ovarian cancer cell line models, xenografts with de novo paclitaxel resistance and tumour samples from two separate trials. The activity of multiple Ad5 vectors, including dl922-947 (E1A CR2-deleted), dl1520 (E1B-55K deleted) and Ad5 WT, was significantly increased in paclitaxel resistant ovarian cancer in vitro and in vivo. This was associated with greater infectivity resulting from increased expression of the primary receptor for Ad5, CAR (coxsackie adenovirus receptor). This, in turn, resulted from increased CAR transcription secondary to histone modification in resistant cells. There was increased CAR expression in intraperitoneal tumours with de novo paclitaxel resistance and in tumours from patients with clinical resistance to paclitaxel. Increased CAR expression did not cause paclitaxel resistance, but did increase inflammatory cytokine expression. Finally, we identified dysregulated cell cycle control as a second mechanism of increased adenovirus efficacy in paclitaxel-resistant ovarian cancer. Ad11 and Ad35, both group B adenoviruses that utilise non-CAR receptors to infect cells, are also significantly more effective in paclitaxel-resistant ovarian cell models. Inhibition of CDK4/6 using PD-0332991 was able both to reverse paclitaxel resistance and reduce adenovirus efficacy. Thus, paclitaxel resistance increases oncolytic adenovirus efficacy via at least two separate mechanisms - if validated further, this information could have future clinical utility to aid patient selection for clinical trials. PMID:25560085

  1. Breath alcohol concentrations in Japanese outpatients following paclitaxel and docetaxel infusion.

    PubMed

    Komagata, H; Yoneda, S; Sakai, H; Isobe, K; Shirai, T; Fujimura, M; Tabei, T; Inoue, K

    2005-01-01

    Patients receiving paclitaxel or docetaxel also receive a significant amount of ethanol, as both products contain ethanol as solvent. Patients in our clinics have occasionally exhibited signs of alcohol intoxication immediately after paclitaxel infusion. In 2002, the Japanese government lowered the minimum ethanol concentration for the definition of drunk driving, with the threshold breath alcohol concentration (BRAC) of 0.15 mg/l. The aim of this study was to measure BRAC in Japanese outpatients treated with paclitaxel or docetaxel and to assess intoxication according to this standard. Fifty-two Japanese patients were enrolled from October 2003 to February 2004. Patient characteristics were as follows: male/female, 13/39: median age, 71 (range: 34-78); breast/lung/ovarian cancer 24/16/12; and paclitaxel/docetaxel treatment: 36/16, respectively. The mean total doses of paclitaxel or docetaxel were 178 mg (range: 107-300) and 53 mg (30-100), respectively. Breath samples were measured three times immediately following the infusion of paclitaxel or docetaxel via ethyl alcohol detector and the mean value was recorded. BRAC was detected in 20 patients (56%) with paclitaxel and in none of the docetaxel patients. BRAC was measured again 30 min after the initial measurement in BRAC-detected cases with the patients' permission. In four of six BRAC-remeasured patients, BRAC became undetectable after 30 min. There was no correlation between the total doses of paclitaxel and BRAC or between the infusion rates of paclitaxel and BRAC. In conclusion, clinicians should recognize the potential for alcohol intoxication with paclitaxel administration. Patients should be instructed to avoid driving on the day of paclitaxel administration. PMID:16402636

  2. Secretory Leukocyte Protease Inhibitor, SLPI, Antagonizes Paclitaxel in Ovarian Cancer Cells

    PubMed Central

    Rasool, Nabila; LaRochelle, William; Zhong, Haihong; Ara, Gulshan; Cohen, Joshua; Kohn, Elise C.

    2009-01-01

    Purpose Ovarian cancer (OvCa) recurrence with development of paclitaxel resistance is an obstacle to long term survival. We demonstrated that secretory leukocyte protease inhibitor (SLPI) is a survival factor for OvCa. We hypothesize SLPI may antagonize paclitaxel injury. Experimental design Differential SLPI induction in response to paclitaxel, and response to stable forced expression of SLPI was demonstrated in A2780-1A9 cells and their paclitaxel-resistant sublines, PTX10 and PTX22 and confirmed with HEY-A8 cells. SLPI-mediated survival was reduced by the MEK inhibitor, U0126 and a humanized neutralizing monoclonal anti-SLPI antibody, CR012. OVCAR3 xenographs tested the role of CR012 in vivo. Results SLPI expression was lower in A2780-1A9 OvCa cells than PTX10 and PTX22 and SLPI was induced by paclitaxel exposure. Stable SLPI expression yielded a proliferation advantage (p=0.01); expression of and response to SLPI in OVCAR3 cells was abrogated by exposure to CR012. SLPI reduced paclitaxel susceptibility of 1A9 and HEY-A8 cells (p?0.05) and SLPI expression did not increase resistance of PTX10 and ?22 cells. Both paclitaxel and SLPI overexpression induced ERK activation. Inhibition of MEK with U0126 increased paclitaxel injury and overcame SLPI-mediated cell protection. It did not reinstate PTX10 sensitivity to paclitaxel, which was associated with AKT activation. Significant inhibition of OVCAR3 xenograft growth was observed with CR012 and paclitaxel, over single agents (p?0.001). Conclusions A two-pronged approach confirmed SLPI overcomes paclitaxel in part through activation of ERK1/2. These results credential SLPI as a molecular target for OvCa and suggest CR012 as a tool for proof of concept. PMID:20068074

  3. Transcriptomic profiling of taxol-resistant ovarian cancer cells identifies FKBP5 and the androgen receptor as critical markers of chemotherapeutic response

    PubMed Central

    Chang, Pu-Yuan; Lu, Hsing-Pang; Chao, Chuck C.-K.

    2014-01-01

    Taxol is a mitotoxin widely used to treat human cancers, including of the breast and ovary. However, taxol resistance (txr) limits treatment efficacy in human patients. To study chemoresistance in ovarian cancer, we established txr ovarian carcinoma cells derived from the SKOV3 cell lineage. The cells obtained were cross-resistant to other mitotoxins such as vincristine while they showed no resistance to the genotoxin cisplatin. Transcriptomic analysis identified 112 highly up-regulated genes in txr cells. Surprisingly, FK506-binding protein 5 (FKBP5) was transiently up-regulated 100-fold in txr cells but showed decreased expression in prolonged culture. Silencing of FKBP5 sensitized txr cells to taxol, whereas ectopic expression of FKBP5 increased resistance to the drug. Modulation of FKBP5 expression produced similar effects in response to vincristine but not to cisplatin. We observed that a panel of newly identified txr genes was trancriptionally regulated by FKBP5 and silencing of these genes sensitized cells to taxol. Notably, immunoprecipitation experiments revealed that FKBP5 forms a protein complex with the androgen receptor (AR), and this complex regulates the transcriptional activity of both proteins. Furthermore, we found that the Akt kinase pathway is regulated by FKBP5. These results indicate that the FKBP5/AR complex may affect cancer cell sensitivity to taxol by regulating expression of txr genes. Our findings suggest that mitotoxin-based treatment against ovarian cancer should be avoided when the Akt/FKBP5/AR axis is activated. PMID:25460502

  4. Short Communication Coating with paclitaxel improves graft survival in a porcine model of

    E-print Network

    Park, Jong-Sang

    implanted four pairs of paclitaxel-coated grafts and four pairs of control grafts in eight Landrace pigsShort Communication Coating with paclitaxel improves graft survival in a porcine model cause of failure of polytetra- fluoroethylene (PTFE) dialysis grafts. We recently reported that coating

  5. Neurotropin reverses paclitaxel-induced neuropathy without affecting anti-tumour efficacy.

    PubMed

    Kawashiri, Takehiro; Egashira, Nobuaki; Itoh, Yoshinori; Shimazoe, Takao; Ikegami, Yoko; Yano, Takahisa; Yoshimura, Megumu; Oishi, Ryozo

    2009-01-01

    Paclitaxel is a commonly used anticancer drug, but it frequently causes peripheral neuropathy. Neurotropin, a non-protein extract from inflamed rabbit skin inoculated with vaccinia virus, has been used to treat various chronic painful conditions. In the present study, we investigated the effect of neurotropin on the paclitaxel-induced neuropathy in rats. Repeated administration of paclitaxel induced mechanical allodynia, cold hyperalgesia, and motor dysfunction. These neuropathies were mostly reversed by the repeated administration of neurotropin. Furthermore, neurotropin ameliorated the paclitaxel-induced axonal degeneration in cultured PC12 and rat dorsal root ganglion cells, and in rat sciatic nerve. In addition, neurotropin did not affect the microtubule aggregation or anti-tumour effect induced by paclitaxel in the tumour cell lines or tumour cells-implanted mice. These results suggest that neurotropin reverses the paclitaxel-induced neuropathy without affecting anti-tumour activity of paclitaxel, and therefore may be useful for the paclitaxel-induced neuropathy in clinical settings. PMID:19027286

  6. Low-Dose Oxaliplatin Enhances the Antitumor Efficacy of Paclitaxel in Human Gastric Cancer Cell Lines

    Microsoft Academic Search

    Jinyu Gu; Hirofumi Yamamoto; Xueying Lu; Chew Yee Ngan; Tadashi Tsujino; Ken Konishi; Ichiro Takemasa; Masataka Ikeda; Hiroshi Nagata; Shusuke Hashimoto; Takeshi Matsuzaki; Mitsugu Sekimoto; Akimitsu Takagi; Morito Monden

    2006-01-01

    Background: The enhanced antitumor effect of paclitaxel when used with oxaliplatin in gastric cancer is reported, however the underlying biological mechanism is unknown. Methods: We tested the cytotoxic activity, apoptosis, and mitotic catastrophe of paclitaxel and oxaliplatin in MKN-28 and MKN-45 gastric cancer cell lines. The modulation of survivin expression was determined by Western blotting. Results: WST-1 assay indicated that

  7. Preparation and biological activity of a paclitaxel-single-walled carbon nanotube complex.

    PubMed

    Fu, X D; Zhang, Y Y; Wang, X J; Shou, J X; Zhang, Z Z; Song, L J

    2014-01-01

    Single-walled carbon nanotubes (SWCNTs) have unique transmembrane abilities. The huge superficial area and abundance of ? electrons confer SWCNTs perfect absorptive capability toward proteins, nucleates, and many drugs. These characteristics make SWCNTs a new and efficient drug carrier. The purpose of this study was to disperse SWCNTs in water and have paclitaxel absorbed onto them in order to construct an asparagine-glycine-arginine (NGR)-SWCNT-Paclitaxel complex as a targeting nanoparticle system. The NGR-SWCNT-Paclitaxel complex was systematically studied, and analytical methods, including spectrophotometry for SWCNTs and high-performance liquid chromatography for paclitaxel, were employed. The preparation and the prescription of the NGR-SWCNT-Paclitaxel complex lyophilized powder were investigated. MCF-7 cancer cells, Sprague-Dawley rats, and S180 tumor-bearing mice were used as experimental subjects to evaluate the in vitro and in vivo activity of NGR-SWCNT-Paclitaxel complex dispersion. The complex dispersion showed obvious inhibition activity against MCF-7 cancer cells. Within 1 h, the NGR-SWCNT-Paclitaxel complex could be transferred to cells, and sustained the release of drugs. In addition, the tumor and liver targeting and improved therapeutic effects of the NGR-SWCNT-Paclitaxel complex were confirmed. PMID:24668633

  8. First line treatment of advanced non-small-cell lung cancer - specific focus on albumin bound paclitaxel.

    PubMed

    Gupta, Neha; Hatoum, Hassan; Dy, Grace K

    2014-01-01

    Lung cancer is the leading cause of cancer mortality worldwide in both men and women. Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for more than 80% of cases. Paclitaxel has a broad spectrum of activity against various malignancies, including NSCLC. Paclitaxel is poorly soluble in water and thus, until recently, its commercially available preparations contained a non-ionic solvent Cremophor EL®. Cremophor EL® improves the solubility of paclitaxel and allows its intravenous administration. However, certain side-effects associated with paclitaxel, such as hypersensitivity reactions, myelosuppression, and peripheral neuropathy, are known to be worsened by Cremophor®. Nanoparticle albumin-bound paclitaxel ([nab-paclitaxel] ABRAXANE® ABI-007) is a new generation formulation of paclitaxel that obviates the need for Cremophor®, resulting in a safer and faster infusion without requiring the use of premedications to avoid hypersensitivity. Albumin-binding receptor-mediated delivery and lack of sequestering Cremophor® micelles allow higher intratumoral concentration of pharmacologically active paclitaxel. Multiple clinical trials have demonstrated a superior tolerability profile of nab-paclitaxel in comparison to solvent-bound paclitaxel (sb-paclitaxel). A recent Phase III trial compared the effects of weekly nab-paclitaxel in combination with carboplatin versus sb-paclitaxel in combination with carboplatin given every 3 weeks for first line treatment of NSCLC. This trial highlights the weekly nab-paclitaxel combination as an alternate treatment option for NSCLC, with higher response rate in squamous cell NSCLC and longer survival in elderly patients. This review will focus on the properties of nab-paclitaxel and its use in the first line treatment of NSCLC. PMID:24399877

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

    PubMed

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

    2013-01-01

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

  10. 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

  11. Apoptosis induced by paclitaxel-loaded copolymer PLA–TPGS in Hep-G2 cells

    NASA Astrophysics Data System (ADS)

    Nguyen, Hoai Nam; Tran Thi, Hong Ha; Le Quang, Duong; Nguyen Thi, Toan; Tran Thi, Nhu Hang; Huong Le, Mai; Thu Ha, Phuong

    2012-12-01

    Paclitaxel is an important anticancer drug in clinical use for treatment of a variety of cancers. The clinical application of paclitaxel in cancer treatment is considerably limited due to its serious poor delivery characteristics. In this study paclitaxel-loaded copolymer poly(lactide)–d-?-tocopheryl polyethylene glycol 1000 succinate (PLA–TPGS) nanoparticles were prepared by a modified solvent extraction/evaporation technique. The characteristics of the nanoparticles, such as surface morphology, size distribution, zeta potential, solubility and apoptosis were investigated in vitro. The obtained spherical nanoparticles were negatively charged with a zeta potential of about ?18 mV with the size around 44 nm and a narrow size distribution. The ability of paclitaxel-loaded PLA–TPGS nanoparticles to induce apoptosis in human hepatocellular carcinoma cell line (Hep-G2) indicates the possibility of developing paclitaxel nanoparticles as a potential universal cancer chemotherapeutic agent.

  12. Submicromolar paclitaxel induces apoptosis in human gastric cancer cells at early G1 phase.

    PubMed

    Lin, H L; Chang, Y F; Liu, T Y; Wu, C W; Chi, C W

    1998-01-01

    Paclitaxel induced apoptosis has been reported in many cancer cell lines, but the relationship between G2/M phase arrest and apoptosis is not clear. We have reported that low dose (10 nM) paclitaxel induced apoptosis in gastric cancer cells without G2/M phase arrest. In this study, SC-M1 gastric cancer cells were synchronized at early G1, late G1, S and G2/M phases by staurosporine, mimosine, hydroxyurea and berberine, respectively. We have found that paclitaxel could not induce apoptosis of gastric cancer cells in late G1, S and G2/M phases; however, paclitaxel induced apoptosis in the early G1 phase. Our results suggest that cells arrested at G2/M phase by paclitaxel eventually entered the early G1 phase then proceeded to apoptosis. PMID:9858922

  13. Water-soluble prodrugs of paclitaxel containing self-immolative disulfide linkers.

    PubMed

    Gund, Machhindra; Khanna, Amit; Dubash, Nauzer; Damre, Anagha; Singh, Kishore S; Satyam, Apparao

    2015-01-01

    A new series of disulfide-containing prodrugs of paclitaxel were designed, synthesized and evaluated against 6 cancer cell lines. Some of these prodrugs exhibited nearly equal or slightly better anticancer activity when compared to that of paclitaxel. These prodrugs contain water-soluble groups such as amino, carboxyl, hydroxyl, amino acids, etc., and exhibited 6-140 fold increase in aqueous solubility when compared to paclitaxel. One of these prodrugs exhibited improved water solubility, better in vitro anticancer activity and significantly superior oral bioavailability in mice when compared to those of paclitaxel. Thus, we have identified a very promising lead compound for further optimization and evaluation as a potentially bioavailable water-soluble prodrug of paclitaxel. PMID:25466201

  14. Taxol-induced unfolded protein response activation in breast cancer cells exposed to hypoxia: ATF4 activation regulates autophagy and inhibits apoptosis.

    PubMed

    Notte, Annick; Rebucci, Magali; Fransolet, Maude; Roegiers, Edith; Genin, Marie; Tellier, Celine; Watillon, Kassandra; Fattaccioli, Antoine; Arnould, Thierry; Michiels, Carine

    2015-05-01

    Understanding the mechanisms responsible for the resistance against chemotherapy-induced cell death is still of great interest since the number of patients with cancer increases and relapse is commonly observed. Indeed, the development of hypoxic regions as well as UPR (unfolded protein response) activation is known to promote cancer cell adaptive responses to the stressful tumor microenvironment and resistance against anticancer therapies. Therefore, the impact of UPR combined to hypoxia on autophagy and apoptosis activation during taxol exposure was investigated in MDA-MB-231 and T47D breast cancer cells. The results showed that taxol rapidly induced UPR activation and that hypoxia modulated taxol-induced UPR activation differently according to the different UPR pathways (PERK, ATF6, and IRE1?). The putative involvement of these signaling pathways in autophagy or in apoptosis regulation in response to taxol exposure was investigated. However, while no link between the activation of these three ER stress sensors and autophagy or apoptosis regulation could be evidenced, results showed that ATF4 activation, which occurs independently of UPR activation, was involved in taxol-induced autophagy completion. In addition, an ATF4-dependent mechanism leading to cancer cell adaptation and resistance against taxol-induced cell death was evidenced. Finally, our results demonstrate that expression of ATF4, in association with hypoxia-induced genes, can be used as a biomarker of a poor prognosis for human breast cancer patients supporting the conclusion that ATF4 might play an important role in adaptation and resistance of breast cancer cells to chemotherapy in hypoxic tumors. PMID:25724736

  15. Molecular cloning and heterologous expression of the C-13 phenylpropanoid side chain-CoA acyltransferase that functions in Taxol biosynthesis

    PubMed Central

    Walker, Kevin; Fujisaki, Shingo; Long, Robert; Croteau, Rodney

    2002-01-01

    The structural pharmacophore of Taxol, responsible for binding the N terminus of the ?-subunit of tubulin to arrest cell proliferation, comprises, in part, the 13-O-(N-benzoyl-3-phenylisoserinoyl) side chain. To identify the side chain transferase of Taxol biosynthesis, a set of transacylases obtained from an enriched cDNA library (constructed from mRNA isolated from Taxus cuspidata cells induced with methyl jasmonate for Taxol production) was screened. A cDNA clone (designated TAX7) encoding a taxoid C-13 O-phenylpropanoyltransferase was isolated which yielded a recombinant enzyme that catalyzes the selective 13-O-acylation of baccatin III with ?-phenylalanoyl CoA as the acyl donor to form N-debenzoyl-2?-deoxytaxol. This enzymatic product was converted to 2?-deoxytaxol by chemical N-benzoylation, and the identity of this derivative was confirmed by spectrometric analyses. The full-length cDNA has an ORF of 1,335 bases and encodes a 445-aa protein with a calculated molecular weight of 50,546. Evaluation of kinetic parameters revealed Km values of 2.4 ± 0.5 ?M and 4.9 ± 0.3 ?M for baccatin III and ?-phenylalanoyl-CoA, respectively. The pH optimum for the recombinant O-(3-amino-3-phenylpropanoyl)transferase is at 6.8. Identification of this clone completes acquisition of the five aroyl/acyltransferases involved in the biosynthesis of Taxol. Application of these transacylase genes in suitable host cells can improve the production yields of Taxol and could enable the preparation of second-generation Taxol analogs possessing greater bioactivity and improved water solubility. PMID:12232048

  16. Pharmacokinetics and pharmacodynamics of nab-paclitaxel in patients with solid tumors: disposition kinetics and pharmacology distinct from solvent-based paclitaxel.

    PubMed

    Chen, Nianhang; Li, Yan; Ye, Ying; Palmisano, Maria; Chopra, Rajesh; Zhou, Simon

    2014-10-01

    The aim of this study was to characterize population pharmacokinetics and the exposure-neutropenia relationship with nanoparticle albumin-bound (nab)-paclitaxel in patients with solid tumors. Plasma and blood concentrations of paclitaxel and neutrophil data were collected from 150 patients with various solid tumors over the nab-paclitaxel dose range of 80-375 mg/m(2). Data were analyzed using nonlinear mixed-effect modeling or logistic regression. Pharmacokinetics of nab-paclitaxel were described by a 3-compartment model with saturable distribution and elimination. The rapid disappearance of circulating paclitaxel was driven by its fast distribution to peripheral compartments; maximum rate for saturable distribution (325000 ?g/h) was 40-fold greater than that for saturable elimination (8070 ?g/h). Albumin was a significant covariate of paclitaxel elimination (P

  17. Physico chemical characterization of a novel anti-cancer agent and its comparison to Taxol(®).

    PubMed

    Shah, Amit K; Wyandt, Christy M; Stodghill, Steven P

    2013-01-01

    Every year several thousand compounds are screened for their anti-cancer activity by a general test procedure amongst which only few selected move past the in vitro screening process. This may be due to the intrinsic property of the drug substance. Therefore, a complete physicochemical characterization of a New Chemical Entity (NCE) is essential to understand the effect of these properties on the in vitro and possibly in vivo behavior of these compounds. Various physicochemical properties such as dissociation constant, octanol-water partition co-efficient, pH solubility, stability, thermal characterization and membrane permeability were evaluated for a novel tubulin-binding agent JCA112 and were compared to that of Taxol(®). The drug exhibited a pKa value of 10.9, log P value of 2.3, pH dependent solubility, and low artificial membrane permeability. Stability of the drug substance in the in vitro screening media suggested a significant degradation during the 48-hour study duration. The results demonstrate that due to low aqueous solubility, limited membrane permeability and due to insufficient stability of JCA112 in the in vitro screening media, the drug exhibited limited anti-cancer activity. Along with challenging physicochemical characteristics, a generalization of the in vitro testing procedure may also result in loss of important anti-cancer agents. As a result, a complete understanding of the physico-chemical properties of the drug leading to prototype formulation with acceptable physico-chemical properties may be required for successful in vitro screening. PMID:22339150

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

    PubMed

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

    2015-07-13

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2015-05-15

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

  1. A novel polymer-paclitaxel conjugate based on amphiphilic triblock copolymer.

    PubMed

    Xie, Zhigang; Guan, Huili; Chen, Xuesi; Lu, Changhai; Chen, Li; Hu, Xiuli; Shi, Quan; Jing, Xiabin

    2007-02-12

    A novel amphiphilic polymer-paclitaxel conjugate P(LGG-paclitaxel)-PEG-P(LGG-paclitaxel) has been prepared. It was derived from its parent polymer P(LGG)-PEG-P(LGG), poly{(lactic acid)-co-[(glycolic acid)-alt-(l-glutamic acid)]}-block-poly(ethylene glycol)-block-poly{(lactic acid)-co-[(glycolic acid)-alt-(l-glutamic acid)]}, which was prepared by ring-opening copolymerization of l-lactide (LLA) with (3s)-benzoxylcarbonylethyl-morpholine-2,5-dione (BEMD) in the presence of dihydroxyl PEG with molecular weight of 4600 as a macroinitiator using stannous octoate (Sn(Oct)(2)) as catalyst, and by subsequent catalytic hydrogenation. It could self-assemble into micelles in an aqueous system with P(LGG-paclitaxel) block in the core and PEG in the shell. ESEM and DLS analysis of the micelles revealed a homogeneous spherical morphology and a unimodal size distribution. In vitro release of paclitaxel from the conjugate micelles showed that its release rate depended on pH value and was higher at lower pH than in neutral condition. In vitro antitumor activity of the paclitaxel conjugate against rat brain glioma C6 cells was evaluated by MTT method. The results showed that the paclitaxel can be released from the conjugate without losing cytotoxicity. PMID:17188776

  2. Effects of goshajinkigan, hachimijiogan, and rokumigan on mechanical allodynia induced by Paclitaxel in mice.

    PubMed

    Andoh, Tsugunobu; Kitamura, Ryo; Fushimi, Hirotoshi; Komatsu, Katsuko; Shibahara, Naotoshi; Kuraishi, Yasushi

    2014-10-01

    Peripheral neuropathy is a major dose-limiting side effect of the chemotherapeutic agent paclitaxel. This study examined whether the three related traditional herbal formulations, goshajinkigan (GJG; Niú Ch? Shèn Qì Wán), hachimijiogan (HJG; B? Wèi Dì Huáng Wán), and rokumigan (RMG; Liù Wèi Wán), would relieve paclitaxel-induced mechanical allodynia in mice. A single intraperitoneal injection of paclitaxel (5 mg/kg) induced mechanical allodynia, which peaked on day 14 after injection. On day 14 after paclitaxel injection, oral administration of GJG (0.1-1.0 g/kg) produced a significant inhibition of established allodynia, but HJG and RMG did not affect the allodynia. Repeated oral administration of GJG (0.1-1.0 g/kg) starting from the day after paclitaxel injection did not affect allodynia development, but significantly inhibited allodynia exacerbation. Repeated oral administration of HJG produced a slight inhibition of allodynia exacerbation, but that of RMG did not. These results suggest that prophylactic administration of GJG is effective in preventing the exacerbation of paclitaxel-induced allodynia. The herbal medicines Plantaginis Semen ( Ch? Qián Z?) and Achyranthis Radix ( Niú X?), which are present in GJG but not in HJG, may contribute to the inhibitory action of GJG on the exacerbation of paclitaxel-induced allodynia. PMID:25379475

  3. Novel core-shell magnetic nanoparticles for Taxol encapsulation in biodegradable and biocompatible block copolymers: preparation, characterization and release properties.

    PubMed

    Filippousi, Maria; Papadimitriou, Sofia A; Bikiaris, Dimitrios N; Pavlidou, Eleni; Angelakeris, Mavroeidis; Zamboulis, Dimitris; Tian, He; Van Tendeloo, Gustaaf

    2013-05-01

    Theranostic polymeric nanocarriers loaded with anticancer drug Taxol and superparamagnetic iron oxide nanocrystals have been developed for possible magnetic resonance imaging (MRI) use and cancer therapy. Multifunctional nanocarriers with a core-shell structure have been prepared by coating superparamagnetic Fe3O4 nanoparticles with block copolymer of poly(ethylene glycol)-b-poly(propylene succinate) with variable molecular weights of the hydrophobic block poly(prolylene succinate). The multifunctional polymer nano-vehicles were prepared using a nanoprecipitation method. Scanning transmission electron microscopy revealed the encapsulation of magnetic nanoparticles inside the polymeric matrix. Energy dispersive X-ray spectroscopy and electron energy loss spectroscopy mapping allowed us to determine the presence of the different material ingredients in a quantitative way. The diameter of the nanoparticles is below 250 nm yielding satisfactory encapsulation efficiency. The nanoparticles exhibit a biphasic drug release pattern in vitro over 15 days depending on the molecular weight of the hydrophobic part of the polymer matrix. These new systems where anti-cancer therapeutics like Taxol and iron oxide nanoparticles (IOs) are co-encapsulated into new facile polymeric nanoparticles, could be addressed as potential multifunctional vehicles for simultaneous drug delivery and targeting imaging as well as real time monitoring of therapeutic effects. PMID:23524084

  4. 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. PMID:25122070

  5. Effect of maceligan on the systemic exposure of paclitaxel: in vitro and in vivo evaluation.

    PubMed

    Qiang, Fu; Lee, Beom-Jin; Ha, Ilho; Kang, Keon Wook; Woo, Eun-Rhan; Han, Hyo-Kyung

    2010-10-01

    This study investigated the effect of macelignan on the P-glycoprotein-mediated drug efflux as well as CYP3A4-mediated drug metabolism and subsequently its in vivo implication on the bioavailability of paclitaxel. The inhibition effect of macelignan on the CYP3A4-mediated metabolism was negligible over the concentration range of 0.01-100muM in rat liver microsome while approximately 33% inhibition was observed at 100muM in human liver microsome, implying that the interaction of macelignan with CYP3A4 might be insignificant at the physiologically achievable concentrations. In contrast, macelignan (20muM) increased the cellular accumulation of paclitaxel by approximately 1.7-fold in NCI/ADR-RES cells overexpressing P-gp, while it did not alter the cellular accumulation of paclitaxel in OVCAR-8 cells lacking P-gp. The effect of macelignan on the systemic exposure of paclitaxel was also examined in rats after the intravenous and oral administration of paclitaxel in the presence and the absence of macelignan. The concurrent use of macelignan significantly (p<0.05) enhanced the oral exposure of paclitaxel in rats while it did not affect the intravenous pharmacokinetics of paclitaxel, implying that macelignan might be more effective to improve the intestinal absorption rather than reducing hepatic elimination. In conclusion, macelignan appeared to be effective to improve the cellular accumulation as well as oral exposure of paclitaxel mainly via the inhibition of P-gp-mediated cellular efflux, suggesting that the concomitant use of macelignan may provide a therapeutic benefit in improving the anticancer efficacy of paclitaxel. PMID:20600879

  6. 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

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

    PubMed

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

    2013-01-01

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

  8. Synthetic galectin-3 inhibitor increases metastatic cancer cell sensitivity to taxol-induced apoptosis in vitro and in vivo.

    PubMed

    Glinsky, Vladislav V; Kiriakova, Galina; Glinskii, Olga V; Mossine, Valeri V; Mawhinney, Thomas P; Turk, James R; Glinskii, Anna B; Huxley, Virginia H; Price, Janet E; Glinsky, Gennadi V

    2009-09-01

    At present, there is no efficient curative therapy for cancer patients with advanced metastatic disease. Targeting of antiapoptotic molecules acting on the mitochondrial apoptosis pathway could potentially augment antimetastatic effect of cytotoxic drugs. Similarly to Bcl-2 family members, beta-galactoside-binding lectin galectin-3 protects cancer cells from apoptosis induced by cytotoxic drugs through the mitochondrial pathway. In this study, we tested the hypothesis that inhibiting galectin-3 antiapoptotic function using a synthetic low-molecular weight carbohydrate-based compound lactulosyl-L-leucine (Lac-L-Leu) will augment apoptosis induced in human cancer cells by paclitaxel and increase its efficacy against established metastases. Treatment with synthetic glycoamine Lac-L-Leu alone reduced the number of established MDA-MB-435Lung2 pulmonary metastases 5.5-fold (P = .032) but did not significantly affect the incidence of metastasis. Treatment with paclitaxel alone (10 mg/kg three times with 3-day intervals) had no significant effect on the incidence or on the number of MDA-MB-435Lung2 metastases. Treatment with Lac-L-Leu/paclitaxel combination decreased both the number (P = .02) and the incidence (P = .001) of pulmonary metastases, causing a five-fold increase in the number of metastasis-free animals from 14% in the control group to 70% in the combination therapy group. The median number of lung metastases dropped to 0 in the combination therapy group compared with 11 in the control (P = .02). Synergistic inhibition of clonogenic survival and induction of apoptosis in metastatic cells by Lac-L-Leu/paclitaxel combination was functionally linked with an increase in mitochondrial damage and was sufficient for the antimetastatic activity that caused a reversal and eradication of advanced metastatic disease in 56% of experimental animals. PMID:19724684

  9. Synthetic Galectin-3 Inhibitor Increases Metastatic Cancer Cell Sensitivity to Taxol-Induced Apoptosis In Vitro and In Vivo1

    PubMed Central

    Glinsky, Vladislav V; Kiriakova, Galina; Glinskii, Olga V; Mossine, Valeri V; Mawhinney, Thomas P; Turk, James R; Glinskii, Anna B; Huxley, Virginia H; Price, Janet E; Glinsky, Gennadi V

    2009-01-01

    At present, there is no efficient curative therapy for cancer patients with advanced metastatic disease. Targeting of antiapoptotic molecules acting on the mitochondrial apoptosis pathway could potentially augment antimetastatic effect of cytotoxic drugs. Similarly to Bcl-2 family members, ?-galactoside-binding lectin galectin-3 protects cancer cells from apoptosis induced by cytotoxic drugs through the mitochondrial pathway. In this study, we tested the hypothesis that inhibiting galectin-3 antiapoptotic function using a synthetic low-molecular weight carbohydrate-based compound lactulosyl-l-leucine (Lac-l-Leu) will augment apoptosis induced in human cancer cells by paclitaxel and increase its efficacy against established metastases. Treatment with synthetic glycoamine Lac-l-Leu alone reduced the number of established MDA-MB-435Lung2 pulmonary metastases 5.5-fold (P = .032) but did not significantly affect the incidence of metastasis. Treatment with paclitaxel alone (10 mg/kg three times with 3-day intervals) had no significant effect on the incidence or on the number of MDA-MB-435Lung2 metastases. Treatment with Lac-l-Leu/paclitaxel combination decreased both the number (P = .02) and the incidence (P = .001) of pulmonary metastases, causing a five-fold increase in the number of metastasis-free animals from 14% in the control group to 70% in the combination therapy group. The median number of lung metastases dropped to 0 in the combination therapy group compared with 11 in the control (P = .02). Synergistic inhibition of clonogenic survival and induction of apoptosis in metastatic cells by Lac-l-Leu/paclitaxel combination was functionally linked with an increase in mitochondrial damage and was sufficient for the antimetastatic activity that caused a reversal and eradication of advanced metastatic disease in 56% of experimental animals. PMID:19724684

  10. Evaluation of the effect of the chiral centers of Taxol on binding to ?-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 ?-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 ?-tubulin. PMID:25854803

  11. Tau-isoform dependent enhancement of taxol mobility through microtubules HyunJoo Park a,b,*, MahnWon Kim a,1

    E-print Network

    Fygenson, Deborah Kuchnir

    Tau-isoform dependent enhancement of taxol mobility through microtubules HyunJoo Park a,b,*, Mahn recovery after photobleaching (FRAP) Microtubules Microtubule-associated protein Tau Rebinding Kinetic modeling Transport though pores Competition a b s t r a c t Tau, a family of microtubule

  12. Preparation, physical characterization and pharmacokinetic study of paclitaxel nanocrystals.

    PubMed

    Wei, Lisha; Ji, Yanxia; Gong, Wei; Kang, Zhenqiao; Meng, Meng; Zheng, Aiping; Zhang, Xiaoyan; Sun, Jianxu

    2014-08-26

    Abstract Paclitaxel (PTX) is a natural broad-spectrum anticancer drug with poor aqueous solubility. PTX nanocrystals were formulated to improve the water solubility, and PTX nanosuspensions were prepared using anti-solvent precipitation, and then organic solvent and surfactants were removed by filtering through a vacuum system. The physical characterization of PTX nanocrystals were measured by transmission electron microscope, X-ray diffraction and differential scanning calorimetry. In addition, saturation solubility, in vitro release, stability and pharmacokinetic characteristics were examined. The average particle size of PTX nanocrystals was ?200?nm, and they had a stable potential and a uniform distribution. Paclitaxel nanocrystals can effectively improve drug solubility and in vitro release. PTX pharmacokinetic and tissue distribution studies were compared after intravenous administration of nanocrystals versus a commercial injection formulation. PTX nanocrystals were rapidly distributed with a longer elimination phase. Moreover, tissue distribution indicated that PTX nanocrystals are mainly absorbed by the liver and spleen and may offer reduced renal and cardiovascular toxicity which may reduce side effects. PMID:25156484

  13. Doxorubicin and paclitaxel loaded microbubbles for ultrasound triggered drug delivery

    PubMed Central

    Cochran, Michael C.; Eisenbrey, John; Ouma, Richard O.; Soulen, Michael; Wheatley, Margaret A.

    2011-01-01

    A polymer ultrasound contrast agent (UCA) developed in our lab has been shown to greatly reduce in size when exposed to ultrasound, resulting in nanoparticles less than 400 nm in diameter capable of escaping the leaky vasculature of a tumor to provide a sustained release of drug. Previous studies with the hydrophilic drug doxorubicin (DOX) demonstrated enhanced drug delivery to tumors when triggered with ultrasound. However the therapeutic potential has been limited due to the relatively low payload of DOX. This study compares the effects of loading the hydrophobic drug paclitaxel (PTX) on the agent’s acoustic properties, drug payload, tumoricidal activity, and the ability to deliver drugs through 400 nm pores. A maximum payload of 129.46 ± 1.80 ?g PTX/mg UCA (encapsulation efficiency 71.92 ± 0.99 %) was achieved, 20 times greater than the maximum payload of DOX (6.2 ?g/mg), while maintaining the acoustic properties. In vitro, the tumoricidal activity of paclitaxel loaded UCA exposed to ultrasound was significantly greater than controls not exposed to ultrasound (p<0.0016). This study has shown that PTX loaded UCA triggered with focused ultrasound have the potential to provide a targeted and sustained delivery of drug to tumors. PMID:21609756

  14. 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 molecules and lipids. The strength of this electrostatic energetic coupling determines the stability of the drug-induced ion pores. These findings may elucidate cytotoxic effects of chemotherapy drugs and aid in the development of novel drugs for a broad spectrum of cancers and other diseases.

  15. A case of relapsed visceral Kaposi's sarcoma with bilateral chylothoraces successfully treated with paclitaxel.

    PubMed

    Natarajan, Pavithra; Miller, Alastair

    2015-07-01

    Chylothorax is a rare complication of visceral Kaposi's sarcoma. We report a case with bilateral chylothoraces secondary to relapsed visceral Kaposi's sarcoma who was successfully treated with paclitaxel chemotherapy. PMID:25122577

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

    NASA Astrophysics Data System (ADS)

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

    2014-05-01

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

  17. Sensitivity and mechanisms of taxol-resistant prostate adenocarcinoma cells to Vernonia amygdalina extract

    PubMed Central

    Cameron, Keyuna S.; Howard, Carolyn B.; Izevbigie, Ernest B.; Hill, Brandon J.; Tchounwou, Paul B.

    2012-01-01

    Prostate cancer (PC) patients once Paclitaxel (TAX) treatment responsive later develop hormone refractory PC, thus becoming TAX-insensitive. This underscores the urgent need to develop novel anti-PC therapies. Vernonia amygdalina (VA) could be one such candidate agent. We have shown that androgen-independent PC-3 cells are sensitive to VA treatment in-vitro. VA extract (0.01, 0.1 and 1mg/ml) inhibited DNA synthesis by 12%, 45%, (P<0.05), and 73% (P<0.01) respectively. In contrast, TAX (0.01, 0.1, and 1?M) failed to significantly affect cell growth, suggesting TAX resistance. We tested molecular mechanisms which may lend to the observed PC-3 cell VA sensitivity/TAX resistance. Though both VA and TAX stimulated MAPK activity, VA’s induction was more intense, but transient, compared to TAX’s sustained action. NF-?B activation was inhibited on average by 50% by either 1mg/ml VA or 1 ?M TAX. VA extract caused 35% and 45% increases in c-Myc activity at 10 and 60 min intervals respectively, with the highest stimulation attained 1 hr after treatment. In contrast, similar levels were attained by TAX rapidly (within 5 min) and were sustained compared to the slow/multiphasic action of VA. VA extract treatments had no effect on AKT gene expression, while TAX treatments yielded a four-fold (P<0.01) increase; and P-glycoprotein (P-gp) activity was inhibited by VA and stimulated by TAX, compared to control (basal ATPase activity). This study shows that TAX-resistant PC-3 cells are sensitive to VA, perhaps explained by differential regulatory patterns of MAPK, c-Myc, AKT, and Pgp activities/expressions. PMID:23238229

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

    PubMed

    Kitamura, Naoko; Sakamoto, Kazuho; Ono, Tomoyuki; Kimura, Junko

    2015-07-01

    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

  19. The BH3 mimetic ABT-737 increases treatment efficiency of paclitaxel against hepatoblastoma

    PubMed Central

    2011-01-01

    Background The primary goal of current chemotherapy in hepatoblastoma (HB) is reduction of tumour volume and vitality to enable complete surgical resection and reduce risk of recurrence or metastatic disease. Drug resistance remains a major challenge for HB treatment. In some malignancies inhibition of anti-apoptotic pathways using small BH3 mimetic molecules like ABT-737 shows synergistic effects in combination with cystotoxic agents in vitro. Now we analysed toxicology and synergistic effects of this approach in HB cells and HB xenografts. Methods Viability was monitored in HB cells (HUH6 and HepT1) and fibroblasts treated with paclitaxel, ABT-737 and a combination of both in a MTT assay. HUH6 xenotransplants in NOD/LtSz-scid IL2R?null mice (NSG) were treated accordingly. Tumour volume and body weight were monitored. Xenografted tumours were analysed by histology and immunohistochemistry (Ki-67 and TUNEL assay). Results ABT-737 reduced viability in HUH6 and HepT1 cells cultures at concentrations above 1 ?M and also enhanced the cytotoxic effect of paclitaxel when used in combination. Thereby paclitaxel could be reduced tenfold to achieve similar reduction of viability of tumour cells. In contrast no toxicity in fibroblasts was observed at the same regiments. Subcutaneous HB (HUH6) treated with paclitaxel (12 mg/kg body weight, n = 7) led to delayed tumour growth in the beginning of the experiment. However, tumour volume was similar to controls (n = 5) at day 25. Combination treatment with paclitaxel and ABT-737 (100 mg/kg, n = 8) revealed significantly 10 fold lower relative tumour volumes compared to control and paclitaxel groups. Paclitaxel dependent toxicity was observed in this mice strain. Conclusions Our results demonstrate enhancement of chemotherapy by using modulators of apoptosis. Further analyses should include improved pharmacological formulations of paclitaxel and BH3 mimetics in order to reduce toxicological effects. Sensitising HB to apoptosis may also render resistant HB susceptible to established chemotherapy regimens. PMID:21854558

  20. Signaling network of paclitaxel-induced apoptosis in the LNCaP prostate cancer cell line

    Microsoft Academic Search

    R Panvichian; K Orth; M. J Pilat; M. L Day; K. C Day; C Yee; J. M Kamradt; K. J Pienta

    1999-01-01

    Objectives. To attempt to identify the relationship of the key regulator molecules in paclitaxel-induced apoptosis using two metastatic cell lines: the human prostate carcinoma LNCaP line and the cervical carcinoma HeLa cell line.Methods. Both LNCaP and HeLa cells were continuously exposed to clinically achievable concentrations of paclitaxel and observed for activation of programmed cell death as measured by cytotoxic dose-response

  1. 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. PMID:22392969

  2. Development of Lipid-Based Nanoparticles for Enhancing the Oral Bioavailability of Paclitaxel

    Microsoft Academic Search

    Deepti Pandita; Alka Ahuja; Viney Lather; Biju Benjamin; Tathagata Dutta; Thirumurthy Velpandian; Roop Krishen Khar

    2011-01-01

    The current research work investigates the potential of solid lipid nanoparticles (SLNs) in improving the oral bioavailability\\u000a of paclitaxel. Paclitaxel-loaded SLNs (PTX-SLNs) were prepared by modified solvent injection method using stearylamine as\\u000a lipid, soya lecithin and poloxamer 188 as emulsifiers. SLNs were characterized in terms of surface morphology, size and size distribution,\\u000a surface chemistry and encapsulation efficiency. Pharmacokinetics and bioavailability

  3. A microarray based expression profiling of paclitaxel and vincristine resistant MCF7 cells

    Microsoft Academic Search

    Meltem Demirel Kars; Özlem Darcansoy I?eri; Ufuk Gündüz

    2011-01-01

    Resistance to the broad spectrum of chemotherapeutic agents in cancer cell lines and tumors has been called multiple drug resistance (MDR). In this study, the molecular mechanisms of resistance to two anticancer agents (paclitaxel and vincristine) in mammary carcinoma cell line MCF-7 were investigated. Drug resistant sublines to paclitaxel (MCF-7\\/Pac) and vincristine (MCF-7\\/Vinc) that were developed from sensitive MCF-7 cells

  4. Paclitaxel Modulates TGF? Signaling in Scleroderma Skin Grafts in Immunodeficient Mice

    Microsoft Academic Search

    Xialin Liu; Shoukang Zhu; Tao Wang; Laura Hummers; Fredrick M Wigley; Pascal J Goldschmidt-Clermont; Chunming Dong

    2005-01-01

    BackgroundSystemic sclerosis (SSc) is characterized by excessive fibrosis and obliterative vascular lesions. Abnormal TGF? activation is implicated in the pathogenesis of SSc. Aberrant TGF?\\/Smad signaling can be controlled by stabilization of microtubules with paclitaxel.Methods and FindingsSSc and healthy human skin biopsies were incubated in the presence or absence of paclitaxel followed by transplantation into severe combined immunodeficient mice. TGF? signaling,

  5. A phase I study of paclitaxel and 5-fluorouracil in advanced gastric cancer

    Microsoft Academic Search

    S. Cascinu; R. Ficarelli; M. A. A. Safi; F. Graziano; G. Catalano; R. Cellerino

    1997-01-01

    This is a phase I study to determine the maximum tolerated dose (MTD) and toxicity of a combination of paclitaxel and 5-Fluorouracil (5-FU) in advanced gastric cancer patients. The patients, refractory to the PELF regimen (5-FU, leucovorin, cisplatin, epidoxorubicin), received weekly 5-FU at the fixed dose of 500 mg\\/m2, and escalating doses of paclitaxel every 3 weeks with a starting

  6. Weekly paclitaxel for heavily treated advanced or recurrent gastric cancer refractory to fluorouracil, irinotecan, and cisplatin

    Microsoft Academic Search

    Rai Shimoyama; Hirofumi Yasui; Narikazu Boku; Yusuke Onozawa; Shuichi Hironaka; Akira Fukutomi; Kentaro Yamazaki; Keisei Taku; Takashi Kojima; Nozomu Machida; Akiko Todaka; Hideharu Tomita; Takeshi Sakamoto; Takahiro Tsushima

    2009-01-01

    Background  Although triweekly administration of paclitaxel is approved for gastric cancer in Japan, currently, the drug is often delivered\\u000a with a weekly schedule because of the equivalent efficacy and lesser toxicity of this dosing schedule as compared with the\\u000a triweekly administration schedule. Weekly administration of paclitaxel as second-line or first-line chemotherapy for gastric\\u000a cancer has been reported to yield a response

  7. Paclitaxel-loaded PLGA nanoparticles: preparation, physicochemical characterization and in vitro anti-tumoral activity

    Microsoft Academic Search

    Cristina Fonseca; Sérgio Simões; Rogério Gaspar

    2002-01-01

    The main objective of this study was to develop a polymeric drug delivery system for paclitaxel, intended to be intravenously administered, capable of improving the therapeutic index of the drug and devoid of the adverse effects of Cremophor® EL. To achieve this goal paclitaxel (Ptx)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (Ptx-PLGA-Nps) were prepared by the interfacial deposition method. The influence of

  8. Poly(sebacic acid-co-ricinoleic acid) biodegradable carrier for paclitaxel—effect of additives

    Microsoft Academic Search

    Ariella Shikanov; Aviva Ezra; Abraham J. Domb

    2005-01-01

    Injectable polymeric formulation for paclitaxel was studied. Poly ricinoleic acid and sebacic acid were synthesized. The effect of additives on the viscosity of polymer, paclitaxel release, and polymer degradation was investigated both in vitro and in vivo. Additives that were used in this study were ricinoleic acid, phospholipid, PEG 400, and PEG 2000. Addition of 20% ricinoleic acid to P(SA:RA)3:7

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

    Microsoft Academic Search

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

    2004-01-01

    Hypersensitivity reactions (HSRs) to paclitaxel are frequently encountered in patients receiving this antitumour drug. Administration of histamine H1- and H2-receptor antagonists and corticosteroids has been shown to reduce significantly the risk of developing an HSR in patients receiving taxanes. In this case report, we describe the fatal outcome of an HSR in a patient receiving paclitaxel despite short-course premedication. The

  10. A New 2?,5?,10?,14?-tetraacetoxy-4(20),11-taxadiene (SIA) Derivative Overcomes Paclitaxel Resistance by Inhibiting MAPK Signaling and Increasing Paclitaxel Accumulation in Breast Cancer Cells

    PubMed Central

    Mei, Mei; Xie, Dan; Zhang, Yi; Jin, Jing; You, Feng; Li, Yan; Dai, Jungui; Chen, Xiaoguang

    2014-01-01

    Tumor resistance due to multiple mechanisms seriously hinders the efficacy of chemotherapy drugs such as paclitaxel. The most widely studied P-glycoprotein inhibitors still have limited ability to reverse resistance in the clinic. In this study, NPB304, a novel Sinenxan A (SIA) derivative, was found to significantly sensitize resistant breast cancer cells to paclitaxel in vitro and in vivo. Treatment with NPB304 increased paclitaxel-induced apoptosis in a p53-dependent manner through PARP cleavage. Importantly, NPB304 enhanced the antitumor effect of paclitaxel in resistant breast tumor xenografts in nude mice without significantly affecting weight loss. NPB304 regulated cell resistance through inhibition of MAPK pathway components, including p-ERK and p-p38. Moreover, NPB304 increased paclitaxel accumulation by affecting P-gp function. In addition to increasing Rhodamine 123 accumulation, NPB304 promoted bidirectional permeability but decreased the efflux ratio of paclitaxel in a Caco-2 monolayer model, thereby increasing the intracellular concentration of paclitaxel. Similarly, NPB304 increased the concentration of paclitaxel in the resistant tumor tissue. Hence, NPB304 is a novel compound that promotes the sensitization of resistant cells to paclitaxel through multiple mechanisms and has the potential for use in combination therapies to treat resistant breast cancer. PMID:25093335

  11. Paclitaxel alters the evoked release of calcitonin gene-related peptide from rat sensory neurons in culture.

    PubMed

    Pittman, Sherry K; Gracias, Neilia G; Vasko, Michael R; Fehrenbacher, Jill C

    2014-03-01

    Peripheral neuropathy (PN) is a debilitating and dose-limiting side effect of treatment with the chemotherapeutic agent, paclitaxel. Understanding the effects of paclitaxel on sensory neuronal function and the signaling pathways which mediate these paclitaxel-induced changes in function are critical for the development of therapies to prevent or alleviate the PN. The effects of long-term administration of paclitaxel on the function of sensory neurons grown in culture, using the release of the neuropeptide calcitonin gene-related peptide (CGRP) as an endpoint of sensory neuronal function, were examined. Dorsal root ganglion cultures were treated with low (10 nM) and high (300 nM) concentrations of paclitaxel for 1, 3, or 5 days. Following paclitaxel treatment, the release of CGRP was determined using capsaicin, a TRPV1 agonist; allyl isothiocyanate (AITC), a TRPA1 agonist; or high extracellular potassium. The effects of paclitaxel on the release of CGRP were stimulant-, concentration-, and time-dependent. When neurons were stimulated with capsaicin or AITC, a low concentration of paclitaxel (10nM) augmented transmitter release, whereas a high concentration (300 nM) reduced transmitter release in a time-dependent manner; however, when high extracellular potassium was used as the evoking stimulus, all concentrations of paclitaxel augmented CGRP release from sensory neurons. These results suggest that paclitaxel alters the function of sensory neurons in vitro, and suggest that the mechanisms by which paclitaxel alters neuronal function may include functional changes in TRP channel activity. The described in vitro model will facilitate future studies to identify the signaling pathways by which paclitaxel alters neuronal sensitivity. PMID:24374060

  12. A phase I study of paclitaxel and altretamine as second-line therapy to cisplatin regimens for ovarian cancer

    Microsoft Academic Search

    Ian Olver; Margaret Davy; Diana Lüftner; So-Hyang Park; Merrill Egorin; Andrew Ellis; Lorraine Webster

    2001-01-01

    Purpose: The efficacy and pharmacokinetics of paclitaxel when combined with altretamine for ovarian cancer were studied. Methods: A group of 30 patients, whose only chemotherapy was one or more cisplatin-based non-paclitaxel-containing regimens and whose ovarian cancer failed to respond or had relapsed within 6 months of their last platinum regimen, received paclitaxel as a 3-h intravenous infusion and altretamine given

  13. Nanoparticle-mediated simultaneous and targeted delivery of paclitaxel and tariquidar overcomes tumor drug resistance.

    PubMed

    Patil, Yogesh; Sadhukha, Tanmoy; Ma, Linan; Panyam, Jayanth

    2009-05-21

    Drug resistance is a major obstacle to the success of cancer chemotherapy. Overexpression of the drug-efflux transporter P-glycoprotein (P-gp) is a key factor contributing to tumor drug resistance. Third generation P-gp inhibitors like tariquidar have shown promising efficacy in early clinical trials. However, for maximum efficacy, it is important to limit the exposure of normal cells and tissues to the efflux inhibitor and the anticancer drug, and temporally colocalize the drug-inhibitor combination in the tumor cells. In this study, we investigated simultaneous and targeted delivery of anticancer drug, paclitaxel, with P-gp modulator, tariquidar, using poly(d,l-lactide-co-glycolide) nanoparticles to overcome tumor drug resistance. Nanoparticles were surface functionalized with biotin for active tumor targeting. Dual agent nanoparticles encapsulating the combination of paclitaxel and tariquidar showed significantly higher cytotoxicity in vitro than nanoparticles loaded with paclitaxel alone. Enhanced therapeutic efficacy of dual agent nanoparticles could be correlated with increased accumulation of paclitaxel in drug-resistant tumor cells. In vivo studies in a mouse model of drug-resistant tumor demonstrated significantly greater inhibition of tumor growth following treatment with biotin-functionalized nanoparticles encapsulating both paclitaxel and tariquidar at a paclitaxel dose that was ineffective in the absence of tariquidar. Taken together, these results suggest that the use of targeted, dual agent nanoparticles delivering a combination of P-gp modulator and anticancer drug is a very promising approach to overcome tumor drug resistance. PMID:19331851

  14. Human Mesenchymal Stem Cells Are Resistant to Paclitaxel by Adopting a Non-Proliferative Fibroblastic State

    PubMed Central

    Bosco, Dale B.; Kenworthy, Rachael; Zorio, Diego A. R.; Sang, Qing-Xiang Amy

    2015-01-01

    Human mesenchymal stem cell (hMSC) resistance to the apoptotic effects of chemotherapeutic drugs has been of major interest, as these cells can confer this resistance to tumor microenvironments. However, the effects of internalized chemotherapeutics upon hMSCs remain largely unexplored. In this study, cellular viability and proliferation assays, combined with different biochemical approaches, were used to investigate the effects of Paclitaxel exposure upon hMSCs. Our results indicate that hMSCs are highly resistant to the cytotoxic effects of Paclitaxel treatment, even though there was no detectable expression of the efflux pump P-glycoprotein, the usual means by which a cell resists Paclitaxel treatment. Moreover, Paclitaxel treatment induces hMSCs to adopt a non-proliferative fibroblastic state, as evidenced by changes to morphology, cellular markers, and a reduction in differentiation potential that is not directly coupled to the cytoskeletal effects of Paclitaxel. Taken together, our results show that Paclitaxel treatment does not induce apoptosis in hMSCs, but does induce quiescence and phenotypic changes. PMID:26029917

  15. Safety and Efficacy of nab-Paclitaxel in the Treatment of Patients with Breast Cancer

    PubMed Central

    Vishnu, Prakash; Roy, Vivek

    2011-01-01

    Taxanes are highly active chemotherapeutic agents in the treatment of early-stage and metastatic breast cancer. Novel formulations have been developed to improve efficacy and decrease toxicity associated with these cytotoxic agents. nab-paclitaxel is a solvent free, albumin-bound 130-nanometer particle formulation of paclitaxel (Abraxane®, Abraxis Bioscience), which was developed to avoid toxicities of the Cremophor vehicle used in solvent-based paclitaxel. In a phase III clinical trial, nab-paclitaxel demonstrated higher response rates, better safety and side-effect profile compared to conventional paclitaxel, and improved survival in patients receiving it as second line therapy. Higher doses can be administered over a shorter infusion time without the need for special infusion sets or pre-medications. It is now approved in the US for treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant therapy, where prior therapy included an anthracycline. Recently, several phase II studies have suggested a role for nab-paclitaxel as a single agent and in combination with other agents for first-line treatment of metastatic breast cancer. PMID:21603258

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

    NASA Astrophysics Data System (ADS)

    Vichansavakul, Kittaya

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

  17. C-Terminus of Clostridium perfringens Enterotoxin Downregulates CLDN4 and Sensitizes Ovarian Cancer Cells to Taxol and Carboplatin

    PubMed Central

    Gao, Zhijian; Xu, Xiaoyin; McClane, Bruce; Zeng, Qing; Litkouhi, Babak; Welch, William R.; Berkowitz, Ross S.; Mok, Samuel C.; Garner, Elizabeth I.O.

    2010-01-01

    Purpose We have previously demonstrated that CLDN4 (encoding claudin-4), a cell tight junction (TJ) protein, is highly expressed in human epithelial ovarian cancers (EOC) but undetectable in normal ovaries. CLDN4 has been identified as a specific receptor for c-terminus of Clostridium perfringens enterotoxin (C-CPE), a nontoxic molecule that may disrupt TJ barrier function and enhance cellular absorption. The purpose of this study was to determine the potential clinical applications of C-CPE and its effects on CLDN4 expression in EOC. Experimental design Using a 3D culture model and monolayer culture of EOC cells, we examined the effects of C-CPE on CLDN4 expression by qRT-PCR, immunoflorescence and Western blot. The synergistic effect of C-CPE to clinically relevant chemotherapies (Taxol and Carboplatin) was observed in EOC culture and xenograft mice. Furthermore, we determined through oligonucleotide microarray analysis the transcript profile alterations dysregulated as a consequence of C-CPE treatment. Results C-CPE treatment decreased protein expression and relocated CLDN4 from cell-cell contact regions to the cytoplasm. Particularly, C-CPE sensitized EOC cells to chemotherapeutic administration at low dosages and significantly inhibited tumor growth in a non-toxic manner. Furthermore, we provided genome-wide molecular evidence that C-CPE treatment is involved in the stimulation of the ubiquitin-proteasome pathway and the inhibition of cell metabolism in EOC cells. Conclusions The addition of C-CPE can enhance the effectiveness of Taxol or Carboplatin and significantly inhibited EOC cell growth in a CLDN4-dependent, suggesting that C-CPE may have promising therapeutic potential for EOC. PMID:21123456

  18. Taxol-induced sensory disturbance is characterized by preferential impairment of myelinated fiber function in cancer patients.

    PubMed

    Dougherty, Patrick M; Cata, Juan P; Cordella, Joseph V; Burton, Allen; Weng, Han-Rong

    2004-05-01

    Taxol produces neuropathic pain with three distinct zones of involvement in the extremities. Most distally is an area of on-going pain and proximal to this is a zone of sensory disturbance but not overt pain. These two areas were confined in all but one case to the glabrous skin of the hands and/or feet. More proximal is an area not recognized by the patients as involved with pain or sensory disturbance yet wherein quantitative sensory tests nevertheless reveal altered sensibility. Impairment of perception to light touch, normally conveyed by myelinated fibers, was dramatically altered in all three areas, being approximately 50-fold greater than normal in areas of pain and sensory disturbance as well as in areas of skin perceived by the patients as not affected. Impairment of perception to sharpness, normally conveyed by small myelinated fibers, was most pronounced in areas of on-going pain, intermediate in areas of sensory disturbance and near baseline in more proximal skin of chemotherapy patients. In contrast to mechanical sensibility, thermal thresholds for warm and heat pain detection were normal throughout. Finally, chemotherapy patients showed paradoxical burning pain to skin cooling that was most pronounced in proximal areas of skin thought to be unaffected by the patients, intermediate in the border zone of altered sensibility and least pronounced in areas of on-going pain. These data suggest that taxol produces a neuropathy characterized by pronounced impairment of function in A-beta myelinated fibers, intermediate impairment of A-delta myelinated fibers, and a relative sparing of C-fibers. PMID:15082135

  19. Temporal relationship of CDK1 activation and mitotic arrest to cytosolic accumulation of cytochrome C and caspase-3 activity during Taxol-induced apoptosis of human AML HL60 cells

    Microsoft Academic Search

    AM Ibrado; CN Kim; K Bhalla

    1998-01-01

    The antimicrotubule anticancer drug, Taxol, suppresses microtubule dynamics, causes mitotic arrest, and induces caspase-3 cleavage and activity resulting in apoptosis of human AML HL-60 cells. Caspase-3 cleavage is triggered by the mitochondrial release and cytosolic accumulation of the electron transfer protein, cytochrome c (cyt c). Taxol-induced G2\\/M transition is mediated by p34cdc-2 (CDK1) which, if prematurely activated, may also trigger

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

    NASA Astrophysics Data System (ADS)

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

    2014-12-01

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

  1. Plasma pharmacokinetics and tissue distribution of paclitaxel in CD2F1 mice.

    PubMed

    Eiseman, J L; Eddington, N D; Leslie, J; MacAuley, C; Sentz, D L; Zuhowski, M; Kujawa, J M; Young, D; Egorin, M J

    1994-01-01

    We defined the pharmacokinetics of paclitaxel after i.v., i.p., p.o., and s.c. administration of 22.5 mg/kg to CD2F1 mice. Additional mice were studied after i.v. bolus dosing at 11.25 mg/kg or 3-h continuous i.v. infusions delivered at 43.24 micrograms kg-1 min-1. Plasma was sampled between 5 min and 40 h after dosing. Brains, hearts, lungs, livers, kidneys, skeletal muscles, and, where applicable, testicles were sampled after i.v. dosing at 22.5 mg/kg. Liquid-liquid extraction followed by isocratic high-performance liquid chromatography (HPLC) with UV detection was used to determine paclitaxel concentrations in plasma and tissues. After i.v. administration to male mice, paclitaxel clearance (CLtb) was 3.25 ml min-1 kg-1 and the terminal half-life (t1/2) was 69 min. After i.v. administration to female mice, paclitaxel CLtb was 4.54 ml min-1 kg-1 and the terminal t1/2 was 43 min. The bioavailability of paclitaxel was approximately 10%, 0, and 0 after i.p., p.o., and s.c. administration, respectively. Paclitaxel bioavailability after i.p. administration was the same when the drug was delivered in a small volume to mimic the delivery method used to evaluate in vivo antitumor efficacy or when it was delivered in a large volume to simulate clinical protocols using i.p. regional therapy. Paclitaxel was not detected in the plasma of mice after i.p. delivery of the drug as a suspension in Klucel: Tween 80. Pharmacokinetic parameters were similar after i.v. delivery of paclitaxel at 22.5 and 11.25 mg/kg; however, the CLtb calculated in these studies was much lower than that associated with 3-h continuous i.v. infusions. After i.v. administration, paclitaxel was distributed extensively to all tissues but the brain and testicle. These data are useful in interpreting preclinical efficacy studies of paclitaxel and predicting human pharmacokinetics through scaling techniques. PMID:7923556

  2. 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. PMID:22076480

  3. HFT-T, a targeting nanoparticle, enhances specific delivery of paclitaxel to folate receptor-positive tumors.

    PubMed

    Wang, Xu; Li, Jun; Wang, Yiqing; Cho, Kwang Jae; Kim, Gloria; Gjyrezi, Ada; Koenig, Lydia; Giannakakou, Paraskevi; Shin, Hyung Ju C; Tighiouart, Mourad; Nie, Shuming; Chen, Zhuo Georgia; Shin, Dong M

    2009-10-27

    Nonspecific distribution of chemotherapeutic drugs (such as paclitaxel) is a major factor contributing to side effects and poor clinical outcomes in the treatment of human head and neck cancer. To develop novel drug delivery systems with enhanced efficacy and minimized adverse effects, we synthesized a ternary conjugate heparin-folic acid-paclitaxel (HFT), loaded with additional paclitaxel (T). The resulting nanoparticle, HFT-T, is expected to retain the antitumor activity of paclitaxel and specifically target folate receptor (FR)-expressing tumors, thereby increasing the bioavailability and efficacy of paclitaxel. In vitro experiments found that HFT-T selectively recognizes FR-positive human head and neck cancer cell line KB-3-1, displaying higher cytotoxicity compared to the free form of paclitaxel. In a subcutaneous KB-3-1 xenograft model, HFT-T administration enhanced the specific delivery of paclitaxel into tumor tissues and remarkably improved antitumor efficacy of paclitaxel. The average tumor volume in the HFT-T treatment group was 92.9 +/- 78.2 mm(3) vs 1670.3 +/- 286.1 mm(3) in the mice treated with free paclitaxel. Furthermore, paclitaxel tumors showed a resurgence of growth after several weeks of treatment, but this was not observed with HFT-T. This indicates that HFT-T could be more effective in preventing tumors from developing drug resistance. No significant acute in vivo toxicity was observed. These results indicate that specific delivery of paclitaxel with a ternary structured nanoparticle (HFT-T) targeting FR-positive tumor is a promising strategy to enhance chemotherapy efficacy and minimize adverse effects. PMID:19761191

  4. Thermosensitive and Mucoadhesive Sol-Gel Composites of Paclitaxel/Dimethyl-?-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)-?-cyclodextrin (DM?CD). 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

  5. Altered beta-tubulin isotype expression in paclitaxel-resistant human prostate carcinoma cells.

    PubMed Central

    Ranganathan, S.; Benetatos, C. A.; Colarusso, P. J.; Dexter, D. W.; Hudes, G. R.

    1998-01-01

    To investigate the role of beta-tubulin isotype composition in resistance to paclitaxel, an anti-microtubule agent, human prostate carcinoma (DU-145) cells were intermittently exposed to increasing concentrations of paclitaxel. Cells that were selected and maintained at 10 nM paclitaxel (Pac-10) were fivefold resistant to the drug. Pac-10 cells accumulated radiolabelled paclitaxel to the same extent as DU-145 cells and were negative for MDR-1. Analysis of Pac-10 and DU-145 cells by flow cytometry showed similar cell cycle patterns. Immunofluorescent staining revealed an overall increase of alpha- and beta-tubulin levels in Pac-10 cells compared with DU-145 cells. Examination of beta-tubulin isotype composition revealed a significant increase in betaIII isotype in the resistant cells, both by immunofluorescence and by western blot analysis. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of the isotypes confirmed the increase observed for the betaIII by exhibiting ninefold higher betaIII mRNA levels and also showed fivefold increase of the betaIVa transcript. In addition, analysis of paclitaxel-resistant cells that were selected at increasing levels of the drug (Pac 2, 4, 6, 8 and 10) exhibited a positive correlation between increasing betaIII levels and increasing resistance to paclitaxel. Increased expression of specific beta-tubulin isotypes and subsequent incorporation into microtubules may alter cellular microtubule dynamics, providing a defence against the anti-microtubule effects of paclitaxel and other tubulin-binding drugs. Images Figure 1 Figure 2 Figure 4 PMID:9484812

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

    PubMed

    Xiao, Juan; Xu, Manman; Hou, Teng; Huang, Yongwen; Yang, Chenlu; Li, Jundong

    2015-09-01

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

  7. Thermosensitive and mucoadhesive sol-gel composites of paclitaxel/dimethyl-?-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)-?-cyclodextrin (DM?CD). 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

  8. 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

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

    PubMed Central

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

    2015-01-01

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

  10. Weekly Paclitaxel in the Treatment of Advanced or Metastatic Breast Cancer Previously Treated or Not Treated with Docetaxel: A Phase II Study

    Microsoft Academic Search

    Reiki Nishimura; Takahiro Ogawa; Masato Kato; Maki Tanaka; Yuzo Hamada; Takao Shibata; Emi Ishikawa; Toshihiro Koga; Shoshu Mitsuyama; Kazuo Tamura

    2005-01-01

    Background: Paclitaxel has been approved for 3-weekly administration in Japan. Recent reports suggest that weekly paclitaxel can achieve a higher tumor response and lower toxicity. Methods: This study was designed to investigate the usefulness and tolerability of weekly paclitaxel by 1-hour infusion in patients with metastatic breast cancer who were previously treated with docetaxel or other anticancer agents. Results: Thirty-five

  11. Improvement of paclitaxel therapeutic index by derivatization and association to a cholesterol-rich microemulsion: in vitro and in vivo studies

    Microsoft Academic Search

    Debora G. Rodrigues; Durvanei A. Maria; Denise C. Fernandes; Claudete J. Valduga; Ricardo D. Couto; Olga C. M. Ibañez; Raul C. Maranhão

    2005-01-01

    A cholesterol-rich microemulsion or nanoparticle termed LDE concentrates in cancer tissues after injection into the bloodstream. Here the cytotoxicity, pharmacokinetics, toxicity to animals and therapeutic action of a paclitaxel lipophilic derivative associated to LDE is compared with those of the commercial paclitaxel. Results show that LDE-paclitaxel oleate is stable. The cytostatic activity of the drug in the complex is diminished

  12. Estrogen increases intracellular p26Bcl2 to p21Bax ratios and inhibits taxol-induced apoptosis of human breast cancer MCF7 cells

    Microsoft Academic Search

    Yue Huang; Swapan Ray; John C. Reed; Ana Maria Ibrado; Caroline Tang; Amir Nawabi; Kapil Bhalla

    1997-01-01

    Recent studies have demonstrated that following estrogen ablation, estrogen responsive breast cancer cells undergo apoptosis. In addition, estrogen receptor (ER) expression has been strongly correlated with the expression of the bcl-2 gene product, p26Bcl-2 protein, which is known to inhibit apoptosis. In the present studies, we investigated whether estrogen affects the intracellular levels of p26Bcl-2 and thereby modulates taxol-induced apoptosis

  13. Berberine modulates expression of mdr1 gene product and the responses of digestive track cancer cells to Paclitaxel

    PubMed Central

    Lin, H-L; Liu, T-Y; Wu, C-W; Chi, C-W

    1999-01-01

    Berberine is the major constituent of Coptis chinese and is commonly used in Chinese herbal medicine to treat patients with gastrointestinal disorders. In this study, using flow cytometry, we have found that a 24-h berberine treatment up-regulated the multidrug-resistant transporter (pgp-170) expression in two oral (KB, OC2), two gastric (SC-M1, NUGC-3) and two colon (COLO 205, CT 26) cancer cell lines. Decreased retention of rhodamine 123 was observed in berberine-treated cells as compared to vehicle control. To examine whether the berberine modulated pgp-170 expression in cancer cells is associated with changes in drug resistance, we determined the cytotoxicity, cell cycle progression and cell morphology of Paclitaxel-treated cells. Paclitaxel (1 nM–10 ?M) treatment for 24 h induced cytotoxicity in OC2, SC-M1 and COLO 205 cells in a dose-dependent manner. Pretreatment of cells with 32 ?M berberine for 24 h prior to Paclitaxel treatment resulted in increased viability as compared to that of Paclitaxel-treated cells. In addition, Paclitaxel-induced apoptosis and/or G2/M arrest in these three cancer cell lines. Pretreatment of cells with berberine prior to Paclitaxel blocked the Paclitaxel-induced cell cycle responses and morphological changes. These results together suggest that berberine modulated the expression and function of pgp-170 that leads to reduced response to Paclitaxel in digestive track cancer cells. © 1999 Cancer Research Campaign PMID:10507765

  14. Silencing survivin results in synergy between methylseleninic acid and paclitaxel against skov3 ovarian cancer cells.

    PubMed

    Azrak, Rami G; Frank, Cheryl L; Ghadersohi, Ali; Rustum, Youcef M

    2008-12-01

    This study evaluates methylseleninic acid (MSeA) improvement of paclitaxel efficacy against human ovarian cancer (skov3) with regard to survivin expression. MSeA and paclitaxel alone and in concurrent or sequential combination treatments were tested. Cell growth/death was evaluated using SRB, trypan blue, colony formation and ELISA assays. Cells were transfected with survivin shRNA and survivin's expression was measured using RT-PCR and Western blots. Drugs interaction was further evaluated using isobologram analyses. Different treatments with MSeA did not enhance paclitaxel's efficacy in the wild type skov3. Silencing survivin had no effect on MSeA or paclitaxel efficacy when used alone or in concurrent combination. After sequential combination treatment, synergy and significant induction of apoptosis were observed in cells transfected with survivin shRNA. However, antagonism and minimal induction of apoptosis were observed in empty or scramble survivin shRNA transfected cells. In conclusion, these data suggest that synergy between MSeA and paclitaxel in skov3 is associated with silencing survivin expression. PMID:18981709

  15. Oxygen-Carbon Nanotubes as a Chemotherapy Sensitizer for Paclitaxel in Breast Cancer Treatment

    PubMed Central

    Wang, Yongkun; Wang, Chuanying; Jia, Yijun; Cheng, Xianhua; Lin, Qing; Zhu, Mingjie; Lu, Yunshu; Ding, Longlong; Weng, Ziyi; Wu, Kejin

    2014-01-01

    Objective To study the in vivo and in vitro effects of adding oxygen carbon nanotubes (CNTs) to chemotherapy for breast cancer. Methods MCF-7 and SK-BR-3 breast cancer cells were co-cultured with paclitaxel and then exposed to oxygen-CNTs under hypoxic conditions. Cell proliferation, viability, and apoptosis rate were analyzed. Hypoxia-inducible factor-1 alpha (HIF-1?) expression was measured using reverse transcription-polymerase chain reaction (RT-PCR) and western blot. Nude mice were used as a human breast cancer model to explore the impact of oxygen-CNTs on the in vivo chemotherapeutic effect of paclitaxel. Results Oxygen-CNTs had no significant effects on the growth of breast cancer cells under normoxia and hypoxia. However, in the hypoxic environment, oxygen-CNTs significantly enhanced the inhibitory effect of paclitaxel on cell proliferation, as well as the apoptosis rate. Under hypoxia, downregulation of HIF-1? and upregulation of caspase-3, caspase-8, caspase-9, LC3 and Beclin-1 were observed when paclitaxel was combined with oxygen-CNT. Furthermore, addition of oxygen-CNTs to chemotherapy was found to significantly reduce tumor weight in the tumor-bearing mice model. Conclusions Oxygen-CNTs can significantly increase the chemotherapeutic effect of paclitaxel on breast cancer cells. Oxygen-CNTs may be a potential chemosensitizer in breast cancer therapy. PMID:25089613

  16. Synergistic interaction of paclitaxel and curcumin with cyclodextrin polymer complexation in human cancer cells.

    PubMed

    Boztas, Ali O; Karakuzu, Ozgur; Galante, Gabriela; Ugur, Zafer; Kocabas, Fatih; Altuntas, Cengiz Z; Yazaydin, A Ozgur

    2013-07-01

    The use of cytotoxic chemotherapic agents is the most common method for the treatment of metastatic cancers. Poor water solubility and low efficiency of chemotherapic agents are among the major hurdles of effective chemotherapy treatments. Curcumin and paclitaxel are well-known chemotherapic agents with poor water solubility and undesired side effects. In this study, a novel drug nanocarrier system was formulated by encapsulating curcumin and paclitaxel in poly(?-cyclodextrin triazine) (PCDT) for the therapy of four cancer models; ovarian, lung, prostate, and breast cancer. Cell viability and colony formation assays revealed enhanced curcumin cytotoxicity upon complexation. Annexin V apoptotic studies showed that the PCDT complexation improved curcumin induced apoptosis in human ovarian cancer cell lines A2780 and SKOV-3, human nonsmall cell lung carcinoma cell line H1299, and human prostate cancer line DU-145, while no significant effect was observed with paclitaxel/PCDT complexation. The bioactivity of combining curcumin and paclitaxel was also investigated. A synergism was found between curcumin and paclitaxel, particularly when complexed with PCDT on A2780, SKOV-3, and H1299 cancer cell lines. PMID:23730903

  17. 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. PMID:23701999

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

    PubMed

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

    2013-01-01

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

  19. Cytotoxicity of paclitaxel in breast cancer is due to chromosome missegregation on multipolar spindles

    PubMed Central

    Zasadil, Lauren M.; Andersen, Kristen A.; Yeum, Dabin; Rocque, Gabrielle B.; Wilke, Lee G.; Tevaarwerk, Amye J.; Raines, Ronald T.; Burkard, Mark E.; Weaver, Beth A.

    2014-01-01

    The blockbuster chemotherapy drug paclitaxel is widely presumed to cause cell death in tumors as a consequence of mitotic arrest, as it does at concentrations routinely used in cell culture. However, we determine here that paclitaxel levels in primary breast tumors are well below those required to elicit sustained mitotic arrest. Instead, cells in these lower concentrations of drug proceed through mitosis without substantial delay and divide their chromosomes on multipolar spindles, resulting in chromosome missegregation and cell death. Consistent with these cell culture data, the majority of mitotic cells in primary human breast cancers contain multipolar spindles after paclitaxel treatment. Contrary to the previous hypothesis, we find that mitotic arrest is dispensable for tumor regression in patients. These results demonstrate that mitotic arrest is not responsible for the efficacy of paclitaxel, which occurs due to chromosome missegregation on highly abnormal, multipolar spindles. This mechanistic insight may be used to improve selection of future anti-mitotic drugs and to identify a biomarker with which to select patients likely to benefit from paclitaxel. PMID:24670687

  20. Constitutive Androstane Receptor Ligands Modulate the Anti-Tumor Efficacy of Paclitaxel in Non-Small Cell Lung Cancer Cells

    PubMed Central

    Fukumasu, Heidge; Rochetti, Arina L.; Pires, Pedro R. L.; Silva, Edson R.; Mesquita, Ligia G.; Strefezzi, Ricardo F.; De Carvalho, Daniel D.; Dagli, Maria L.

    2014-01-01

    Background Lung tumors are the leading cause of cancer deaths worldwide and paclitaxel has proven to be useful for patients with lung cancer, however, acquired resistance is a major problem. To overcome this problem, one promising option is the use of Constitutive Androstane Receptor (CAR) ligands in combination with chemotherapeutics against cancer cells. Therefore, we wish to elucidate the effects of CAR ligands on the antineoplastic efficacy of paclitaxel in lung cancer cells. Methodology/Principal Findings Our results from cell viability assays exposing CAR agonist or inverse-agonist to mouse and human lung cancer cells modulated the antineoplastic effect of paclitaxel. The CAR agonists increased the effect of Paclitaxel in 6 of 7 lung cancer cell lines, whereas the inverse-agonist had no effect on paclitaxel cytotoxicity. Interestingly, the mCAR agonist TCPOBOP enhanced the expression of two tumor suppressor genes, namely WT1 and MGMT, which were additively enhanced in cells treated with CAR agonist in combination with paclitaxel. Also, in silico analysis showed that both paclitaxel and CAR agonist TCPOBOP docked into the mCAR structure but not the inverse agonist androstenol. Paclitaxel per se increases the expression of CAR in cancer cells. At last, we analyzed the expression of CAR in two public independent studies from The Cancer Genome Atlas (TCGA) of Non Small Cell Lung Cancer (NSCLC). CAR is expressed in variable levels in NSCLC samples and no association with overall survival was noted. Conclusions/Significance Taken together, our results demonstrated that CAR agonists modulate the antineoplastic efficacy of paclitaxel in mouse and human cancer cell lines. This effect was probably related by the enhanced expression of two tumor suppressor genes, viz. WT1 and MGMT. Most of NSCLC cases present CAR gene expression turning it possible to speculate the use of CAR modulation by ligands along with Paclitaxel in NSCLC therapy. PMID:24959746

  1. Radiation recall phenomenon presenting as myositis triggered by carboplatin plus paclitaxel and related literature review.

    PubMed

    Maeng, Chi Hoon; Park, Jun Sang; Lee, Seung Ah; Kim, Dong Hwan; Yun, Dong Hwan; Yoo, Seung-Don; Kim, Hee-Sang; Chon, Jinmann

    2014-01-01

    While most case reports to date are radiation recall dermatitis, radiation recall myositis, which is a distinct form of radiation recall phenomenon caused by carboplatin plus paclitaxel, has not been reported. We treated a 57-year-old female patient who suffered from recurrent cervical cancer. When the patient developed a new left sacral metastasis, salvage radiotherapy (total dose 60 Gy) was administered. Four weeks later, chemotherapy using carboplatin plus paclitaxel was initiated. Four months after chemotherapy, the patient complained of severe pain in her left buttock. On magnetic resonance imaging (MRI), edematous changes and increased signal densities of left gluteus maximus and medius muscles were noted suggesting myositis. The border of the high signal intensity territory of the muscles was sharp and clearly corresponded with the recent irradiation field. We concluded that the patient had radiation recall myositis triggered by paclitaxel-carboplatin. Symptoms were controlled by analgesics, and there was no recurrence. PMID:25579560

  2. A Case of Biphasic Pulmonary Blastoma Treated with Carboplatin and Paclitaxel plus Bevacizumab

    PubMed Central

    Sakata, Shinya; Saeki, Sho; Hirooka, Sayuri; Hirosako, Susumu; Kohrogi, Hirotsugu

    2015-01-01

    Background. Pulmonary blastoma is a rare lung tumor similar to fetal lung tissues. Surgical resection at early stage is more curative than other treatments, but there is no standard treatment in unresectable cases. We show a case treated with carboplatin and paclitaxel plus bevacizumab. Case. A 68-year-old man received surgical resection and was diagnosed with biphasic pulmonary blastoma (pT3N0M0 stage IIB). Metastasis to the spleen was detected six weeks after the surgery. Carboplatin, paclitaxel, and bevacizumab were administered and showed an effect on the metastasis. Four courses of the chemotherapy were completed, but a metastasis was found and the metastatic tumor in the spleen was enlarged. After that, chemotherapy was not effective afterward and he died of the progression of biphasic pulmonary blastoma on the 292nd day of illness. Conclusion. In this case, chemotherapy with carboplatin and paclitaxel plus bevacizumab was temporarily efficacious for biphasic pulmonary blastoma.

  3. A2780 human ovarian cancer cells with acquired paclitaxel resistance display cancer stem cell properties

    PubMed Central

    HAN, XIAOFENG; DU, FANGFANG; JIANG, LI; ZHU, YIFEI; CHEN, ZHEN; LIU, YANJUN; HONG, TINGTING; WANG, TENG; MAO, YONG; WU, XIAOHONG; BRUCE, IAIN C.; JIN, JIAN; MA, XIN; HUA, DONG

    2013-01-01

    The use of chemotherapy to treat cancer is effective, but chemoresistance reduces this efficacy. Chemotherapy resistance involves several mechanisms, including the cancer stem cell (CSC) concept. The aim of the present study was to assess whether paclitaxel-resistant epithelial ovarian carcinoma is capable of generating cells with CSC-like properties. Using the paclitaxel-resistant A2780/PTX cell line, it was demonstrated that high aldehyde dehydrogenase 1 (ALDH1) activity identifies CSCs from diverse sources. Furthermore, the A2780/PTX cells had a strong ability to form colonies in soft agar assays. Notably, it was demonstrated that the inhibition of the PI3K signaling pathway abolished colony formation. These data suggest that there is a link between paclitaxel resistance and CSC enrichment. It is possible that therapeutic benefits, such as the restoration of chemosensitivity or the suppression of tumorigenicity, may be enabled by gaining further insights into the mechanisms underlying chemoresistance and the generation of CSCs. PMID:24179511

  4. [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. PMID:25963691

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

    PubMed Central

    Kim, Youngji; Jung, Woojin

    2015-01-01

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

  6. [Exudative onycholysis and acute bacterial paronychia related to BIBF-1120 and paclitaxel: response to topical therapy].

    PubMed

    Freites-Martínez, Azael; Martinez-Sánchez, Diego; de Pablo, Nieves Puente; Calderón-Komaromy, Angélica; Córdoba, Susana; Burbujo, Jesús

    2014-03-01

    A case of a 50 years-old breast cancer patient treated with weekly paclitaxel and BIBF 1120 is reported herein. At the end of the twelfth cycle of chemotherapy, the patient developed distal onycholysis with intense hyponychium serous exudates, pain and malodor in all her fingernails. It was treated with topical fusidic acid and 1% methylprednisolone aceponate two times daily, with an excellent clinical response from the first three days of treatment. Bacterial paronychia with nail plate loss of the fifth left fingernail was observed a week after the topical therapy was started, with positive cultures for Methicillin susceptible Staphylococcus aureus. There are few reported cases of exudative onycholysis associated with chemotherapy. However, these are especially related to paclitaxel. No recurrences of nail disturbances were observed weeks after the end of chemotherapy. Topical corticosteroids and fusidic acid could be considered as a therapeutic option when exudative onycholysis related to paclitaxel is established PMID:24758102

  7. Programmed Hydrolysis in Designing Paclitaxel Prodrug for Nanocarrier Assembly

    PubMed Central

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

    2015-01-01

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

  8. Stable and efficient Paclitaxel nanoparticles for targeted glioblastoma therapy.

    PubMed

    Mu, Qingxin; Jeon, Mike; Hsiao, Meng-Hsuan; Patton, Victoria K; Wang, Kui; Press, Oliver W; Zhang, Miqin

    2015-06-01

    Development of efficient nanoparticles (NPs) for cancer therapy remains a challenge. NPs are required to have high stability, uniform size, sufficient drug loading, targeting capability, and ability to overcome drug resistance. In this study, the development of a NP formulation that can meet all these challenging requirements for targeted glioblastoma multiform (GBM) therapy is reported. This multifunctional NP is composed of a polyethylene glycol-coated magnetic iron oxide NP conjugated with cyclodextrin and chlorotoxin (CTX) and loaded with fluorescein and paclitaxel (PTX) (IONP-PTX-CTX-FL). The physicochemical properties of the IONP-PTX-CTX-FL are characterized by transmission electron microscope, dynamic light scattering, and high-performance liquid chromatography. The cellular uptake of NPs is studied using flow cytometry and confocal microscopy. Cell viability and apoptosis are assessed with the Alamar Blue viability assay and flow cytometry, respectively. The IONP-PTX-CTX-FL had a uniform size of ?44 nm and high stability in cell culture medium. Importantly, the presence of CTX on NPs enhanced the uptake of the NPs by GBM cells and improved the efficacy of PTX in killing both GBM and GBM drug-resistant cells. The IONP-PTX-CTX-FL demonstrated its great potential for brain cancer therapy and may also be used to deliver PTX to treat other cancers. PMID:25761648

  9. Enhancement on oral absorption of paclitaxel by multifunctional pluronic micelles.

    PubMed

    Li, Yimu; Bi, Yiling; Xi, Yanwei; Li, Lingbing

    2013-02-01

    The aim of the present study is to synthesize Pluronic F127-polyethylenimine-folate (PF127-PEI-FA) copolymer, construct a mixed micelle system with PF127-PEI-FA copolymer and Pluronic P123 (PP123) and to evaluate the potential of these mixed micelles as an oral drug delivery system for paclitaxel (PTX). The results of intestinal absorption revealed that the PTX-loaded micelles displayed superior permeability across intestinal barrier than free drug and PF127-PEI-FA/PP123 mixed micelles exhibited the strongest permeability across intestinal barrier. These results were also proved by the studies on cytotoxicity and cell uptake tests. The mechanism was demonstrated in connection with inhibition of the efflux mediated by intestinal P-glycoprotein (P-gp) and enhancement of the electrostatic interaction of positive micelles with the negative intestinal epithelial cells, thereby promoting the permeation across the intestinal wall. The presence of verapamil and Pluronic both improved the intestinal absorption of PTX, which further certified the effect of Pluronic on P-gp inhibition. Pharmacokinetic study demonstrated that the area under the plasma concentration-time curve (AUC(0?36 h)) of PTX-loaded micelles was three times greater than the PTX solution (dissolved in a 50/50 (vol/vol) mixture of Cremophore EL/dehydrated ethanol) (p < 0.05). In general PF127-PEI-FA/PP123 mixed micelles were proved to be potential oral drug delivery system for PTX. PMID:23126604

  10. Pharmacokinetics and biodistribution of paclitaxel-loaded microspheres.

    PubMed

    Yan, F; Tang, S; Fu, Q

    2012-04-01

    Paclitaxel(PTX)-loaded microspheres composed of poly(D,L-lactide-co-glycolide) (PLGA) were prepared by an O/W emulsion solvent evaporation method. This study was designed to investigate the preparation, in vitro release, in vivo pharmacokinetics and tissue distribution of a PTX-loaded microspheres system. Microspheres are characterized according to drug loading, size and shape. With a dynamic light scattering sizer and a transmission electron microscopy, it is shown that the PTX-loaded microspheres had a mean size of approximately 10.24 µm with narrow size distribution and a spherical shape. The in vitro release profiles indicate that the release of PTX from the microspheres exhibit a sustained release behavior. A similar phenomenon is observed in a pharmacokinetic study in rats, in which AUC of the microspheres formulation were 3.7-fold higher than that of PTX injection. The biodistribution study in mice showed that the PTX-loaded microspheres not only decreased drug uptake by liver, but also increased distribution of drug in lung. These results suggest that PTX-loaded microspheres may efficiently load, protect and retain PTX in both in vitro and in vivo environments, and could be a useful drug carrier for i. v. administration of PTX. PMID:22270845

  11. A thermally responsive biopolymer conjugated to an acid-sensitive derivative of paclitaxel stabilizes microtubules, arrests cell cycle, and induces apoptosis.

    PubMed

    Moktan, Shama; Ryppa, Claudia; Kratz, Felix; Raucher, Drazen

    2012-02-01

    Poor aqueous solubility limits the therapeutic index of paclitaxel as an anti-cancer drug. Synthesis of soluble prodrugs of paclitaxel, or conjugation of the drug to macromolecular carriers have been reported to increase its water-solubility. Macromolecular drug carriers have an added advantage of targeting the drug to the tumor site due to the abnormal tumor blood and lymphatic vasculature. This study describes a thermally responsive macromolecular carrier, elastin-like polypeptide (ELP) for the delivery of paclitaxel. Paclitaxel was bound to ELP by conjugation with the 6-maleimidocaproyl hydrazone derivative of paclitaxel, an acid-sensitive paclitaxel prodrug, for the potential treatment of breast cancer. Focused hyperthermia above a specific transition temperature at the site of a tumor causes ELP to aggregate and accumulate, thereby increasing the local concentration of the drug cargo. The paclitaxel prodrug described here bears an acid-sensitive linker that is cleavable at the lysosomal/endosomal pH, which allows a controlled intracellular release of the drug. The ELP-delivered paclitaxel in the presence of hyperthermia inhibits MCF-7 cell proliferation by stabilizing the microtubule structures, arresting the cells at the G2/M stage, and inducing apoptosis in a manner similar to conventional paclitaxel. It also inhibits proliferation of a paclitaxel resistant MCF-7 cell line. These data provide an in vitro proof of concept for the use of ELP as a delivery vehicle of paclitaxel. PMID:20938714

  12. Paclitaxel plus gallium nitrate and filgrastim in patients with refractory malignancies: a phase I trial.

    PubMed

    Sandler, A; Fox, S; Meyers, T; Christou, A; Weber, G; Gonin, R; Loehrer, P J; Einhorn, L H; Dreicer, R

    1998-04-01

    To determine the maximally tolerated dose of paclitaxel with and without filgrastim (G-CSF) when administered as a 24-hour intravenous infusion after a 120-hour infusion of gallium nitrate at a fixed dose of 300 mg/m2/24 hours, 40 patients were entered onto a trial lasting from September 1994 to September 1996. Eligibility included a diagnosis of an advanced malignancy not amenable to curative therapy and up to one previous chemotherapy regimen for metastatic disease. Gallium was administered at a fixed dose of 300 mg/m2/day as a continuous intravenous infusion for 120 hours. Paclitaxel starting at 90 mg/m2 was given concurrently with the last 24 hours of the gallium as a 24-hour intravenous infusion. Cycles were repeated every 21 days. Once the maximum tolerated dose (MTD) of paclitaxel was reached, G-CSF (5 microg/kg/day days 7-16) was added and paclitaxel dose escalation continued. The MTD for paclitaxel without G-CSF was 110 mg/m2 and 225 mg/m2 with G-CSF, with neutropenia being the dose-limiting toxicity. A partial response was noted in a patient who had thymoma and a complete response was achieved in a patient who had colon cancer. The recommended phase II dosage is gallium nitrate at 300 mg/m2/day over 120 hours, with paclitaxel at 110 mg/m2 over 24 hours without G-CSF or 225 mg/m2 over 24 hours with G-CSF and 0.5 mg calcitriol on days 1 through 7. Further trials of this modified regimen for outpatient administration are in progress. PMID:9537208

  13. Developmental changes in phosphorylation of MAP-2 and synapsin I in cytosol and taxol polymerised microtubules from chicken brain.

    PubMed

    Koszka, C; Brent, V A; Rostas, J A

    1991-06-01

    In cytosol, cyclic AMP stimulated phosphorylation of microtubule associated protein-2 (MAP-2) increased from 2 days to adult in proportion to the increase in the concentration of MAP-2. By contrast, the calmodulin stimulated phosphorylation of MAP-2 decreased in proportion to the decrease in the concentration of calmodulin stimulated protein kinase II (CMK II). Similarly, the cAMP stimulated phosphorylation of the site on synapsin I labeled by the cAMP stimulated protein kinase (PKA) changed little during development whereas the calcium/calmodulin stimulated phosphorylation of the CMK II site decreased dramatically in proportion to the decrease in the concentration of CMK II. The decrease in the concentration of CMK II which occurs in cytosol during synapse maturation was also observed in taxol polymerised microtubules and the effects of the change in the relative concentrations of CMK II and PKA on the phosphorylation of MAP-2 and synapsin I in this fraction were similar to that observed in the cytosol. These results are consistent with the hypothesis that the developmental changes in phosphorylation of endogenous substrates by PKA is controlled largely by changes in the concentration of those substrates, whereas the concentration of CMK II is limiting so that the developmental changes in the phosphorylation of endogenous substrates by CMK II are a function of the concentration of CMK II itself as well as the concentration of endogenous substrates. Some possible functional consequences of this during synapse maturation are discussed. PMID:1686473

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

    PubMed

    K?z?l?ahin, Sadi; Nalbantsoy, Ay?e; Yava?o?lu, 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 ?g/mL Tax. The MTT results indicated that OLA-Tax combinations exhibited cytotoxicity against PC3 at doses of 30 nM+10 ?g-Tax, 15 nM+5 ?g-Tax and 7.5 nM+2.5 ?g-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. PMID:25134457

  15. Autophagy promotes paclitaxel resistance of cervical cancer cells: involvement of Warburg effect activated hypoxia-induced factor 1-?-mediated signaling

    PubMed Central

    Peng, X; Gong, F; Chen, Y; Jiang, Y; Liu, J; Yu, M; Zhang, S; Wang, M; Xiao, G; Liao, H

    2014-01-01

    Paclitaxel is one of the most effective chemotherapy drugs for advanced cervical cancer. However, acquired resistance of paclitaxel represents a major barrier to successful anticancer treatment. In this study, paclitaxel-resistant HeLa sublines (HeLa-R cell lines) were established by continuous exposure and increased autophagy level was observed in HeLa-R cells. 3-Methyladenine or ATG7 siRNA, autophagy inhibitors, could restore sensitivity of HeLa-R cells to paclitaxel compared with parental HeLa cells. To determine the underlying molecular mechanism, differentially expressed proteins between HeLa and HeLa-R cells were identified by two-dimensional gel electrophoresis coupled with electrospray ionization quadrupole time-of-flight MS/MS. We found glycolysis-associated proteins were upregulated in HeLa-R cell lines. Inhibition of glycolysis by 2-deoxy-D-glucose or koningic acid could decrease autophagy and enhance sensitivity of HeLa-R cells to paclitaxel. Moreover, glycolysis could activate HIF1-?. Downregulation of HIF1-? by specific siRNA could decrease autophagy and resensitize HeLa-R cells to paclitaxel. Taken together, a possible Warburg effect activated HIF1-?-mediated signaling-induced autophagic pathway is proposed, which may provide new insight into paclitaxel chemoresistance. PMID:25118927

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

    PubMed Central

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

    2015-01-01

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

  17. 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 ?mol/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 ?mol/L of losartan inhibits both CYP2C8 and CYP3A4 in HLMs. In summary, losartan inhibited paclitaxel metabolism, with concentrations over 50 ?mol/L in HLMs. The CYP2C8*3 allele carriers are likely susceptible to the interactions of losartan and CYP3A4 inhibitors to paclitaxel metabolism. PMID:25424246

  18. nab-Paclitaxel in Combination With Weekly Carboplatin With Concurrent Radiotherapy in Stage III Non-Small Cell Lung Cancer

    PubMed Central

    Lu, Bo; Horn, Leora; Shyr, Yu; Keedy, Vicki

    2015-01-01

    Lessons Learned The concomitant use of weekly nab-paclitaxel and carboplatin with concurrent radiotherapy was demonstrated to be a safe therapeutic approach in this phase I trial of 10 evaluable patients with stage III NSCLC. Despite the lack of systemic glucocorticoids, there were no reported infusion reactions or cases of peripheral neuropathy in this trial, both of which are known to occur with the use of paclitaxel. Background. Unresectable stage III non-small cell lung cancer (NSCLC) has a 5-year survival rate of 20%, and concurrent chemoradiotherapy results in significant toxicity with the use of current chemotherapeutic agents. nab-Paclitaxel was approved by the U.S. Food and Drug Administration in October 2012 for use along with carboplatin in advanced NSCLC. This study was undertaken to determine the maximum tolerated dose and dose-limiting toxicities (DLTs) of weekly nab-paclitaxel given in combination with carboplatin and concurrent radiotherapy in patients with unresectable stage III NSCLC. Methods. Escalating doses of once-weekly nab-paclitaxel were given along with once-weekly carboplatin area under the plasma concentration time curve (AUC) of 2 and concurrent radiotherapy 66 Gy in 33 fractions, followed by 2 cycles of carboplatin and nab-paclitaxel consolidation chemotherapy. Results. Eleven patients were enrolled and received treatment per protocol, with 10 evaluable for efficacy and toxicity. At dose level 1 (nab-paclitaxel 60 mg/m2), 2 DLTs were observed: esophagitis and radiation dermatitis. Six patients were enrolled at dose level 0 (nab-paclitaxel 40 mg/m2) with no DLTs. Nine of 10 evaluable patients had a partial response. Conclusion. Concurrent chemoradiotherapy with nab-paclitaxel 40 mg/m2 and carboplatin AUC 2 is a safe and well-tolerated therapeutic regimen in patients with stage III NSCLC. A separate phase I/II study to evaluate the efficacy of this regimen is under way. PMID:25845992

  19. Validated HPLC Method for the Determination of Paclitaxel-related Substances in an Intravenous Emulsion Loaded with a Paclitaxel–Cholesterol Complex

    PubMed Central

    Xia, X. J.; Peng, J.; Zhang, P. X.; Jin, D. J.; Liu, Y. L.

    2013-01-01

    A high-performance liquid chromatography method was developed for the determination of related substances in an intravenous emulsion loaded with a paclitaxel–cholesterol complex. The separation was achieved using Agilent Eclipse XDB-C18 column (150×4.6 mm, 3.5 ?m), which was kept at 40°. The gradient mobile phase consisted of acetonitrile and water with a flow rate of 1.2 ml/min. The ultraviolet detection wavelength was set at 227 nm. The preparation of the sample solution began with the addition of anhydrous sodium sulphate to break the emulsion. Then, methanol and ethyl ether were added to pick up the drug and remove the accessories of the emulsion by extraction and centrifugation. Finally, paclitaxel was enriched by a nitrogen blow method and resolved with a mixture of methanol:glacial acetic acid (200:1). The method was proven to be selective, sensitive, robust, linear, repeatable, accurate and suitable for the determination of paclitaxel-related substances in the emulsion formulations, and the major degradation products in the potential pharmaceutical product were 7-epipaclitaxel and 10-deacetylpaclitaxel. PMID:24591742

  20. Peptide-conjugated biodegradable nanoparticles as a carrier to target paclitaxel to tumor neovasculature

    Microsoft Academic Search

    De-Hong Yu; Qin Lu; Jing Xie; Chao Fang; Hong-Zhuan Chen

    2010-01-01

    Antiangiogenic cancer therapy can be achieved through the targeted delivery of antiangiogenic agents to the endothelial cells of tumor neovasculature. In the present study, we developed a drug delivery system (DDS), nanoparticles conjugated with K237-(HTMYYHHYQHHL) peptides for tumor neovasculature targeting drug delivery. Paclitaxel, a chemotherapeutic agent with potent antiangiogenic activity, was used as a prototype drug. We synthesized the aldehyde

  1. Delivery of paclitaxel from cobalt–chromium alloy surfaces without polymeric carriers

    Microsoft Academic Search

    Gopinath Mani; Celia E. Macias; Marc D. Feldman; Denes Marton; Sunho Oh; C. Mauli Agrawal

    2010-01-01

    Polymer-based carriers are commonly used to deliver drugs from stents. However, adverse responses to polymer coatings have raised serious concerns. This research is focused on delivering drugs from stents without using polymers or any carriers. Paclitaxel (PAT), an anti-restenotic drug, has strong adhesion towards a variety of material surfaces. In this study, we have utilized such natural adhesion property of

  2. Designing Paclitaxel Drug Delivery Systems Aimed at Improved Patient Outcomes: Current Status and Challenges

    PubMed Central

    Surapaneni, Madhu S.; Das, Sudip K.; Das, Nandita G.

    2012-01-01

    Paclitaxel is one of the most widely used and effective antineoplastic agents derived from natural sources. It has a wide spectrum of antitumor activity, particularly against ovarian cancer, breast cancer, nonsmall cell lung cancer, head and neck tumors, Kaposi's sarcoma, and urologic malignancies. It is a highly lipophilic compound with a log P value of 3.96 and very poor aqueous solubility of less than 0.01?mg/mL. In addition, the compound lacks functional groups that are ionizable which could potentially lead to an increase in its solubility with the alteration in pH. Therefore, the delivery of paclitaxel is associated with substantial challenges. Until the introduction of Abraxane, only commercial formulation was solution of paclitaxel in cremophor, which caused severe side effects. However, in recent years, a number of approaches have been reported to solubilize paclitaxel using cosolvents and inclusion complexes. In addition, innovative approaches have been reported for passive targeting of tumors using nanoparticles, nanosuspensions, liposomes, emulsions, micelles, implants, pastes and gels. All approaches for delivery of improved therapeutic outcome have been discussed in this paper. PMID:22934190

  3. Paclitaxel and Platinum Chemotherapy for Malignant Mixed Mullerian Tumors of the Ovary

    Microsoft Academic Search

    Linda R. Duska; Audrey Garrett; Gamal H. Eltabbakh; Esther Oliva; Richard Penson; Arlan F. Fuller

    2002-01-01

    Objective. Malignant mixed müllerian tumor (MMMT) of the ovary is a rare tumor with a dismal prognosis. The most effective therapy is unknown. The current study was undertaken to characterize a group of patients treated as if they had aggressive epithelial ovarian tumors, with cytoreductive surgery and combination paclitaxel\\/platinum chemotherapy.Methods. Retrospective analysis of data obtained from tumor registry and hospital

  4. Investigation of Paclitaxel Resistant R306C Mutation in ?-Tubulin-A Computational Approach.

    PubMed

    Verma, Kanika; Ramanathan, K

    2015-07-01

    Paclitaxel is the most effective chemotherapeutic agent used for the treatment of a broad spectrum of solid tumors. However, observed paclitaxel resistance in clinical trials presents one of the major obstacles for cancer chemotherapy. Most importantly, resistance due to ?-tubulin mutations (R306C) has been intensely debated in recent years. Despite all efforts, mechanism of resistance is still not well understood. In this study, computational techniques were employed to uncover the effect of R306C mutation in the ?-tubulin structure and its function. The tools such as I-Mutant, CUPSAT and Fold-X were employed to address the consequence of R306C mutation in the structural stability of ?-tubulin. Further, molecular docking and molecular dynamics study was employed to understand the functional impact of ?-tubulin mutation. Our results suggest that the R306C mutation causes a significant reduction in the binding affinity between ?-tubulin and paclitaxel. Further, docked complex analysis indicates that destruction of conservative hydrogen bond maintained by the residues Arg282 and Gly360 should be responsible for the large conformation changes of the binding pocket in R306C mutant. Finally, molecular dynamics simulations study confirms the stable binding of paclitaxel with native type ?-tubulin structure rather than mutant (R306C) type. We certainly believe that this study will provide useful guidance for the development of novel inhibitors that are less susceptible to drug resistance. J. Cell. Biochem. 116: 1318-1324, 2015. © 2015 Wiley Periodicals, Inc. PMID:25735511

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

    PubMed Central

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

    2015-01-01

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

  6. Designing Paclitaxel drug delivery systems aimed at improved patient outcomes: current status and challenges.

    PubMed

    Surapaneni, Madhu S; Das, Sudip K; Das, Nandita G

    2012-01-01

    Paclitaxel is one of the most widely used and effective antineoplastic agents derived from natural sources. It has a wide spectrum of antitumor activity, particularly against ovarian cancer, breast cancer, nonsmall cell lung cancer, head and neck tumors, Kaposi's sarcoma, and urologic malignancies. It is a highly lipophilic compound with a log P value of 3.96 and very poor aqueous solubility of less than 0.01?mg/mL. In addition, the compound lacks functional groups that are ionizable which could potentially lead to an increase in its solubility with the alteration in pH. Therefore, the delivery of paclitaxel is associated with substantial challenges. Until the introduction of Abraxane, only commercial formulation was solution of paclitaxel in cremophor, which caused severe side effects. However, in recent years, a number of approaches have been reported to solubilize paclitaxel using cosolvents and inclusion complexes. In addition, innovative approaches have been reported for passive targeting of tumors using nanoparticles, nanosuspensions, liposomes, emulsions, micelles, implants, pastes and gels. All approaches for delivery of improved therapeutic outcome have been discussed in this paper. PMID:22934190

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

    E-print Network

    Park, Jong-Sang

    A Novel Technique for Loading of Paclitaxel-PLGA Nanoparticles onto ePTFE Vascular Grafts Hyun Jung(lactic-co- glycolic acid) (PLGA) nanoparticles (Ptx-PLGA-NPs) were prepared by the emulsion-solvent evaporation method and spin penetration techniques. Scanning electron microscope (SEM) images of various stages of Ptx-PLGA

  8. Gemcitabine and paclitaxel combinations in non-small cell lung cancer.

    PubMed

    Dombernowsky, P; Giaccone, G; Sandler, A; Schwartsmann, G

    1998-08-01

    Gemcitabine and paclitaxel are new cytotoxic agents that have been used both as single agents and in combination, particularly with cisplatin, in the therapy of non-small cell lung cancer (NSCLC) with promising results. The lack of overlapping toxicities and different mechanisms of action of gemcitabine and paclitaxel make the combination of these drugs appealing in the treatment of NSCLC. A number of phase I and II trials are evaluating the use of this combination of cytotoxic agents as first-line therapy and as second-line therapy in patients with advanced NSCLC. In ongoing phase II trials using a 21-day schedule, the combination of gemcitabine and paclitaxel therapy appears to be well-tolerated, with response rates ranging from 29% to 58% and hematologic toxicities that are mild to moderate in severity. Other reported toxicities included alopecia, fatigue, and flu-like symptoms, which were also mild to moderate. However, grade 2/3 neurotoxicity was also reported. In conclusion, preliminary results from these early phase II trials of gemcitabine/paclitaxel combination therapy in advanced NSCLC are encouraging. PMID:9728584

  9. Therapeutic potential of paclitaxel-radiation treatment of a murine ovarian carcinoma

    Microsoft Academic Search

    Luka Milas; Yoshihiro Saito; Nancy Hunter; Christopher G. Milross; Kathryn A. Mason

    1996-01-01

    Background. Paclitaxel has been shown to radiosensitize tumor cells in culture by arresting them in the most radiosensitive G2 and M cell cycle phases. In vivo preclinical studies are now necessary to obtain full insight into the radiopotentiating potential of this drug and its ability to increase the therapeutic gain of radiotherapy. We tested its ability to enhance the tumor

  10. Pharmacokinetic Evaluation of Paclitaxel in South Indian Cancer Patients: A Prospective Study

    PubMed Central

    Vasantha, J; Kannan, G; Goud, T; Palani, T; Vanitha, R; Anitha, R; Priya, JMM

    2011-01-01

    Paclitaxel is a promising drug in the treatment of different solid tumors. It exhibits nonlinear pharmacokinetics, particularly when administered as a constant rate infusion for shorter duration (e.g., 3 h). Because of the nonlinearity, relatively small changes in dose may lead to large changes in peak plasma concentration and total drug exposure. The study was conducted to evaluate the pharmacokinetics of different doses of paclitaxel administered intravenously as an infusion. A prospective study was conducted in 23 cancer patients aged between 28 and 74 years, treated with paclitaxel (130, 200, 230, and 260 mg/m2) over 3 h as constant rate infusion. Plasma samples were collected from all patients at 0, 1, and 3 h and for five patients at 5 and 13 h and paclitaxel concentrations were determined using high-performance liquid chromatography method. The overall mean clearance was found to be 47.5847 ± 142.028 l/h; the mean volume of distribution was 142.028 ± 73.438 l; mean elimination rate constant was 0.336 ± 0.002/h; mean half-life was 2.086 ± 0.009 h; mean area under the curve (AUC) was 5.5917 ± 2.707 mg/ml*h; and the mean of mean residence time was 2.980 ± 0.0131 h. Paclitaxel showed nonlinear kinetics and the pharmacokinetic parameters calculated were similar to those quoted in the literature. The peak plasma concentration at 130 mg dose level was 2 ?/ml, but an increase in dose was not associated with proportional increase in plasma concentration. No significant difference was found between pharmacokinetic parameters such as clearance, volume of distribution, and AUC at different dose levels. PMID:22224040

  11. Inhibition of Notch Signaling in Combination with Paclitaxel Reduces Platinum-Resistant Ovarian Tumor Growth

    PubMed Central

    Groeneweg, Jolijn W.; DiGloria, Celeste M.; Yuan, Jing; Richardson, William S.; Growdon, Whitfield B.; Sathyanarayanan, Sriram; Foster, Rosemary; Rueda, Bo R.

    2014-01-01

    Introduction: Ovarian cancer (OvCa) is the most lethal gynecologic malignancy in the United States because of chemoresistant recurrent disease. Our objective was to investigate the efficacy of inhibiting the Notch pathway with a ?-secretase inhibitor (GSI) in an OvCa patient-derived xenograft model as a single agent therapy and in combination with standard chemotherapy. Methods: Immunocompromised mice bearing xenografts derived from clinically platinum-sensitive human ovarian serous carcinomas were treated with vehicle, GSI (MRK-003) alone, paclitaxel and carboplatin (P/C) alone, or the combination of GSI and P/C. Mice bearing platinum-resistant xenografts were given GSI with or without paclitaxel. Gene transcript levels of the Notch pathway target Hes1 were analyzed using RT-PCR. Notch1 and Notch3 protein levels were evaluated. The Wilcoxon rank-sum test was used to assess significance between the different treatment groups. Results: Expression of Notch1 and 3 was variable. GSI alone decreased tumor growth in two of three platinum-sensitive ovarian tumors (p?paclitaxel was significantly more effective than GSI alone and paclitaxel alone in all platinum-resistant ovarian tumors (all p?paclitaxel. These findings suggest inhibition of the Notch pathway in concert with taxane therapy may hold promise for treatment of platinum-resistant OvCa. PMID:25072022

  12. Carboplatin and paclitaxel as first-line treatment of unresectable or metastatic esophageal or gastric cancer.

    PubMed

    Prithviraj, G K; Baksh, K; Fulp, W; Meredith, K; Hoffe, S; Shridhar, R; Almhanna, K

    2014-08-25

    Survival in patients with metastatic esophageal and gastric cancer is dismal. No standard treatment has been established. Carboplatin/paclitaxel is active in both advanced gastric and esophageal cancer. Here we retrospectively present our single center experience. Between 1998 and 2013, a total of 134 patients with metastatic esophageal and gastric adenocarcinoma treated with carboplatin/paclitaxel (carboplatin predominantly area under the curve 5 and paclitaxel predominantly 175?mg/m(2) ) every 3 weeks as first-line therapy were identified. Baseline characteristics, response to therapy, toxicities, and survival in this patient population were evaluated. Overall survival was defined as date from diagnosis to death or last follow up, and progression-free survival was defined at time from cycle 1 to, progression or last follow up. Kaplan-Meier curves were fit to estimate overall and progression-free survival. Of the 134 patients evaluated, the median age at diagnosis was 65 years. Disease control rate was 62.6% (complete response: 11%, partial response: 28%, stable disease: 33%). Median overall survival from date of initial diagnosis was 15.5 months (95% confidence interval [CI] 1.06-1.5). Median progression-free survival from date of initiation of carboplatin and paclitaxel was 5.3 months (95% CI 0.34-0.5). Grade III or greater toxicity occurred in 26.1% of patients. The most common grade III toxicities were neutropenia and neuropathy, present in 14.2% and 3.7% of the total study population, respectively. In patients with metastatic or unresectable esophageal or gastric cancer, the combination of carboplatin and paclitaxel is well tolerated with comparable overall survival and progression-free survival to existing regimens in this population. PMID:25155802

  13. Phase I trial of weekly cisplatin, irinotecan and paclitaxel in patients with advanced gastrointestinal cancer

    PubMed Central

    Radovich, Delia; O’Reilly, Eileen; Schwartz, Gary; Schrag, Deborah; Saltz, Leonard B.; Kelsen, David P.; Kepler, Stacey; Ilson, David H.

    2011-01-01

    Summary Objectives To determine the maximum tolerated dose (MTD), toxicities, and suitable dose for weekly 1-h paclitaxel combined with weekly cisplatin and irinotecan to treat advanced gastrointestinal malignancies. Methods Thirty patients with metastatic or locally advanced (unresectable or recurrent) gastrointestinal solid tumors were enrolled on this single-center, phase I study. Patients were treated with paclitaxel given over 1h at 1 of 4 dose levels (40, 50, 65, or 80 mg/m2). Paclitaxel was followed by fixed doses of cisplatin (30 mg/m2) and irinotecan (50 mg/m2). All treatment was administered sequentially, once a week, in 6-week cycles (4 weeks on, 2 weeks off). Dose-limiting toxicity (DLT) was defined as a 2-week delay in treatment for grade 3 or 4 non-hematologic toxicity, neutropenic fever, a 1-week delay for grade 4 hematologic toxicity, or a 2-week delay for grade 3 hematologic toxicity. Results Thirty patients were recruited; 28 patients were assessable for safety. Most of the patients (70%) had no prior chemotherapy. The primary first-cycle DLTs were neutropenia, diarrhea, and nausea. Paclitaxel at 65 mg/m2 was defined as the MTD. The most common grade 3–4 toxicities observed during all cycles were neutropenia (57%), febrile neutropenia (11%), diarrhea (29%), fatigue (29%), and nausea (18%). No patients had G-CSF (Neupogen, Amgen Inc., Thousand Oaks, CA) support. Responses were observed in gastric, esophageal, and pancreatic cancers. Conclusion Paclitaxel at 65 mg/m2, cisplatin (30 mg/m2), and irinotecan (50 mg/m2) given weekly can be safely administered to patients with solid tumor malignancies. To improve cumulative toxicities, a schedule modification was required (3-week cycle; 2-on, 1-off) Neutropenia was the most common DLT. This combination showed substantial activity, particularly in patients with gastric and esophageal adenocarcinoma, and phase II evaluation could be considered. PMID:18956138

  14. 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. PMID:23615724

  15. 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. PMID:22898996

  16. Biweekly Docetaxel-Irinotecan Treatment with Filgrastim Support Is Highly Active in Antracycline-Paclitaxel-Refractory Breast Cancer Patients

    Microsoft Academic Search

    Giuseppe Frasci; Giuseppe D’Aiuto; Renato Thomas; Pasquale Comella; Maurizio Di Bonito; Liliana Lapenta; Massimiliano D’Aiuto; Gerardo Botti; Paolo Vallone; Vincenzo De Rosa; Roberta D’Aniello; Renato Giordano; Giuseppe Comella

    2005-01-01

    Purpose: To evaluate the feasibility and activity of combination treatment with docetaxel (DTX) and irinotecan (CPT-11), given together every other week, combined with filgrastim support, in anthracycline- and paclitaxel-pretreated breast cancer (BC) patients. Patients and Methods: Advanced BC patients pretreated with anthracycline- and paclitaxel-based chemotherapy were eligible. DTX (80 mg\\/m2) and CPT-11 (100 mg\\/m2) were given biweekly with filgrastim support

  17. Paclitaxel-induced apoptosis in non–small cell lung cancer cell lines is associated with increased caspase-3 activity

    Microsoft Academic Search

    Tracey L. Weigel; Michael T. Lotze; Peter K. Kim; Andrew A. Amoscato; James D. Luketich; Christine Odoux

    2000-01-01

    Objective: Our objective was to determine whether paclitaxel-induced apoptosis in human lung cancer cells is Fas dependent. Methods: Human lung cancer cell lines were evaluated for morphologic evidence of apoptosis, DNA fragmentation (TUNEL positivity), and caspase-3 activation after paclitaxel treatment. Human lung adenocarcinoma, squamous cell carcinoma, undifferentiated lung carcinoma, and bronchoalveolar carcinoma cell lines were each cultured in 10 ?mol\\/L

  18. Effects of gamma-linolenic acid and oleic acid on paclitaxel cytotoxicity in human breast cancer cells

    Microsoft Academic Search

    J. A. Menéndez; M. del Mar Barbacid; S. Montero; E. Sevilla; E. Escrich; M. Solanas; H. Cortés-Funes; R. Colomer

    2001-01-01

    It has been suggested that dietary interventions may improve the effectiveness of cancer chemotherapy. We have examined the combined in vitro cytotoxicity of paclitaxel and the fatty acids gamma-linolenic acid (GLA, 18:3n-6) and oleic acid (OA, 18:1n-9) in human breast carcinoma MDA-MB-231 cells. The effect of fatty acids on paclitaxel chemosensitivity was determined by comparing IC50 and IC70 (50 and

  19. FoxO3a transcriptional regulation of Bim controls apoptosis in paclitaxel-treated breast cancer cell lines

    Microsoft Academic Search

    A. Sunters; S. Fernandez de Mattos; M. Stahl; J. J. Brosens; G. Zoumpoulidou; C. A. Saunders; P. J. Coffer; R. H. Medema; R. C. Coombes; E. W.-F. Lam

    2003-01-01

    Paclitaxel is used to treat breast cancers, but the mechanisms by which it induces apoptosis are poorly understood. Consequently, we have studied the role of the FoxO transcription factors in determining cellular response to paclitaxel. Western blotting revealed that in a panel of nine breast cancer cell lines expression of FoxO1a and FoxO3a correlated with the expression of the pro-apoptotic

  20. Paclitaxel and vinorelbine cause synergistic increases in apoptosis but not in microtubular disruption in human lung adenocarcinoma cells (A-549)

    Microsoft Academic Search

    Michael Jung; Steven Grunberg; Cynthia Timblin; Sylke Buder-Hoffman; Pamela Vacek; Douglas J. Taatjes; Brooke T. Mossman

    2004-01-01

    Concurrent administration of paclitaxel and vinorelbine results in cytotoxicity in vivo and in vitro in a number of tumor cell lines, yet the mechanisms of enhanced cell killing are undefined. In studies here, we show that low concentrations (1 nM) of paclitaxel and vinorelbine in combination result in enhanced cell killing by apoptosis ( PP<0.05) alone, but not vinorelbine, were not

  1. Proteomic analysis of the proteins that are associated with the resistance to paclitaxel in human breast cancer cells.

    PubMed

    Chen, Siying; Dong, Qian; Hu, Sasa; Cai, Jiangxia; Zhang, Weipeng; Sun, Jinyao; Wang, Taotao; Xie, Jiao; He, Hairong; Xing, Jianfeng; Lu, Jun; Dong, Yalin

    2014-02-01

    Cancers frequently develop resistance to paclitaxel but the underlying molecular mechanisms remain to be determined. We have investigated the proteins that are associated with the paclitaxel resistance in human breast cancer MCF-7 cells using proteomic analysis. Paclitaxel resistant human breast cancer MCF-7 cells (MCF-7/P) were established by escalating the concentrations of paclitaxel to drug-sensitive MCF-7 cells (MCF-7/S). The global protein profiles of MCF-7/P and MCF-7/S were compared using two-dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS). Eleven proteins were upregulated while six proteins were downregulated in MCF-7/P cells. Western blot and real-time PCR analyses showed that the protein and mRNA levels of heterogeneous nuclear ribonucleoprotein (hnRNP C1/C2), SET nuclear oncogene (SET), aspartate aminotransferase (AAT), transgelin-2 (TAGLN2) were increased, while those of nucleoside-diphosphate kinase A (NDKA) were decreased in MCF-7/P cells. Accordingly, knockdown of TAGLN2 by siRNA sensitized MCF-7/P cells to paclitaxel and reduced the multidrug resistance (MDR). Our identification of differential proteins, particularly transgelin-2, provides new insights into the mechanism of MDR to paclitaxel and novel biological targets for breast cancer treatment. PMID:24292090

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

    PubMed Central

    2014-01-01

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

  3. Phase I clinical trial of hepatic arterial infusion of paclitaxel in patients with advanced cancer and dominant liver involvement

    PubMed Central

    Letourneau, Katherine; Fu, Siqing; Hong, David; Naing, Aung; Wheler, Jennifer; Uehara, Cynthia; McRae, Stephen E.; Wen, Sijin; Kurzrock, Razelle

    2011-01-01

    Purpose The survival of patients with liver metastases from solid tumors is poor. We conducted a phase I study of hepatic arterial infusion (HAI) paclitaxel in patients with advanced cancer and predominant liver involvement. Methods Patients were treated with HAI paclitaxel 150–275 mg/m2 (and 15,000 IU heparin intraarterially) every 28 days. A “3 + 3” study design was used. Results Twenty-six patients were treated (median age, 59 years). Diagnoses were colorectal cancer (n = 10), breast cancer (n = 7), and other (n = 9). The median number of prior therapies was four (range, 0–10). The maximum tolerated dose (MTD) was HAI paclitaxel 225 mg/m2. Dose-limiting toxicities (DLTs) included Grade 3 neuropathy (1 of 5 patients) at HAI paclitaxel 275 mg/m2 and Grade 4 thrombocytopenia and neutropenia, and Grade 3 mucositis (1 of 4 patients) at 250 mg/m2. None of the eight patients treated with HAI paclitaxel 225 mg/m2 experienced a DLT. The most common toxicities were nausea and peripheral neuropathy. Of 22 patients evaluable for response, 3 (13.6%) patients had SD for ?4 months (colorectal cancer, n = 1; thyroid cancer, n = 1; and hepatocellular carcinoma, n = 1; duration of response was 4 months, 7.1 months, and 22.2+ months, respectively). Conclusion The MTD of HAI paclitaxel was 225 mg/m2. This regimen was well tolerated and had antitumor activity in selected patients. PMID:20941597

  4. Biodegradable polymersomes as carriers and release systems for paclitaxel using Oregon Green® 488 labeled paclitaxel as a model compound.

    PubMed

    Lee, Jung Seok; Feijen, Jan

    2012-03-10

    Oregon Green® 488 labeled paclitaxel (Flutax) loaded biodegradable polymersomes (Flutax-Ps) based on methoxy poly(ethylene glycol)-b-poly(d,l-lactide) (mPEG-PDLLA), methoxy poly(ethylene glycol)-b-poly(?-caprolactone) (mPEG-PCL) or a mixture of the block copolymers (50:50, w/w) were prepared (abbreviated as Flutax-Ps (L), Flutax-Ps (C) and Flutax-Ps (LC), respectively). For the formation of the Ps, the corresponding block copolymers and Flutax were dissolved in THF and the THF solution was injected into an aqueous phase. Flutax-Ps with a size less than 150nm were obtained, which had Flutax entrapment efficiencies higher than 55% (polymer concentration: 1mg/ml; Flutax concentration up to 100?g/ml). A sustained and complete release of Flutax was observed for Flutax-Ps (L) over one month with no initial burst. Flutax was released much slower from Ps (C) than from Ps (L) (49.9% after one month), which is probably due to differences in the crystallinity and rate of degradation of the consisting copolymers. The release rate of Flutax from Ps (LC) was in between those of Ps (L) and Ps (C). The in vitro cytotoxicity of Flutax-Ps (L) using cultured SKBR3 breast cancer cells was compared with that of empty Ps (L) and a Cremophor® EL/ethanol formulation (50:50, v/v) with Flutax (FCE) or without Flutax (CE). At a Flutax concentration of 5?g/ml, about 67% reduction in the viability of SKBR3 cells was observed for Flutax-Ps (L) after 3days exposure, while the FCE formulation reduced the cell viability for more than 90% under the same conditions. Empty Ps (L) showed a low toxicity of about 10% and the CE formulation exhibited a cytotoxicity higher than 54% without Flutax, indicating that the high reduction in SKBR3 cell viability for FCE is associated with the toxicity of the Cremophor® EL formulation. PMID:22063005

  5. Requirement of Osteopontin in the migration and protection against Taxol-induced apoptosis via the ATX-LPA axis in SGC7901 cells

    PubMed Central

    2011-01-01

    Background Autotaxin (ATX) possesses lysophospholipase D (lyso PLD) activity, which converts lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA). The ATX-LPA signaling axis has been implicated in angiogenesis, chronic inflammation and tumor progression. Osteopontin (OPN) is an important chemokine involved in the survival, proliferation, migration, invasion and metastasis of gastric cancer cells. The focus of the present study was to investigate the relationship between the ATX-LPA axis and OPN. Results In comparison with non-treated cells, we found that the ATX-LPA axis up-regulated OPN expression by 1.92-fold in protein levels and 1.3-fold in mRNA levels. The ATX-LPA axis activates LPA2, Akt, ERK and ELK-1 and also protects SGC7901 cells from apoptosis induced by Taxol treatment. Conclusions This study provides the first evidence that expression of OPN induced by ATX-LPA axis is mediated by the activation of Akt and MAPK/ERK pathways through the LPA2 receptor. In addition, OPN is required for the protective effects of ATX-LPA against Taxol-induced apoptosis and ATX-LPA-induced migration of SGC7901 cells. PMID:21406114

  6. Fabrication of Micro and Nanoparticles of Paclitaxel-loaded Poly L Lactide for Controlled Release using Supercritical Antisolvent Method: Effects of Thermodynamics and Hydrodynamics

    E-print Network

    Lee, Lai Yeng

    This paper presents the fabrication of controlled release devices for anticancer drug paclitaxel using supercritical antisolvent method. The thermodynamic and hydrodynamic effects during supercritical antisolvent process ...

  7. Nanoparticle albumin-bound paclitaxel in a patient with locally advanced breast cancer and taxane-induced skin toxicity: a case report

    PubMed Central

    2014-01-01

    Introduction Taxanes have demonstrated effectiveness in the treatment of breast cancer, the most common type of cancer in women. The toxicity profile of taxanes (including skin toxicities) induces dose adjustment, delay, or discontinuation, which prevents a sufficient dose intensity to achieve a response. Nanoparticle albumin-bound paclitaxel, a solvent-free form of paclitaxel, prevents toxicities and reduces the pharmacokinetic interferences between paclitaxel and other drugs. Case presentation We describe the case of a 55-year-old Caucasian woman with locally advanced breast cancer treated with neoadjuvant therapy who developed secondary skin toxicity due to delayed hypersensitivity to taxanes. She received Adriamycin® (doxorubicin), cyclophosphamide and docetaxel and developed toxicity that promoted treatment delay and a switch to weekly paclitaxel. After the third and fourth weeks of treatment, paclitaxel toxicities also induced treatment delay and paclitaxel was switched to nanoparticle albumin-bound paclitaxel. She completed the five planned nanoparticle albumin-bound paclitaxel cycles with acceptable tolerability (including persistent grade 2 neuropathy) and without dose delay or adjustments. Clinical response was achieved although pathological response was not good. Conclusions Nanoparticle albumin-bound paclitaxel treatment is a good option for patients with breast cancer with taxanes-related skin toxicity. This drug allows the treatment to be completed with acceptable tolerance in our case. PMID:24386978

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

    PubMed Central

    Beutler, Bryce D.; Cohen, Philip R.

    2015-01-01

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

  9. pH-responsive high-density lipoprotein-like nanoparticles to release paclitaxel at acidic pH in cancer chemotherapy

    PubMed Central

    Shin, Jae-Yoon; Yang, Yoosoo; Heo, Paul; Lee, Ji-Chun; Kong, ByoungJae; Cho, Jae Youl; Yoon, Keejung; Shin, Cheol-Su; Seo, Jin-Ho; Kim, Sung-Gun; Kweon, Dae-Hyuk

    2012-01-01

    Background Nanoparticles undergoing physicochemical changes to release enclosed drugs at acidic pH conditions are promising vehicles for antitumor drug delivery. Among the various drug carriers, high-density lipoprotein (HDL)-like nanoparticles have been shown to be beneficial for cancer chemotherapy, but have not yet been designed to be pH-responsive. Methods and results In this study, we developed a pH-responsive HDL-like nanoparticle that selectively releases paclitaxel, a model antitumor drug, at acidic pH. While the well known HDL-like nanoparticle containing phospholipids, phosphatidylcholine, and apolipoprotein A-I, as well as paclitaxel (PTX-PL-NP) was structurally robust at a wide range of pH values (3.8–10.0), the paclitaxel nanoparticle that only contained paclitaxel and apoA-I selectively released paclitaxel into the medium at low pH. The paclitaxel nanoparticle was stable at physiological and basic pH values, and over a wide range of temperatures, which is a required feature for efficient cancer chemotherapy. The homogeneous assembly enabled high paclitaxel loading per nanoparticle, which was 62.2% (w/w). The molar ratio of apolipoprotein A-I and paclitaxel was 1:55, suggesting that a single nanoparticle contained approximately 110 paclitaxel particles in a spherical structure with a 9.2 nm diameter. Among the several reconstitution methods applied, simple dilution following sonication enhanced the reconstitution yield of soluble paclitaxel nanoparticles, which was 0.66. As a result of the pH responsiveness, the anticancer effect of paclitaxel nanoparticles was much more potent than free paclitaxel or PTX-PL-NP. Conclusion The anticancer efficacy of both paclitaxel nanoparticles and PTX-PL-NP was dependent on the expression of scavenger receptor class B type I, while the killing efficacy of free paclitaxel was independent of this receptor. We speculate that the pH responsiveness of paclitaxel nanoparticles enabled efficient endosomal escape of paclitaxel before lysosomal break down. This is the first report on pH-responsive nanoparticles that do not contain any synthetic polymer. PMID:22745543

  10. Nab-paclitaxel and gemcitabine for the treatment of patients with metastatic pancreatic cancer.

    PubMed

    Borazanci, Erkut; Von Hoff, Daniel D

    2014-09-01

    Adenocarcinoma of the pancreas or pancreatic cancer as we will refer to it here, is a cancer of poor prognosis with a high mortality, particularly in the advanced or metastatic setting. Until 2011 and the Phase III results of FOLFIRINOX, standard treatment options were limited to gemcitabine. Combination therapy had shown either a lack of or very limited improvement versus monotherapy with gemcitabine. With the positive results of the MPACT study in 2013 showing improved survival with nab-paclitaxel plus gemcitabine combination therapy, there are now more options for oncologists to treat patients with advanced pancreatic cancer. This paper will highlight the Phase I/II and Phase III trials of nab-paclitaxel plus gemcitabine along with discussing their biology and further possible development in treating patients with pancreatic cancer. PMID:24882381

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

    PubMed

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

    2014-09-01

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

  12. 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

  13. [A case of stage IV breast cancer with improved cancer pain using bevacizumab and paclitaxel].

    PubMed

    Ishiyama, Tomoharu; Jinguu, Akira; Matsumoto, Hidekazu; Kikuchi, Jirou; Suzuki, Tomonobu

    2015-03-01

    A 65-year-old woman with a right breast tumor and right arm pain was seen in our hospital. She was diagnosed with scirrhous carcinoma (Stage IV, hormone receptor-positive, and HER2-negative) with pleural effusion and metastasis to the lung, liver, bone, and multiple lymph nodes. Systemic chemotherapy with biweekly bevacizumab and weekly paclitaxel was administered, and an opioid (oxycodone 40 mg/day) was administered for pain control. At the end of the first course, the patient's pain was improved, and the opioid dose was reduced (oxycodone 20 mg/day). The patient had a partial response (PR) over 24 treatment courses (1 year 10 months), and good pain control was obtained. Bevacizumab and paclitaxel therapy successfully brought about a rapid and good response and improved the patient's quality of life as palliative chemo- therapy. PMID:25812505

  14. Different Administration Strategies with Paclitaxel Induce Distinct Phenotypes of Multidrug Resistance in Breast Cancer Cells

    PubMed Central

    Jiang, Donghai; Sui, Meihua; Zhong, Wangyan; Huang, Yuan; Fan, Weimin

    2013-01-01

    Both dose-dense and dose-escalation chemotherapy are administered in clinic. By approximately imitating the schedules of dose-dense and dose-escalation administration with paclitaxel, two novel multidrug resistant (MDR) cell lines Bads-200 and Bats-72 were successfully developed from drug-sensitive breast cancer cell line BCap37, respectively. Different from Bads-200, Bats-72 exhibited stable MDR and significantly enhanced migratory and invasive properties, indicating that they represented two different MDR phenotypes. Our results showed that distinct phenotypes of MDR could be induced by altered administration strategies with a same drug. Administrating paclitaxel in conventional dose-escalation schedule might induce recrudescent tumor cells with stable MDR and increased metastatic capacity. PMID:23499896

  15. Targeted delivery of paclitaxel using folate-decorated poly(lactide)–vitamin E TPGS nanoparticles

    Microsoft Academic Search

    Jie Pan; Si-Shen Feng

    2008-01-01

    We synthesized nanoparticles (NPs) of the blend of two-component copolymers for targeted chemotherapy with paclitaxel used as model drug. One component is poly(lactide)–d-?-tocopheryl polyethylene glycol succinate (PLA–TPGS), which is of desired hydrophobic–lipophilic balance, and another is TPGS–COOH, which facilitates the folate conjugation for targeting. The nanoparticles of the two-copolymer blend at various component ratio were prepared by the solvent extraction\\/evaporation

  16. Effect of maceligan on the systemic exposure of paclitaxel: In vitro and in vivo evaluation

    Microsoft Academic Search

    Fu Qiang; Beom-Jin Lee; Ilho Ha; Keon Wook Kang; Eun-Rhan Woo; Hyo-Kyung Han

    2010-01-01

    This study investigated the effect of macelignan on the P-glycoprotein-mediated drug efflux as well as CYP3A4-mediated drug metabolism and subsequently its in vivo implication on the bioavailability of paclitaxel. The inhibition effect of macelignan on the CYP3A4-mediated metabolism was negligible over the concentration range of 0.01–100?M in rat liver microsome while approximately 33% inhibition was observed at 100?M in human

  17. Successful use of bevacizumb and paclitaxel in a male breast cancer with liver metastases

    PubMed Central

    Huang, Du-Ping; Ye, Xiao-He; Jin, Chun

    2014-01-01

    Breast cancer in men is a rare cancer manifestation. In this article we report a case of male breast cancer with liver metastases, which showed a good response to a combined treatment of bevacizumb and paclitaxel, suggesting a useful option for the first-line treatment of patients with recurrent HER2-negative male breast cancer. And further assessment in a randomized clinical trial is needed. PMID:25356184

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

    PubMed Central

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

    2015-01-01

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

  19. Biodegradable microfiber implants delivering paclitaxel for post-surgical chemotherapy against malignant glioma

    Microsoft Academic Search

    Sudhir H. Ranganath; Chi-Hwa Wang

    2008-01-01

    Paclitaxel-loaded biodegradable implants in the form of microfiber discs and sheets were developed using electrospinning technique and investigated against malignant glioma in vitro and in vivo. The fibrous matrices not only provide greater surface area to volume ratio for effective drug release rates but also give the much needed implantability into tumor resected cavity in post-surgical glioma chemotherapy. Poly-(d,l-lactide-co-glycolide) (PLGA)

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

    SciTech Connect

    Ho, T.-F. [Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Department of Medical Technology, Central Taiwan University of Science and Technology, Taichung, Taiwan (China); Peng, Y.-T.; Chuang, S.-M.; Lin, S.-C.; Feng, B.-L. [Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Lu, C.-H. [Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Department of Obstetrics and Gynecology, Taichung Veterans General Hospital, Taichung, Taiwan (China); Yu, W.-J. [Department of Chemical Engineering, National Cheng Kung University, Tainan, Taiwan (China); Chang, J.-S. [Department of Chemical Engineering, National Cheng Kung University, Tainan, Taiwan (China); Sustainable Environment Research Center, National Cheng Kung University, Tainan, Taiwan (China)], E-mail: changjs@mail.ncku.edu.tw; Chang, C.-C. [Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China)], E-mail: chia_che@dragon.nchu.edu.tw

    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.

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

    Microsoft Academic Search

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

    2011-01-01

    Angiogenesis plays a prominent role in cancer progression. Anti-angiogenic therapy therefore, either alone or in combination with conventional cytotoxic therapy, offers a promising therapeutic approach. Paclitaxel (PTX) is a widely-used potent cytotoxic drug that also exhibits anti-angiogenic effects at low doses. However, its use, at its full potential, is limited by severe side effects. Here we designed and synthesized a

  2. Enhanced cytotoxicity of a polymer–drug conjugate with triple payload of paclitaxel

    Microsoft Academic Search

    Rotem Erez; Ehud Segal; Keren Miller; Ronit Satchi-Fainaro; Doron Shabat

    2009-01-01

    The development of targeting approaches to selectively release chemotherapeutic drugs into malignant tissue is a major challenge in anticancer therapy. We have synthesized an N-(2-hydroxypropyl)-methacrylamide (HPMA) copolymer–drug conjugate with an AB3 self-immolative dendritic linker. HPMA copolymers are known to accumulate selectively in tumors. The water-soluble polymer–drug conjugate was designed to release a triple payload of the hydrophobic drug paclitaxel as

  3. Safety and Efficacy of Sirolimus- and Paclitaxel-Eluting Coronary Stents

    Microsoft Academic Search

    Gregg W. Stone; Jeffrey W. Moses; Stephen G. Ellis; Joachim Schofer; Keith D. Dawkins; Marie-Claude Morice; Antonio Colombo; Erick Schampaert; Eberhard Grube; Ajay J. Kirtane; Donald E. Cutlip; Martin Fahy; Stuart J. Pocock; Roxana Mehran; Martin B. Leon

    2010-01-01

    A b s t r ac t Results The 4-year rates of stent thrombosis were 1.2% in the sirolimus-stent group versus 0.6% in the bare-metal-stent group (P = 0.20) and 1.3% in the paclitaxel-stent group versus 0.9% in the bare-metal-stent group (P = 0.30). However, after 1 year, there were five episodes of stent thrombosis in patients with sirolimus-eluting stents

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

    PubMed Central

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

    2014-01-01

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

  5. Dose-dense epirubicin and cyclophosphamide followed by weekly Paclitaxel in node-positive breast cancer.

    PubMed

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

    2014-01-01

    Background. Adding taxanes to anthracycline-based adjuvant chemotherapy has shown significant improvement in node-positive breast cancer patients but the optimal dose schedule has still remained undetermined. Objectives. The feasibility of dose-dense epirubicin in combination with cyclophosphamide (EC) followed by weekly paclitaxel as adjuvant chemotherapy in node-positive breast cancer patients was investigated. Methods. All patients were treated with epirubicin (100?mg/m(2)) and cyclophosphamide (600?mg/m(2)) every two weeks for four cycles with daily Pegfilgrastim (G-CSF) that was administered 3-10 days after each cycle of epirubicin and cyclophosphamide infusion which followed by (80?mg/m(2)) paclitaxel for twelve consecutive weeks. Results. Sixty consecutive patients were analyzed, of whom 57 patients (95%) completed the regimen and no case of toxicity-related death was observed. Grade 3/4 hematologic toxicity was uncommon and the most common grade 3/4 nonhematological adverse event was neuropathy disorders. Conclusions. Dose-dense epirubicin and cyclophosphamide followed by weekly paclitaxel with G-CSF support is a well-tolerated and feasible regimen in node-positive breast cancer patients without serious complications. PMID:25276426

  6. Persistent chemoneuropathy in patients receiving the plant alkaloids paclitaxel and vincristine

    PubMed Central

    Boyette-Davis, Jessica A.; Cata, Juan P.; Driver, Larry C.; Novy, Diane M.; Bruel, Brian M.; Mooring, Deidre L.; Wendelschafer-Crabb, Gwen; Kennedy, William R.; Dougherty, Patrick M.

    2012-01-01

    Purpose Chemoneuropathy remains a painful, burdensome complication of cancer treatment for patients receiving a range of chemotherapeutics, yet the cause and persistence of this condition are not fully documented. This study was designed to quantify the longevity of and contributions to neuropathy following treatment with the plant alkaloids paclitaxel and vincristine. Methods Quantitative sensory testing was conducted approximately 18 months apart on 14 patients, seven of which had been treated with paclitaxel and seven with vincristine and compared to data from 18 healthy control subjects. In addition, skin biopsies were obtained to investigate changes in the density of Meissner’s corpuscles and epidermal nerve fibers (ENFs), the loss of which is thought to contribute to multiple forms of neuropathy. Results Impairments in motor skills, as measured by a grooved peg-board, were found. Deficits in touch detection were observed using von Frey monofilaments, as were changes in sharpness detection using a weighted needle device. Using a Peltier device, warmth and heat detection were impaired. These deficits were consistent across time. Remarkably, the average length of time patients reported painful neuropathy was over four and a half years. Skin biopsies were found to be deficient in Meissner’s corpuscles and ENFs. Conclusions The combination of widespread deficits in sensory testing and decreases in skin innervation for cancer patients receiving paclitaxel or vincristine document a persistent polyneuropathy which severely impacts these patients. Decreases in Meissner’s corpuscles and ENFs indicate a possible mechanism for the neuropathy. PMID:23228992

  7. 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

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

    PubMed

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

    2014-11-01

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

  9. 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

  10. Double layer paclitaxel delivery systems based on bioresorbable terpolymer with shape memory properties.

    PubMed

    Musia?-Kulik, Monika; Kasperczyk, Janusz; Smola, Anna; Dobrzy?ski, Piotr

    2014-04-25

    The growing interest in the bioresorbable polymers contributed to developing a number of commercially available controlled drug delivery systems. Due to a variety of drugs and their physicochemical properties, there is a necessity of choosing an appropriate drug carrier. Terpolymer with shape memory properties was used to obtain double layer matrices composed of drug free matrix and paclitaxel containing layer. The in vitro degradation and drug release study were conducted at 37 °C in PBS (pH 7.4). The investigated materials were characterized by GPC (gel permeation chromatography) and DSC (differential scanning calorimetry). HPLC (high-pressure liquid chromatography) was applied to analyze the amount of released paclitaxel. The main purpose of this work was to determine the usefulness of the studied terpolymer as an anti-restenotic drug vehicle. Based on the obtained results it was established that polymer's degradation proceeded regularly and provided even paclitaxel release profiles. Double layer systems allowed to modify the amount of released drug which may be considered while developing the self-expanding drug-eluting stents tailoring different clinical indications. PMID:24491529

  11. Paclitaxel loaded niosome nanoparticle formulation prepared via reverse phase evaporation method: an in vitro evaluation.

    PubMed

    Zarei, M; Norouzian, D; Honarvar, B; Mohammadi, M; Shamabadi, H Ebrahimi; Akbarzadeh, A

    2013-03-15

    Niosoms are nanoparticles used in drug delivery systems. Niosomes are prepared by various methods. In this research niosoms were prepared by reverse phase evaporation and the factors affecting the niosomes formation were studied. Percent of paclitaxel pegylated and non-pegylated prepared with Span 60 were 95 and 92, respectively while for those of pegylated and non-pegylated niosomes with Span 20, 94 and 90, respectively. In addition, the average diameters of pegylated and no-pegylated prepared with Span 60 and 20 were determined to be 191, 214, 244 and 284 nm, respectively. The amount of released drug (48 h) from pegylated and non pegylated formulations in the presence of Spans 60 and 20 were 8, 10, 6, 7%, respectively. Cytotoxicities ofpaclitaxel niosom polyethyleneglycol, paclitaxel niosome and free paclitaxel on MCF-7 cell line after 48 hours were studied by MTT assay. The results showed the formulation prepared with Span 60 is more effective than that of Span 20 and the IC50 of the former was decreased twice while IC50 of the later decreased 1.5 times. PMID:24498794

  12. Solubility enhancement of paclitaxel using a linear-dendritic block copolymer.

    PubMed

    Zhou, Zhengyuan; D'Emanuele, Antony; Attwood, David

    2013-08-16

    The solubilising capacities of micelles of a linear-dendritic copolymer (BE-PAMAM), formed by conjugating the poly(butylene oxide) (B)-poly(ethylene oxide) (E) block copolymer B16E42 (BE) with a G2 PAMAM dendrimer, have been compared with those of the diblock copolymer B16E42 for the anti-cancer drug paclitaxel. The BE-PAMAM copolymer showed a greater solubility enhancement than BE under equivalent conditions. Drug-loading efficiency was improved using a solvent-loading method compared with the conventional solution-loading method. The solubility of paclitaxel was increased 3700-fold by micellar encapsulation in a 2% (w/v) BE-PAMAM copolymer solution at 37°C using this solubilisation technique. Dynamic light scattering and transmission electron microscopy studies indicated a transition of spherical to worm-like micelles of the BE copolymer induced by the encapsulation of drug molecules. A sustained release of encapsulated drug was observed, with approximately 80% and 60% paclitaxel being released from 2% (w/v) solutions of BE and BE-PAMAM respectively after 24h of dialysis at 37°C. PMID:23651641

  13. Blocking IL1? Pathway Following Paclitaxel Chemotherapy Slightly Inhibits Primary Tumor Growth but Promotes Spontaneous Metastasis.

    PubMed

    Voloshin, Tali; Alishekevitz, Dror; Kaneti, Limor; Miller, Valeria; Isakov, Elina; Kaplanov, Irena; Voronov, Elena; Fremder, Ella; Benhar, Moran; Machluf, Marcelle; Apte, Ron N; Shaked, Yuval

    2015-06-01

    Acquired resistance to therapy is a major obstacle in clinical oncology, and little is known about the contributing mechanisms of the host response to therapy. Here, we show that the proinflammatory cytokine IL1? is overexpressed in response to paclitaxel chemotherapy in macrophages, subsequently promoting the invasive properties of malignant cells. In accordance, blocking IL1?, or its receptor, using either genetic or pharmacologic approach, results in slight retardation of primary tumor growth; however, it accelerates metastasis spread. Tumors from mice treated with combined therapy of paclitaxel and the IL1 receptor antagonist anakinra exhibit increased number of M2 macrophages and vessel leakiness when compared with paclitaxel monotherapy-treated mice, indicating a prometastatic role of M2 macrophages in the IL1?-deprived microenvironment. Taken together, these findings demonstrate the dual effects of blocking the IL1 pathway on tumor growth. Accordingly, treatments using "add-on" drugs to conventional therapy should be investigated in appropriate tumor models consisting of primary tumors and their metastases. Mol Cancer Ther; 14(6); 1385-94. ©2015 AACR. PMID:25887886

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

    PubMed

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

    2014-01-01

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

  15. A microarray based expression profiling of paclitaxel and vincristine resistant MCF-7 cells.

    PubMed

    Kars, Meltem Demirel; I?eri, Ozlem Darcansoy; Gündüz, Ufuk

    2011-04-25

    Resistance to the broad spectrum of chemotherapeutic agents in cancer cell lines and tumors has been called multiple drug resistance (MDR). In this study, the molecular mechanisms of resistance to two anticancer agents (paclitaxel and vincristine) in mammary carcinoma cell line MCF-7 were investigated. Drug resistant sublines to paclitaxel (MCF-7/Pac) and vincristine (MCF-7/Vinc) that were developed from sensitive MCF-7 cells (MCF-7/S) were used. cDNA microarray analysis was performed for the RNA samples of sensitive and resistant cells in duplicate experiments. GeneSpring GX 7.3.1 Software was used in data analysis. The results indicated that the upregulation of MDR1 gene is the dominating mechanism of the paclitaxel and vincristine drug resistance. Additionally the upregulation of the genes encoding the detoxifying enzymes (i.e. GSTP1) was observed. Significant downregulation of apoptotic genes (i.e. PDCD2/4/6/8) and upregulation of some cell cycle regulatory genes (CDKN2A, CCNA2 etc.) was seen which may be in close relation to MDR in breast cancer. Drug resistant cancer cells exhibit different gene expression patterns depending on drug treatment, and each drug resistance phenotype is probably genetically different. Further functional studies are needed to demonstrate the complete set of genes contributing to the drug resistance phenotype in breast cancer cells. PMID:21320484

  16. Paclitaxel-associated subungual pyogenic granuloma: report in a patient with breast cancer receiving paclitaxel and review of drug-induced pyogenic granulomas adjacent to and beneath the nail.

    PubMed

    Paul, Laura J; Cohen, Philip R

    2012-02-01

    Subungual and periungual pyogenic granuloma occur in association with certain systemic medications. Paclitaxel is an antitumor drug of the taxane family used in the management of breast cancer. Taxanes have many associated nail changes that may occur in patients receiving either docetaxel or paclitaxel for systemic chemotherapy. The nail changes in a 68-year-old woman with metastatic breast cancer who presented for nail changes after receiving 12 cycles of weekly paclitaxel are described herein: nail plate red-brown discoloration, onycholysis with leukonychia, proximal subungual hemorrhage, and subungual pyogenic granuloma. The literature on systemic medications associated with the development of subungual and periungual pyogenic granulomas is reviewed; drugs associated with the development of pyogenic granuloma at the locations include antineoplastics, antiretrovirals, epidermal growth factor receptor inhibitors, immunosuppressants and retinoids. In conclusion, subungual pyogenic granuloma can occur not only in patients receiving docetaxel, but also in patients treated with paclitaxel. And, paclitaxel should be included in the list of drugs associated with the occurrence of subungual pyogenic granuloma. PMID:22270214

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

    PubMed

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

    2011-07-14

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

  18. Enhanced oral paclitaxel absorption with vitamin E-TPGS: Effect on solubility and permeability in vitro, in situ and in vivo

    Microsoft Academic Search

    Manthena V. S. Varma; Ramesh Panchagnula

    2005-01-01

    Solubility and permeability being important determinants of oral drug absorption, this study was aimed to investigate the effect of d-?-tocopheryl polyethylene glycol 1000 succinate (TPGS) on the solubility and intestinal permeability of paclitaxel in vitro, in situ and in vivo, in order to estimate the absorption enhancement ability of TPGS. Aqueous solubility of paclitaxel is significantly enhanced by TPGS, where

  19. ARTICLES Randomized Intergroup Trial of Cisplatin-Paclitaxel Versus Cisplatin-Cyclophosphamide in Women With Advanced Epithelial Ovarian Cancer: Three-Year Results

    Microsoft Academic Search

    Martine J. Piccart; Kamma Bertelsen; Keith James; Jim Cassidy; Constantino Mangioni; Ernst Simonsen; Gavin Stuart; Stan Kaye; Ignace Vergote; Robert Grimshaw; Ronald J. Atkinson; Ken D. Swenerton; Claes Trope; Mario Nardi; Janne Kaern; Salvatore Tumolo; Petra Timmers; Josee-Anne Roy; Francois Lhoas; Berit Lindvall; Monica Bacon; Angelo Birt; Joern Erik Andersen; Benny Zee; James Paul; Benoît Baron; Sergio Pecorelli

    Background: A randomized trial conducted by the Gyneco- logic Oncology Group (GOG, study #111) in the United States showed a better outcome for patients with advanced ovarian cancer on the paclitaxel-cisplatin regimen than for those on a standard cyclophosphamide-cisplatin regimen. Before considering the paclitaxel-cisplatin regimen as the new \\

  20. Phase 2 Trial of Single Agent Ifosfamide\\/Mesna in Patients with Platinum\\/Paclitaxel Refractory Ovarian Cancer Who Have Not Previously Been Treated with an Alkylating Agent

    Microsoft Academic Search

    Maurie Markman; Alexander Kennedy; Gregory Sutton; Jean Hurteau; Kenneth Webster; Gertrude Peterson; Barbara Kulp; Jerome Belinson

    1998-01-01

    Ifosfamide has been shown to possess modest activity in patients with platinum\\/cyclophosphamide refractory ovarian cancer. Current standard initial chemotherapy for ovarian cancer does not include an alkylating agent (paclitaxel substituting for cyclophosphamide). To evaluate the activity of ifosfamide in patients with refractory ovarian cancer who had not previously received an alkylating agent, 21 patients with platinum\\/paclitaxel refractory disease were treated

  1. Thiamet-G-mediated inhibition of O-GlcNAcase sensitizes human leukemia cells to microtubule-stabilizing agent paclitaxel.

    PubMed

    Ding, Ning; Ping, Lingyan; Shi, Yunfei; Feng, Lixia; Zheng, Xiaohui; Song, Yuqin; Zhu, Jun

    2014-10-24

    Although the microtubule-stabilizing agent paclitaxel has been widely used for treatment of several cancer types, particularly for the malignancies of epithelia origin, it only shows limited efficacy on hematological malignancies. Emerging roles of O-GlcNAcylation modification of proteins in various cancer types have implicated the key enzymes catalyzing this reversible modification as targets for cancer therapy. Here, we show that the highly selective O-GlcNAcase (OGA) inhibitor thiamet-G significantly sensitized human leukemia cell lines to paclitaxel, with an approximate 10-fold leftward shift of IC50. Knockdown of OGA by siRNAs or inhibition of OGA by thiamet-G did not influence the cell viability. Furthermore, we demonstrated that thiamet-G binds to OGA in competition with 4-methylumbelliferyl N-acetyl-?-d-glucosaminide dehydrate, an analogue of O-GlcNAc UDP, thereby suppressing the activity of OGA. Importantly, inhibition of OGA by thiamet-G decreased the phosphorylation of microtubule-associated protein Tau and caused alterations of microtubule network in cells. It is noteworthy that paclitaxel combined with thiamet-G resulted in more profound perturbations on microtubule stability than did either one alone, which may implicate the underlying mechanism of thiamet-G-mediated sensitization of leukemia cells to paclitaxel. These findings thus suggest that a regimen of paclitaxel combined with OGA inhibitor might be more effective for the treatment of human leukemia. PMID:25268318

  2. [A case of bone marrow carcinomatosis with disseminated intravascular coagulation arising from breast cancer successfully treated with paclitaxel plus bevacizumab].

    PubMed

    Kawai, Hiroshi; Sugimoto, Ryoma; Miyauchi, Syunsaku; Yoshida, Ryosuke; Waki, Naohisa; Hirayama, Shin; Ishizaki, Masahiro; Nishi, Hideyuki; Yamashita, Kazuki

    2014-11-01

    We report a case of bone marrow carcinomatosis with disseminated intravascular coagulation (DIC) originating from metastatic breast cancer that was treated with paclitaxel plus bevacizumab. A woman in her 30s was diagnosed with bone marrow carcinomatosis arising from metastatic breast cancer 2 years previously. Pathologically, estrogen receptor (ER) and progesterone receptor(PgR) / -positive and human epidermal growth factor receptor 2(HER2/neu)-negative scirrhous carcinoma was diagnosed. She improved after treatment with paclitaxel plus bevacizumab and zoledronic acid. Subsequently, she was treated with hormonal therapy(tamoxifen plus luteinizing-hormone-releasing hormone [LH-RH]agonist) for 7 months. Because progressive bone metastasis was identified and tumor markers increased, the patient was administered paclitaxel plus bevacizumab again. Fifteen days after chemotherapy was initiated, DIC developed. Chemotherapy was continued without decreasing the dose, and recombinant human soluble thrombomodulin (rTM) was added. The DIC resolved in 5 days. After 6 courses of paclitaxel plus bevacizumab, improvement of tumor markers and bone metastasis was observed. Paclitaxel plus bevacizumab can be effective for treatment of bone marrow carcinomatosis with DIC originating from metastatic breast cancer. PMID:25731388

  3. Taxol biosynthesis: Molecular cloning of a benzoyl- CoA:taxane 2?-O-benzoyltransferase cDNA from Taxus and functional expression in Escherichia coli

    PubMed Central

    Walker, Kevin; Croteau, Rodney

    2000-01-01

    A cDNA clone encoding a taxane 2?-O-benzoyltransferase has been isolated from Taxus cuspidata. The recombinant enzyme catalyzes the conversion of 2-debenzoyl-7,13-diacetylbaccatin III, a semisynthetic substrate, to 7,13-diacetylbaccatin III, and thus appears to function in a late-stage acylation step of the Taxol biosynthetic pathway. By employing a homology-based PCR cloning strategy for generating acyltransferase oligodeoxynucleotide probes, several gene fragments were amplified and used to screen a cDNA library constructed from mRNA isolated from methyl jasmonate-induced Taxus cells, from which several full-length acyltransferases were obtained and individually expressed in Escherichia coli. The functionally expressed benzoyltransferase was confirmed by radio-HPLC, 1H-NMR, and combined HPLC-MS verification of the product, 7,13-diacetylbaccatin III, derived from 2-debenzoyl-7,13-diacetylbaccatin III and benzoyl-CoA as cosubstrates in the corresponding cell-free extract. The full-length cDNA has an open reading frame of 1,320 base pairs and encodes a protein of 440 residues with a molecular weight of 50,089. The recombinant benzoyltransferase has a pH optimum of 8.0, Km values of 0.64 mM and 0.30 mM for the taxoid substrate and benzoyl-CoA, respectively, and is apparently regiospecific for acylation of the 2?-hydroxyl group of the functionalized taxane nucleus. This enzyme may be used to improve the production yields of Taxol and for the semisynthesis of drug analogs bearing modified aroyl groups at the C2 position. PMID:11095755

  4. 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. PMID:22177224

  5. Preparative isolation of paclitaxel and related taxanes from cell cultures of Taxus chinensis using reversed-phase flash chromatography.

    PubMed

    Liang, Zhi-Kun; Huang, Ruo-Gu; Xie, Zhi-Sheng; Xu, Xin-Jun

    2015-01-01

    In this study, paclitaxel, baccatin III, taxuyunnanine C and sinenxane C were successfully separated by reversed-phase flash chromatography on a manually packed C18 column from Taxus chinensis cell culture extract. The crude cell culture extract was first treated with Al2O3 column chromatography and then divided into two parts: fraction 1 and fraction 2. Ten milligrams of baccatin III and 19 mg of paclitaxel were obtained from 100 mg dried fraction 1. Fifty-two milligrams of taxuyunnanine C and 11 mg sinenxane C were obtained from 100 mg dried fraction 2. The purities of the four compounds were 98.02%, 98.53%, 98.93% and 98.76%, respectively. Their structures were characterised by using UV, MS and NMR. These results indicate that paclitaxel and related taxanes including baccatin III can be obtained from cell culture in a highly pure state using reversed-phase flash chromatography. PMID:25109635

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

    PubMed Central

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

    2014-01-01

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

  7. [Nab-Paclitaxel with platinum chemotherapy as sixth-line therapy for a non-small cell lung cancer patient].

    PubMed

    Ishiura, Yoshihisa; Shiba, Yasutaka; Terasaki, Yasushi; Hinoue, Yoshinobu; Ishida, Youichi; Segawa, Masataka; Saitoh, Katsuhiko; Hirokami, Norikazu; Kasahara, Kazuo; Fujimura, Masaki

    2015-04-01

    A 48-year-old woman was admitted to our hospital for sixth-line chemotherapy. A chest X-ray film and computed tomographic (CT) scan revealed a right-sided massive tumor with multiple lung tumors. Repeated treatment with carboplatin (AUC 6) on day 1 and nab-paclitaxel (100mg/m2) on days 1, 8, and 15, every 28 days were effective in this patient. Chemotherapy with nab-paclitaxel may be effective for patients with multi-recurrent adenocarcinoma. PMID:25963700

  8. Encapsulation of paclitaxel into a bio-nanocomposite. A study combining inelastic neutron scattering to thermal analysis and infrared spectroscopy

    NASA Astrophysics Data System (ADS)

    Martins, Murillo L.; Orecchini, Andrea; Aguilera, Luis; Eckert, Juergen; Embs, Jan; Matic, Aleksander; Saeki, Margarida J.; Bordallo, Heloisa N.

    2015-01-01

    The anticancer drug paclitaxel was encapsulated into a bio-nanocomposite formed by magnetic nanoparticles, chitosan and apatite. The aim of this drug carrier is to provide a new perspective against breast cancer. The dynamics of the pure and encapsulated drug were investigated in order to verify possible molecular changes caused by the encapsulation, as well as to follow which interactions may occur between paclitaxel and the composite. Fourier transformed infrared spectroscopy, thermal analysis, inelastic and quasi-elastic neutron scattering experiments were performed. These very preliminary results suggest the successful encapsulation of the drug.

  9. [Feasibility, activity, and change in the level of blood paclitaxel concentration after weekly paclitaxel therapy for a patient with recurrent ovarian cancer].

    PubMed

    Ishioka, S; Sagae, S; Kudo, R

    2001-07-01

    The patient was a 59-year-old woman with recurrent ovarian cancer. A CT scan of the abdomen showed enlargement of abdominal para-aortic lymph nodes (PAN) after the primary operation and 8 cycles of the combination chemotherapy with paclitaxel (TXL) and carboplatinum (CBDCA). As a second line chemotherapy for the patient, weekly administration of TXL (60 mg/m2/week x 3 weeks) was given. The toxicity was acceptable and less pronounced than with the standard TXL + CBDCA therapy. Peak blood TXL concentration, about 90 ng/ml, was achieved 4 hours after the administration of TXL. The blood TXL concentration was below the detectable limit 48 h after the administration of TXL. An almost 50% shrinkage in the size of the PAN was obtained after 2 cycles of treatment. Good QOL is being maintained without any repeated aggravation of the tumor. PMID:11478132

  10. Effects of mitochondrial poisons on the neuropathic pain produced by the chemotherapeutic agents, paclitaxel and oxaliplatin

    PubMed Central

    Xiao, Wen Hua; Bennett, Gary J.

    2011-01-01

    The dose-limiting side-effect of taxane, platinum-complex, and other kinds of anti-cancer drugs is a chronic, distal, bilaterally symmetrical, sensory peripheral neuropathy that is often accompanied by neuropathic pain. Work with animal models of these conditions suggests that the neuropathy is a consequence of toxic effects on mitochondria in primary afferent sensory neurons. If this is true, then additional mitochondrial insult ought to make the neuropathic pain worse. This prediction was tested in rats with painful peripheral neuropathy due to the taxane agent, paclitaxel, and the platinum-complex agent, oxaliplatin. Rats with established neuropathy were given one of three mitochondrial poisons: rotenone (an inhibitor of respiratory Complex I), oligomycin (an inhibitor of ATP synthase), and auranofin (an inhibitor of the thioredoxin-thioredoxin reductase mitochondrial anti-oxidant defense system). All three toxins significantly increased the severity of paclitaxel-evoked and oxaliplatin-evoked mechano-allodynia and mechano-hyperalgesia while having no effect on the mechano-sensitivity of chemotherapy naïve rats. Chemotherapy-evoked painful peripheral neuropathy is associated with an abnormal spontaneous discharge in primary afferent A-fibers and C-fibers. Oligomycin, at the same dose that exacerbated allodynia and hyperalgesia, significantly increased the discharge frequency of spontaneously discharging A-fibers and C-fibers in both paclitaxel-treated and oxaliplatin-treated rats, but did not evoke any discharge in naïve control rats. These results implicate mitochondrial dysfunction in the production of chemotherapy-evoked neuropathic pain and suggest that drugs that have positive effects on mitochondrial function may be of use in its treatment and prevention. PMID:22244441

  11. Effects of mitochondrial poisons on the neuropathic pain produced by the chemotherapeutic agents, paclitaxel and oxaliplatin.

    PubMed

    Xiao, Wen Hua; Bennett, Gary J

    2012-03-01

    The dose-limiting side effect of taxane, platinum-complex, and other kinds of anticancer drugs is a chronic, distal, bilaterally symmetrical, sensory peripheral neuropathy that is often accompanied by neuropathic pain. Work with animal models of these conditions suggests that the neuropathy is a consequence of toxic effects on mitochondria in primary afferent sensory neurons. If this is true, then additional mitochondrial insult ought to make the neuropathic pain worse. This prediction was tested in rats with painful peripheral neuropathy due to the taxane agent, paclitaxel, and the platinum-complex agent, oxaliplatin. Rats with established neuropathy were given 1 of 3 mitochondrial poisons: rotenone (an inhibitor of respiratory Complex I), oligomycin (an inhibitor of adenosine triphosphate synthase), and auranofin (an inhibitor of the thioredoxin-thioredoxin reductase mitochondrial antioxidant defense system). All 3 toxins significantly increased the severity of paclitaxel-evoked and oxaliplatin-evoked mechano-allodynia and mechano-hyperalgesia while having no effect on the mechano-sensitivity of chemotherapy-naïve rats. Chemotherapy-evoked painful peripheral neuropathy is associated with an abnormal spontaneous discharge in primary afferent A fibers and C fibers. Oligomycin, at the same dose that exacerbated allodynia and hyperalgesia, significantly increased the discharge frequency of spontaneously discharging A fibers and C fibers in both paclitaxel-treated and oxaliplatin-treated rats, but did not evoke any discharge in naïve control rats. These results implicate mitochondrial dysfunction in the production of chemotherapy-evoked neuropathic pain and suggest that drugs that have positive effects on mitochondrial function may be of use in its treatment and prevention. PMID:22244441

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

    PubMed

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

    2015-06-01

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

  13. Neurosteroid 3?-Androstanediol Efficiently Counteracts Paclitaxel-Induced Peripheral Neuropathy and Painful Symptoms

    PubMed Central

    Taleb, Omar; Mensah-Nyagan, Ayikoe Guy

    2013-01-01

    Painful peripheral neuropathy belongs to major side-effects limiting cancer chemotherapy. Paclitaxel, widely used to treat several cancers, induces neurological symptoms including burning pain, allodynia, hyperalgesia and numbness. Therefore, identification of drugs that may effectively counteract paclitaxel-induced neuropathic symptoms is crucial. Here, we combined histopathological, neurochemical, behavioral and electrophysiological methods to investigate the natural neurosteroid 3?-androstanediol (3?-DIOL) ability to counteract paclitaxel-evoked peripheral nerve tissue damages and neurological symptoms. Prophylactic or corrective 3?-DIOL treatment (4 mg/kg/2days) prevented or suppressed PAC-evoked heat-thermal hyperalgesia, cold-allodynia and mechanical allodynia/hyperalgesia, by reversing to normal, decreased thermal and mechanical pain thresholds of PAC-treated rats. Electrophysiological studies demonstrated that 3?-DIOL restored control values of nerve conduction velocity and action potential peak amplitude significantly altered by PAC-treatment. 3?-DIOL also repaired PAC-induced nerve damages by restoring normal neurofilament-200 level in peripheral axons and control amount of 2’,3’-cyclic-nucleotide-3’-phosphodiesterase in myelin sheaths. Decreased density of intraepidermal nerve fibers evoked by PAC-therapy was also counteracted by 3?-DIOL treatment. More importantly, 3?-DIOL beneficial effects were not sedation-dependent but resulted from its neuroprotective ability, nerve tissue repairing capacity and long-term analgesic action. Altogether, our results showing that 3?-DIOL efficiently counteracted PAC-evoked painful symptoms, also offer interesting possibilities to develop neurosteroid-based strategies against chemotherapy-induced peripheral neuropathy. This article shows that the prophylactic or corrective treatment with 3?-androstanediol prevents or suppresses PAC-evoked painful symptoms and peripheral nerve dysfunctions in rats. The data suggest that 3?-androstanediol-based therapy may constitute an efficient strategy to explore in humans for the eradication of chemotherapy-induced peripheral neuropathy. PMID:24260511

  14. Protein Kinase C Isoform Expression and Activity Alter Paclitaxel Resistance in Vitro

    Microsoft Academic Search

    Lugen Chen; Robert A. Burger; Gretchen M. Zaunbrecher; Huaxu Cheng; A. Jeannine Lincoln; Maria-Claudia Mallarino; Bradley J. Monk; Shafiq A. Khan

    1999-01-01

    Objective.The aim of this study was to assess the relationship of protein kinase C (PKC) isoform expression and functional activity to the development of multidrug resistance in gynecologic malignancies.Methods.Paclitaxel-resistant subclones (T30 and T30-Res) of the Mes-sa human uterine sarcoma cell line were selected through exposure to paclitaxelin vitro.Indices of relative drug resistance were determined by the MTT (3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2H-tetrazolium bromide) assay.

  15. The effect of p53 gene expression on the inhibition of cell proliferation by paclitaxel

    Microsoft Academic Search

    Fumio Sakashita; Shinji Osada; Masao Takemura; Hisashi Imai; Hiroyuki Tomita; Kenichi Nonaka; Takao Takahashi; Mitsuru Seishima

    2008-01-01

    Background\\/Aims  We evaluated the relationship between p53 status and paclitaxel (PTX)-induced inhibition of the growth of human stomach cancer\\u000a cells.\\u000a \\u000a \\u000a \\u000a Materials and methods  We made use of two human stomach cancer cell lines, MKN45 and MKN28. Growth inhibition in response to PTX was evaluated by\\u000a MTT method. We used flow cytometry to monitor the cell cycle and western blot analysis to evaluate

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

    PubMed

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

    2015-05-01

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

  17. Alpha-carotene inhibits metastasis in Lewis lung carcinoma in vitro, and suppresses lung metastasis and tumor growth in combination with taxol in tumor xenografted C57BL/6 mice.

    PubMed

    Liu, Yi-Zhen; Yang, Chih-Min; Chen, Jen-Yin; Liao, Junn-Wang; Hu, Miao-Lin

    2015-06-01

    This study aimed to investigate the anti-metastatic activity of ?-carotene (AC) in Lewis lung carcinoma (LLC) and in combination with taxol in LLC-xenografted C57BL/6 mice. Cell culture studies reveal that AC significantly inhibited invasion, migration and activities of matrix metalloproteinase (MMP)-2, -9 and urokinase plasminogen activator but increased protein expression of tissue inhibitor of MMP (TIMP)-1, -2 and plasminogen activator inhibitor (PAI)-1. These effects of AC are similar to those of ?-carotene at the same concentration (2.5?M). AC (2.5?M) also significantly inhibited integrin ?1-mediated phosphorylation of focal adhesion kinase (FAK) which then decreased the phosphorylation of MAPK family. Findings from the animal model reveal that AC treatment (5mg/kg) alone significantly decreased lung metastasis without affecting primary tumor growth, whereas taxol treatment (6mg/kg) alone exhibited significant inhibition on both actions, as compared to tumor control group. AC treatment alone significantly decreased protein expression of integrin ?1 but increased protein expression of TIMP-1 and PAI-1 without affecting protein expression of TIMP-2 and phosphorylation of FAK in lung tissues, whereas taxol treatment alone significantly increased protein expression of TIMP-1, PAI-1 and TIMP-2 but decreased protein expression of integrin ?1 and phosphorylation of FAK. The combined treatment produced stronger actions on lung metastasis and lung tissues protein expression of TIMP-1, TIMP-2 and PAI-1. Overall, we demonstrate that AC effectively inhibits LLC metastasis and suppresses lung metastasis in combination with taxol in LLC-bearing mice, suggesting that AC could be used as an anti-metastatic agent or as an adjuvant for anti-cancer drugs. PMID:25736483

  18. Proteinase-activated receptor 2 sensitizes transient receptor potential vanilloid 1, transient receptor potential vanilloid 4, and transient receptor potential ankyrin 1 in paclitaxel-induced neuropathic pain.

    PubMed

    Chen, Y; Yang, C; Wang, Z J

    2011-10-13

    Paclitaxel chemotherapy is limited by a long-lasting painful neuropathy that lacks an effective therapy. In this study, we tested the hypothesis that paclitaxel may release mast cell tryptase, which activates protease-activated receptor 2 (PAR2) and, subsequently, protein kinases A and C, resulting in mechanical and thermal (both heat and cold) hypersensitivity. Correlating with the development of neuropathy after repeated administration of paclitaxel, mast cell tryptase activity was found to be increased in the spinal cord, dorsal root ganglia, and peripheral tissues in mice. FSLLRY-amide, a selective PAR2 antagonist, blocked paclitaxel-induced neuropathic pain behaviors in a dose- and time-dependent manner. In addition, blocking downstream signaling pathways of PAR2, including phospholipase C (PLC), protein kinase A (PKA), and protein kinase C? (PKC), effectively attenuated paclitaxel-induced mechanical, heat, or cold hypersensitivity. Furthermore, sensitized pain response was selectively inhibited by antagonists of transient receptor potential (TRP) V1, TRPV4, or TRPA1. These results revealed specific cellular signaling pathways leading to paclitaxel-induced neuropathy, including the activation of PAR2 and downstream enzymes PLC, PKC?, and PKA and resultant sensitization of TRPV1, TRPV4, and TRPA1. Targeting one or more of these signaling molecules may present new opportunities for the treatment of paclitaxel-induced neuropathy. PMID:21763756

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

    PubMed Central

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

    2013-01-01

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

  20. Multicentric phase II trial of gemcitabine plus epirubicin plus paclitaxel as first-line chemotherapy in metastatic breast cancer

    Microsoft Academic Search

    F Cappuzzo; F Mazzoni; A Gennari; S Donati; B Salvadori; C Orlandini; G L Cetto; A Molino; E Galligioni; M Mansutti; S Tumolo; A Lucentini; F Valduga; S Bartolini; L Crinò; P F Conte

    2004-01-01

    In this phase II, multicentre trial, patients with metastatic breast cancer (MBC) were treated with a combination of gemcitabine, epirubicin and paclitaxel (GET). The primary objective of this study was to determine the tolerability and activity in terms of complete responce (CR) and overall response rate of the GET combination in this patient population. Patients with no prior treatment for

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

    PubMed

    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

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

    NASA Astrophysics Data System (ADS)

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

    2013-10-01

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

  3. PLGA\\/TPGS Nanoparticles for Controlled Release of Paclitaxel: Effects of the Emulsifier and Drug Loading Ratio

    Microsoft Academic Search

    Li Mu; Si-Shen Feng

    2003-01-01

    Purpose. We successfully manufactured nanoparticles of biodegradable polymers for controlled release of paclitaxel. TPGS (d-a-tocopheryl polyethylene glycol 1000 succinate) could be a novel material to make nanoparticles of high drug encapsulation efficiency (EE) and desired physicochemical and pharmaceutical properties of the drug loaded nanoparticles. Among various controlling parameters in the process, the present work is to elucidate the effects of

  4. Paclitaxel/sirolimus combination coated drug-eluting stent: in vitro and in vivo drug release studies.

    PubMed

    Ma, Xiaodong; Oyamada, Shizu; Gao, Fan; Wu, Tim; Robich, Michael P; Wu, Hao; Wang, Xingwei; Buchholz, Bryan; McCarthy, Stephen; Gu, Zhiyong; Bianchi, Cesario F; Sellke, Frank W; Laham, Roger

    2011-03-25

    Paclitaxel and sirolimus are the two major drugs for the treatment of coronary arterial disease in current drug-eluting stents. The two drugs can effectively inhibit the in-stent restenosis through their independent pathways and show synergistic effect in preventing tumor tissue growth. We hypothesize that the combination of the two drugs in a drug-eluting stent (DES) can also effectively suppress the neointima growth in the stented artery. The present work was focused on the investigation of paclitaxel/sirolimus combination release profiles from a novel biodegradable polymer (poly (D, L-lactide-co-glycolide)/amorphous calcium phosphate, PLGA/ACP) coated stent both in vitro and in vivo. For the in vitro, the drug releasing profiles were characterized by measuring the drug concentration in a drug release medium (Dulbecco's phosphate buffered saline, DPBS, pH 7.4) at predetermined time points. For the in vivo, a rat aorta stenting model was employed. The results showed that both paclitaxel and sirolimus had a two-phase release profile both in vitro and in vivo, which is similar to the drug release profile of their individual coated DESs, and there is no evident of interference between two drugs. The data suggest that paclitaxel and sirolimus can be combined pharmacokinetically in a DES for the treatment of coronary arterial diseases. PMID:21126843

  5. Low-dose paclitaxel ameliorates renal fibrosis in rat UUO model by inhibition of TGF-?\\/Smad activity

    Microsoft Academic Search

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

    2010-01-01

    Transforming growth factor-? (TGF-?) 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-? signaling pathway. Aberrant TGF-?\\/Smad signaling can be modulated by stabilization of microtubules with paclitaxel. In this study, we

  6. Carboplatin plus paclitaxel for advanced or recurrent uterine malignant mixed mullerian tumors. The British Columbia Cancer Agency experience

    Microsoft Academic Search

    Paul J. Hoskins; Nhu Le; Susan Ellard; Ursula Lee; Lee Ann Martin; Kenneth D. Swenerton; Anna V. Tinker

    2008-01-01

    ObjectivesUterine MMMTs are aggressive malignancies that are rarely cured by purely local therapies. Effective chemotherapy is needed. The phase III proven, ifosfamide-based combinations are inconvenient and costly. Carboplatin and paclitaxel (CT) are easy to deliver and is effective against endometrial carcinoma and should be against MMMT (as they are now regarded as epithelial in nature).

  7. Proteomic Profiling of Paclitaxel Treated Cells Identifies a Novel Mechanism of Drug Resistance Mediated by PDCD4.

    PubMed

    Xu, Hui; Dephoure, Noah; Sun, Huiying; Zhang, Haiyuan; Fan, Fangfang; Liu, Jiawei; Ning, Xuelian; Dai, Shaochun; Liu, Baogang; Gao, Min; Fu, Songbin; Gygi, Steven P; Zhou, Chunshui

    2015-06-01

    Paclitaxel (PTX) is a widely used chemotherapeutic drug effective against numerous cancers. To elucidate cellular pathways targeted by PTX and identify novel mechanisms of PTX resistance, we used a SILAC based quantitative proteomic approach to evaluate global changes of cellular protein abundance in HeLa cells. We identified 347 proteins involved in a number of biological processes including spindle assembly, mitotic exit, and extracellular adhesion whose abundance changes upon PTX treatment. Notably, the tumor suppressor PDCD4 involved in translation suppression was down-regulated by PTX. We demonstrated that PDCD4 is a cell-cycle regulated protein and that changes in its abundance are sufficient to alter PTX sensitivity in multiple human cancer cell lines. Immunoprecipitation of PDCD4-RNA complexes and RT-PCR revealed that PDCD4 mediated PTX sensitivity acts through its interaction with mRNA of UBE2S, a ubiquitin K11 linkage conjugating enzyme critical for mitotic exit. Lastly, high levels of PDCD4 in lung cancer tissues are positively correlated with the longer overall survival time of the examined lung cancer patients with PTX involved adjuvant therapy. Therefore, our proteomic screen for paclitaxel targets not only provided novel insight into the cellular resistance to paclitaxel via the PDCD4-mitotic exit regulation axis, but also offered a predictive biomarker for paclitaxel-based personalized chemotherapy in the treatment of lung cancer. PMID:25928036

  8. A complete metal jacket case using ten paclitaxel-eluting stents for multiple de novo coronary artery lesions

    Microsoft Academic Search

    Soon Yong Suh; Seung-Woon Rha; Cheol Ung Choi; Jin Won Kim; Eung Ju Kim; Chang Gyu Park; Hong Seog Seo; Dong Joo Oh

    2007-01-01

    Although full metal jacket using drug-eluting stent (DES) for a single coronary artery disease has sparsely been described before, there is no report of safety and efficacy of complete metal jacket from left main (LM) to three major coronary arteries. We report a complete metal jacket case using 10 paclitaxel-eluting stents (PES; Taxus™, Boston Scientific) for a triple vessel diffuse

  9. 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

  10. AFM-Detected Apoptotic Changes in Morphology and Biophysical Property Caused by Paclitaxel in Ishikawa and HeLa Cells

    PubMed Central

    Park, Eun Kuk; Jung, Min-Hyung; Yoon, Kyung-Sik; Park, Hun-Kuk

    2012-01-01

    The apoptosis of cancer cells is associated with changes in the important cell properties including morphology, surface roughness and stiffness. Therefore, the changes in morphology and biophysical properties can be a good way of evaluating the anticancer activity of a drug. This study examined the effect of paclitaxel on the properties of Ishikawa and HeLa cells using atomic force microscopy (AFM), and the relationship between the changes in morphology and the biophysical properties and apoptosis was discussed. The viability and proliferation of the cells were analyzed using the methylthiazol tetrazolium (MTT) method and a TUNEL assay to confirm cellular apoptosis due to a paclitaxel treatment. AFM observations clearly showed the apoptotic morphological and biophysical changes in Ishikawa and HeLa cells. After the paclitaxel treatment, the cell membrane was torn and holed, the surface roughness was increased, and the stiffness was decreased. These changes were observed more apparently after a 24 h treatment and in Ishikawa cells compared to HeLa cells. The MTT and TUNEL assays results revealed the Ishikawa cells to be more sensitive to paclitaxel than HeLa cells and definite apoptosis occurred after a 24 h treatment. These results showed good agreement with the AFM results. Therefore, research on the morphological and biophysical changes by AFM in cancer cells will help to evaluate the anticancer activities of the drugs. PMID:22272274

  11. Tumor therapy with a urokinase plasminogen activator-activated anthrax lethal toxin alone and in combination with paclitaxel

    PubMed Central

    Wein, Alexander N.; Liu, Shihui; Zhang, Yi; McKenzie, Andrew T.; Leppla, Stephen H.

    2013-01-01

    PA-U2, an engineered anthrax protective antigen that is activated by urokinase was combined with wild-type lethal factor in the treatment of Colo205 colon adenocarcinoma in vitro and B16-BL6 mouse melanoma in vitro and in vivo. This therapy was also tested in combination with the small molecule paclitaxel, based on prior reports suggesting synergy between ERK1/2 inhibition and chemotherapeutics. Colo205 was sensitive to PA-U2/LF while B16-BL6 was not. For the combination treatment of B16-BL6, paclitaxel showed a dose response in vitro, but cells remained resistant to PA-U2/LF even in the presence of paclitaxel. In vivo, each therapy slowed tumor progression, and an additive effect between the two was observed. Since LF targets tumor vasculature while paclitaxel is an anti-mitotic, it is possible the agents were acting against different cells in the stroma, precluding a synergistic effect. The engineered anthrax toxin PA-U2/LF warrants further development and testing, possibly in combination with an anti-angiogenesis therapy such as sunitinib or sorafinib. PMID:22843210

  12. 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. PMID:23465827

  13. 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. PMID:24274601

  14. Molecular responses of vascular smooth muscle cells to paclitaxel-eluting bioresorbable stent materials.

    PubMed

    Nguyen, Kytai Truong; Shaikh, Nishat; Wawro, Debra; Zhang, Sheng; Schwade, Nathan D; Eberhart, Robert C; Tang, Liping

    2004-06-01

    We studied the influence of paclitaxel, eluted from poly(L-lactic acid) (PLLA), on cultured vascular smooth muscle cell (VSMC) proliferation as a model of bioresorbable stent-induced restenosis. We blended paclitaxel in cast PLLA films (P-PLLA), demonstrating controlled release of the drug, then studied VSMC adhesion, proliferation, and gene expression profiles. No difference in cell adhesion was found between P-PLLA and PLLA controls (105 +/- 12% of PLLA controls). However, P-PLLA significantly reduced VSMC proliferation (40 +/- 15% of PLLA controls, p < 0.05). Using cDNA microarray technology, we identified major effects of P-PLLA, including: upregulation of genes related to apoptosis, anti-proliferation and antioxidation; and suppression of cell cycle regulators and cell survival markers. The expression patterns indicate that P-PLLA regulates gene expression and cell functions via new pathways, including receptor tyrosine kinase (RTKs), mitogen-activated protein kinase (MAPKs), and protein kinase (PKs, e.g., PKA) pathways, in addition to the stabilization of polymerized-microtubules. PMID:15127398

  15. Excipient effects on in vitro cytotoxicity of a novel paclitaxel self-emulsifying drug delivery system.

    PubMed

    Gursoy, Neslihan; Garrigue, Jean-Sebastien; Razafindratsita, Alain; Lambert, Gregory; Benita, Simon

    2003-12-01

    Paclitaxel is a potent chemotherapeutic agent currently administered intravenously in polyoxyethylated castor oil (Cremophor EL) and dehydrated ethanol (1:1) for the treatment of solid tumors. The objective of this work was to develop a novel self-emulsifying drug delivery system (SEDDS) devoid of cremophor for the i.v./oral delivery of paclitaxel and to investigate the in vitro cytotoxicity of the combined excipients. The SEDDS formulations were characterized in terms of droplet size using a ternary phase diagram. The Caco-2 cell line was used to monitor the cytotoxicity of the excipients. Cell viability was determined colorimetrically at 570 nm utilizing the MTT assay. The distribution of the formulations on the phase diagram indicated the presence of macroemulsions ( approximately 1 microm), submicron emulsions (50-200 nm), and microemulsions (below 10 nm). An increase in the sodium deoxycholate excipient content led to an increase in physical stability but caused more chemical degradation of the drug and more cytotoxicity. The drug in the novel SEDDS was chemically stable for at least 1 year when kept as a two-part formulation. The drug loading was increased by approximately fivefold compared to the marketed i.v. formulation; the excipients presented a significantly reduced cytotoxicity and led to a stable microemulsion. PMID:14603486

  16. Molecular dynamics of paclitaxel encapsulated by salicylic acid-grafted chitosan oligosaccharide aggregates.

    PubMed

    Wang, Xiao-Ying; Zhang, Ling; Wei, Xiao-Hong; Wang, Qi

    2013-02-01

    Chitosan oligosaccharide (COS) derivatives have attracted significant interest in drug delivery systems because of their well-known low toxicity, excellent biocompatibility, and biodegradability. Paclitaxel-loaded nanoparticles based on salicylic acid-grafted chitosan oligosaccharide (COS/SA) were synthesized and characterized. Then, in order to understand the mechanism of the actions of the paclitaxel (PTX) encapsulated by COS/SA, all-atom molecular dynamics simulations were performed to analyze the aggregation of COS/SA molecules. The van der Waals and hydrophobic interactions are the major driving forces for the drug encapsulation process. Electrostatic and hydrogen-bonding interactions also play helpful roles in the COS/SA aggregation. Analyses of the radial distribution function and solvent accessible surface area indicate that the COS/SA nanoparticles are highly hydrosoluble and that the nanoparticles can significantly enhance the aqueous solubility of a hydrophobic drug. Different drug loading systems are also investigated in this work, and the best theoretical drug loading is found to be 10% (w/w). The present work provides insights into the mechanism of the atomic structures of drug-loaded polymeric nanoparticles and presents new perspective for the design of drug delivery systems with desirable properties. PMID:23219327

  17. Release modeling and comparison of nanoarchaeosomal, nanoliposomal and pegylated nanoliposomal carriers for paclitaxel.

    PubMed

    Movahedi, Fatemeh; Ebrahimi Shahmabadi, Hasan; Alavi, Seyed Ebrahim; Koohi Moftakhari Esfahani, Maedeh

    2014-09-01

    Breast cancer is the most prevalent cancer among women. Recently, delivering by nanocarriers has resulted in a remarkable evolution in treatment of numerous cancers. Lipid nanocarriers are important ones while liposomes and archaeosomes are common lipid nanocarriers. In this work, paclitaxel was used and characterized in nanoliposomal and nanoarchaeosomal form to improve efficiency. To increase stability, efficiency and solubility, polyethylene glycol 2000 (PEG 2000) was added to some samples. MTT assay confirmed effectiveness of nanocarriers on MCF-7 cell line and size measuring validated nano-scale of particles. Nanoarchaeosomal carriers demonstrated highest encapsulation efficiency and lowest release rate. On the other hand, pegylated nanoliposomal carrier showed higher loading efficiency and less release compared with nanoliposomal carrier which verifies effect of PEG on improvement of stability and efficiency. Additionally, release pattern was modeled using artificial neural network (ANN) and genetic algorithm (GA). Using ANN modeling for release prediction, resulted in R values of 0.976, 0.989 and 0.999 for nanoliposomal, pegylated nanoliposomal and nanoarchaeosomal paclitaxel and GA modeling led to values of 0.954, 0.951 and 0.976, respectively. ANN modeling was more successful in predicting release compared with the GA strategy. PMID:24867099

  18. Anti-tumor Activity of Triolimus: A Novel Multi-Drug Loaded Micelle Containing Paclitaxel, Rapamycin and 17-AAG

    PubMed Central

    Hasenstein, Jason R.; Shin, Ho-Chul; Kasmerchak, Kelsey; Buehler, Darya; Kwon, Glen S.; Kozak, Kevin R.

    2012-01-01

    Triolimus is a first-in-class, multi-drug loaded micelle containing paclitaxel, rapamycin and 17-AAG. In this study, we examine the anti-tumor mechanisms of action, efficacy and toxicity of Triolimus in vitro and in vivo. In vitro cytotoxicity testing of Triolimus was conducted using two aggressive adenocarcinomas including the lung cancer cell line, A549, and breast cancer cell line, MDA-MB-231. The three-drug combination of paclitaxel, rapamycin and 17-AAG displayed potent cytotoxic synergy in both A549 and MDA-MB-231 cell lines. Mechanistically, the drug combination inhibited both the Ras/Raf/MAPK and PI3K/Akt/mTOR pathways. Triolimus was advanced into tumor xenograft models for assessment of efficacy, toxicity and mechanisms of action. In vivo, a three-infusion schedule of Triolimus inhibited A549 and MDA-MB-231 tumor growth far more potently than paclitaxel-containing micelles and effected tumor cures in MDA-MB-231 tumor-bearing animals. Tumor growth delays resulted from a doubling in tumor cell apoptosis and a 50% reduction in tumor cell proliferation compared to paclitaxel-containing micelles. Enhanced anti-tumor efficacy was achieved without clinically significant increases in acute toxicity. Thus, Triolimus displays potent synergistic activity in vitro and anti-tumor activity in vivo with comparable toxicity to paclitaxel. These observations provide strong support for further development of Triolimus and an important proof of concept for safe, effective nanoparticle-based delivery of three complementary anti-cancer agents. PMID:22896668

  19. Poly (?-glutamic acid) based combination of water-insoluble paclitaxel and TLR7 agonist for chemo-immunotherapy.

    PubMed

    Seth, Anushree; Heo, Min Beom; Lim, Yong Taik

    2014-09-01

    Advanced anti-cancer regimens are being introduced for more effective cancer treatment with improved life expectancy. In this research, immuno-stimulating agent toll-like receptor-7 (TLR-7) agonist-imiquimod and low dose chemotherapeutic agent-paclitaxel were synergized to demonstrate tumor therapy along with anti-tumor memory effect. Both therapeutic agents being water insoluble were dispersed in water with the help of water soluble polymer: poly (?-glutamic acid) (?-PGA) using a co-solvent systems leading to formation of micro-dispersions of drugs. Paclitaxel and imiquimod formed crystalline microstructures in the size range of 2-3 ?m and were stably dispersed in ?-PGA matrix for more than 6 months. Paclitaxel and combination of paclitaxel and imiquimod had significant tumor killing effect in-vitro on various tumor cell lines, while antigen presenting cells (dendritic cells-DCs) treated with the same concentration of imiquimod along with the combination led to enhanced proliferation (250%). In DCs, enhanced secretion of pro-inflammatory and Th1 cytokines was observed in cells co-treated with paclitaxel and imiquimod dispersed in ?-PGA. When administered by intra-tumoral injection in mouse melanoma tumor model, the treatment with combination exemplified drastic inhibition of tumor growth leading to 70% survival as compared to individual components with 0% survival at day 41. The anti-tumor response generated was also found to have systemic memory response since the vaccinated mice significantly deferred secondary tumor development at distant site 6 weeks after treatment. The relative number and activation status of DCs in-vivo was found to be dramatically increased in case of mice treated with combination. The dramatic inhibition of tumor treated with combination is expected to be mediated by both chemotherapeutic killing of tumor cells followed by uptake of released antigen by the DCs and due to enhanced proliferation and activation of the DCs. PMID:24954733

  20. The overexpression of P21-activated kinase 5 (PAK5) promotes paclitaxel-chemoresistance of epithelial ovarian cancer.

    PubMed

    Li, Diyou; Yao, Xiaohong; Zhang, Ping

    2013-11-01

    P21-activated kinase 5 (PAK5) is the recently identified member of the group II p21-activated kinases (PAKs) family, which is characterized by a highly conserved amino-terminal Cdc42/Rac interactive binding domain and a carboxyl terminal kinase domain. However, the role of PAK5 in gynecological cancers has not been evaluated so far. It is remarkable that we found PAK5 was overexpressed in epithelial ovarian cancer (EOC), which is faced with an obstacle of paclitaxel resistance. Therefore, in this study, we aim to examine the PAK5 expression during EOC progression, the role of PAK5 in malignant progression of EOC and the probable relationship between PAK5 and EOC paclitaxel resistance. By immunohistochemistry, our results showed that PAK5 expression was increased with EOC progression through the adenoma to carcinoma sequence, with the highest expression level in invasive and metastatic EOCs. Furthermore, the expression level of PAK5 was also found to increase in accordance with the development of EOC Federation International of Gynecology and Obstetrics stages (P = 0.038) and differentiation grades (P = 0.008). Remarkably, those patients who recurred within 6 months after accepting tumor reductive surgery and the following carboplatin + paclitaxel chemotherapy had the highest PAK5 expression (P = 0.015). Moreover, in in vitro studies, we found that SK-OV-3 cell growth was decreased while paclitaxel chemosensitivity was correspondingly increased with the down-regulation of PAK5. Taken together, our study demonstrated that PAK5 is correlated to human EOC and increased PAK5 expression promotes EOC progression, and PAK5 regulates EOC cell paclitaxel chemoresistance. PMID:23877225

  1. A Phase Ib Study of Safety and Pharmacokinetics of Ramucirumab in Combination With Paclitaxel in Patients With Advanced Gastric Adenocarcinomas

    PubMed Central

    Ueda, Shinya; Gotoh, Masahiro; Gao, Ling; Doi, Toshihiko

    2015-01-01

    Lessons Learned The pharmacokinetic results of this phase Ib study of ramucirumab combined with paclitaxel as second-line therapy in Japanese patients with metastatic gastric or gastro-esophageal junction adenocarcinoma are in line with previous ramucirumab studies. This combination at the doses and schedule given did not result in any dose-limiting toxicities and appeared to be safe and well tolerated. Background. This phase Ib study evaluated the tolerability and pharmacokinetics of ramucirumab, an anti-VEGFR-2 antibody, combined with paclitaxel as second-line therapy in Japanese patients with metastatic gastric or gastroesophageal junction adenocarcinoma after first-line therapy with fluoropyrimidines and/or platinum. Methods. Patients received ramucirumab 8 mg/kg on days 1 and 15 and paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28-day cycle. Safety analyses included all patients (n = 6). Results. No dose-limiting toxicities occurred in the first cycle. All patients experienced ?1 treatment-emergent adverse event (TEAE); 5 patients experienced grade ?3 TEAEs. There were two deaths caused by disease progression. The best overall responses were stable disease (n = 5) and partial response (n = 1). Patients received ramucirumab and paclitaxel for a median of 12.5 weeks (range: 11.4–42.7 weeks) and 12.2 weeks (range: 11.0–41.0 weeks), respectively. Following a single dose of ramucirumab IV infusion 8 mg/kg, clearance was ?0.017 L/hour, half-life (t1/2) was 138 to 225 hours, and steady-state volume of distribution (Vss) was ?3 L. Conclusion. The ramucirumab/paclitaxel combination appears to be well-tolerated in Japanese patients with advanced gastric adenocarcinomas. These results are in line with previous ramucirumab pharmacokinetic studies as anticipated. PMID:25888272

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

    PubMed

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

    2015-03-01

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

  3. Enhanced Excitability of Primary Sensory Neurons and Altered Gene Expression of Neuronal Ion Channels in Dorsal Root Ganglion in Paclitaxel-Induced Peripheral Neuropathy

    PubMed Central

    Zhang, Haijun; Dougherty, Patrick M.

    2014-01-01

    Background The mechanism of chemotherapy-induced peripheral neuropathy after paclitaxel treatment is not well understood. Given the poor penetration of paclitaxel into central nervous system, peripheral nervous system is most at risk. Methods Intrinsic membrane properties of dorsal root ganglion (DRG) neurons were studied by intracellular recordings. Multiple-gene real-time Polymerase Chain Reaction array was used to investigate gene expression of DRG neuronal ion channels. Results Paclitaxel increased the incidence of spontaneous activity from 4.8% to 27.1% in large and from 0% to 33.3% in medium-sized neurons. Paclitaxel decreased the rheobase (nA) from 1.6 ± 0.1 to 0.8 ± 0.1 in large, from 1.5 ± 0.2 to 0.6 ± 0.1 in medium-sized, and from 1.6 ± 0.2 to 1.0 ± 0.1 in small neurons. After paclitaxel, other characteristics of membrane properties in each group remained the same except that A? neurons showed shorter action potential fall time (ms) (1.0 ± 0.2, n = 10 vs. 1.8 ± 0.3, n = 9, paclitaxel vs. vehicle). Meanwhile, real-time polymerase chain reaction array revealed an alteration in expression of some neuronal ion channel genes including upregulation of HCN1 (fold change 1.76 ± 0.06) and Nav1.7 (1.26 ± 0.02) and downregulation of Kir channels (Kir1.1, 0.73 ± 0.05, Kir3.4, 0.66 ± 0.06) in paclitaxel-treated animals. Conclusions The increased neuronal excitability and the changes in gene expression of some neuronal ion channels in DRG may provide insight into the molecular and cellular basis of paclitaxel neuropathy, which may lead to novel therapeutic strategies. PMID:24534904

  4. O -(2-[ 18 F]fluoroethyl)- l -tyrosine PET for monitoring the effects of convection-enhanced delivery of paclitaxel in patients with recurrent glioblastoma

    Microsoft Academic Search

    G. Pöpperl; R. Goldbrunner; F. J. Gildehaus; F. W. Kreth; P. Tanner; M. Holtmannspötter; J. C. Tonn; K. Tatsch

    2005-01-01

    Purpose  Convection-enhanced delivery (CED) of paclitaxel is a new locoregional approach for patients with recurrent glioblastoma. The aim of this study was to evaluate O-(2-[18F]fluoroethyl)-l-tyrosine (FET) positron emission tomography (PET) in monitoring the effects of this type of direct drug delivery.Methods  Eight patients with recurrent glioblastoma underwent CED of paclitaxel, which was infused over stereotactically placed catheters into the tumour. FET PET

  5. Proteinase-activated receptor 2 sensitizes transient receptor potential vanilloid 1, transient receptor potential vanilloid 4, and transient receptor potential ankyrin 1 in paclitaxel-induced neuropathic pain

    Microsoft Academic Search

    Y. Chen; C. Yang; Z. J. Wang

    2011-01-01

    Paclitaxel chemotherapy is limited by a long-lasting painful neuropathy that lacks an effective therapy. In this study, we tested the hypothesis that paclitaxel may release mast cell tryptase, which activates protease-activated receptor 2 (PAR2) and, subsequently, protein kinases A and C, resulting in mechanical and thermal (both heat and cold) hypersensitivity. Correlating with the development of neuropathy after repeated administration

  6. Second-line paclitaxel in non-small cell lung cancer initially treated with cisplatin: a study by the European Lung Cancer Working Party

    Microsoft Academic Search

    T Berghmans; J J Lafitte; J Lecomte; C G Alexopoulos; O Van Cutsem; V Giner; A Efremidis; M C Berchier; T Collon; A P Meert; A Scherpereel; V Ninane; N Leclercq; M Paesmans; J P Sculier

    2007-01-01

    In the context of a phase III trial comparing in advanced non-small cell lung cancer (NSCLC) sequential to conventional administration of cisplatin-based chemotherapy and paclitaxel, we evaluated the activity of paclitaxel as second-line chemotherapy and investigated any relation of its efficacy with the type of failure after cisplatin. Patients received three courses of induction GIP (gemcitabine, ifosfamide, cisplatin). Non-progressing patients

  7. Phase II study of weekly paclitaxel and trastuzumab in anthracycline- and taxane-pretreated patients with HER2-overexpressing metastatic breast cancer

    Microsoft Academic Search

    S Gori; M Colozza; A M Mosconi; E Franceschi; C Basurto; R Cherubini; A Sidoni; A Rulli; C Bisacci; V De Angelis; L Crinò; M Tonato

    2004-01-01

    Synergism between anti-HER2 monoclonal antibody (trastuzumab) and paclitaxel has been shown in vitro and in vivo. In previous experiences, weekly administration of trastuzumab and paclitaxel has shown significant activity in metastatic breast cancer. In this phase II study, we evaluated the activity and the toxicity of this weekly regimen in anthracycline- and taxane-pretreated patients with HER2-overexpressing metastatic breast cancer. Between

  8. Paclitaxel administration on days 1 and 8 every 21 days in anthracycline-pretreated metastatic breast cancer patients. A multicenter phase II trial

    Microsoft Academic Search

    M. Donadio; E. Manzin; A. Berruti; A. Bottini; G. Gorzegno; S. Danese; E. DeFabiani; M. G. Sarobba; V. Lorusso; F. Castiglione; G. Moro; O. Bertetto; C. Bumma; L. Dogliotti

    2001-01-01

    Paclitaxel is now included in second- and even first-line regimens in advanced breast cancer. The optimal dose and schedule of this drug, however, still remain a matter of investigation. A group of 57 consecutive patients with advanced breast cancer previously treated with anthracycline-containing regimens were submitted to treatment with single-agent paclitaxel administered at 130 mg\\/m2 on days 1 and 8

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

    PubMed

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

    2015-01-01

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

  10. Use of cholesterol-rich nanoparticles that bind to lipoprotein receptors as a vehicle to paclitaxel in the treatment of breast cancer: pharmacokinetics, tumor uptake and a pilot clinical study

    Microsoft Academic Search

    Luís A. Pires; Roberto Hegg; Claudete J. Valduga; Sílvia R. Graziani; Débora G. Rodrigues; Raul C. Maranhão

    2009-01-01

    Purpose  In animal experiments paclitaxel oleate associated with a cholesterol-rich nanoemulsion concentrated in the neoplastic tissues\\u000a and showed reduced toxicity and increased antitumor activity compared with paclitaxel-Cremophor EL. Here, a clinical study\\u000a was performed in breast cancer patients to evaluate the tumoral uptake, pharmacokinetics and toxicity of paclitaxel associated\\u000a to nanoemulsions.\\u000a \\u000a \\u000a \\u000a Methods  Twenty-four hours before mastectomy [3H]-paclitaxel oleate associated with [14C]-cholesteryl oleate-nanoemulsion

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

    PubMed

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

    2014-11-01

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

  12. Cyclosporin a aerosol improves the anticancer effect of Paclitaxel aerosol in mice.

    PubMed Central

    Knight, Vernon; Koshkina, N. V.; Golunski, E.; Roberts, L. E.; Gilbert, B. E.

    2004-01-01

    Paclitaxel (PTX) is a lipophilic agent with broad anticancer activity. In the present study we examined the antitumor effect and toxicity of co-administration of cyclosporine A (CsA) and PTX in liposomal aerosol using the Renca lung metastases mouse model. The untreated and PTX-only groups exhibited cancer growth while CsA aerosol plus PTX had more favorable effects on tumor growth. Weight loss was seen in mice treated with CsA/PTX+CsA by day 9 to 22. Histopathological examination showed no toxicity following treatment. The findings offer evidence that a combination of CsA and PTX may be suitable for aerosol treatment of lung cancer if it is possible to control toxicity of the therapy. Images Fig. 1 PMID:17060982

  13. Paclitaxel loaded carrier based biodegradable polymeric implants: Preparation and in vitro characterization.

    PubMed

    Hiremath, Jagadeesh G; Khamar, Nirav S; Palavalli, Subhash G; Rudani, Chetan G; Aitha, Rajeshkumar; Mura, Prasanthkumar

    2013-01-01

    The objective of this study was to develop paclitaxel (PTX) loaded poly(?-caprolactone) (PCL) based tiny implants. ?-Cyclodextrin (?-CD) and polyethylene glycol (PEG 6000) were used to enhance solubility and release of the drug in the phosphate buffer saline pH 7.4. Implants were evaluated in terms of color, shape, thickness, surface area, weight, drug content. Developed implants were characterized for their surface morphology (SEM analysis), drug physical state by thermal analysis (DSC studies), crystalline nature (XRD studies) and drug excipients compatibility (FT-IR spectroscopy). Macroscopically all the tiny implants were white in color and cylindrical in shape with smooth surfaces. PTX was entrapped within implants in the polymeric amorphous form. In vitro drug release studies showed prolonged and controlled release of PTX with zero order and Korsmeyer-Peppas model being exhibited. Excipients and method of preparation did not affect chemical stability of PTX. PMID:23960822

  14. Design and development of paclitaxel-loaded bovine serum albumin nanoparticles for brain targeting.

    PubMed

    Bansal, Amit; Kapoor, Deepak N; Kapil, Rishi; Chhabra, Neha; Dhawan, Sanju

    2011-06-01

    Bovine serum albumin (BSA) nanoparticles loaded with paclitaxel (PTX) were prepared using a desolvation technique. A 32 full factorial design (FFD) was employed to formulate nanoparticles. Nanoparticles were characterized for particle size by photon correlation spectroscopy and surface morphology by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Encapsulation efficiency, zeta potential and particle yield were also determined. Response surface linear modelling (RSLM) was used to predict the optimal formulation. Various models were applied to determine the release mechanism from PTX nanoparticles. The effect of drug-polymer ratio on the release profile of formulations was observed and was applied to determine the suitability of the predicted optimal formulation. A preliminary study to determine the feasibility of targeting the prepared nanoparticles to brain was also carried out using mice as in vivo models. PMID:21684843

  15. Anti-tumor activity of paclitaxel through dual-targeting lipoprotein-mimicking nanocarrier.

    PubMed

    Chen, Conghui; Hu, Haiyang; Qiao, Mingxi; Zhao, Xiuli; Wang, Yinjie; Chen, Kang; Chen, Dawei

    2015-05-01

    In the present study, we devised a strategy that paclitaxel (PTX) with lipid and octadecylamine were prepared to lipid nanoparticle (PTX-LNP) with positive charge, folic acid-modified bovine serum albumin (FB)-coated surface of PTX-LNP through electrostatic attraction and generated the lipoprotein-mimicking nanocomplex (FB-PTX-LNP) for dual-targeting therapy. Bovine serum albumin (BSA) was used as the protein model due to its specific targeting to tumor by increased transendothelial gp60-mediated transport and increased intratumoral accumulation as a result of the secreted protein, acidic and rich in cysteine (SPARC)-albumin interaction. The further conjugating folic acid to BSA achieved the dual active targeting. In vitro cytotoxicity tests suggested FB-PTX-LNP and BSA-PTX-LNP exhibited significantly higher cytotoxic activity against MCF-7 and HepG2 cells compared to PTX-LNP. The cellular uptake experiments indicated that FB-coumarin-6-LNP modified with dual-targeting had a faster and greater cellular uptake when compared to BSA-coumarin-6-LNP and coumarin-6-LNP by MCF-7 cells. Thus, both BSA and FA did play roles in in vitro cytotoxicity and cellular uptake. Furthermore, the targeting ability and therapeutic efficacy of FB-PTX-LNP were assessed in vivo. FB-PTX-LNP produced very marked targeting ability and anti-tumor activity in MDA-MB-231 tumor-bearing mice. These results indicate the protein-lipid nanocomplex FB-PTX-LNP is a potential nanocarrier for Paclitaxel dual-targeting to tumor. PMID:25539074

  16. Hyperthermic intraperitoneal chemotherapy with cisplatin and paclitaxel in advanced ovarian cancer: a multicenter prospective observational study

    PubMed Central

    Coccolini, Federico; Campanati, Luca; Catena, Fausto; Ceni, Valentina; Jimenez Cruz, Jorge; Lotti, Marco; Magnone, Stefano; Napoli, Josephine; Rossetti, Diego; De Iaco, Pierandrea; Frigerio, Luigi; Pinna, Antonio; Runnebaum, Ingo; Ansaloni, Luca

    2015-01-01

    Objective Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have been recently reported with favorable oncological outcomes as treatment of advanced epithelial ovarian cancer (EOC). The aim of this study was to demonstrate the feasibility of CRS+HIPEC with cisplatin and paclitaxel for the treatment of advanced EOC. Methods This is a prospective observational study of 54 patients, from April 2007 to October 2013, with primary or recurrent peritoneal carcinomatosis due to EOC. The mean age was 54.51±9.34. Thirty patients (59%) had primary EOC, and 24 patients (41%) had recurrent disease. Results Mean peritoneal cancer index was 10.11 (range, 0 to 28), complete cytoreduction (CC0) was achieved for 47 patients (87%), CC1 for seven patients (13%). Patients with suboptimal cytoreduction (CC2 and CC3) were not included in the study. The mean stay in intensive care unit was 4.73±5.51 days and the mean hospitalization time was 24.0±10.03 days. We did not observe any intraoperative death. Seven patients (13%) required additional operations. Three patients (5.6%) died within 30 days from the procedure. Severe complications were seen in 19 patients (35.2%). During the follow-up period, disease recurred in 33 patients (61.1%); the median disease-free survival time was 12.46 months and the median overall survival time was 32.91 months. Conclusion CRS+HIPEC with cisplatin and paclitaxel for advanced EOC is feasible with acceptable morbidity and mortality. Additional follow-up and further studies are needed to determine the effects of HIPEC on long term survival. PMID:25376916

  17. Maackia amurensis agglutinin enhances paclitaxel induced cytotoxicity in cultured non-small cell lung cancer cells.

    PubMed

    Chhetra Lalli, Rakhee; Kaur, Kiranjeet; Dadsena, Shashank; Chakraborti, Anuradha; Srinivasan, Radhika; Ghosh, Sujata

    2015-08-01

    Maackia amurensis agglutinin (MAA) is gaining recognition as the potential diagnostic agent for cancer. Previous studies from our laboratory have demonstrated that this lectin could interact specifically with the cells and biopsy samples of non-small cell lung cancer (NSCLC) origin but not with normal lung fibroblast cells. Moreover, this lectin was also found to induce apoptosis in NSCLC cells. Further, the biological activity of this lectin was shown to survive gastrointestinal proteolysis and inhibit malignant cell growth and tumorigenesis in mice model of melanoma thereby indicating the therapeutic potential of this lectin. Paclitaxel is one of the widely used traditional chemotherapeutic drugs for treatment of NSCLC but it exerts side-effects on normal healthy cells too. Studies have revealed that lectins have potential to act as an adjuvant chemotherapeutic agent in cancer of different origin. Thus, in the present study, an attempt was made to assess the chemo-adjuvant role of MAA in three types of NSCLC cell lines [adenocarcinoma cell line (A549), squamous cell carcinoma cell line (NCI-H520) and large cell carcinoma cell line (NCI-H460)]. We have observed that the non-cytotoxic concentration of this lectin was able to enhance the cytotoxic activity of Paclitaxel even at low dose by inducing apoptosis through intrinsic/mitochondrial pathway in all the three types of NSCLC cell lines, although the involvement of extrinsic pathway of apoptosis in case of NCI-H460 cell line could not be ruled out. Further, this lectin was also found to augment the chemo-preventive activity of this drug by arresting cells in G2-M phase of the cell cycle. Collectively, our results have suggested that Maackia amurensis agglutinin may have the potential to be used as adjuvant chemotherapeutic agent in case of NSCLC. PMID:25978938

  18. Comparison of sirolimus versus paclitaxel eluting stents for treatment of coronary in-stent restenosis.

    PubMed

    Airoldi, Flavio; Briguori, Carlo; Iakovou, Ioannis; Stankovic, Goran; Biondi-Zoccai, Giuseppe; Carlino, Mauro; Chieffo, Alaide; Montorfano, Matteo; Cosgrave, John; Michev, Iassen; Rogacka, Renata; Sangiorgi, Giuseppe Massimo; Colombo, Antonio

    2006-04-15

    In patients with in-stent restenosis (ISR) inside bare metal stents, drug-eluting stents reduce the recurrence of restenosis compared with balloon angioplasty. However, few data are available about this therapeutic modality in the case of diffuse restenosis. The aim of this study was to evaluate the immediate and mid-term outcome of sirolimus- and paclitaxel-eluting stent implantation in diffuse ISR and determine the predictors of clinical and angiographic restenosis recurrence. A series of 161 consecutive patients with 194 diffuse ISR lesions (>10 mm) treated with drug-eluting stent implantation were evaluated. Major adverse cardiac events were defined as death, myocardial infarction, and the need for target lesion revascularization. During a mean follow-up of 8.2 +/- 3.4 months, the cumulative incidence of major adverse cardiac events was 19% in the SES group and 24% in the PES group (p = 0.56). Angiographic follow-up was performed in 80% of the lesions. The overall restenosis rate was 22% and was not significantly different between lesions treated with sirolimus-eluting (20%) or paclitaxel-eluting (25%, p = 0.55) stents. The incidence of restenosis was higher in diabetics (32%) than in nondiabetics (16%, odds ratio 2.5, 95% confidence interval 1.1 to 5.5, p = 0.02). By multivariate analysis, diabetes was confirmed to be the only independent predictor of recurrent restenosis (odds ratio 3.53, 95% confidence interval 1.39 to 9.02, p = 0.008). In conclusion, drug-eluting stent implantation for diffuse ISR is associated with acceptable clinical and angiographic results. The association of diffuse restenosis and diabetes mellitus is an unfavorable condition leading to a high risk of recurrence. PMID:16616023

  19. A double-blind, randomized phase II study of dicycloplatin plus paclitaxel versus carboplatin plus paclitaxel as first-line therapy for patients with advanced non-small-cell lung cancers

    PubMed Central

    Liu, Ke-Jun; Guan, Zhong-Zhen; Liang, Ying; Yang, Xu-Qing; Peng, Jin; Huang, He; Shao, Qing-Xiang; Wang, Meng-Zhao; Zhu, Yun-Zhong; Wu, Chang-Ping; Wang, Shao-Bin; Xiong, Jian-Ping; Bai, Yu-Xian; Yu, Shi-Ying; Zhang, Yang; Hu, Xiao-Hua; Feng, Ji-Feng; Wu, Shi-Xiu; Jiao, Shun-Chang; Zhou, Cai-Cun; Wang, Jie

    2014-01-01

    Introduction The aim of this study was to compare the efficacy and toxicity of dicycloplatin plus paclitaxel with those of carboplatin plus paclitaxel as first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). Material and methods In this study, 240 NSCLC patients with stage IIIB (with pleural effusion) and stage IV disease were randomly assigned (1: 1) to receive dicycloplatin 450 mg/m2 or carboplatin AUC = 5, in combination with paclitaxel 175 mg/m2 (D + P or C + P) every 3 weeks for up to 4 to 6 cycles. The primary endpoint was response rate. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and adverse events. Results The response rates for the D + P and C + P arm were 36.44% and 30.51%, respectively (p = 0.33). The median PFS was 5.6 months in the D + P arm and 4.7 months in the C + P arm (p = 0.31). The median OS was 14.9 months for D + P and 12.9 months for C + P (p = 0.37). Adverse events in the two arms were well balanced. The most common grade 3/4 adverse event was hematologic toxicity. Conclusions Patients treated with D + P had similar response and survival rates to those treated with C + P, and toxicities of both treatments were generally tolerable. PMID:25276156

  20. Pluronic P105/F127 mixed micelles for the delivery of docetaxel against Taxol-resistant non-small cell lung cancer: optimization and in vitro, in vivo evaluation

    PubMed Central

    Chen, Liangcen; Sha, Xianyi; Jiang, Xinyi; Chen, Yanzuo; Ren, Qiuyue; Fang, Xiaoling

    2013-01-01

    The aim of this work was to establish a novel polymeric mixed micelle composed of Pluronic P105 and F127 copolymers loaded with the poorly soluble antitumor drug docetaxel (DTX) against Taxol-resistant non-small cell lung cancer. A central composite design was utilized to optimize the preparation process, helping to improve drug solubilization efficiency and micelle stability. Prepared by a thin-film hydration method, the average size of the optimized mixed micelle was 23 nm, with a 92.40% encapsulation ratio and a 1.81% drug-loading efficiency. The optimized formulation showed high storage stability in lyophilized form, with 95.7% of the drug content remaining after 6 months’ storage at 4°C. The in vitro cytotoxicity assay showed that the IC50 values for Taxotere® and mixed micelles were similar for A549, while on A549/Taxol cell lines, DTX-loaded P105/F127 mixed micelles showed a superior hypersensitizing effect; their IC50 value (0.059 ?g/mL) was greatly reduced compared to those of Taxotere injections (0.593 ?g/mL). The in vivo pharmacokinetic study showed that the mixed-micelle formulation achieved a 1.85-fold longer mean residence time in circulation and a 3.82-fold larger area under the plasma concentration-time curve than Taxotere. In addition, therapeutic improvement of mixed micelles in vivo against A549/Taxol was obtained. The tumor inhibition rate of the micelles was 69.05%, versus 34.43% for Taxotere (P < 0.01). Therefore, it could be concluded from the results that DTX-loaded P105/F127 mixed micelles might serve as a potential antitumor drug delivery system to overcome multidrug resistance in lung cancer. PMID:23319859

  1. Evaluation of paclitaxel rearrangement involving opening of the oxetane ring and migration of acetyl and benzoyl groups.

    PubMed

    Pyo, Sang-Hyun; Cho, Jin-Suk; Choi, Ho-Joon; Han, Byung-Hee

    2007-02-19

    The stability of drug is a critical factor in quality control, drug efficacy, safety, storage, and production conditions. The rearrangement of paclitaxel, which involves opening of the oxetane ring and migration of acetyl group occurred on heating a powder of purified paclitaxel. Subsequently, the unusual migration of benzoyl groups progressed rapidly in organic solvents. These rearrangement derivatives were isolated carefully. The structures of the intermediate derivative A and the product derivative B were confirmed using (1)H NMR, high performance liquid chromatography (HPLC), and mass spectrometry. We proposed the rearrangement pathway here for the first time. Neither derivative exhibited bioactivity in SKOV3 (ovarian cancer) or MDA-MB-435 (breast cancer) cell culture assays. PMID:17029668

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

    PubMed Central

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

    2010-01-01

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

  3. Secondary breast angiosarcoma and paclitaxel-dependent prolonged disease control: report of two cases and review of the literature.

    PubMed

    Gambini, Donatella; Visintin, Roberto; Locatelli, Elisa; Bareggi, Claudia; Galassi, Barbara; Runza, Letterio; Blundo, Concetta; Sosnovskikh, Irina; Tomirotti, Maurizio

    2015-01-01

    Secondary breast angiosarcomas are a well-known entity generally characterized by a poor outcome, especially in patients with advanced disease. Among the drugs with demonstrated activity, taxane derivatives are one of the most effective histology-driven treatments against angiosarcomas. We report two cases of secondary breast angiosarcoma, both characterized by a very peculiar behavior towards paclitaxel. Both patients showed local recurrence of angiosarcoma after primary surgery, and they achieved complete remission following treatment with weekly paclitaxel. When a locoregional recurrence was observed as a result of a brief treatment interruption or a treatment delay, a new complete remission was rapidly achieved with the resumption of the drug, without evidence of any significant adverse effects. PMID:25744864

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

    PubMed Central

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

    2013-01-01

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

  5. Phase II Radiation therapy oncology group trial of weekly paclitaxel and conventional external beam radiation therapy for supratentorial glioblastoma multiforme

    Microsoft Academic Search

    Corey J. Langer; James Ruffer; Harker Rhodes; Rebecca Paulus; Kevin Murray; Benjamin Movsas; Walter Curran

    2001-01-01

    Purpose: Fractionated external beam radiotherapy (EBRT) ± carmustine (BCNU) is the standard of care for patients with glioblastoma multiforme (GBM), but survival results remain poor. Preclinical studies indicate synergy between RT and paclitaxel (TAX) in astrocytoma cell lines. Phase I studies in GBM have demonstrated a maximum tolerated dose for TAX of 225 mg\\/m2\\/3 h\\/week × 6, during EBRT, with

  6. A phase I clinical trial of bavituximab and paclitaxel in patients with HER2 negative metastatic breast cancer.

    PubMed

    Chalasani, Pavani; Marron, Marilyn; Roe, Denise; Clarke, Kathryn; Iannone, Maria; Livingston, Robert B; Shan, Joseph S; Stopeck, Alison T

    2015-07-01

    Bavituximab is a chimeric monoclonal antibody that targets phosphatidylserine (PS). PS is externalized on cells in the tumor microenvironment when exposed to hypoxia and/or other physiological stressors. On attaching to PS, bavituximab is thought to promote antitumor immunity through its effects on PS receptors in monocytes, and myeloid-derived suppressor cells, as well as trigger antitumor effects by inducing an antibody-dependent cellular cytotoxicity on tumor-associated endothelial cells. We conducted a phase I clinical trial of bavituximab in combination with paclitaxel in patients with HER2-negative metastatic breast cancer. Patients were treated with weekly paclitaxel (80 mg/m(2) for 3/4 weeks) and weekly bavituximab (3 mg/kg for 4/4 weeks). Correlative studies included the measurement of circulating microparticles, endothelial cells, and apoptotic tumor cells by flow cytometry. Fourteen patients with metastatic breast cancer were enrolled; all were evaluable for toxicity and 13 were evaluable for response. Treatment resulted in an overall response rate (RR) of 85% with a median progression-free survival (PFS) of 7.3 months. Bone pain, fatigue, headache, and neutropenia were the most common adverse effects. Infusion-related reactions were the most common adverse event related to bavituximab therapy. Correlative studies showed an increase in the PS-expressing apoptotic circulating tumor cells in response to bavituximab, but not with paclitaxel. No changes in the number of circulating endothelial cells or apoptotic endothelial cells were observed with therapy. Platelet and monocyte-derived microparticles decreased after initiation of bavituximab. Bavituximab in combination with paclitaxel is well tolerated for treatment of patients with metastatic breast cancer with promising results observed in terms of clinical RRs and PFS. The toxicity profile of bavituximab is notable for manageable infusion-related reactions with no evidence for increased thrombogenicity. Recent preclinical data suggest that bavituximab can also promote antitumor immune activity that should be explored in future clinical trials. PMID:25826750

  7. Chemotherapeutic engineering: Vitamin E TPGS-emulsified nanoparticles of biodegradable polymers realized sustainable paclitaxel chemotherapy for 168 h in vivo

    Microsoft Academic Search

    Si-Shen Feng; Lingyun Zhao; Zhiping Zhang; Gajadhar Bhakta; Khin Yin Win; Yuancai Dong; Shu Chien

    2007-01-01

    A full spectrum of proof-of-concept research from nanoparticle preparation and characterization, in vitro drug release, cellular uptake and cytotoxicity, to in vivo pharmacokinetics and xenograft tumor model is developed in this paper to demonstrate how nanoparticles of biodegradable polymers can be applied to formulate anticancer drugs to avoid use of toxic adjuvant and to enable sustained and controlled chemotherapy. Paclitaxel-loaded

  8. [A case of curative surgery for HER2-positive gastric cancer after chemotherapy using paclitaxel combined with trastuzumab].

    PubMed

    Okubo, Satoshi; Kawabata, Ryohei; Kimura, Yutaka; Kawase, Tomono; Ishigaki, Takahiko; Amano, Kouji; Munakata, Satoru; Fukunaga, Mutsumi; Ohzato, Hiroki

    2014-11-01

    A 74-year-old man was diagnosed with unresectable HER2-positive gastric cancer due to metastases to distant lymph nodes. Paclitaxel combined with trastuzumab was administered as third-line chemotherapy. After 4 courses of therapy, the metastases to distant lymph nodes disappeared with no evidence of progressive disease. Downstaging by chemotherapy made curative treatment feasible and he underwent distal gastrectomy. The patient has been free from recurrent disease 13 months after surgery. PMID:25731503

  9. The Role of Apaf1, Caspase9, and Bid Proteins in Etoposide- or Paclitaxel-induced Mitochondrial Events during Apoptosis

    Microsoft Academic Search

    Charles L. Perkins; Guofu Fang; Caryn Nae Kim; Kapil N. Bhalla

    2000-01-01

    Ectopic overexpression of Apaf-1 (2.5-fold) in human acute myeloge- nous leukemia HL-60 cells (HL-60\\/Apaf-1 cells) induced apoptosis and sensitized HL-60\\/Apaf-1 cells to etoposide- and paclitaxel-induced apo- ptosis (C. Perkins et al., Cancer Res., 58: 4561- 4566, 1998). In this report, we demonstrate that in HL-60\\/Apaf-1 cells, the activity of caspase-9 and -3 induced by Apaf-1 overexpression was associated with a

  10. Effect of synthetic eel calcitonin, elcatonin, on cold and mechanical allodynia induced by oxaliplatin and paclitaxel in rats.

    PubMed

    Aoki, Manahito; Mori, Asami; Nakahara, Tsutomu; Sakamoto, Kenji; Ishii, Kunio

    2012-12-01

    Oxaliplatin and paclitaxel are commonly used anti-cancer drugs, but they frequently cause peripheral neuropathic pain. In this study, we investigated the effect of elcatonin, a synthetic eel calcitonin, on oxaliplatin- and paclitaxel-induced neuropathy in rats. The rats were treated with a single dose of oxaliplatin (6 mg/kg, i.p.) or repeated doses of paclitaxel (2 mg/kg, i.p.) on 4 alternate days. Both treatments resulted in cold and mechanical allodynia. We assessed the anti-allodynic effects of subcutaneously administered elcatonin (20 U/kg/day) by using a newly developed method to provide cold stimulation (8°C) directly to the hind paw of the rats and by using the von Frey test. Elcatonin almost completely reversed the effects of both cold and mechanical allodynia. To determine the mechanism of this anti-allodynic effect, we examined the effect of elcatonin on neuropathy induced by intraplantar injection of two organic compounds: allyl isothiocyanate (1 nmol/paw), which activates transient receptor potential ankyrin-1 channels, and menthol (1.28 ?mol/paw), which activates transient receptor potential ankyrin-1 and melastatin-8. Pre-administration of elcatonin almost completely prevented cold and mechanical allodynia from being induced by both compounds. These results suggest that elcatonin attenuates oxaliplatin- and paclitaxel-induced neuropathic pain by inhibiting the cellular signaling related to transient receptor potential ankyrin-1 and melastatin-8. Thus, we conclude that administration of elcatonin may improve the quality of life of cancer patients receiving chemotherapy. PMID:23001015

  11. A complete metal jacket case using ten paclitaxel-eluting stents for multiple de novo coronary artery lesions.

    PubMed

    Suh, Soon Yong; Rha, Seung-Woon; Choi, Cheol Ung; Kim, Jin Won; Kim, Eung Ju; Park, Chang Gyu; Seo, Hong Seog; Oh, Dong Joo

    2007-02-01

    Although full metal jacket using drug-eluting stent (DES) for a single coronary artery disease has sparsely been described before, there is no report of safety and efficacy of complete metal jacket from left main (LM) to three major coronary arteries. We report a complete metal jacket case using 10 paclitaxel-eluting stents (PES; Taxus, Boston Scientific) for a triple vessel diffuse de novo coronary diseases who refused coronary artery bypass graft. PMID:17126931

  12. Synergistic antitumor effect of ?-pinene and ?-pinene with paclitaxel against non-small-cell lung carcinoma (NSCLC).

    PubMed

    Zhang, Z; Guo, S; Liu, X; Gao, X

    2015-04-01

    The objective of the present research work was to evaluate the synergistic interactions between Paclitaxel (PAC) with ?-pinene and ?-pinene using isobolographic method against non-small-cell lung cancer cells (NSCLC). This type of interaction between an established drug and a new compound is expected to enhance the efficacy of paclitaxel in combination as compared in isolation. Further, cell cycle analysis was carried out using flow cytometric analysis. Phase contrast microscopy was used to assess the effect of paclitaxel, ?-pinene and ?-pinene alone and in combination with each other in order to evaluate the effect of combination on cell apoptosis. Further, mitochondrial membrane potential was monitored in non-small-cell lung cancer cells (NSCLC) when treated with paclitaxel, ?-pinene and ?-pinene alone and in combination. The results revealed that the combination of PAC with ?-pinene or with ?-pinene showed a plotted curve below the straight line, generating a substantial synergistic effect. The effects of the following combinations were examined utilizing isobolograms: PAC and ?-pinene and PAC and ?-pinene. The combination of PAC and ?-pinene as well as of PAC and ?-pinene actually generated a synergistic effect. We also examined the effects of these compounds on the cell cycle distributions of A549 cells by flow cytometric analysis. The percentage of sub-G0/G1-phase cells was decreased on the addition of ?-pinene to PAC, while the population of G0/G1 cells was increased. The morphological changes characteristic of apoptosis like chromatin condensation and fragmentation of the nucleus were seen in PAC+?-pinene and PAC+?-pinene treated NSCLC cells. PMID:25188609

  13. Phase II study of capecitabine in combination with paclitaxel in patients with anthracycline-pretreated advanced\\/metastatic breast cancer

    Microsoft Academic Search

    N Batista; G Perez-Manga; M Constenla; A Ruiz; F Carabantes; J Castellanos; M Gonzalez Barón; K Villman; M Söderberg; J Ahlgren; J Casinello; P Regueiro; A Murias

    2004-01-01

    The addition of oral capecitabine to docetaxel improves response rate, time to progression (TTP) and overall survival in anthracycline-pretreated metastatic breast cancer (MBC). This phase II study evaluates the efficacy and safety of a 21-day cycle of oral capecitabine (1000 mg m?2 twice daily, days 1–14) plus i.v. paclitaxel (175 mg m?2, day 1) in anthracycline-pretreated advanced\\/MBC. In all, 73

  14. Randomised phase II study comparing dose-escalated weekly paclitaxel vs standard-dose weekly paclitaxel for patients with previously treated advanced gastric cancer

    PubMed Central

    Shitara, K; Yuki, S; Tahahari, D; Nakamura, M; Kondo, C; Tsuda, T; Kii, T; Tsuji, Y; Utsunomiya, S; Ichikawa, D; Hosokawa, A; Ishiguro, A; Sakai, D; Hironaka, S; Oze, I; Matsuo, K; Muro, K

    2014-01-01

    Background: This randomised phase II trial compared dose-escalated weekly paclitaxel (wPTX) vs standard-dose wPTX for patients with previously treated advanced gastric cancer (AGC). Methods: Ninety patients were randomised to a standard dose of wPTX (80?mg?m?2) or an escalated dose of wPTX (80–120?mg?m?2) to assess the superiority of overall survival (OS) with a one-sided alpha error of 0.3 and a power of 0.8. Results: The median OS showed a trend towards longer survival in the dose-escalated arm (11.8 vs 9.6 months; hazard ratio (HR), 0.75; one-sided P=0.12), although it was statistically not significant. The median progression-free survival (PFS) was significantly longer in the dose-escalated arm (4.3 vs 2.5 months, HR, 0.55; P=0.017). Objective response rate was 30.3% with dose escalation and 17.1% with standard dose (P=0.2). The frequency of all grades of neutropenia was significantly higher with dose escalation (88.7% vs 60.0%, P=0.002); however, no significant difference was observed in the proportion of patients experiencing grade 3 or more (40.9% vs 31.1%, P=0.34). Conclusion: Dose-escalated wPTX in patients with pretreated AGC met our predefined threshold of primary end point, OS (P<0.3); however, it did not show a significantly longer OS. Progression-free survival was significantly better with dose escalation. PMID:24281004

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

    PubMed

    Gui, Qi; Xu, Chengcheng; Li, Dapeng; Zhuang, Liang; Xia, Shu; Yu, Shiying

    2015-09-01

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

  16. A multicenter phase I study of pazopanib in combination with paclitaxel in first-line treatment of patients with advanced solid tumors.

    PubMed

    Kendra, Kari L; Plummer, Ruth; Salgia, Ravi; O'Brien, Mary E R; Paul, Elaine M; Suttle, A Benjamin; Compton, Natalie; Xu, Chun-Fang; Ottesen, Lone H; Villalona-Calero, Miguel A

    2015-02-01

    This study was designed to evaluate the safety, pharmacokinetics, and clinical activity of pazopanib combined with paclitaxel to determine the recommended phase II dose in the first-line setting in patients with advanced solid tumors. Patients were enrolled in a 3+3 dose-escalation design to determine the maximum tolerated regimen (MTR) of once daily pazopanib plus paclitaxel administered every 3 weeks at four dose levels (DL1-4). Safety, pharmacokinetics, pharmacogenetics, and disease assessments were performed. Twenty-eight patients received treatment. One patient at DL1 had dose-limiting toxicity (DLT) of elevated hepatic enzymes. After pazopanib discontinuation, liver enzyme concentrations remained high until a concurrent medication, simvastatin, was discontinued. This patient had the defective CYP2C8*3*3 genotype. At DL2, 1 patient had DLT of elevated hepatic enzymes with rash and 1 patient had DLT of rash. The MTR was paclitaxel 150 mg/m(2) plus pazopanib 800 mg. The most common toxicities were alopecia, fatigue, hypertension, nausea, diarrhea, dysgeusia, neutropenia, myalgia, hair color changes, and peripheral neuropathy. Coadministration of pazopanib and paclitaxel resulted in a 38% increase in systemic exposure to paclitaxel, relative to administration of paclitaxel alone, at the MTR. Of the 28 patients treated with the combination, 10 achieved a partial response and 10 achieved stable disease of ?12 weeks. Pazopanib 800 mg daily plus paclitaxel 150 mg/m(2) every 3 weeks was the recommended phase II dose, with a manageable safety profile, and with clinical activity in both melanoma and non-small cell lung cancer that suggest further evaluation of this combination is warranted. PMID:25504632

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

    PubMed

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

    2014-12-01

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

  18. Efficient drug delivery of Paclitaxel glycoside: a novel solubility gradient encapsulation into liposomes coupled with immunoliposomes preparation.

    PubMed

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

    2014-01-01

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

  19. [A case of clear cell carcinoma of the ovary responding to a paclitaxel-carboplatin combination chemotherapy].

    PubMed

    Fujiwara, K; Maehata, K; Kohno, I; Yoden, E; Imajo, Y; Mikami, Y

    2000-12-01

    Clear cell carcinoma of the ovary is believed to be chemoresistant; therefore, choosing anticancer agents is often difficult. In this report we present a case of ovarian clear cell carcinoma that showed a significant response to a combination chemotherapy with paclitaxel and carboplatin. The patient is a 51-year-old Japanese female with a history of Gn-RH treatment for endometriosis that was terminated three years before the presentation of this disease. She was referred to our hospital because of a huge abdominal mass. The initial surgery revealed the tumor was a clear cell carcinoma of the left ovary, showing a predominantly solid growth pattern as well as papillary and tubular patterns. Both architectural and nuclear grades were interpreted as 3, and mitotic count was up to 5/10 high-power fields. Therefore, the tumor was considered to be grade 2. A huge para-aortic lymph node metastasis was not resectable. Combination chemotherapy using paclitaxel at 175 mg/m2 in 3 hr intravenous infusion followed by intraperitoneal infusion of carboplatin at AUC of 7.5 as a bolus was administered. The regression rate of the para-aortic lymph node metastasis was 85%, lasting more than 5 months. We believe that the combination of paclitaxel and carboplatin is one treatment choice for clear cell carcinoma of the ovary. PMID:11142173

  20. miR-145 sensitizes ovarian cancer cells to paclitaxel by targeting Sp1 and Cdk6.

    PubMed

    Zhu, Xiaolan; Li, Yuefeng; Xie, Chanjuan; Yin, Xinming; Liu, Yueqin; Cao, Yuan; Fang, Yue; Lin, Xin; Xu, Yao; Xu, Wenlin; Shen, Huiling; Wen, Jian

    2014-09-15

    Multidrug resistance (MDR) remains a major obstacle to effective chemotherapy treatment in ovarian cancer. In our study, paclitaxel-resistant ovarian cancer patients and cell lines had decreased miR-145 levels and expressed high levels of Sp1 and Cdk6. Introducing miR-145 into SKOV3/PTX and A2780/PTX cells led to a reduction in Cdk6 and Sp1 along with downregulation of P-gp and pRb. These changes resulted in increased accumulation of antineoplastic drugs and G1 cell cycle arrest, which rendered the cells more sensitive to paclitaxel in vitro and in vivo. These effects could be reversed by reintroducing Sp1 or Cdk6 into cells expressing high levels of miR-145, resulting in restoration of P-gp and pRb levels. Furthermore, we confirmed that both Cdk6 and Sp1 are targets of miR-145. Intriguingly, demethylation with 5-aza-dC led to reactivation of miR-145 expression in drug-resistant ovarian cancer cell lines, which also resulted in increased sensitivity to paclitaxel. Collectively, these findings begin to elucidate the role of miR-145 as an important regulator of chemoresistance in ovarian cancer by controlling both Cdk6 and Sp1. PMID:24510775

  1. Low-dose paclitaxel improves the therapeutic efficacy of recombinant adenovirus encoding CCL21 chemokine against murine cancer.

    PubMed

    Chen, Ping; Luo, Shan; Wen, Yan-Jun; Li, Yu-Hua; Li, Jiong; Wang, Yong-Sheng; Du, Li-Cheng; Zhang, Ping; Tang, Jiao; Yang, Da-Bing; Hu, Huo-Zhen; Zhao, Xia; Wei, Yu-Quan

    2014-11-01

    Secondary lymphoid tissue chemokine (SLC/CCL21), one of the CC chemokines, exerts potent antitumor immunity by co-localizing T cells and dendritic cells at the tumor site and is currently tested against human solid tumors. Here, we investigated whether the combination of recombinant adenovirus encoding murine CCL21 (Ad-mCCL21) with low-dose paclitaxel would improve therapeutic efficacy against murine cancer. Immunocompetent mice bearing B16-F10 melanoma or 4T1 breast carcinoma were treated with either Ad-mCCL21, paclitaxel, or both agents together. Our results showed that Ad-mCCL21 + low-dose paclitaxel more effectively reduced the growth of tumors as compared with either treatment alone and significantly prolonged survival time of the tumor-bearing animals. These antitumor effects of the combined therapy were linked to altered cytokine network at the tumor site, enhanced apoptosis of tumor cells, and decreased formation of new vessels in tumors. Importantly, the combined therapy elicited a strong therapeutic antitumor immunity, which could be partly abrogated by the depletion of CD4(+) or CD8(+) T lymphocytes. Collectively, these preclinical evaluations may provide a combined strategy for antitumor immunity and should be considered for testing in clinical trials. PMID:25230206

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

    PubMed

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

    2013-04-01

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

  3. Antitumor activity of photo-stimulated zinc oxide nanoparticles combined with paclitaxel or cisplatin in HNSCC cell lines.

    PubMed

    Hackenberg, Stephan; Scherzed, Agmal; Harnisch, Wilma; Froelich, Katrin; Ginzkey, Christian; Koehler, Christian; Hagen, Rudolf; Kleinsasser, Norbert

    2012-09-01

    Zinc oxide nanoparticles (ZnO-NPs) exhibit photocatalytic properties and are used in sunscreen cosmetics and for the degradation of environmental pollutants. Furthermore, ZnO-NPs have proven to induce tumor-selective cell death in human squamous cell carcinoma (HNSCC) in vitro. The aim of the current study was to evaluate cytotoxic effects of UVA-1-activated ZnO-NPs in combination with paclitaxel and cisplatin in HNSCC. Three HNSCC cell lines (HLaC-78, Cal-27 and PJ-41) were incubated with ZnO-NPs at concentrations of 0.02 and 0.2 ?g/ml in combination with paclitaxel (0.5-5 nM) or cisplatin (0.03-3 ?M) for 24 h. Afterwards, cells were irradiated with UVA-1 for 15 min. Viability was measured by MTT assay, fluorescein-diacetate (FDA) test and annexin/propidiumiodide flow cytometry. A significant decrease in viable cells could be observed in all three HNSCC cell lines treated by photocatalytic therapy with 0.2 ?g/cm(2) ZnO-NPs alone. A combination with paclitaxel or cisplatin at low concentrations resulted in a further increase in cytotoxicity in vitro revealing a synergistic effect. Flow cytometry revealed a combination of apoptosis and necrosis. These results indicate that photocatalytic therapy of HNSCC with ZnO-NPs could enhance the cytotoxic action of chemotherapeutic agents synergistically, indicating a promising potential for ZnO-NPs in antitumor applications. PMID:22722055

  4. Resistance to cisplatin and paclitaxel does not affect the sensitivity of human ovarian cancer cells to antiprogestin-induced cytotoxicity

    PubMed Central

    2014-01-01

    Background Antiprogestin compounds have been shown to be effective in blocking the growth of ovarian cancer cells of different genetic backgrounds. Herein we studied the anti-ovarian cancer effect of a series of antiprogestins sharing the chemical backbone of the most characterized antiprogestin, mifepristone, but with unique modifications in position C-17 of the steroid ring. We assessed the effect of mifepristone-like antiprogestins on the growth of ovarian cancer cells sensitive to the standard combination therapy cisplatin-paclitaxel or made double-resistant upon six cycles of pulse-selection with the drugs used at clinically relevant concentrations and exposure times. Methods IGROV-1 and SKOV-3 cells were pulsed with 20 ?M cisplatin for 1 h followed by 100 nM paclitaxel for 3 h once a week for six weeks. The cells that did not die and repopulate the culture after the chemotherapies were termed Platinum-Taxane-EScape cells (PTES). Parental cells were compared against their PTES derivatives in their responses to further platinum-taxane treatments. Moreover, both ovarian cancer cells and their PTES siblings were exposed to escalating doses of the various antiprogestin derivatives. We assessed cell growth, viability and sub-G1 DNA content using microcapillary cytometry. Cyclin-dependent kinase inhibitors p21cip1 and p27kip1 and cleavage of downstream caspase-3 substrate PARP were used to assess whether cell fate, as a consequence of treatment, was limited to cytostasis or progressed to lethality. Results Cells subjected to six pulse-selection cycles of cisplatin-paclitaxel gave rise to sibling derivatives that displayed ~2-7 fold reduction in their sensitivities to further chemotherapy. However, regardless of the sensitivity the cells developed to the combination cisplatin-paclitaxel, they displayed similar sensitivity to the antiprogestins, which blocked their growth in a dose-related manner, with lower concentrations causing cytostasis, and higher concentrations causing lethality. Conclusions Antiprogestins carrying a backbone similar to mifepristone are cytotoxic to ovarian cancer cells in a manner that does not depend on the sensitivity the cells have to the standard ovarian cancer chemotherapeutics, cisplatin and paclitaxel. Thus, antiprogestin therapy could be used to treat ovarian cancer cells showing resistance to both platinum and taxanes. PMID:24795781

  5. Phase I trial and pharmacological study of a 3-hour paclitaxel infusion in children with refractory solid tumours: a SFOP study

    PubMed Central

    Doz, F; Gentet, J C; Pein, F; Frappaz, D; Chastagner, P; Moretti, S; Vassal, G; Arditti, J; Tellingen, O Van; Iliadis, A; Catalin, J

    2001-01-01

    The maximum tolerated dose of paclitaxel administered by 24-hour continuous infusion in children is known. Short infusion might offer equivalent antitumour efficacy and reduced haematological toxicity, without increasing the allergic risk. Our aims were to determine the maximum tolerated dose and the pharmacokinetics of paclitaxel in children when administered in 3-h infusion every 3 weeks. Patients older than 6 months, younger than 20 years with refractory malignant solid tumours were eligible when they satisfied standard haematological, renal, hepatic and cardiologic inclusion criteria with life expectancy exceeding 8 weeks. Paclitaxel was administered as a 3-hour infusion after premedication (dexamethasone, dexchlorpheniramine). Pharmacokinetic analysis and solvent assays (ethanol, cremophor) were performed during the first course. 20 courses were studied in 17 patients; 4 dosage levels were investigated (240 to 420?mg/m2). No dose-limiting haematological toxicity was observed. Severe acute neurological and allergic toxicity was encountered. One treatment-related death occurred just after the infusion at the highest dosage. Delayed peripheral neurotoxicity and moderate allergic reactions were also encountered. Pharmacokinetic analysis showed dose-dependent clearance of paclitaxel and elevated blood ethanol and Cremophor EL levels. Although no limiting haematological toxicity was reached, we do not recommend this paclitaxel schedule in children because of its acute neurological toxicity. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11237379

  6. Large-scale purification of 13-dehydroxybaccatin III and 10-deacetylpaclitaxel, semi-synthetic precursors of paclitaxel, from cell cultures of Taxus chinensis.

    PubMed

    Pyo, Sang-Hyun; Choi, Ho-Joon; Han, Byung-Hee

    2006-08-01

    The taxane derivatives 13-dehydroxybaccatin III (13-DHB III) and 10-deacetylpaclitaxel (10-DAP) can be used as semi-synthetic precursors of paclitaxel. These precursors were isolated in a simple and economical procedure during purification of paclitaxel from plant cell culture extracts. No additional costs for cell culture or extraction by silica-gel low-pressure chromatography were incurred. Precipitation from dichloromethane/n-hexane followed by HPLC on ODS and silica-gel resins resulted in paclitaxel of 99.5% purity with 80% overall yield. ODS low-pressure chromatography and THF/n-hexane precipitation yielded 13-dehydroxybaccatin III at >99% purity with 87.1% overall yield, and ODS low-pressure chromatography alone yielded 10-deacetylpaclitaxel at >90% purity with 93.4% overall yield. These compounds are of sufficient purity for use in semi-synthesis of paclitaxel. Both compounds were obtained in high yield at >99.5% purity using ODS-HPLC. The procedures described allow the simultaneous purification of 13-dehydroxybaccatin III, 10-deacetylpaclitaxel, and paclitaxel with only minimal additional expense for reagents or equipment. PMID:16716338

  7. High Id1 expression, a generally negative prognostic factor, paradoxically predicts a favorable prognosis for adjuvant paclitaxel plus cisplatin therapy in surgically treated lung cancer patients

    PubMed Central

    Cheng, Yu-Jen; Lee, Yi-Chen; Chiu, Wen-Chin; Tsai, Jen-Wei; Su, Yu-Han; Hung, Amos C.; Chang, Po-Chih; Huang, Chih-Jen; Chai, Chee-Yin; Yuan, Shyng-Shiou F.

    2014-01-01

    Adjuvant chemotherapy is commonly given to surgically treated non-small-cell lung cancer (NSCLC) patients. However, the prerequisite for chemotherapy needs to be scrutinized in order to maximize the benefits to patients. In this study, we observed that NSCLC cells with high Id1 protein expression were vulnerable to the treatment of paclitaxel and cisplatin. In addition, paclitaxel and cisplatin caused Id1 protein degradation through ubiquitination. In the nude mice xenograft model, the tumor growth was reduced to a large degree in the Id1-overexpressing group upon treatment with paclitaxel and cisplatin. Furthermore, immunohistochemical staining for Id1 followed by Kaplan-Meier survival analysis showed that surgically treated NSCLC patients with high Id1 expression in primary tumor tissues had better disease-free and overall survivals after adjuvant paclitaxel and cisplatin chemotherapy. In summary, our current data suggest that Id1, a generally negative prognostic factor, predicts a favorable prognosis in the case of surgically treated NSCLC patients receiving the definitive adjuvant chemotherapy. The distinct role of Id1 reported in this study may arise from the phenomenon of Id1 dependence of NSCLC cells for survival, which renders the cancer cells additionally susceptive to the adjuvant chemotherapy with paclitaxel and cisplatin. PMID:25344919

  8. Antiproliferative efficacies but minor drug transporter inducing effects of paclitaxel, cisplatin, or 5-fluorouracil in a murine xenograft model for head and neck squamous cell carcinoma.

    PubMed

    Theile, Dirk; Gal, Zoltan; Warta, Rolf; Rigalli, Juan Pablo; Lahrmann, Bernd; Grabe, Niels; Herold-Mende, Christel; Dyckhoff, Gerhard; Weiss, Johanna

    2014-04-01

    Drug-induced multidrug resistance (MDR) has been linked to overexpression of drug transporting proteins in head and neck squamous cell carcinoma (HNSCC) in vitro. The aim of this work was to reassess these findings in a murine xenograft model. NOD-SCID mice xenotransplanted with 10 (6) HNO97 cells were treated for four consecutive weeks with weekly paclitaxel, biweekly cisplatin (both intraperitoneal), or 5-fluorouracil (5-FU, administered by osmotic pump). Tumor volume and body weight were weekly documented. Expression of drug transporters and Ki-67 marker were examined using quantitative real-time polymerase chain reaction and/or immunohistochemistry. Both paclitaxel and cisplatin significantly reduced tumor volumes after 2-3 weeks. 5-FU-treated animals had significantly lower body weights after 2 or 4 weeks of chemotherapy. None of the drugs affected expression of drug transporters at the mRNA level. However, P-glycoprotein (Pgp) protein expression was increased by paclitaxel (P<0.01). Ki-67 expression did not change during treatment irrespective of the drug applied. Paclitaxel and cisplatin are effectively tumor volume reducing drugs in a murine xenograft model of HNSCC. Paclitaxel enhanced Pgp expression at the protein level, but not at the mRNA level suggesting transcriptional induction to be of minor relevance. In contrast, posttranscriptional mechanisms or Darwinian selection of intrinsically drug transporter overexpressing MDR cells might lead to iatrogenic chemotherapy resistance in HNSCC. PMID:24448417

  9. Combretastatin A-1 phosphate potentiates the antitumor activity of carboplatin and paclitaxel in a severe combined immunodeficiency disease (SCID) mouse model of human ovarian carcinoma.

    PubMed

    Staflin, K; Järnum, S; Hua, J; Honeth, G; Kannisto, P; Lindvall, M

    2006-01-01

    In search for new therapeutic modalities to target epithelial ovarian carcinomas, we investigated the effect of the antiangiogenic drug combretastatin A-1 phosphate (CA1P) as a single treatment or in combination with established therapy, ie, carboplatin and paclitaxel. Five different human epithelial ovarian carcinoma cell lines were inoculated subcutaneously into FOX CHASE CB-77 severe combined immunodeficiency disease (SCID) mice. When tumors reached a volume of approximately 100 mm(3), the treatment was initiated. All drugs were given intraperitoneally at weekly doses. CA1P was more effective as an antitumor agent than combretastatin A-4 phosphate as a single-drug treatment or in combination with carboplatin and paclitaxel. CA1P had a strong tumor outgrowth inhibiting effect on four out of five tumors included in this study. Comparing animals receiving CA1P with animals receiving a combination of carboplatin and paclitaxel, CA1P was more effective on two out of three tested tumors, whereas carboplatin and paclitaxel were more effective on one out of three of the tumors. We show that treatment of human ovarian carcinomas with CA1P in the SCID mouse model results in a strong antitumor effect both as a single-drug treatment and as an enhancement of the therapeutic effect in a combination treatment protocol with carboplatin and paclitaxel. PMID:16884365

  10. In vitro cross-resistance and collateral sensitivity in seven resistant small-cell lung cancer cell lines: preclinical identification of suitable drug partners to taxotere, taxol, topotecan and gemcitabin.

    PubMed Central

    Jensen, P. B.; Holm, B.; Sorensen, M.; Christensen, I. J.; Sehested, M.

    1997-01-01

    The acquisition of drug-resistant tumour cells is the main problem in the medical treatment of a range of malignant diseases. In recent years, three new classes of anti-cancer agents, each with a novel mechanism of action, have been brought forward to clinical trials. These are the topoisomerase I (topo I) poisons topotecan and irinotecan, which are both camptothecin derivatives, the taxane tubulin stabilizers taxol and taxotere and, finally, the antimetabolite gemcitabin, which is active in solid tumours. The process of optimizing their use in a combination with established agents is very complex, with numerous possible drug and schedule regimens. We describe here how a broad panel of drug-resistant small-cell lung cancer (SCLC) cell lines can be used as a model of tumour heterogeneity to aid in the selection of non-cross-resistant regimens. We have selected low-fold (3-10x) drug-resistant sublines from a classic (NCI-H69) and a variant (OC-NYH) SCLC cell line. The resistant cell lines include two sublines with different phenotypes towards alkylating agents (H69/BCNU and NYH/CIS), two sublines with different phenotypes against topo I poisons (NYH/CAM and NYH/TPT) and three multidrug resistant (MDR) sublines (H69/DAU, NYH/VM, and H69/VP) with combinations of mdr1 and MRP overexpression as well as topoisomerase II (topo II) down-regulation or mutation. Sensitivity to 20 established and new agents was measured in a standardized clonogenic assay. Resistance was highly drug specific. Thus, none of the cell lines was resistant to all drugs. In fact, all resistant cell lines exhibited patterns of collateral sensitivity to various different classes of drugs. The most intriguing pattern was collateral sensitivity to gemcitabin in two cell lines and to ara-C in five drug-resistant cell lines, i.e. in all lines except the lines resistant to topo I poisons. Next, all sensitivity patterns in the nine cell lines were compared by correlation analysis. A high correlation coefficient (CC) for a given pair of compounds indicates a similar pattern in response in the set of cell lines. Such data corroborate the view that there is cross-resistance among the drugs. A numerically low coefficient indicates that the two drugs are acting in different ways, suggesting a lack of cross-resistance between the drugs, and a negative correlation coefficient implies that two drugs exhibit collateral sensitivity. The most negative CCs (%) to the new drug leads were: taxotere-carmustine (BCNU) (-75), taxol-cisplatin (-58), ara-C-taxol (-25), gemcitabin-doxorubicin (-32), camptotecin-VM26 (-41) and topotecan-VP16 (-17). The most negative correlations to the clinically important agent VP-16 were: cisplatin (-70); BCNU (-68); camptothecin (-38); bleomycin (-33), gemcitabin (-32); ara-C (-21); topotecan (-17); melphalan (-3); and to the other main drug in SCLC treatment cisplatin were: doxorubicin (-70); VP-16 (-70); VM-26 (-69); mAMSA (-64); taxotere (-58); taxol (-58). Taxol and taxotere were highly correlated (cross-resistant) to VP-16 (0.76 and 0.81 respectively) and inversely correlated to cisplatin (both -0.58). Similarly, camptothecin and topotecan were correlated to cisplatin but inversely correlated to VP-16 and other topo II poisons. From the sensitivity data, we conclude that collateral sensitivity and lack of cross-resistance favours a cisplatin-taxane or topo I-topo II poison combination, whereas patterns of cross-resistance suggest that epipodophyllotoxin-taxane or topo I poison-cisplatin combinations may be disadvantageous. PMID:9062409

  11. Drugs Approved for Ovarian Cancer

    MedlinePLUS

    ... Questions to Ask Your Doctor about Treatment Research Drugs Approved for Ovarian, Fallopian Tube, or Primary Peritoneal ... Platinol-AQ (Cisplatin) Taxol (Paclitaxel) Thiotepa Topotecan Hydrochloride Drug Combinations Used in Ovarian, Fallopian Tube, or Primary ...

  12. Nanoparticle mediated co-delivery of paclitaxel and a TLR-4 agonist results in tumor regression and enhanced immune response in the tumor microenvironment of a mouse model.

    PubMed

    Roy, Aniruddha; Singh, Manu Smriti; Upadhyay, Pramod; Bhaskar, Sangeeta

    2013-03-10

    Inefficiency of cancer chemotherapy to improve life expectancy in majority of patients raises serious concern and warrants development of novel therapeutic strategies. Immunotherapy in combination with chemotherapy has shown promising outcomes in recent years. Herein, we report better tumor regression and enhancement of antitumor immune response at the tumor microenvironment by co-delivery of paclitaxel and a TLR4 agonist through a PLGA based nanoparticle preparation (TLNP). Particle characterization showed high encapsulation of both components and retention of their biological activities. In vivo tumor regression studies demonstrated clear benefit of TLNP over the paclitaxel. The mean tumor volume of the TLNP treated animals was found to be 40% less than that of the Paclitaxel treated animals. Flow cytometric analysis of tumor infiltrating immune cells indicated activation of antigen presenting cells and T-cells providing evidence of Th1 immune response. In vivo results are promising and could pave way for novel chemo-immunotherapeutic treatment modality. PMID:23376226

  13. Sulfatide-containing lipid perfluorooctylbromide nanoparticles as paclitaxel vehicles targeting breast carcinoma

    PubMed Central

    Li, Xiao; Qin, Fei; Yang, Li; Mo, Liqian; Li, Lei; Hou, Lianbing

    2014-01-01

    Targeted nanoparticle (NP) delivery vehicles are emerging technologies, the full potential of which has yet to be realized. Sulfatide is known to bind to extracellular matrix glycoproteins that are highly expressed in breast tumors. In this study, we report for the first time the combination of sulfatide and lipid perfluorooctylbromide NPs as a targeted breast cancer delivery vehicle for paclitaxel (PTX). PTX-sulfatide-containing lipid perfluorooctylbromide NPs (PTX-SNPs) were prepared using the emulsion/solvent evaporation method. PTX-SNPs exhibited a spherical shape, small particle size, high encapsulation efficiency, and a biphasic release in phosphate-buffered solution. The cytotoxicity study and cell apoptosis assay revealed that blank sulfatide-containing lipid perfluorooctylbromide NPs (SNPs) had no cytotoxicity, whereas PTX-SNPs had greater EMT6 cytotoxicity levels than PTX-lipid perfluorooctylbromide NPs (PTX-NPs) and free PTX. An in vitro cellular uptake study revealed that SNPs can deliver greater amounts of drug with more efficient and immediate access to intracellular targets. In vivo biodistribution measured using high-performance liquid chromatography confirmed that the PTX-SNPs can target breast tumor tissues to increase the accumulation of PTX in these tissues. The in vivo tumor inhibition ability of PTX-SNPs was remarkably higher than PTX-NPs and free PTX. Furthermore, toxicity studies suggested that the blank SNPs had no systemic toxicity. All results suggested that SNPs may serve as efficient PTX delivery vehicles targeting breast carcinoma. PMID:25170267

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

    PubMed

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

    2015-07-15

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

  15. Carcinoma of Unknown Primary Site Treated with Carboplatin + Paclitaxel + Bevacizumab + Erlotinib and Its Maintenance Chemotherapy

    PubMed Central

    Yasui, Hirotoshi; Sato, Kazuhide; Takeyama, Yoshihiro; Kato, Toshio; Hashimoto, Hiroyuki; Fukui, Yasutaka; Yoshihisa, Nagashima; Maeda, Matsuyoshi; Gonda, Hideo; Suzuki, Ryujiro

    2014-01-01

    About 3% of all cancer patients suffer from carcinoma of unknown primary site (CUP). In spite of its rarity, we will encounter them. While CUPs manifest a wide variety of clinical presentations, they have often resulted in poor prognosis. Although platinum/taxane combination chemotherapy, e.g. carboplatin (CBDCA) + paclitaxel (PTX) is widely used for patients suffering from CUP, the response rate is only about 30–40% and the median overall survival (OS) is only 9 months, which means that improvement is needed. Among the new regimens, the combination of CBDCA, PTX, bevacizumab (BEV) and erlotinib is thought to be highly promising. Herein, we report a case with CUP treated with this regimen and his maintenance therapy. Our patient was a 75-year-old man who was admitted with a left neck lump. CT revealed systemic massive lymphadenopathy. In spite of various investigations for primary origin, he was diagnosed with CUP and treated with CBDCA + PTX + BEV + erlotinib (AUC 6 + 175 mg/m2 + 15 mg/kg + 150 mg). Since the evaluation of the efficacy indicated partial response, maintenance chemotherapy (BEV and erlotinib) was performed. Chemotherapy was continued for 9 months until the patient was in a progressive disease state with meningeal dissemination. He died 12 months after the initiation of chemotherapy, which is a longer period than the previously reported OS. Of note, according to our case, CBDCA + PTX + BEV + erlotinib and its maintenance chemotherapy are feasible and well tolerated for CUP. PMID:25298764

  16. Layer-by-layer assembly of chitosan stabilized multilayered liposomes for paclitaxel delivery.

    PubMed

    Chen, Meng-Xia; Li, Bai-Kun; Yin, Deng-Ke; Liang, Jie; Li, Shan-Shan; Peng, Dai-Yin

    2014-10-13

    Paclitaxel (PTX) loaded multilayered liposomes were prepared using layer-by-layer assembly in an effort to improve the stabilization of the liposomal compositions for PTX delivery. Stearyl amine was used to provide positive charge to the PTX-liposomes, and subsequently coated with anionic polyacrylic acid (PAA) followed by cationic chitosan. Various process variables were optimized and the optimum formulation was found to have particle size of 215 ± 17 nm, zeta potential of +27.9 ± 3.4 mV and encapsulation efficiency of 70.93 ± 2.39%. The lyophilized chitosan-PAA-PTX-liposomes formulation was stable in simulated gastrointestinal fluids and at different environmental conditions (4 °C and 25 °C). In vitro drug release experiments demonstrated that chitosan-PAA-PTX-liposomes formulation exhibited obvious sustained release behaviors compared to PTX-liposomes. Furthermore, chitosan-PAA-PTX-liposomes formulation revealed enhanced PTX induced cytotoxicity in human cervical cancer cell culture experiments compared to PTX-liposomes. In conclusion, the approach presented herein will provide a promising solution for PTX delivery. PMID:25037355

  17. Delivery of paclitaxel and berbamine by polymeric carriers to cure gastric cancer.

    PubMed

    Zhu, Lingjun; Zhang, Bin; Lu, Xiaowei; Shu, Yongqian; Liu, Baorui

    2013-01-01

    Successful chemotherapy needs to reduce the toxic side effects against normal tissues and avoid the detriments caused by intolerable solvents. Drug delivery systems using soluble polymeric nanoparticles tend to be the focus. In the current study, core-shell structure nanoparticles were prepared from block copolymer of methoxy poly(ethylene glycol)-polycaprolactone (mPE-PCL). Paclitaxel (PTX) and berbamine (BA) were incorporated into mPEG-PCL nanoparticles. It was found in our study that PTX and BA can be incorporated into the nanoparticles with high encapsulation efficiency. In vitro release study showed that PTX and BA were released from nanoparticles in a sustained manner. In vitro cytotoxicity studies indicated that PTX/BA coloaded nanoparticles (PTX/BA-np) show dose- and time-dependent cytotoxicity again BGC823 cells. Furthermore, intratumoral administration was applied to improve the tumor-targeted delivery in the in vivo evaluation. Compared with free drugs, PTX/BA-np exhibited superior antitumor effect by delaying tumor growth when delivered intratumorally. These results suggest that PTX/BA-np are effective to inhibit the growth of human gastric cancer and merit more research to evaluate the feasibility of clinical application. PMID:23879166

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

    PubMed

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

    2015-01-01

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

  19. Nanohybrid systems of non-ionic surfactant inserting liposomes loading paclitaxel for reversal of multidrug resistance.

    PubMed

    Ji, Xiufeng; Gao, Yu; Chen, Lingli; Zhang, Zhiwen; Deng, Yihui; Li, Yaping

    2012-01-17

    Three new nanohybrid systems of non-ionic surfactant inserting liposomes loading paclitaxel (PTX) (NLPs) were prepared to overcome multidrug resistance (MDR) in PTX-resistance human lung cancer cell line. Three non-ionic surfactants, Solutol HS 15 (HS-15), pluronic F68 (PF-68) and cremophor EL (CrEL) were inserted into liposomes by film hydration method to form NLPs with an average size of around 110, 180 and 110 nm, respectively. There was an obvious increase of rhodamin 123 (Rh123) accumulation in A549/T cells after treated with nanohybrid systems loading Rh123 (NLRs) when compared with free Rh123 or liposomes loading Rh123 without surfactants (LRs), which indicated the significant inhibition effects of NLRs on drug efflux. The P-gp detection and ATP determination demonstrated that BNLs could not only interfere P-gp expression on the membrane of drug resistant cells, but also decrease ATP level in the cells. The cytotoxicity of NLPs against A549/T cells was higher than PTX loaded liposomes without surfactants (LPs), and the best result was achieved after treated with NLPs2. The apoptotic assay and the cell cycle analysis showed that NLPs could induce more apoptotic cells in drug resistant cells when compared with LPs. These results suggested that NLPs could overcome MDR by combination of drug delivery, P-gp inhibition and ATP depletion, and showed potential for treatment of MDR. PMID:22001531

  20. Paclitaxel-liposome-microbubble complexes as ultrasound-triggered therapeutic drug delivery carriers.

    PubMed

    Yan, Fei; Li, Lu; Deng, Zhiting; Jin, Qiaofeng; Chen, Juanjuan; Yang, Wei; Yeh, Chih-Kuang; Wu, Junru; Shandas, Robin; Liu, Xin; Zheng, Hairong

    2013-03-28

    Liposome-microbubble complexes (LMC) have become a promising therapeutic carrier for ultrasound-triggered drug delivery to treat malignant tumors. However, the efficacy for ultrasound-assisted chemotherapy in vivo and the underlying mechanisms remain to be elucidated. Here, we investigated the feasibility of using paclitaxel-liposome-microbubble complexes (PLMC) as possible ultrasound (US)-triggered targeted chemotherapy against breast cancer. PTX-liposomes (PL) were conjugated to the microbubble (MB) surface through biotin-avidin linkage, increasing the drug-loading efficiency of MBs. The significant increased release of payloads from liposome-microbubble complexes was achieved upon US exposure. We used fluorescent quantum dots (QDs) as a model drug to show that released QDs were taken up by 4T1 breast cancer cells treated with QD-liposome-microbubble complexes (QLMC) and US, and uptake depended on the exposure time and intensity of insonication. We found that PLMC plus US inhibited tumor growth more effectively than PL plus US or PLMC without US, not only in vitro, but also in vivo. Histologically, the inhibition of tumor growth appeared to result from increased apoptosis and reduced angiogenesis in tumor xenografts. In addition, a significant increase of drug concentration in tumors was observed in comparison to treatment with non-conjugated PL or PLMC without US. The significant increase in an antitumor efficacy of PLMC plus US suggests their potential use as a new targeted US chemotherapeutic approach to inhibit breast cancer growth. PMID:23306023

  1. A targeting drug delivery system for ovarian carcinoma: transferrin modified lipid coated paclitaxel-loaded nanoparticles.

    PubMed

    Li, R; Zhang, Q; Wang, X-y; Chen, X-g; He, Y-x; Yang, W-y; Yang, X

    2014-10-01

    The transferring modified lipid coated PLGA nanoparticles, as a targetable vector, were developed for the targeting delivery of anticancer drugs with paclitaxel (PTX) as a model drug to the ovarian carcinoma, which combines the advantages and avoids disadvantages of polymeric nanoparticles and liposomes in drug delivery. A transmission electron microscopy (TEM) confirmed the lipid coating on the polymeric core. Physicochemical characterizations of TFLPs, such as particle size, zeta potential, morphology, encapsulation efficiency, and in vitro PTX release, were also evaluated. In the cellular uptake study, the TFLPs were more efficiently endocytosed by the A2780 cells with high expression of transferrin receptors than HUVEC cells without the transferrin receptors. Furthermore, the anticancer efficacy of TFLPs on the tumor spheroids was stronger than that of lipid coated PLGA nanoparticles (LPs) and PLGA nanoparticles. In the in vivo study, the TFLPs showed the best inhibition effect of the tumor growth for the ovarian carcinoma-bearing mice. In brief, the TFLPs were proved to be an efficient targeting drug delivery system for ovarian carcinoma. PMID:24443309

  2. Blood viscosity as a sensitive indicator for paclitaxel induced oxidative stress in human whole blood

    PubMed Central

    Harisa, Gamaleldin I.

    2014-01-01

    In this study, the in vitro effects of paclitaxel (PTX) and Cremophor-EL (CrEL) on blood viscosity and oxidative stress markers were investigated. Whole-blood samples were collected from healthy volunteers and co-incubated with PTX, CrEL or their combination then compared with control blood samples. After a 24 h incubation time, the whole-blood viscosity (WBV), erythrocyte sedimentation rate (ESR), levels of whole-blood malondialdehyde (MDA), protein carbonyl content (PCC) and reduced glutathione (GSH) were determined. Moreover, plasma nitrite and plasma sialic acid (SA) values were measured. The present results revealed that the incubation of blood samples with PTX, CrEL or PTX plus CrEL significantly increased the values of WBV, ESR, MDA and PCC compared to control samples. In contrast, a significant decrease in levels of GSH, SA and nitrite was observed after incubation of blood samples with tested agents compared to control. The effects of tested agents on the measured parameters were more pronounced in the case of blood samples treated with PTX plus CrEL. The present study demonstrates that PTX-induced oxidative stress is associated with an increase of WBV. PMID:25685043

  3. In vitro effect of 5-fluorouracil and paclitaxel on Echinococcus granulosus larvae and cells.

    PubMed

    Pensel, P E; Albani, C; Gamboa, G Ullio; Benoit, J P; Elissondo, M C

    2014-12-01

    Human cystic echinococcosis is a zoonosis caused by the metacestode stage of the tapeworm Echinococcus granulosus. Although benzimidazole compounds such as albendazole and mebendazole have been the cornerstone of chemotherapy for the disease, there is often no complete recovery after treatment. Hence, in searching for novel treatment options, we examined the in vitro efficacies of 5-fluorouracil (5-FU) and paclitaxel (PTX) against E. granulosus germinal cells, protoscoleces and cysts. 5-FU or PTX inhibited the growth of E. granulosus cells in a time dependent manner. Although both treatments had a protoscolicidal effect, 5-FU had a considerably stronger effect than PTX. 5-FU produced a dose- and time-dependent effect, provoking the complete loss of viability after 24 days of incubation. Moreover, cysts did not develop following the inoculation of treated protoscoleces into mice. The loss of viability was slower in PTX treated protoscoleces, reaching to approximately 60% after 30 days. The results of the in vitro treatment with 5-FU and PTX were similar in secondary murine cysts. The employment of SEM and TEM allowed us to examine, at an ultrastructural level, the effects induced by 5-FU and PTX on E. granulosus germinal cells, protoscoleces and murine cysts. In conclusion, the data obtained clearly demonstrated that 5-FU and PTX at clinically achievable concentrations inhibit the survival of larval cells, protoscoleces and metacestodes. In vivo studies to test the antiparasitic activities of 5-FU and PTX are currently being undertaken on the murine model of cystic echinococcosis. PMID:25088684

  4. Solid-Nanoemulsion Preconcentrate for Oral Delivery of Paclitaxel: Formulation Design, Biodistribution, and ? Scintigraphy Imaging

    PubMed Central

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

    2014-01-01

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

  5. Covalent Polyisobutylene-Paclitaxel Conjugates for Controlled Release from Potential Vascular Stent Coatings.

    PubMed

    Trant, John F; McEachran, Matthew J; Sran, Inderpreet; Turowec, Bethany A; de Bruyn, John R; Gillies, Elizabeth R

    2015-07-01

    The development of covalent polyisobutylene (PIB)-paclitaxel (PTX) conjugates as a potential approach to controlling drug release from vascular stent coatings is described. PIB-PTX materials containing ?24 and ?48 wt % PTX, conjugated via ester linkages, were prepared. The PTX release profiles were compared with those of physical mixtures of PTX with carboxylic acid-functionalized PIB and with the triblock copolymer polystyrene-b-PIB-b-polystyrene (SIBS). Covalent conjugation led to significantly slower drug release. Atomic force microscopy imaging of coatings of the materials suggested that the physical mixtures exhibited multiple domains corresponding to phase separation, whereas the materials in which PTX was covalently conjugated appeared homogeneous. Coatings of the conjugated materials on stainless steel surfaces suffered less surface erosion than the physically mixed materials, remained intact, and adhered well to the surface throughout the thirty-five day study. Tensile testing and rheological studies suggested that the incorporation of PTX into the polymer introduces similar physical changes to the PIB as the incorporation of a glassy polystyrene block does in SIBS. Cytotoxicity assays showed that the coatings did not release toxic levels of PTX or other species into a cell culture medium over a 24 h period, yet the levels of PTX in the materials were sufficient to prevent C2C12 cells from adhering to and proliferating on them. Overall, these results indicate that covalent PIB-PTX conjugates have promise as coatings for vascular stents. PMID:26066902

  6. Poly(ethylene glycol)-block-poly(?-caprolactone) micelles for combination drug delivery: evaluation of paclitaxel, cyclopamine and gossypol in intraperitoneal xenograft models of ovarian cancer.

    PubMed

    Cho, Hyunah; Lai, Tsz Chung; Kwon, Glen S

    2013-02-28

    Ovarian cancer is the most lethal gynecological malignancy, characterized by a high rate of chemoresistance. Current treatment strategies for ovarian cancer focus on novel drug combinations of cytotoxic agents and molecular targeted agents or novel drug delivery strategies that often involve intraperitoneal (IP) injection. Poly(ethylene glycol)-block-poly(?-caprolactone) (PEG-b-PCL) micelles were loaded with paclitaxel (cytotoxic agent), cyclopamine (hedgehog inhibitor), and gossypol (Bcl-2 inhibitor). After physicochemical studies focusing on combination drug solubilization, 3-drug PEG-b-PCL micelles were evaluated in vitro in 2-D and 3-D cell culture and in vivo in xenograft models of ovarian cancer, tracking bioluminescence signals from ES-2 and SKOV3 human ovarian cancer cell lines after IP injection. 3-Drug PEG-b-PCL micelles were not significantly more potent in 2-D cell culture in comparison to paclitaxel; however, they disaggregated ES-2 tumor spheroids, whereas single drugs or 2-drug combinations only slowed growth of ES-2 tumor spheroids or had no noticeable effects. In ES-2 and SKOV3 xenograft models, 3-drug PEG-b-PCL micelles had significantly less tumor burden than paclitaxel based on bioluminescence imaging, 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET imaging, and overall survival. (18)F-FLT-PET images clearly showed that 3-drug PEG-b-PCL micelles dramatically reduce tumor volumes over paclitaxel and vehicle controls. In summary, PEG-b-PCL micelles enable the IP combination drug delivery of paclitaxel, cyclopamine and gossypol, resulting in tumor growth inhibition and prolonged survival over paclitaxel alone. These results validate a novel treatment strategy for ovarian cancer based on drug combinations of cytotoxic agents and molecular targeted agents, delivered concurrently by a nanoscale drug delivery system, e.g. PEG-b-PCL micelles. PMID:23246471

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

    SciTech Connect

    Yajun, E, E-mail: eyj7681@yahoo.com.cn [Affiliated Hospital of Hebei University, Department of Interventional Radiology (China); He Nengshu, E-mail: eyajun@hotmail.com; Fan Hailun, E-mail: mydream510@yahoo.com.cn [Tianjin Institute of Radiology, General Hospital of Tianjin Medical University, Department of Radiology (China)

    2013-08-01

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

  8. Cost-effectiveness analyses of docetaxel versus paclitaxel once weekly in patients with metastatic breast cancer in progression following anthracycline chemotherapy, in Spain

    Microsoft Academic Search

    Carmen Frías; Javier Cortés; Miguel Ángel Seguí; Itziar Oyagüez; Miguel Ángel Casado

    2010-01-01

    Objectives  Our aim was to evaluate the cost-effectiveness of docetaxel versus weekly paclitaxel regimen in patients with metastatic breast\\u000a cancer previously treated with anthracycline from the Spanish National Health Service (NHS) perspective.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  A Markov model with a 21-day cycle duration was developed to estimate total treatment-related costs and clinical benefits\\u000a over 5 years of docetaxel (100 mg\\/m2) and weekly paclitaxel (80

  9. Phase I dose finding study evaluating the combination of bendamustine with weekly paclitaxel in patients with pre-treated metastatic breast cancer: RiTa trial

    Microsoft Academic Search

    Sibylle Loibl; Caroline Murmann; Katrin Schwedler; Mathias Warm; Lothar Müller; Georg Heinrich; Valentina Nekljudova; Gunter von Minckwitz

    2009-01-01

    Purpose  The aim of the RiTa trial is to establish a feasible combination of bendamustine and paclitaxel in a weekly schedule in anthracycline\\u000a pre-treated metastatic breast cancer patients.\\u000a \\u000a \\u000a \\u000a Methods  Starting dose of bendamustine was 50 mg\\/m² and was stepwise increased by 10 mg\\/m² up to 70 mg\\/m². The starting dose of paclitaxel\\u000a was 60 mg\\/m² and was increased up to 90 mg\\/m². There are five pre-defined dose

  10. Phase II Study of Paclitaxel plus the Protein Kinase C Inhibitor Bryostatin-1 in Advanced Pancreatic Carcinoma

    PubMed Central

    Lam, Anthony; Sparano, Joseph A.; Vinciguerra, Vincent; Ocean, Allyson J.; Christos, Paul; Hochster, Howard; Camacho, Fernando; Goel, Sanjay; Mani, Sridhar; Kaubisch, Andreas

    2012-01-01

    Purpose To determine the efficacy and toxicity of the protein kinase C inhibitor bryostatin-1 plus paclitaxel in patients with advanced pancreatic carcinoma. Methods Each treatment cycle consisted of paclitaxel 90 mg/m2 by intravenous (IV) infusion over 1 hour on days 1, 8, and 15, plus bryostatin 25 mcg/m2 as a 1 hour IV infusion on days 2, 9, and 16, given every 28 days. Patients were evaluated for response after every 2 treatment cycles, and continued therapy until disease progression or prohibitive toxicity. The primary objective was to determine whether the combination produced a response rate of at least 30%. Results Nineteen patients with locally advanced or metastatic pancreatic adenocarcinoma received a total of 52 cycles of therapy (range 1-10). Patients received the combination as first-line therapy for advanced disease (N=5) or after prior chemotherapy used alone or in combination with local therapy. No patients had a confirmed objective response. The median time to treatment failure was 1.9 months (95% confidence intervals 1.2, 2.6 months). Reasons for discontinuing therapy included progressive disease or death in 14 patients (74%) or because of adverse events or patient choice in 5 patients (26%). The most common grade 3 to 4 toxicities included leukopenia in 26%, anemia in 11%, myalgias in 11%, gastrointestinal bleeding in 11%, infection in 10%, and thrombosis in 10%. Conclusion The combination of weekly paclitaxel and bryostatin-1 is not an effective therapy for patients with advanced pancreatic carcinoma. PMID:19738452

  11. Intensity-Modulated Radiation Therapy with Concurrent Carboplatin and Paclitaxel for Locally Advanced Head and Neck Cancer: Toxicities and Efficacy

    PubMed Central

    Vlacich, Gregory; Diaz, Roberto; Thorpe, Steven W.; Murphy, Barbara A.; Kirby, Wyndee; Sinard, Robert J.; Shakhtour, Bashar; Shyr, Yu; Murphy, Patrick; Netterville, James L.; Yarbrough, Wendell G.

    2012-01-01

    Background. Intensity-modulated radiation therapy (IMRT) and alternative chemotherapy regimens strive to maintain efficacy while minimizing toxicity in locally advanced head and neck cancer (LAHNC) treatment. Our experience with concurrent IMRT and taxane-based chemotherapy is presented. Methods. A retrospective review of 150 consecutive patients with LAHNC treated with IMRT and concurrent taxane-based chemotherapy with curative intent was performed. The IMRT fractionation regimen consisted of 69.3 Gy to gross disease (2.1 Gy/fraction) and 56.1 Gy to prophylactic nodal sites (1.7 Gy/fraction). Weekly paclitaxel (30 mg/m2) and carboplatin (area under the concentration–time curve [AUC], 1) were given concurrently to all patients, and 69% received weekly induction with paclitaxel (60 mg/m2) and carboplatin (AUC, 2). Results. Over 90% of patients received the prescribed radiation dose. Ninety-six percent completed five or more cycles of concurrent chemotherapy, with similar tolerability for induction chemotherapy. A percutaneous endoscopic gastrostomy (PEG) tube was required in 80 patients, with 10 maintaining PEG use >18 months. Acute grade 4 mucositis and dermatitis developed in 2.0% and 4.0% of patients, respectively. No patient experienced nadir sepsis, grade ?3 late xerostomia, or significant nephropathy or gastrointestinal toxicity. Median follow-up was 30 months. The 3-year locoregional control rate was 83.2% with disease-free survival and overall survival rates of 78.8% and 76.5%, respectively. Conclusion. Rates of acute and late toxicities were low, with excellent radiation dose delivery and impressive tumor control at 3 years, suggesting that concurrent carboplatin and paclitaxel with IMRT is a reasonable therapeutic option for the curative treatment of LAHNC. PMID:22550060

  12. Anti-HIF-1alpha antibody-conjugated pluronic triblock copolymers encapsulated with Paclitaxel for tumor targeting therapy.

    PubMed

    Song, Hua; He, Rong; Wang, Kan; Ruan, Jing; Bao, Chenchen; Li, Na; Ji, Jiajia; Cui, Daxiang

    2010-03-01

    Targeted uptake of nanoscale controlled release polymer micelles encapsulated with drugs represents a potential powerful therapeutic technology. Herein we reported the development of anti-HIF-1alpha antibody-conjugated unimolecular polymer nano micelles filled with Paclitaxel for cancer targeting therapy. Pluronic triblock copolymers(Poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), PEO-block-PPO-block-PEO) P123 were functionalized with terminal carboxylic groups, and were characterized by infrared (IR) spectroscopy, nuclear magnetic resonance (NMR), thermogravimetric analysis (TGA), and differential scanning calorimetric (DSC). The amphiphilic copolymer nano micelles encapsulated with Paclitaxel were fabricated by self-assembly means, and then were conjugated with anti-HIF-1alpha antibody, the resultant anti-HIF-1alpha conjugated nano micelles filled with PTX (anti-HIF-1alpha-NMs-PTX nanocomposites) were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM), and incubated with stomach cancer MGC-803 cells and HDF fibroblast cells, these treated cells were analyzed by MTT and cell-ELISA. The nanocomposites composed of anti-HIF-1alpha conjugated nano micelles filled with CdTe quantum dots were also prepared, and incubated with stomach cancer MGC-803 cells and HDF fibroblast cells for 24 h, then were observed by fluorescent microscope. Results showed that the anti-HIF-1alpha-NMs-PTX nanocomposites were successfully prepared, bound with stomach cancer MGC-803 cells specifically, were internalized, and released PTX inside cancer cells, and selectively killed cancer cells. In conclusion, unique anti-HIF-1alpha antibody-conjugated nano micelles filled with Paclitaxel can target and selectively kill cancer cells with over-expression of HIF-1alpha, and has great potential in clinical tumor targeting imaging and therapy. PMID:20004970

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

    SciTech Connect

    Citrin, Deborah [Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (United States)], E-mail: citrind@mail.nih.gov; Mansueti, John; Likhacheva, Anna; Sciuto, Linda [Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (United States); Albert, Paul S. [Biometric Research Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD (United States); Rudy, Susan F. [Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD (United States); Cooley-Zgela, Theresa [Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (United States); Cotrim, Ana [National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States); Solomon, Beth [Speech Language Pathology Section, Rehabilitation Medicine Department, National Institutes of Health, Bethesda, MD (United States); Colevas, A. Dimitrios [Head and Neck Oncology Program, Stanford Cancer Center, Stanford University, Stanford, CA (United States); Russo, Angelo [Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (United States); Morris, John C. [Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (United States); Herscher, Laurie [Department of Radiation Oncology, Suburban Hospital, Bethesda, MD (United States); Smith, Sharon [Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (United States)] (and others)

    2009-07-15

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

  14. Honokiol enhances paclitaxel efficacy in multi-drug resistant human cancer model through the induction of apoptosis.

    PubMed

    Wang, Xu; Beitler, Jonathan J; Wang, Hong; Lee, Michael J; Huang, Wen; Koenig, Lydia; Nannapaneni, Sreenivas; Amin, A R M Ruhul; Bonner, Michael; Shin, Hyung Ju C; Chen, Zhuo Georgia; Arbiser, Jack L; Shin, Dong M

    2014-01-01

    Resistance to chemotherapy remains a major obstacle in cancer therapy. This study aimed to evaluate the molecular mechanism and efficacy of honokiol in inducing apoptosis and enhancing paclitaxel chemotherapy in pre-clinical multi-drug resistant (MDR) cancer models, including lineage-derived human MDR (KB-8-5, KB-C1, KB-V1) and their parental drug sensitive KB-3-1 cancer cell lines. In vitro analyses demonstrated that honokiol effectively inhibited proliferation in KB-3-1 cells and the MDR derivatives (IC50 ranging 3.35 ± 0.13 µg/ml to 2.77 ± 0.22 µg/ml), despite their significant differences in response to paclitaxel (IC50 ranging 1.66 ± 0.09 ng/ml to 6560.9 ± 439.52 ng/ml). Honokiol induced mitochondria-dependent and death receptor-mediated apoptosis in MDR KB cells, which was associated with inhibition of EGFR-STAT3 signaling and downregulation of STAT3 target genes. Combined treatment with honokiol and paclitaxel synergistically augmented cytotoxicity in MDR KB cells, compared with treatment with either agent alone in vitro. Importantly, the combined treatment significantly inhibited in vivo growth of KB-8-5 tumors in a subcutaneous model. Tumor tissues from the combination group displayed a significant inhibition of Ki-67 expression and an increase in TUNEL-positive cells compared with the control group. These results suggest that targeting multidrug resistance using honokiol in combination with chemotherapy drugs may provide novel therapeutic opportunities. PMID:24586249

  15. Ultrasound-mediated destruction of paclitaxel and oxygen loaded lipid microbubbles for combination therapy in ovarian cancer xenografts.

    PubMed

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

    2015-05-28

    We have synthesized multifunctional oxygen and paclitaxel loaded microbubbles (OPLMBs) for ultrasound mediated delivery of combination therapy in an ovarian cancer xenograft model. In comparison with other therapeutic options, intravenous injection of OPLMBs followed by ultrasound mediation yielded a superior therapeutic outcome. Immunohistochemical analyses of the dissected tumor tissue confirmed the increased tumor apoptosis and the reduced VEGF expression after treatment. Western Blot tests further confirmed the decreased expressions of HIF-1? and P-gp. Our experiment suggests that ultrasound mediation of OPLMBs may provide a promising drug delivery strategy for the combination treatment of ovarian cancer. PMID:25754815

  16. Race Does Not Impact Outcome for Advanced Ovarian Cancer Patients Treated With Cisplatin/Paclitaxel

    PubMed Central

    Farley, John H.; Tian, Chunqiao; Rose, G. Scott; Brown, Carol L.; Birrer, Michael; Maxwell, G. Larry

    2015-01-01

    BACKGROUND The objectives of this study were to confirm whether racial disparity exists with regard to outcome between black women and white women with ovarian cancer and to identify factors associated with the administration of adjuvant treatment that had an impact on survival. METHODS A retrospective review of 97 black women and 1392 white women with International Federation of Gynecology and Obstetrics stage III/IV ovarian carcinoma was performed. All patients received paclitaxel combined with cisplatin while participating in 1 of 7 Gynecologic Oncology Group clinical trials. The treatment parameters that were reviewed included relative dose, relative time, and relative dose intensity. The treatment parameters and outcomes were compared between black patients and white patients. RESULTS There were no differences in relative dose (0.90 vs 0.89), relative time (1.02 vs 0.99), or relative dose intensity (0.90 vs 0.91) received between black patients and white patients. Black women had less grade 3 and 4 leukopenia (53% vs 63%; P < .05) and gastrointestinal toxicity (10% vs 19%; P < .05) than white women. Performance status >0, age ?70 years, and mucinous histology were associated with not completing treatment (P < .001). The median progression-free survival was 16.2 months for black patients and 16.1 months for white patients, and the median overall survival was 37.9 months and 39.7 months, respectively (P > .05 for all). CONCLUSIONS When they received similar treatment, there was no difference in clinical outcome between black women and white women with advanced stage epithelial ovarian cancer when they received similar treatment as participants in Gynecologic Oncology Group clinical trials. Black patients may experience less severe gastrointestinal toxicity or leukopenia compared with whites when treated with platinum-based chemotherapy. PMID:19536873

  17. Paclitaxel delivery from cobalt-chromium alloy surfaces using self-assembled monolayers.

    PubMed

    Mani, Gopinath; Torres, Nelson; Oh, Sunho

    2011-06-01

    Polymer-based platforms in drug-eluting stents (DESs) can cause adverse reactions in patients. Hence, the development of a polymer-free drug delivery platform may reduce adverse reactions to DES. In this study, the use of a polymer-free platform, self-assembled monolayers (SAMs), is explored for delivering an antiproliferative drug [paclitaxel (PAT)] from a stent material [cobalt-chromium ((Co-Cr) alloy]. Initially, carboxylic acid terminated phosphonic acid SAMs were coated on Co-Cr alloy. Two different doses (25 and 100 ?g/cm²) of PAT were coated on SAM coated Co-Cr surfaces using a microdrop deposition method. Also, control experiments were carried out to coat PAT directly on Co-Cr surfaces with no SAM modification. The PAT coated specimens were characterized using the Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and atomic force microscopy (AFM). FTIR spectra showed the successful deposition of PAT on SAM coated and control-Co-Cr surfaces. SEM images showed islands of high density PAT crystals on SAM coated surfaces, while low density PAT crystals were observed on control-Co-Cr alloy. AFM images showed molecular distribution of PAT on SAM coated as well as control-Co-Cr alloy surfaces. In vitro drug release studies showed that PAT was released from SAM coated Co-Cr surfaces in a biphasic manner (an initial burst release in first 7 days was followed by a slow release for up to 35 days), while the PAT was burst released from control-Co-Cr surfaces within 1-3 days. Thus, this study demonstrated the use of SAMs for delivering PAT from Co-Cr alloy surfaces for potential use in drug-eluting stents. PMID:21721838

  18. Dual Targeting Biomimetic Liposomes for Paclitaxel/DNA Combination Cancer Treatment

    PubMed Central

    Liu, Guo-Xia; Fang, Gui-Qing; Xu, Wei

    2014-01-01

    Combinations of chemotherapeutic drugs with nucleic acid has shown great promise in cancer therapy. In the present study, paclitaxel (PTX) and DNA were co-loaded in the hyaluronic acid (HA) and folate (FA)-modified liposomes (HA/FA/PPD), to obtain the dual targeting biomimetic nanovector. The prepared HA/FA/PPD exhibited nanosized structure and narrow size distributions (247.4 ± 4.2 nm) with appropriate negative charge of ?25.40 ± 2.7 mV. HA/FA/PD (PTX free HA/FA/PPD) showed almost no toxicity on murine malignant melanoma cell line (B16) and human hepatocellular carcinoma cell line (HepG2) (higher than 80% cell viability), demonstrating the safety of the blank nanovector. In comparison with the FA-modified PTX/DNA co-loaded liposomes (FA/PPD), HA/FA/PPD showed significant superiority in protecting the nanoparticles from aggregation in the presence of plasma and degradation by DNase I. Moreover, HA/FA/PPD could also significantly improve the transfection efficiency and cellular internalization rates on B16 cells comparing to that of FA/PPD (p < 0.05) and PPD (p < 0.01), demonstrating the great advantages of dual targeting properties. Furthermore, fluorescence microscope and flow cytometry results showed that PTX and DNA could be effectively co-delivered into the same tumor cell via HA/FA/PPD, contributing to PTX/DNA combination cancer treatment. In conclusion, the obtained HA/FA/PPD in the study could effectively target tumor cells, enhance transfection efficiency and subsequently achieve the co-delivery of PTX and DNA, displaying great potential for optimal combination therapy. PMID:25177862

  19. Dissecting paclitaxel-microtubule association: quantitative assessment of the 2'-OH group.

    PubMed

    Sharma, Shubhada; Lagisetti, Chandraiah; Poliks, Barbara; Coates, Robert M; Kingston, David G I; Bane, Susan

    2013-04-01

    Paclitaxel (PTX) is a microtubule-stabilizing agent that is widely used in cancer chemotherapy. This structurally complex natural product acts by binding to ?-tubulin in assembled microtubules. The 2'-hydroxyl group in the flexible side chain of PTX is an absolute requirement for activity, but its precise role in the drug-receptor interaction has not been specifically investigated. The contribution of the 2'-OH group to the affinity and tubulin-assembly efficacy of PTX has been evaluated through quantitative analysis of PTX derivatives possessing side chain deletions: 2'-deoxy-PTX, N-debenzoyl-2'-deoxy-PTX, and baccatin III. The affinity of 2'-deoxy-PTX for stabilized microtubules was more than 100-fold lower than that of PTX and only ~3-fold greater than the microtubule affinity of baccatin III. No microtubule binding activity was detected for the analogue N-debenzoyl-2'-deoxy-PTX. The tubulin-assembly efficacy of each ligand was consistent with the microtubule binding affinity, as was the trend in cytotoxicities. Molecular dynamics simulations revealed that the 2'-OH group of PTX can form a persistent hydrogen bond with D26 within the microtubule binding site. The absence of this interaction between 2'-deoxy-PTX and the receptor can account for the difference in binding free energy. Computational analyses also provide a possible explanation for why N-debenzoyl-2'-deoxy-PTX is inactive, in spite of the fact that it is essentially a substituted baccatin III. We propose that the hydrogen bonding interaction between the 2'-OH group and D26 is the most important stabilizing interaction that PTX forms with tubulin in the region of the C-13 side chain. We further hypothesize that the substituents at the 3'-position function to orient the 2'-OH group for a productive hydrogen bonding interaction with the protein. PMID:23473345

  20. Synergistic co-delivery of doxorubicin and paclitaxel using multi-functional micelles for cancer treatment.

    PubMed

    Duong, Hoang Hanh Phuoc; Yung, Lin-Yue Lanry

    2013-09-15

    The main purposes of this study are to demonstrate the synergistic anticancer drug systems with the combined doxorubicin (D) and paclitaxel (P) via the aid of cell penetrating and cell targeting moieties for enhancing the cancer therapeutic effect. Firstly, the synergistic effect of combined free drugs (D/P) was investigated to obtain the suitable dose combination for subsequent studies. The combination of free drugs D/P at molar ratio of 1/0.2 shows synergistic therapeutic effect compared with the treatment of a free single drug D or P. Secondly, sustainable release systems of two single drug-loaded micelles, (i) co-delivered D-FOL micelle & P-FOL micelle system and (ii) co-delivered D-TAT/FOL micelle & P-TAT/FOL micelle system, at D/P molar ratio of 1/0.2 were investigated. The results show synergistic effect with the higher efficacy of the TAT/FOL system compared to FOL only system. Finally, a dual D/P-loaded system with sustainable release rate, synergistic drug interaction, selective targeting to cancer cells and high cell penetrating ability was designed. The D/P-TAT/FOL micelles exhibit an IC50 value of 0.172 ?M D/0.043 ?M P, which is much lower than the IC50 values of the single drug-loaded micelles without functionalization (3.873 ?M for D-micelles and 0.790 ?M for P-micelles). Overall, this newly developed dual encapsulation of D and P in the multifunctional carrier would be a promising technology for cancer treatment. PMID:23792465

  1. Intratumoral delivery of paclitaxel using a thermosensitive hydrogel in human tumor xenografts.

    PubMed

    Kim, Jung Ho; Lee, Joo-Ho; Kim, Kwang-Suck; Na, Kun; Song, Soo-Chang; Lee, Jaehwi; Kuh, Hyo-Jeong

    2013-01-01

    Poly(organophosphazene), a novel thermosensitive hydrogel, is an injectable drug delivery system (DDS) that transforms from sol to gel at body temperature. Paclitaxel (PTX) is a mitotic inhibitor used in the treatment of various solid tumors. Due to its poor solubility in water and efflux systems in the gastrointestinal tract, PTX is a good candidate for local DDS. Here, we evaluated the penetration kinetics of PTX released from the PTX-poly(organophosphazene) hydrogel mixture in multicellular layers (MCLs) of human cancer cells. We also investigated the tumor pharmacokinetics of PTX (60 mg/kg) when administered as an intratumoral injection using poly(organophosphazene) in mice with human tumor xenografts. When PTX was formulated at 0.6 % w/w into a 10 % w/w hydrogel, the in vitro and in vivo release were found to be 40 and 90 % of the dose, respectively, in a sustained manner over 4 weeks. Exposure of MCLs to PTX-hydrogel showed time-dependent drug penetration and accumulation. In mice, the hydrogel mass was well retained over 6 weeks, and the PTX concentration in the tumor tissue was maximal at 14 days, which rapidly decreased and coincided with rebound tumor growth after 14 days of suppression. These data indicate that PTX-hydrogel should be intratumorally injected every 14 days, or drug release duration should be prolonged in order to achieve a long-term antitumor effect. Overall, poly(organophosphazene) represents a novel thermosensitive DDS for intratumoral delivery of PTX, which can accommodate a large dose of the drug in addition to reducing its systemic exposure by restricting biodistribution to tumor tissue alone. PMID:23371803

  2. Expression of sorafenib targets in melanoma patients treated with carboplatin, paclitaxel and sorafenib

    PubMed Central

    Jilaveanu, Lucia; Zito, Christopher; Lee, Sandra J.; Nathanson, Katherine L.; Camp, Robert L.; Rimm, David L.; Flaherty, Keith T.; Kluger, Harriet M.

    2013-01-01

    Background Sorafenib, a multi-target kinase inhibitor, inhibits members of the MAPK pathway and receptor tyrosine kinases, including VEGF-R2. Sorafenib, carboplatin and paclitaxel (SCP) has anti-tumor activity in melanoma patients, but no association was found between response and activating B-RafV600E mutations. We assessed expression of sorafenib targets in SCP-treated patient specimens and evaluated the association with response and progression free survival. Experimental Design Using Automated QUantitative Analysis (AQUA®), we quantified expression of VEGF-R1, VEGF-R2, VEGF-R3, FGF-R1, PDGF-R?, c-Kit, B-Raf, C-Raf, MEK1 and ERK1/2 in pre-treatment specimens from 46 patients. Furthermore, we assessed ERK1/2 expression in 429 archival melanomas. Results VEGF-R2 expression was significantly higher in patients with a complete or partial response (P=0.0435), whereas ERK1/2 was higher in patients who did not respond (P=0.0417). High ERK1/2 was an independent predictor of poor survival. High ERK1/2 was associated with decreased survival in the archival melanoma cohort, suggesting that high ERK1/2 expressing tumors are biologically more aggressive. All of the six patients with both high VEGF-R2 and low ERK1/2 responded to SCP. Conclusions High VEGF-R2 expression is associated with response to SCP in melanoma, whereas high ERK1/2 is associated with resistance. Collection of specimens from SCP-treated melanoma patients in a cooperative group phase III trial comparing this regimen to the chemotherapy alone is ongoing, and confirmation of these findings is necessary. These markers might be useful for predicting response to sorafenib when given with other chemotherapies and in other diseases, resulting in possible elimination of unnecessary treatment of patients unlikely to respond. PMID:19188183

  3. Efficacy of dual-functional liposomes containing paclitaxel for treatment of lung cancer.

    PubMed

    Wang, Rong-Hua; Cao, Hong-Mei; Tian, Zhi-Ju; Jin, Bo; Wang, Qing; Ma, Hong; Wu, Jing

    2015-02-01

    This study was mainly focused on the development of a dual-ligand liposomal delivery system for targeting the delivery of paclitaxel (PTX) to lung cancer. The specific ligand peptide HAIYPRH (T7) and the cationic cell-penetrating peptide TAT were connected with phospholipid via a polyethylene glycol (PEG) spacer to prepare the dual-ligand liposomes (T7/TAT-LP-PTX). Physicochemical characterizations of T7/TAT-LP-PTX, such as particle size, ? potential, morphology, encapsulation efficiency, and in vitro PTX release, were also evaluated. In the cellular uptake study, the T7/TAT-LP endocytosed by the A549 cells was 2.26-, 3.48- and 8.56-fold higher than TAT-LP, T7-LP and LP, respectively. The IC50 values of TAT-LP-PTX, T7-LP-PTX and LP-PTX were much higher than those of T7/TAT-LP-PTX, respectively. The homing specificity of T7/TAT-LP was evaluated on the tumor spheroids, which revealed that T7/TAT-LP was more efficaciously internalized in tumor cells than TAT-LP, T7-LP and LP, respectively. Compared to LP, TAT-LP and T7-LP, T7/TAT-LP showed the strongest cell uptake property, and the highest accumulation ability in tumor spheroids in vitro. In the in vivo study, the T7/TAT-LP-PTX exhibited the best inhibitory effect of tumor growth for A549-bearing mice. Collectively, these results suggested that T7/TAT-LP-PTX is a promising drug delivery system for the treatment of lung cancer. PMID:25482610

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

    PubMed Central

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

    2011-01-01

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

  5. Effect of integrin receptor-targeted liposomal paclitaxel for hepatocellular carcinoma targeting and therapy

    PubMed Central

    CHEN, LIYU; LIU, YANBIN; WANG, WEIYA; LIU, KAI

    2015-01-01

    The major aim of the present study was to develop an integrin receptor-targeted liposomal paclitaxel (PTX) to enhance the targeting specificity and therapeutic effect of PTX on hepatocellular carcinoma (HCC) cells. The specific Arg-Gly-Asp (RGD) ligand was conjugated to 1,2-distearoylphosphatidylethanolamine-polyethylene glycol 2000 to prepare the RGD-modified liposomes (RGD-LP). Furthermore, physicochemical characteristics of RGD-LP, including particle size, ? potential, encapsulation efficiency and in vitro PTX release, were evaluated. RGD-modified liposomes were selected as the carrier for the present study, as they exhibit good biocompatibility and are easy to modify using RGD. The cellular uptake efficacy of RGD-LP by HepG2 cells was 3.3-fold higher than that of liposomes without RGD, indicating that RGD-LP may specifically target HepG2 cells by overexpressing integrin ?v?3 receptors. The RGD modification appeared to enhance the anti-proliferative activity of LP-PTX against HepG2 cells, with the extent of anti-proliferative activity dependent on the concentration of PTX and the incubation time. Additionally, evaluation of the homing specificity and anticancer efficacy of RGD-LP on the tumor spheroids indicated that solid tumor penetration was enhanced by the modification of RGD. In agreement with these in vitro findings, in vivo investigations demonstrated that RGD-LP-PTX exhibited a greater inhibitory effect on tumor growth in HepG2-bearing mice than LP-PTX or free PTX. Thus, RGD-LPs may represent an efficient targeted PTX delivery system for the treatment of patients with HCC. PMID:26170980

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

    PubMed Central

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

    2015-01-01

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

  7. Development and evaluation of a novel TPGS-mediated paclitaxel-loaded PLGA-mPEG nanoparticle for the treatment of ovarian cancer.

    PubMed

    Lv, Wen; Cheng, Lihua; Li, Baohua

    2015-01-01

    One of the major obstacles to successful paclitaxel (PTX) chemotherapy is toxic side effects, which are often due to the conventional surfactants used, such as Cremophor EL. PTX is characterized by its hydrophobicity and insolubility, which limit its application in ovarian cancer therapy. The aim of this study was to develop Cremophor EL-free PTX-loaded methoxy poly(ethylene glycol)-block-(lactic-co-glycolic acid) copolymers (PLGA-mPEG) nanoparticles (NPs) using d-?-tocopheryl polyethylene glycol 1000 succinate (TPGS) as a novel emulsifier. The ability of nanoparticles loaded with paclitaxel (NP-PTX) to inhibit tumor growth was assessed in vitro and in vivo. The acute toxicity of NP-PTX was also evaluated in vivo. We found that paclitaxel was efficiently encapsulated into PLGA-mPEG NPs with a low concentration of TPGS as the emulsifier. The synthesized NP-PTX demonstrated the desired diameter of 80 nm as characterized by transmission electron microscopy. The NP-PTX also exhibited a sustained release of loaded PTX over 4 d with the same chemotherapeutic efficiency and reduced side effects. NP-PTX-treated cells showed slightly lower cytotoxic responses compared with those treated with free PTX at the same concentration. In vivo studies confirmed that NP-PTX significantly enhanced the median lethal dose of paclitaxel by 10-fold, and a similar effect on the inhibition of tumor growth was achieved in nude mice. PMID:25451039

  8. Evaluation of the anti-tumor and anti-angiogenic effect of paclitaxel and thalidomide on the xenotransplanted oral squamous cell carcinoma

    Microsoft Academic Search

    Hoon Myoung; Seong-Doo Hong; Young-Youn Kim; Sam-Pyo Hong; Myung-Jin Kim

    2001-01-01

    Angiogenesis is an essential process for the growth and invasion of cancer. However, it is uncertain that anti-angiogenic effects can be a major treatment strategy of oral cancer. The aim of this study was to investigate whether thalidomide and paclitaxel, which are known to be potent inhibitors of angiogenesis, have inhibitory effects on the growth of oral squamous cell carcinoma

  9. miR-23a Targets Interferon Regulatory Factor 1 and Modulates Cellular Proliferation and Paclitaxel-Induced Apoptosis in Gastric Adenocarcinoma Cells

    PubMed Central

    Zhu, Li-hua; Liu, Min; Li, Xin; Tang, Hua

    2013-01-01

    MicroRNAs are a class of non-coding RNAs that function as key regulators of gene expression at the post-transcriptional level. In our previous research, we found that miR-23a was significantly up-regulated in human gastric adenocarcinoma cells. In the current study, we demonstrate that miR-23a suppresses paclitaxel-induced apoptosis and promotes the cell proliferation and colony formation ability of gastric adenocarcinoma cells. We have identified tumor suppressor interferon regulator factor 1 (IRF1) as a direct target gene of miR-23a. We performed a fluorescent reporter assay to confirm that miR-23a bound to the IRF1 mRNA 3?UTR directly and specifically. The ectopic expression of IRF1 markedly promoted paclitaxel-induced apoptosis and inhibited cell viability and colony formation ability, whereas the knockdown of IRF1 had the opposite effects. The restoration of IRF1 expression counteracted the effects of miR-23a on the paclitaxel-induced apoptosis and cell proliferation of gastric adenocarcinoma cells. Quantitative real-time PCR showed that miR-23a is frequently up-regulated in gastric adenocarcinoma tissues, whereas IRF1 is down-regulated in cancer tissues. Altogether, these results indicate that miR-23a suppresses paclitaxel-induced apoptosis and promotes cell viability and the colony formation ability of gastric adenocarcinoma cells by targeting IRF1 at the post-transcriptional level. PMID:23785404

  10. Phase III Study of Cisplatin With or Without Paclitaxel in Stage IVB, Recurrent, or Persistent Squamous Cell Carcinoma of the Cervix: A Gynecologic Oncology Group Study

    Microsoft Academic Search

    David H. Moore; John A. Blessing; Richard P. McQuellon; Howard T. Thaler; David Cella; Jo Benda; David S. Miller; George Olt; Stephanie King; John F. Boggess; Thomas F. Rocereto

    2004-01-01

    Purpose To determine whether cisplatin plus paclitaxel (CP) improved response rate, progression-free survival (PFS), or survival compared with cisplatin alone in patients with stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix. Patients and Methods Eligible patients with measurable disease, performance status (PS) 0 to 2, and adequate hematologic, hepatic, and renal function received either cisplatin 50 mg\\/m

  11. Feasibility studies of dermal delivery of paclitaxel with binary combinations of ethanol and isopropyl myristate: role of solubility, partitioning and lipid bilayer perturbation

    Microsoft Academic Search

    Ramesh Panchagnula; Hariraghuram Desu; Amit Jain; Sateesh Khandavilli

    2005-01-01

    In the current investigation, paclitaxel (PCL) delivery into the different layers of skin, vehicle optimization and relationship between vehicle composition and the relative contribution of solubility, partition and diffusion towards drug transport has been outlined. Saturation solubility of PCL was determined in ethanol (EtOH), isopropyl myristate (IPM) and their binary combinations, and partition studies performed to study the probability of

  12. Polylactide-based paclitaxel-loaded nanoparticles fabricated by dispersion polymerization: characterization, evaluation in cancer cell lines, and preliminary biodistribution studies.

    PubMed

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

    2014-08-01

    The macromonomer method was used to prepare cross-linked, paclitaxel-loaded polylactide (PLA)-polyethylene glycol (stealth) nanoparticles using free-radical dispersion polymerization. The method can facilitate the attachment of other molecules to the nanoparticle surface to make it multifunctional. Proton nuclear magnetic resonance and Fourier transform infrared spectra confirm the synthesis of PLA macromonomer and cross-linking agent. The formation of stealth nanoparticles was confirmed by scanning and transmission electron microscopy. The drug release isotherm of paclitaxel-loaded nanoparticles shows that the encapsulated drug is released over 7 days. In vitro cytotoxicity assay in selected breast and ovarian cancer cell lines reveal that the blank nanoparticle is biocompatible compared with medium-only treated controls. In addition, the paclitaxel-loaded nanoparticles exhibit similar cytotoxicity compared with paclitaxel in solution. Confocal microscopy reveals that the nanoparticles are internalized by MCF-7 breast cancer cells within 1 h. Preliminary biodistribution studies also show nanoparticle accumulation in tumor xenograft model. The nanoparticles are suitable for the controlled delivery of bioactive agents. PMID:24961596

  13. Drug interactions and cytotoxic effects of paclitaxel in combination with carboplatin, epirubicin, gemcitabine or vinorelbine in breast cancer cell lines and tumor samples

    Microsoft Academic Search

    Gottfried Konecny; Michael Untch; Dennis Slamon; Malgorzata Beryt; Steffen Kahlert; Margret Felber; Elena Langer; Sandra Lude; Hermann Hepp; Mark Pegram

    2001-01-01

    The purpose of this study was to analyze the drug interactions of paclitaxel (PTX) with epirubicin (EPI), carboplatin (CBDCA), gemcitabine (GEM) and vinorelbine (VIN) in human breast cancer cells and compare the cytotoxic activity of each drug combination in primary breast cancer samples. These experiments were intended to identify the most active agents in combination with PTX, and to provide

  14. The Effect of Seal Oil on Paclitaxel Induced Cytotoxicity and Apoptosis in Breast Carcinoma MCF7 and MDA-MB-231 Cell Lines

    Microsoft Academic Search

    Zheyu Wang; Krista Butt; Lili Wang; Hu Liu

    2007-01-01

    Some studies have suggested that ?-3 polyunsaturated fatty acids (PUFAs) have an inhibitory effect on the growth of cancer cells and therefore have the potential to increase the efficacy of cancer chemotherapeutic drugs. Considering that ?-3 PUFAs are present abundantly in harp seal oil, we investigated the effect of seal oil on the cytotoxicity and apoptosis induced by paclitaxel in

  15. Molecular mechanism of the schedule-dependent synergistic interaction in EGFR-mutant non-small cell lung cancer cell lines treated with paclitaxel and gefitinib

    Microsoft Academic Search

    Hua Cheng; She-Juan An; Song Dong; Yi-Fang Zhang; Xu-Chao Zhang; Zhi-Hong Chen; Jian-Su; Yi-Long Wu

    2011-01-01

    BACKGROUND: Chemotherapy combined concurrently with TKIs produced a negative interaction and failed to improve survival when compared with chemotherapy or TKIs alone in the treatment of non-small cell lung cancer (NSCLC). The present study investigated the sequence-dependent interaction between paclitaxel and gefitinib and clarified the underlying mechanism. METHODS: The effects on cell proliferation, EGFR signaling pathway, and TGF? expression were

  16. Everolimus in combination with paclitaxel and carboplatin in patients with metastatic melanoma: a phase II trial of the Sarah Cannon Research Institute Oncology Research Consortium.

    PubMed

    Hauke, Ralph J; Infante, Jeffrey R; Rubin, Mark S; Shih, Kent C; Arrowsmith, Edward R; Hainsworth, John D

    2013-12-01

    This phase II trial examined the efficacy and toxicity of first-line treatment with everolimus, paclitaxel, and carboplatin in patients with advanced melanoma. Seventy patients with metastatic or locally advanced unresectable melanoma who had been untreated previously with chemotherapy or targeted agents received first-line treatment with everolimus (5 mg, orally, daily), paclitaxel (175 mg/m, intravenous, every 3 weeks), and carboplatin (area under the curve 6.0, intravenous, every 3 weeks). Response to treatment was assessed every 6 weeks; responding and stable patients received six cycles of paclitaxel and carboplatin, and subsequently continued single-agent everolimus until disease progression or unacceptable toxicity. Twelve patients (17%) showed objective responses (all partial); an additional 27 patients showed measurable tumor shrinkage. After a median follow-up of 15 months, the median progression-free survival was 4.0 months (95% confidence interval 2.8-5.0 months); the median survival for the entire group was 10.1 months. Myelosuppression was the most common grade 3/4 toxicity; 70% of patients experienced at least one episode of grade 3/4 toxicity while on study. Although this regimen was active in the first-line treatment of advanced melanoma, there was no suggestion of improved efficacy when compared with previous results with paclitaxel/carboplatin alone. Further study of this combination is not recommended. PMID:23969699

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

    PubMed

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

    2012-01-01

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

  18. Transplant-mediated enhancement of spinal cord GABAergic inhibition reverses paclitaxel-induced mechanical and heat hypersensitivity.

    PubMed

    Bráz, João M; Wang, Xidao; Guan, Zhonghui; Rubenstein, John L; Basbaum, Allan I

    2015-06-01

    Decreased spinal cord GABAergic inhibition is a major contributor to the persistent neuropathic pain that can follow peripheral nerve injury. Recently, we reported that restoring spinal cord GABAergic signaling by intraspinal transplantation of cortical precursors of GABAergic interneurons from the embryonic medial ganglionic eminence (MGE) can reverse the mechanical hypersensitivity (allodynia) that characterizes a neuropathic pain model in the mouse. We show that MGE cell transplants are also effective against both the mechanical allodynia and the heat hyperalgesia produced in a paclitaxel-induced chemotherapy model of neuropathic pain. To test the necessity of GABA release by the transplants, we also studied the utility of transplanting MGE cells from mice with a deletion of VGAT, the vesicular GABA transporter. Transplants from these mice, in which GABA is synthesized but cannot be stored or released, had no effect on mechanical hypersensitivity or heat hyperalgesia in the paclitaxel model. Taken together, these results demonstrate the therapeutic potential of GABAergic precursor cell transplantation in diverse neuropathic pain models and support our contention that restoration of inhibitory controls through release of GABA from the transplants is their mode of action. PMID:25760475

  19. Incorporation of paclitaxel solid dispersions with poloxamer188 or polyethylene glycol to tune drug release from poly(?-caprolactone) films.

    PubMed

    Shen, Yanqing; Lu, Fei; Hou, Jingwen; Shen, Yuanyuan; Guo, Shengrong

    2013-08-01

    Here we report the application of solid dispersion (SD) technique to improve paclitaxel (PTX) release from poly(?-caprolactone) (PCL)-based film. Paclitaxel solid dispersions (SDs) with either poloxamer188 (PXM) or polyethylene glycol (PEG) were successfully prepared by a melting method and then incorporated into PCL films, which were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), differential scanning calorimetry (DSC) and In vitro drug release/dissolution studies. It was found that PTX was faster released from the SDs than the corresponding physical mixtures (PMs) or PTX alone. For the PCL films with almost the same PTX loading, drug release from films containing SDs was remarkably faster than that from the film directly incorporated with PTX particles, and the films containing SDs with PXM exhibited a faster drug release than those with PEG. An increase In the content of PXM had no significant influence on PTX release from the films containing SDs. Incorporation of a higher content of SDs led to slower drug release from PCL films, indicating that PTX loading had a dominating effect on drug release. Through this study, we demonstrated the feasibility of the application of SD technique on the improvement of PTX release from PCL films and offered some beneficial information on modulating drug release behavior by changing the compositions and contents of the SDs-loaded PCL films. PMID:22803692

  20. Phase I/II study of trastuzumab, paclitaxel, cisplatin and radiation for locally advanced, HER2 overexpressing, esophageal adenocarcinoma

    SciTech Connect

    Safran, Howard [Brown University Oncology Group, Providence, RI (United States)]. E-mail: hsafran@lifespan.org; Di Petrillo, Thomas [Brown University Oncology Group, Providence, RI (United States); Akerman, Paul [Brown University Oncology Group, Providence, RI (United States); Ng, Thomas [Brown University Oncology Group, Providence, RI (United States); Evans, Devon [Brown University Oncology Group, Providence, RI (United States); Steinhoff, Margaret [Brown University Oncology Group, Providence, RI (United States); Benton, David [Brown University Oncology Group, Providence, RI (United States); Purviance, John [Brown University Oncology Group, Providence, RI (United States); Goldstein, Lisa [Brown University Oncology Group, Providence, RI (United States); Tantravahi, Umadevi [Brown University Oncology Group, Providence, RI (United States); Kennedy, Teresa R.N. [Brown University Oncology Group, Providence, RI (United States)

    2007-02-01

    Purpose: To determine the overall survival for patients with locally advanced, HER2 overexpressing, esophageal adenocarcinoma receiving trastuzumab, paclitaxel, cisplatin, and radiation on a Phase I-II study. Methods and Materials: Patients with adenocarcinoma of the esophagus without distant organ metastases and 2+/3+ HER2 overexpression by immunohistochemistry (IHC) were eligible. All patients received cisplatin 25 mg/m{sup 2} and paclitaxel 50 mg/m{sup 2} weekly for 6 weeks with radiation therapy (RT) 50.4 Gy. Patients received trastuzumab at dose levels of 1, 1.5, or 2 mg/kg weekly for 5 weeks after an initial bolus of 2, 3, or 4 mg/kg. Results: Nineteen patients were entered: 7 (37%) had celiac adenopathy, and 7 (37%) had retroperitoneal, portal adenopathy, or scalene adenopathy. Fourteen of 19 patients (74%) had either 3+ HER2 expression by immunohistochemistry, or an increase in HER2 gene copy number by HER2 gene amplification or high polysomy by fluorescence in situ hybridization. The median survival of all patients was 24 months and the 2-year survival was 50%. Conclusions: Assessment of the effect of trastuzumab in the treatment of patients with esophageal adenocarcinoma overexpressing HER2 is limited by the small number of patients in this study. Overall survival, however, was similar to prior studies without an increase in toxicity. Evaluation of HER2 status should be performed in future trials for patients with adenocarcinoma of the esophagus that investigate therapies targeting the HER family.

  1. Strong and Sustained Response to Treatment with Carboplatin plus Nab-Paclitaxel in a Patient with Metastatic, Triple-Negative, BRCA1-Positive Breast Cancer

    PubMed Central

    Shakir, Abdur R.

    2014-01-01

    Our case describes a 51-year-old female, diagnosed in April 2008 with a triple-negative, BRCA1-positive, infiltrating ductal carcinoma of the left breast. Initial platinum-based therapy resulted in a complete regression until November 2009, when a recurrence of the disease was detected. As no evidence of metastasis was found, a dose-dense regimen of doxorubicin plus cyclophosphamide was administered, followed by paclitaxel. The patient was actively monitored until March 2012, when brain metastases were discovered and successfully treated with whole-brain radiation therapy. Three months later, the patient experienced severe abdominal pain, and CT scans revealed extensive metastatic disease, including a large mass in the abdomen and more than 20 bilateral pulmonary metastases. Treatment commenced with carboplatin plus nab-paclitaxel. However, carboplatin was stopped after 4 cycles due to persistent neutropenia, and nab-paclitaxel was continued as monotherapy. Whole-body CT scans performed in October 2012 and March 2013 revealed a significant response to therapy, and the patient reported feeling well and being fully mobile. No treatment-related adverse events were observed. A routine brain MRI scan carried out on April 18, 2013, revealed a recurrence of brain metastases; however, CT scans confirmed that disease progression was not systemic, but confined to the central nervous system. Despite the initiation of treatment with irinotecan plus temozolomide on April 24, the patient died on July 2, 2013. The author believes that this case is the first report of a robust response to nab-paclitaxel monotherapy in triple-negative BRCA1-positive breast cancer, and that it supports further studies of nab-paclitaxel in this aggressive indication. PMID:24847251

  2. Phase I/II study of S-1 combined with paclitaxel in patients with unresectable and/or recurrent advanced gastric cancer.

    PubMed

    Mochiki, E; Ohno, T; Kamiyama, Y; Aihara, R; Haga, N; Ojima, H; Nakamura, J; Ohsawa, H; Nakabayashi, T; Takeuchi, K; Asao, T; Kuwano, H

    2006-12-18

    Both paclitaxel and S-1 are effective against gastric cancer, but the optimal regimen for combined chemotherapy with these drugs remains unclear. This phase I/II study was designed to determine the maximum tolerated dose (MTD), recommended dose (RD), dose-limiting toxicity (DLT), and objective response rate of paclitaxel in combination with S-1. S-1 was administered orally at a fixed dose of 80 mg m-2 day-1 from days 1 to 14 of a 28-day cycle. Paclitaxel was given intravenously on days 1, 8, and 15, starting with a dose of 40 mg m-2 day-1. The dose was increased in a stepwise manner to 70 mg m-2. Treatment was repeated every 4 weeks unless disease progression was confirmed. In the phase I portion, 17 patients were enrolled. The MTD of paclitaxel was estimated to be 70 mg m-2 because 40% of the patients given this dose level (two of five) had DLT. The RD was determined to be 60 mg m-2. In the phase II portion, 24 patients, including five with assessable disease who received the RD in the phase I portion, were evaluated. The median number of treatment courses was six (range: 1-17). The incidence of the worst-grade toxicity in patients given the RD was 28 and 8%, respectively. All toxic effects were manageable. The response rate was 54.1%, and the median survival time was 15.5 months. Our phase I/II trial showed that S-1 combined with paclitaxel is effective and well tolerated in patients with advanced gastric cancer. PMID:17133268

  3. A Phase I Pharmacokinetic and Pharmacodynamic Correlative Study of the Antisense Bcl-2 Oligonucleotide G3139, in Combination with Carboplatin and Paclitaxel, in Patients with Advanced Solid Tumors

    PubMed Central

    Liu, Glenn; Kolesar, Jill; McNeel, Douglas G.; Leith, Catherine; Schell, Kathy; Eickhoff, Jens; Lee, Fred; Traynor, Anne; Marnocha, Rebecca; Alberti, Dona; Zwiebel, James; Wilding, George

    2010-01-01

    Purpose This phase I trial assessed the safety and tolerability of G3139 when administered in combination with carboplatin and paclitaxel chemotherapy. The effect of G3139 treatment on Bcl-2 expression in peripheral blood mononuclear cells (PBMC) and paired tumor biopsies was also determined. Experimental Design Patients with advanced solid malignancies received various doses of G3139 (continuous i.v. infusion days 1–7), carboplatin (day 4), and paclitaxel (day 4), repeated in 3-week cycles, in a standard cohort-of-three dose-escalation schema. Changes in Bcl-2/Bax transcription/expression were assessed at baseline and day 4 (pre-chemotherapy) in both PBMCs and paired tumor biopsies. The pharmacokinetic interactions between G3139 and carboplatin/paclitaxel were measured. Results Forty-two patients were evaluable for safety analysis. Primary toxicities were hematological (myelosuppression and thrombocytopenia). Dose-escalation was stopped with G3139 at 7 mg/kg/day, carboplatin at AUC 6, and paclitaxel at 175 mg/m2 due to significant neutropenia seen in cycle 1, and safety concerns in further escalating chemotherapy in this phase I population. With G3139 at 7 mg/kg/day, 13 patients underwent planned tumor biopsies, of which 12 matched pairs were obtained. Quantitative increases in intratumoral G3139 with decreases in intratumoral Bcl-2 gene expression were seen. This paralleled a decrease in Bcl-2 protein expression observed in PBMCs. Conclusions Although the MTD was not reached, the observed toxicities were consistent with what one would expect from carboplatin and paclitaxel alone. In addition, we show that achievable intratumoral G3139 concentrations can result in Bcl-2 down-regulation in solid tumors and PBMCs. PMID:18451239

  4. The effects of opioid receptor antagonists on electroacupuncture-produced anti-allodynia/hyperalgesia in rats with paclitaxel-evoked peripheral neuropathy

    PubMed Central

    Meng, Xianze; Zhang, Yu; Li, Aihui; Xin, Jiajia; Lao, Lixing; Ren, Ke; Berman, Brian M.; Tan, Ming; Zhang, Rui-Xin

    2011-01-01

    Research supports the effectiveness of acupuncture for conditions such as chronic low back and knee pain. In a five-patient pilot study the modality also improved the symptoms of chemotherapy-induced neuropathic pain. Using an established rat model of paclitaxel-induced peripheral neuropathy, we evaluated the effect of electroacupuncture (EA) on paclitaxel-induced hyperalgesia and allodynia that has not been studied in an animal model. We hypothesize that EA would relieve the paclitaxel-induced mechanical allodynia and hyperalgesia, which was assessed 30 minutes after EA using von Frey filaments. Beginning on day 13, the response frequency to von Frey filaments (4-15 g) was significantly increased in paclitaxel-injected rats compared to those injected with vehicle. EA at 10Hz significantly (p<0.05) decreased response frequency at 4-15 g compared to sham EA; EA at 100Hz only decreased response frequency at 15 g stimulation. Compared to sham EA plus vehicle, EA at 10Hz plus either a ?, ?, or ? opioid receptor antagonist did not significantly decrease mechanical response frequency, indicating that all three antagonists blocked EA inhibition of allodynia and hyperalgesia. Since we previously demonstrated that ? and ? but not ? opioid receptors affect EA anti-hyperalgesia in an inflammatory pain model, these data show that EA inhibits pain through different opioid receptors under varying conditions. Our data indicate that EA at 10Hz inhibits mechanical allodynia/hyperalgesia more potently than does EA at 100Hz. Thus, EA significantly inhibits paclitaxel-induced allodynia/hyperalgesia through spinal opioid receptors, and EA may be a useful complementary treatment for neuropathic pain patients. PMID:21872220

  5. Paclitaxel releasing films consisting of poly(vinyl alcohol)-graft-poly(lactide-co-glycolide) and their potential as biodegradable stent coatings.

    PubMed

    Westedt, Ulrich; Wittmar, Matthias; Hellwig, Michael; Hanefeld, Phillip; Greiner, Andreas; Schaper, Andreas K; Kissel, Thomas

    2006-03-10

    Although substantial progress in catheter and stent design has contributed to the success of percutaneous transluminal angioplasty (PTA) of atherosclerotic disease, the incidence of restenosis caused by in-stent neointimal hyperplasia remains a serious problem. Therefore, stents with a non-degradable polymer coating showing controlled release of active ingredients have become an attractive option for the site-specific delivery of anti-restenotic agents. Biodegradable coatings using polyesters, namely poly(lactic-co-glycolic acid) (PLGA) and different poly(vinyl alcohol)-graft-poly(lactic-co-glycolic acid) (PVA-g-PLGA) as paclitaxel-eluting stent coating materials were investigated here to evaluate their influence on the release kinetic. Whereas PLGA showed sigmoid release behavior, the paclitaxel release from PVA-g-PLGA films was continuous over 40 days without initial drug burst. Wide angle X-ray diffraction confirmed that paclitaxel is dissolved in the polymer matrix. Paclitaxel crystallization can be observed at a drug load of > or =10%. The effect of drug loading on polymer degradation was studied in films prepared from PVA300-g-PLGA30 with paclitaxel loadings of 5% and 15% over a time period of 6 weeks. The results suggest a surface-like erosion mechanism in films. A model stent (Jostent peripheral) coated with Parylene N, a poly(p-xylylene) (PPX) derivate, was covered with a second layer of PVA300-g-PLGA15, and PVA300-g-PLGA30 by using airbrush method. Morphology of coated stents, and film integrity after expansion from 3.12 to 5 mm was investigated by scanning electron microscopy (SEM). The devices resisted mechanical stress during stent expansion and merit further investigation under in vivo conditions. PMID:16466824

  6. Oral co-administration of elacridar and ritonavir enhances plasma levels of oral paclitaxel and docetaxel without affecting relative brain accumulation

    PubMed Central

    Hendrikx, J J M A; Lagas, J S; Wagenaar, E; Rosing, H; Schellens, J H M; Beijnen, J H; Schinkel, A H

    2014-01-01

    Background: The intestinal uptake of the taxanes paclitaxel and docetaxel is seriously hampered by drug efflux through P-glycoprotein (P-gp) and drug metabolism via cytochrome P450 (CYP) 3A. The resulting low oral bioavailability can be boosted by co-administration of P-gp or CYP3A4 inhibitors. Methods: Paclitaxel or docetaxel (10?mg/kg) was administered to CYP3A4-humanised mice after administration of the P-gp inhibitor elacridar (25?mg?kg?1) and the CYP3A inhibitor ritonavir (12.5?mg?kg?1). Plasma and brain concentrations of the taxanes were measured. Results: Oral co-administration of the taxanes with elacridar increased plasma concentrations of paclitaxel (10.7-fold, P<0.001) and docetaxel (four-fold, P<0.001). Co-administration with ritonavir resulted in 2.5-fold (paclitaxel, P<0.001) and 7.3-fold (docetaxel, P<0.001) increases in plasma concentrations. Co-administration with both inhibitors simultaneously resulted in further increased plasma concentrations of paclitaxel (31.9-fold, P<0.001) and docetaxel (37.4-fold, P<0.001). Although boosting of orally applied taxanes with elacridar and ritonavir potentially increases brain accumulation of taxanes, we found that only brain concentrations, but not brain-to-plasma ratios, were increased after co-administration with both inhibitors. Conclusions: The oral availability of taxanes can be enhanced by co-administration with oral elacridar and ritonavir, without increasing the brain penetration of the taxanes. PMID:24781280

  7. Specific tumor delivery of paclitaxel using glycolipid-like polymer micelles containing gold nanospheres

    PubMed Central

    You, Jian; Wang, Zuhua; Du, Yongzhong; Yuan, Hong; Zhang, Peizun; Zhou, Jialin; Liu, Fei; Li, Chun; Hu, Fuqiang

    2014-01-01

    It is difficult for most of drug delivery system to really display a temporal and spatial release of entrapped drug once the systems are iv administrated. We hypothesized that the photothermal effect, mediated by a near-infrared (NIR) laser and hollow gold nanospheres (HAuNS), can modulate paclitaxel (PTX) release from polymer micelles, and further result in the enhanced antitumor activity of the micelles. We loaded PTX and HAuNS, which display strong plasmon absorption in the NIR region, into glycolipid-like polymer micelles with an excellent cell internalization capability. The surface of the micelles was conjugated successfully with a peptide, which has the specific-binding with EphB4, a member of the Eph family of receptor tyrosine kinases overexpressed on cell membrane of numerous tumors, to increase the delivery of PTX into tumor cells. Rapid and repetitive drug release from our polymer (HP-TCS) micelles could be readily achieved upon NIR laser irradiation. Our data demonstrated the specific-delivery of HPTCS micelles into positive-EphB4 tumors using a duel-tumor model after iv administration during the whole experiment process (1-48h). Interestingly, significantly higher uptake of the micelles by SKOV3 tumors (positive-EphB4) than A549 tumors (negtive-EphB4) was observed, with increased ratio on experiment time. However, the specific cell uptake was observed only during the short incubation time (1-4h) in vitro. Our data also indicated the treatment of tumor cells with the micelles followed by NIR laser irradiation showed significantly greater toxicity activity than the treatment with the micelles alone, free PTX and the micelles (without PTX loading) plus NIR laser irradiation. The enhanced toxicity activity to tumor cells should be attributed to the enhanced drug cellular uptake mediated by the glycolipid-like micelles, chemical toxicity of the released drug from the micelles due to the trigger of NIR laser, and the photothermal ablation under NIR laser irradiation. PMID:23510855

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

    PubMed Central

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

    2015-01-01

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

  9. Phase III trial of nonpegylated liposomal doxorubicin in combination with trastuzumab and paclitaxel in HER2-positive metastatic breast cancer

    PubMed Central

    Baselga, J.; Manikhas, A.; Cortés, J.; Llombart, A.; Roman, L.; Semiglazov, V. F.; Byakhov, M.; Lokanatha, D.; Forenza, S.; Goldfarb, R. H.; Matera, J.; Azarnia, N.; Hudis, C. A.; Rozencweig, M.

    2014-01-01

    Background Nonpegylated liposomal doxorubicin liposomal doxorubicin, (Myocet™; Sopherion Therapeutics, Inc Canada, and Cephalon, Europe) (NPLD; Myocet®) in combination with trastuzumabHerceptin® (Hoffmann-La Roche) has shown promising activity and cardiac safety. We conducted a randomized phase III trial of first-line NPLD plus trastuzumab and paclitaxel (Pharmachemie B.V.) (MTP) versus trastuzumab plus paclitaxel (TP) in patients with human epidermal growth factor 2 receptor (HER2)-positive metastatic breast cancer. Patients and Methods Patients were randomly assigned to NPLD (M, 50 mg/m2 every 3 weeks for six cycles), trastuzumab (T, 4 mg/kg loading dose followed by 2 mg/kg weekly), and paclitaxel (P, 80 mg/m2 weekly) or T + P at the same doses until progression or toxicity. The primary efficacy outcome was progression-free survival (PFS). Results One hundred and eighty-one patients were allocated to receive MTP, and 183 to TP. Median PFS was 16.1 and 14.5 months with MTP and TP, respectively [hazard ratio (HR) 0.84; two-sided P = 0.174]. In patients with estrogen receptor (ER)- and progesterone receptor (PR)-negative tumors, PFS was 20.7 and 14.0 months, respectively [HR 0.68; 95% confidence interval (CI) 0.47–0.99]. Median overall survival (OS) was 33.6 and 28.9 months with MTP and TP, respectively (HR 0.79; two-sided P = 0.083). In ER- and PR-negative tumors, OS was 38.2 and 27.9 m