Sample records for paclitaxel taxol taxolreg

  1. How Taxol/paclitaxel kills cancer cells

    PubMed Central

    Weaver, Beth A.

    2014-01-01

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

  2. [Taxol (paclitaxel) as second-line therapy in breast and ovarian cancer].

    PubMed

    Borovik, R; Steiner, M; Atad, J; Sneiderman, B; Rosenberg, T; Palti, S

    1998-04-15

    Results of chemotherapy with taxol (paclitaxel) in 55 patients with recurrent breast and ovarian cancer were reviewed. Taxol was given as a 3-hour infusion, every 3 weeks, on an outpatient basis. There was complete or partial response in 8 patients (23%) with breast cancer and 10 (50%) with ovarian cancer. Performance status and previous response to adriamycin were important prognostic factors. Toxicity was manageable. Treatment had to be stopped for hypersensitivity reactions in only 2 patients. Taxol given in an ambulatory clinic is safe and effective. PMID:10911422

  3. Characterization of paclitaxel (Taxol) sensitivity in human glioma- and medulloblastoma-derived cell lines.

    PubMed Central

    Tseng, S. H.; Bobola, M. S.; Berger, M. S.; Silber, J. R.

    1999-01-01

    Paclitaxel (Taxol), a cytotoxic natural product that disrupts microtubule integrity, is being clinically evaluated for use against gliomas. We examined paclitaxel-induced killing in seven cell lines derived from human malignant astrocytic gliomas and medulloblastomas with the goal of characterizing range of sensitivity, contribution of P-glycoprotein 170-mediated drug efflux to resistance, and cross-resistance with alkylating agents. Exposure to paclitaxel for 8 h or less produced biphasic survival curves for all lines, with 40-75% of cells comprising a subpopulation that was 9-26 times more resistant to paclitaxel than the more sensitive fraction. Increasing exposure to 24 h eliminated the resistant subpopulation, increasing sensitivity 50- to 400-fold. The dose producing one log of kill (LD10) after a 24-h exposure ranged from 4 to 18 nM, comparable to concentrations in the cerebrospinal fluid of brain tumor patients given a 3-h infusion of paclitaxel. Concurrent exposure to paclitaxel and either nimodipine or verapamil, inhibitors of P-glycoprotein activity, did not increase sensitivity, demonstrating that the fivefold range in sensitivity was not due to P-glycoprotein-mediated drug efflux. Importantly, there was no correlation between LD10 for paclitaxel and LD10 for 1,3-bis(2-chloroethyl)-1-nitrosourea, streptozotocin, and temozolomide, indicating no expression of cross-resistance to these different classes of tumoricidal agents. Our results suggest that greater clinical efficacy of paclitaxel against malignant brain tumors may be obtained by infusion for 24 h or longer and support the use of paclitaxel in combination with alkylating agents. PMID:11550305

  4. Paclitaxel (Taxol)-induced NF-kappaB translocation in murine macrophages.

    PubMed Central

    Perera, P Y; Qureshi, N; Vogel, S N

    1996-01-01

    Interaction of bacterial lipopolysaccharide (LPS) with macrophages results in the induction of a cascade of cytokines that mediate the varied effects of LPS. An early intracellular signaling event that follows receptor engagement is the activation of transcription factor NF-kappaB. Nf-kappaB has been shown to be important for the induction of many LPS-inducible cytokine genes, including tumor necrosis factor alpha, interleukin-1beta, and interleukin-6. Previously, we and others have shown that the antitumor agent paclitaxel (Taxol) is able to mimic bacterial LPS in its ability to activate murine macrophages. In this report, we have extended these findings by demonstrating that paclitaxel, like LPS, is able to stimulate the translocation of primarily p50-p65 heterodimers of NF-kappaB to the nucleus. This activation is dose dependent and requires a concentration of > or =5 microM paclitaxel. The kinetics of NF-kappaB activation by paclitaxel are slower than those of LPS: by 15 min poststimulation, LPS-induced NF-kappaB activation was readily detected, whereas the paclitaxel-induced NF-kappaB activation was minimal. Moreover, paclitaxel- and protein-free LPS-induced translocation of NF-kappaB was seen only in macrophages derived from LPS-responsive C3H/OuJ mice and not from the LPS-hyporesponsive C3H/HeJ mice, a finding that is consistent with those of previous genetic studies linking paclitaxel responsiveness to the Lps gene. Finally, the LPS structural antagonist Rhodobacter sphaeroides diphosphoryl lipid A inhibited both LPS-and paclitaxel-induced NF-kappaB activation, suggesting a common receptor component in this activation. PMID:8641795

  5. Synthesis and Bioactivity of a Side Chain Bridged Paclitaxel: A Test of the T-Taxol Conformation

    PubMed Central

    Hodge, Mathis; Chen, Qiao-Hong; Bane, Susan; Sharma, Shubhada; Loew, Maura; Banerjee, Abhijit; Alcaraz, Ana A.; Snyder, James P.

    2009-01-01

    A knowledge of the bioactive tubulin-binding conformation of paclitaxel (Taxol™) is crucial to a full understanding of the bioactivity of this important anticancer drug, and potentially also to the design of simplified analogs. The bioactive conformation has been shown to be best approximated by the T-Taxol conformation. As a further test of this conclusion, the paclitaxel analog 4 was designed as a compound which has all the chemical functionality necessary for activity, but which cannot adopt the T-Taxol conformation. The synthesis and bioassay of 4 confirmed its lack of activity, and thus provided further support for the T-Taxol conformation as the bioactive tubulin-binding conformation. PMID:19359169

  6. Transport of paclitaxel (Taxol) across the blood-brain barrier in vitro and in vivo

    PubMed Central

    Fellner, Stephan; Bauer, Björn; Miller, David S.; Schaffrik, Martina; Fankhänel, Martina; Spruß, Thilo; Bernhardt, Günther; Graeff, Claudia; Färber, Lothar; Gschaidmeier, Harald; Buschauer, Armin; Fricker, Gert

    2002-01-01

    Paclitaxel concentrations in the brain are very low after intravenous injection. Since paclitaxel is excluded from some tumors by p-glycoprotein (p-gp), the same mechanism may prevent entry into the brain. In vitro, paclitaxel transport was examined in capillaries from rat brains by confocal microscopy using BODIPY Fl-paclitaxel. Western blots and immunostaining demonstrated apical expression of p-gp in isolated endothelial cells, vessels, and tissue. Secretion of BODIPY Fl-paclitaxel into capillary lumens was specific and energy-dependent. Steady state luminal fluorescence significantly exceeded cellular fluorescence and was reduced by NaCN, paclitaxel, and SDZ PSC-833 (valspodar), a p-gp blocker. Leukotriene C4 (LTC4), an Mrp2-substrate, had no effect. Luminal accumulation of NBDL-cyclosporin, a p-gp substrate, was inhibited by paclitaxel. In vivo, paclitaxel levels in the brain, liver, kidney, and plasma of nude mice were determined after intravenous injection. Co-administration of valspodar led to increased paclitaxel levels in brains compared to monotherapy. Therapeutic relevance was proven for nude mice with implanted intracerebral human U-118 MG glioblastoma. Whereas paclitaxel did not affect tumor volume, co-administration of paclitaxel (intravenous) and PSC833 (peroral) reduced tumor volume by 90%. Thus, p-gp is an important obstacle preventing paclitaxel entry into the brain, and inhibition of this transporter allows the drug to reach sensitive tumors within the CNS. PMID:12417570

  7. Exploration of paclitaxel (Taxol) as a treatment for malignant tumors in cats: a descriptive case series.

    PubMed

    Kim, Jennifer; Doerr, Mary; Kitchell, Barbara E

    2015-02-01

    Paclitaxel, an effective chemotherapeutic agent in human oncology, has received little evaluation in feline patients. The diluent used to solubilize paclitaxel, polyoxyethylated castor oil (Cremophor EL), causes anaphylactoid reactions in human and dogs, which limits enthusiasm for use of this agent in veterinary oncology. Nine feline patients with measurable malignant tumors were treated with paclitaxel at a dosage of 80 mg/m(2) intravenously every 21 days for up to two doses. Adverse effects, including evidence of toxicity and anaphylactoid reactions, were assessed. Tumor response, progression and patient time to progression (TTP) were also recorded. Adverse effects included grade III and IV thrombocytopenia, grade III gastrointestinal signs (vomiting and constipation) and hypersensitivity reactions, seen in a total of five patients. Anaphylactoid reactions resolved with appropriate management. Stable disease and partial response were observed in 56% of feline patients. Median TTP was 28 days (range 15-45 days). Intravenous paclitaxel is a safe treatment option for feline malignant tumor patients. Future investigation is warranted to explore the effectiveness and appropriate application of this agent for specific tumor types. PMID:24820996

  8. Comparative proteomic analysis of paclitaxel sensitive A549 lung adenocarcinoma cell line and its resistant counterpart A549Taxol

    Microsoft Academic Search

    Qiang-ling Sun; Hui-fang Sha; Xiao-hua Yang; Guo-liang Bao; Jing Lu; Yin-yin Xie

    2011-01-01

    Purpose  Paclitaxel is used as the first-line chemotherapy for Non-Small Cell Lung Cancer (NSCLC), but acquired resistance becomes\\u000a a critical problem. Several mechanisms have been proposed in paclitaxel resistance, but they are not sufficient to exhaustively\\u000a explain this resistance emergence. To better investigate molecular resistance mechanisms, a comparative proteomic approach\\u000a was carried out to identify differentially expressed proteins between human lung

  9. Fabrication, characterization and in vitro release of paclitaxel (Taxol ®) loaded poly (lactic-co-glycolic acid) microspheres prepared by spray drying technique with lipid\\/cholesterol emulsifiers

    Microsoft Academic Search

    L Mu; S. S Feng

    2001-01-01

    Spray dry technique was applied to produce paclitaxel loaded microspheres of biodegradable poly (lactic-co-glycolic acid) (PLGA) as an alternative delivery system. Various emulsifiers such as l-?-dipalmitoyl-phosphatidylcholine (DPPC), cholesterol, polyvinyl alcohol (PVA), gelatin were incorporated in order to achieve high encapsulating efficiency of paclitaxel in the microspheres and desired properties for a sustained release. Atomic force microscopy (AFM) and scanning electron

  10. 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

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

    PubMed Central

    Kingston, David G. I.

    2007-01-01

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

  12. Flare on Bone Scintigraphy Following Taxol Chemotherapy for Metastatic Breast Cancer

    Microsoft Academic Search

    Jesse A. Schneider; Chaitanya R. Divgi; Andrew M. Scott; Homer A. Macapinlac; Andrew D. Seidman; Stanley J. Goldsmith; Steven M. Larson

    Our goal was to determine if a healing flare response seen on bone scintigraphy occurs following chemotherapy with Taxol (paclitaxel; Bristol-Myers Squibb Co, Princeton, NJ), a novel antimicrotubule agent for metastatic breast cancer. Methods: We performed 74 bone scans on 21 females with breast cancer and bone métastases entering a Phase II trial of Taxol chemo therapy with granulocyte colony

  13. Paclitaxel Nano-Delivery Systems: A Comprehensive Review

    PubMed Central

    Ma, Ping; Mumper, Russell J.

    2013-01-01

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

  14. Paclitaxel Injection

    MedlinePLUS

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

  15. Isolation of anticancer drug TAXOL from Pestalotiopsis breviseta with apoptosis and B-Cell lymphoma protein docking studies

    PubMed Central

    Kathiravan, G.; Sureban, Sripathi M.; Sree, Harsha N.; Bhuvaneshwari, V.; Kramony, Evelin

    2012-01-01

    Background: Extraction and investigation of TAXOL from Pestalotiopsis breviseta (Sacc.) using protein docking, which is a computational technique that samples conformations of small molecules in protein-binding sites. Scoring functions are used to assess which of these conformations best complements the protein binding site and active site prediction. Materials and Methods: Coelomycetous fungi P. breviseta (Sacc.) Steyaert was screened for the production of TAXOL, an anticancer drug. Results: TAXOL production was confirmed by the following methods: Ultraviolet (UV) spectroscopic analysis, Infrared analysis, High performance liquid chromatography analysis (HPLC), and Liquid chromatography mass spectrum (LC-MASS). TAXOL produced by the fungi was compared with authentic TAXOL, and protein docking studies were performed. Conclusion: The BCL2 protein of human origin showed a higher affinity toward the compound paclitaxel. It has the binding energy value of ?13.0061 (KJ/Mol) with four hydrogen bonds. PMID:24808664

  16. A novel self-microemulsifying formulation of paclitaxel for oral administration to patients with advanced cancer

    Microsoft Academic Search

    S A Veltkamp; B Thijssen; J S Garrigue; G Lambert; F Lallemand; F Binlich; A D R Huitema; B Nuijen; A Nol; J H Beijnen; J H M Schellens

    2006-01-01

    To explore the parmacokinetics, safety and tolerability of paclitaxel after oral administration of SMEOF#3, a novel Self-Microemulsifying Oily Formulation, in combination with cyclosporin A (CsA) in patients with advanced cancer. Seven patients were enrolled and randomly assigned to receive oral paclitaxel (SMEOF#3) 160 mg+CsA 700 mg on day 1, followed by oral paclitaxel (Taxol®) 160 mg+CsA 700 mg on day

  17. Differential Taxol-dependent arrest of transformed and nontransformed cells in the G1 phase of the cell cycle, and specific-related mortality of transformed cells

    PubMed Central

    1996-01-01

    Taxol (paclitaxel) induces a microtubule hyperassembled state, and effectively blocks cells in mitosis. Here we report that Taxol also induces a stable late-G1 block in nontransformed REF-52 and WI-38 mammalian fibroblast cells, but not in T antigen-transformed cells of the same parental lineage. G1 arrest is characterized by partially dephosphorylated pRb, and inactive cdk2 kinase. Nontransformed cells recover normally from Taxol arrest. In contrast, T antigen transformed cells continue inappropriately past both G1 and G2-M in the presence of Taxol, and undergo a rapid death upon release. These results demonstrate a microtubule sensitive step in G1 regulation of nontransformed fibroblast cells. Also, Taxol selectively induces death of transformed cells, possibly because they slip the Taxol-dependent G1 arrest, as well as G2/M arrest, which are both specific to nontransformed cells. PMID:8909543

  18. Paclitaxel Arrests Growth of Intracellular Toxoplasma gondii

    PubMed Central

    Estes, Randee; Vogel, Nicolas; Mack, Douglas; McLeod, Rima

    1998-01-01

    Addition of paclitaxel (Taxol) at a concentration of 1 ?M to Toxoplasma gondii-infected human foreskin fibroblasts 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 inhibition was irreversible, since the arrested intracellular form was incapable of leaving the host cell, infecting new cells, and initiating the growth of tachyzoites with normal morphology. Specifically, when paclitaxel was added to infected cells for 4 days and then removed by washing and the infected, paclitaxel-treated cells were cultured for 4 more days, there were no remaining T. gondii organisms with normal morphology. Syncytium-like structures in the cultures that were infected and treated with paclitaxel for 8 days were similar in appearance to those in preparations of infected paclitaxel-treated fibroblasts that had been cultured for 24 to 48 h. Pretreatment of the tachyzoites for 1 h with paclitaxel followed by the removal of the paclitaxel by repeatedly centrifuging and resuspending the parasites in fresh medium without paclitaxel and then adding fresh medium prior to culture of the parasites with fibroblasts did not prevent their invasion of fibroblasts but did affect their subsequent ability to replicate within fibroblasts. Pretreatment of the fibroblasts with paclitaxel also diminished subsequent replication of T. gondii in such host cells after 8 days. Thus, paclitaxel alters the ability of T. gondii to replicate in host cells. Inhibition of parasite microtubules by such compounds at concentrations which do not interfere with the function of host cell microtubules may be useful for development of novel medicines to treat T. gondii infections in the future. PMID:9687403

  19. Success Story: Taxol

    Cancer.gov

    Paclitaxel, the most well-known natural-source cancer drug in the United States, is derived from the bark of the Pacific yew tree (Taxus brevifolia) and is used in the treatment of breast, lung, and ovarian cancer, as well as Kaposi's sarcoma.

  20. Nanomedicine-nanoemulsion formulation improves safety and efficacy of the anti-cancer drug paclitaxel according to preclinical assessment.

    PubMed

    Lee, King C; Maturo, Claudia; Rodriguez, Robert; Nguyen, Hoang-Lan; Shorr, Robert

    2011-08-01

    Paclitaxel is an important anticancer drug and is currently used to treat a variety of cancers, including ovarian carcinomas, breast cancer, non-small cell lung cancer, and AIDS-related Kaposi's sarcoma. The objectives of the studies were to assess and compare the safety and efficacy of EmPAC (a newly developed nanoemulsion formulation of paclitaxel) versus Taxol (the injectable formulation of paclitaxel involving the use of polyethylated or polyoxyl castor oil currently used in the clinic). The objectives were also to investigate the mechanism for the improved safety and efficacy of EmPAC over Taxol. These results showed that EmPAC had better anti-tumor efficacy than Taxol, according to in vitro cell culture studies and studies in animal tumor models. EmPAC had improved anti-tumor efficacy even in tumor cell lines that are known to be multi-drug resistant. Part of the mechanism of action for the improved efficacy may be related to EmPAC inducing greater cellular uptake of paclitaxel into tumor cells than Taxol did, according to the in vitro cell culture radioactive-labeled studies and in vitro cell culture antibody studies. It may also partly be because EmPAC delivered more paclitaxel to the tumor mass than Taxol, while the delivery of paclitaxel to other tissues (e.g., blood, muscle, liver, spleen, kidney and lung) were similar between the two formulations of paclitaxel, according to studies in animals with tumor xenograft. EmPAC also had better safety than Taxol according to toxicology studies in rabbits. This may be because EmPAC does not contain the toxic ingredients used in formulating Taxol (such as polyethylated or polyoxyl castor oil). These results support the clinical development of the nanoemulsion formulation of paclitaxel. PMID:22103064

  1. Ototoxicity of paclitaxel in rat cochlear organotypic cultures.

    PubMed

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

    2014-11-01

    Paclitaxel (taxol) is a widely used antineoplastic drug employed alone or in combination to treat many forms of cancer. Paclitaxel blocks microtubule depolymerization thereby stabilizing microtubules and suppressing cell proliferation and other cellular processes. Previous reports indicate that paclitaxel can cause mild to moderate sensorineural hearing loss and some histopathologic changes in the mouse cochlea; however, damage to the neurons and the underlying cell death mechanisms are poorly understood. To evaluate the ototoxicity of paclitaxel in more detail, cochlear organotypic cultures from postnatal day 3 rats were treated with paclitaxel for 24 or 48 h with doses ranging from 1 to 30 ?M. No obvious histopathologies were observed after 24h treatment with any of the paclitaxel doses employed, but with 48 h treatment, paclitaxel damaged cochlear hair cells in a dose-dependent manner and also damaged auditory nerve fibers and spiral ganglion neurons (SGN) near the base of the cochlea. TUNEL labeling was negative in the organ of Corti, but positive in SGN with karyorrhexis 48 h after 30 ?M paclitaxel treatment. In addition, caspase-6, caspase-8 and caspase-9 labeling was present in SGN treated with 30 ?M paclitaxel for 48 h. These results suggest that caspase-dependent apoptotic pathways are involved in paclitaxel-induced damage of SGN, but not hair cells in cochlea. PMID:25181333

  2. Differential Taxol-dependent arrest of transformed and nontransformed cells in the G1 phase of the cell cycle, and specific-related mortality of transformed cells

    Microsoft Academic Search

    Marc O. Trielli; Paul R. Andreassen; Franqoise B. Lacroix; Robert L. Margolis

    1996-01-01

    Taxol (paclitaxel) induces a microtubule hyperassembled state, and effectively blocks cells in mi- tosis. Here we report that Taxol also induces a stable late-G1 block in nontransformed REF-52 and WI-38 mammalian fibroblast cells, but not in T antigen-trans- formed cells of the same parental lineage. G1 arrest is characterized by partially dephosphorylated pRb, and inactive cdk2 kinase. Nontransformed cells recover

  3. Spontaneous T-cell responses against peptides derived from the Taxol resistance–associated gene-3 (TRAG-3) protein in cancer patients

    Microsoft Academic Search

    Anders Meier; Sine Reker; Inge Marie Svane; Lars Holten-Andersen; Jürgen C. Becker; Ib Søndergaard; Mads Hald Andersen; Per thor Straten

    2005-01-01

    Expression of the cancer-testis antigen Taxol resistance–associated gene-3 (TRAG-3) protein is associated with acquired paclitaxel (Taxol) resistance, and is expressed in various cancer types; e.g., breast cancer, leukemia, and melanoma. Thus, TRAG-3 represents an attractive target for immunotherapy of cancer. To identify HLA-A*02.01–restricted epitopes from TRAG-3, we screened cancer patients for spontaneous cytotoxic T-cell responses against TRAG-3–derived peptides. The TRAG-3

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

    NASA Astrophysics Data System (ADS)

    Guo, Wen-jing; Chen, Tong-sheng

    2010-02-01

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

  5. MicroRNA-125b Confers the Resistance of Breast Cancer Cells to Paclitaxel through Suppression of Pro-apoptotic Bcl-2 Antagonist Killer 1 (Bak1) Expression*

    PubMed Central

    Zhou, Ming; Liu, Zixing; Zhao, Yuhua; Ding, Yan; Liu, Hao; Xi, Yaguang; Xiong, Wei; Li, Guiyuan; Lu, Jianrong; Fodstad, Oystein; Riker, Adam I.; Tan, Ming

    2010-01-01

    Paclitaxel (Taxol) is an effective chemotherapeutic agent for treatment of cancer patients. Despite impressive initial clinical responses, the majority of patients eventually develop some degree of resistance to Taxol-based therapy. The mechanisms underlying cancer cells resistance to Taxol are not fully understood. MicroRNA (miRNA) has emerged to play important roles in tumorigenesis and drug resistance. However, the interaction between the development of Taxol resistance and miRNA has not been previously explored. In this study we utilized a miRNA array to compare the differentially expressed miRNAs in Taxol-resistant and their Taxol-sensitive parental cells. We verified that miR-125b, miR-221, miR-222, and miR-923 were up-regulated in Taxol-resistant cancer cells by real-time PCR. We further investigated the role and mechanisms of miR-125b in Taxol resistance. We found that miR-125b was up-regulated in Taxol-resistant cells, causing a marked inhibition of Taxol-induced cytotoxicity and apoptosis and a subsequent increase in the resistance to Taxol in cancer cells. Moreover, we demonstrated that the pro-apoptotic Bcl-2 antagonist killer 1 (Bak1) is a direct target of miR-125b. Down-regulation of Bak1 suppressed Taxol-induced apoptosis and led to an increased resistance to Taxol. Restoring Bak1 expression by either miR-125b inhibitor or re-expression of Bak1 in miR-125b-overexpressing cells recovered Taxol sensitivity, overcoming miR-125-mediated Taxol resistance. Taken together, our data strongly support a central role for miR-125b in conferring Taxol resistance through the suppression of Bak1 expression. This finding has important implications in the development of targeted therapeutics for overcoming Taxol resistance in a number of different tumor histologies. PMID:20460378

  6. Divergent effect of taxol on proliferation, apoptosis and nitric oxide production in MHH225 CD34 positive and U937 CD34 negative human leukaemia cells

    Microsoft Academic Search

    O Al-alami; J Sammons; J. H Martin; H. T Hassan

    1998-01-01

    Paclitaxel (Taxol) has been shown to be clinically effective in treatment of patients with breast and ovarian cancer. It has also shown promising results in various other solid tumours. Paclitaxel has induced apoptosis in the G2\\/M phase of the cell cycle in both HL-60 and U937 human leukaemia cells. A recent study has shown a dose-dependent cytotoxicity for both taxanes:

  7. Genome sequencing and analysis of the paclitaxel-producing endophytic fungus Penicillium aurantiogriseum NRRL 62431

    PubMed Central

    2014-01-01

    Background Paclitaxel (Taxol™) is an important anticancer drug with a unique mode of action. The biosynthesis of paclitaxel had been considered restricted to the Taxus species until it was discovered in Taxomyces andreanae, an endophytic fungus of T. brevifolia. Subsequently, paclitaxel was found in hazel (Corylus avellana L.) and in several other endophytic fungi. The distribution of paclitaxel in plants and endophytic fungi and the reported sequence homology of key genes in paclitaxel biosynthesis between plant and fungi species raises the question about whether the origin of this pathway in these two physically associated groups could have been facilitated by horizontal gene transfer. Results The ability of the endophytic fungus of hazel Penicillium aurantiogriseum NRRL 62431 to independently synthesize paclitaxel was established by liquid chromatography-mass spectrometry and proton nuclear magnetic resonance. The genome of Penicillium aurantiogriseum NRRL 62431 was sequenced and gene candidates that may be involved in paclitaxel biosynthesis were identified by comparison with the 13 known paclitaxel biosynthetic genes in Taxus. We found that paclitaxel biosynthetic gene candidates in P. aurantiogriseum NRRL 62431 have evolved independently and that horizontal gene transfer between this endophytic fungus and its plant host is unlikely. Conclusions Our findings shed new light on how paclitaxel-producing endophytic fungi synthesize paclitaxel, and will facilitate metabolic engineering for the industrial production of paclitaxel from fungi. PMID:24460898

  8. 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

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

    PubMed Central

    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

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

    E-print Network

    Chen, Wilfred

    2003 Abstract This paper reports the development, characterization, and application of a separation; Fluorescence polarization; Plasma; Cancer Paclitaxel, better known by its trade name Taxol, has demonstrated of the slow reaction rate due to limited mass transport and diffusional re- sistance across the solid

  11. Paclitaxel induces axonal microtubules polar reconfiguration and impaired organelle transport: implications for the pathogenesis of paclitaxel-induced polyneuropathy

    Microsoft Academic Search

    A. Shemesh; Micha E. Spira

    2010-01-01

    In differentiated axons almost all microtubules (MTs) uniformly point their plus ends towards the axonal tip. The uniform\\u000a polar pattern provides the structural substrate for efficient organelle transport along axons. It is generally believed that\\u000a the mass and pattern of MTs polar orientation remain unchanged in differentiated neurons. Here we examined long-term effects\\u000a of the MTs stabilizing reagent paclitaxel (taxol)

  12. 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

  13. Inhibition of paclitaxel-induced decreases in calcium signaling.

    PubMed

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

    2012-11-01

    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

  14. 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

  15. Arsenic Trioxide Suppresses Paclitaxel-Induced Mitotic Arrest

    PubMed Central

    Duan, Qing; Komissarova, Elena; Dai, Wei

    2014-01-01

    To human health, arsenic exhibits the property of a double-edged sword. Arsenic compounds such as As2O3 is effective for the treatment of relapsed/refractory acute promyelocytic leukemia, whereas chronic exposure to environmental arsenic is associated with the development of a variety of common cancers. Because As2O3 is capable of inhibiting tubulin polymerization and inducing mitotic arrest, we examined whether there existed any functional interaction between As2O3 and paclitaxel, a well-known microtubule poison. Flow cytometry and fluorescence microscopy revealed that although As2O3 alone caused a moderate level of mitotic arrest, it greatly attenuated paclitaxel-induced mitotic arrest in cells with p53 deficiency. Western blot analysis showed that As2O3 significantly blocked phosphorylation of BubR1, Cdc20, and Cdc27 in cells treated with paclitaxel, suggesting that arsenic compromised the activation of the spindle checkpoint. Our further studies revealed that the attenuation of paclitaxel-induced mitotic arrest by As2O3 resulted primarily from sluggish cell cycle progression at S phase but not enhanced mitotic exit. The clinical efficacy of taxol is associated with its ability to induce mitotic arrest and subsequent mitotic catastrophe. Our observations that As2O3 has a negative impact on the cell cycle checkpoint activation by taxol should have significant clinical implications. PMID:19397590

  16. 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

  17. 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

  18. Clinical trials in restenosis with 7-hexanoyltaxol and paclitaxel-eluting stents.

    PubMed

    Doggrell, Sheila A

    2004-09-01

    Restenosis rates are lower with stent implantation than with balloon angioplasty. Nevertheless, even with the use of stenting, restenosis still occurs in approximately a third of patients with diabetes, small coronary vessels and long lesions. Animal studies with paclitaxel (Taxol, Bristol-Myers Squibb)-eluting stents, mainly in endothelium-denuded normal vessels, have shown that although paclitaxel reduces restenosis in the short-term, this may only delay rather than prevent restenosis. In clinical trials, stents eluting the paclitaxel derivative, 7-hexanoyltaxol, or paclitaxel without a polymer, also delay rather than prevent restenosis. Slowing the release of paclitaxel with a polymer base in the TAXUS trade mark series of clinical trials reduced the revascularization rate at 12 months, indicating that polymer-based paclitaxel is effective for longer periods of time. Further follow-up is necessary to determine whether polymer-based release of paclitaxel represents a longer delay or prevention of restenosis. To date, paclitaxel is showing promise as an eluting agent to prevent restenosis associated with stenting. PMID:15350175

  19. A liposomal formulation able to incorporate a high content of Paclitaxel and exert promising anticancer effect.

    PubMed

    Kan, Pei; Tsao, Chih-Wan; Wang, Ae-June; Su, Wu-Chou; Liang, Hsiang-Fa

    2011-01-01

    A liposome formulation for paclitaxel was developed in this study. The liposomes, composed of naturally unsaturated and hydrogenated phosphatidylcholines, with significant phase transition temperature difference, were prepared and characterized. The liposomes exhibited a high content of paclitaxel, which was incorporated within the segregated microdomains coexisting on phospholipid bilayer of liposomes. As much as 15% paclitaxel to phospholipid molar ratio were attained without precipitates observed during preparation. In addition, the liposomes remained stable in liquid form at 4°C for at least 6 months. The special composition of liposomal membrane which could reduce paclitaxel aggregation could account for such a capacity and stability. The cytotoxicity of prepared paclitaxel liposomes on the colon cancer C-26 cell culture was comparable to Taxol. Acute toxicity test revealed that LD(50) for intravenous bolus injection in mice exceeded by 40?mg/kg. In antitumor efficacy study, the prepared liposomal paclitaxel demonstrated the increase in the efficacy against human cancer in animal model. Taken together, the novel formulated liposomes can incorporate high content of paclitaxel, remaining stable for long-term storage. These animal data also demonstrate that the liposomal paclitaxel is promising for further clinical use. PMID:21490755

  20. Paclitaxel-Conjugated PAMAM Dendrimers Adversely Affect Microtubule Structure through Two Independent Modes of Action

    PubMed Central

    Cline, Erika N.; Li, Ming-Hsin; Choi, Seok Ki; Herbstman, Jeffrey F.; Kaul, Neha; Meyhöfer, Edgar; Skiniotis, Georgios; Baker, James R.; Larson, Ronald G.; Walter, Nils G.

    2013-01-01

    Paclitaxel (Taxol®) is an anti-cancer drug that induces mitotic arrest via microtubule hyperstabilization, but causes side effects due to its hydrophobicity and cellular promiscuity. The targeted cytotoxicity of hydrophilic paclitaxel-conjugated polyamidoamine (PAMAM) dendrimers has been demonstrated in cultured cancer cells. Mechanisms of action responsible for this cytotoxicity are unknown—i.e., whether the cytotoxicity is due to paclitaxel stabilization of microtubules — as is whether paclitaxel is released intracellularly from the dendrimer. To determine whether the conjugated paclitaxel can bind microtubules, we used a combination of ensemble and single microtubule imaging techniques in vitro. We demonstrate that these conjugates adversely affect microtubules by: (1) promoting the polymerization and stabilization of microtubules in a paclitaxel-dependent manner; and (2) bundling pre-formed microtubules in a paclitaxel-independent manner, potentially due to protonation of tertiary amines in the dendrimer interior. Our results provide mechanistic insights into the cytotoxicity of paclitaxel-conjugated PAMAM dendrimers and uncover unexpected risks of using such conjugates therapeutically. PMID:23391096

  1. Tau induces cooperative Taxol binding to microtubules

    E-print Network

    Ross, Jennifer

    are two ligands that stabilize the microtubule (MT) lattice. Taxol is an anti-mitotic drug that binds of neurodegenerative diseases, such as Alzheimer's disease, Pick's disease, and frontotemporal dementia

  2. Sensitizing the Therapeutic Efficacy of Taxol with Shikonin in Human Breast Cancer Cells

    PubMed Central

    Li, Wenjuan; Liu, Joan; Jackson, Kasey; Shi, Runhua; Zhao, Yunfeng

    2014-01-01

    Shikonin, a small-molecule natural product which inhibits the activity of pyruvate kinase M2 (PKM2), has been studied as an anti-cancer drug candidate in human cancer models. Here, our results demonstrate that shikonin is able to sensitize human breast cancer cells to chemotherapy by paclitaxel (taxol). Human breast adenocarcinoma MBA-MD-231 cells, which have higher levels of PKM2 expression and activity compared with MCF-7 cells, were selected to study further. The concentrations of shikonin and taxol were first selected at which they did not significantly induce cytotoxicity when treated alone, whereas the combination induced apoptosis. Surprisingly, PKM2 activity was decreased by shikonin, but not by the combination treatment. To identify the potential targets of this combination, human phospho-kinase antibody array analysis was performed and results indicated that the combination treatment inhibited the activation of ERK, Akt, and p70S6 kinases, which are known to contribute to breast cancer progression. Finally, how the combination affects breast cancer cell growth in vivo was tested using a xenograft tumor model. The results indicated that shikonin plus taxol prolonged animal survival and reduced tumor size than the vehicle treatment group. In summary, our results suggest that shikonin has a potential as an adjuvant for breast cancer therapy. PMID:24710512

  3. Warburg effect in chemosensitivity: Targeting lactate dehydrogenase-A re-sensitizes Taxol-resistant cancer cells to Taxol

    PubMed Central

    2010-01-01

    Background Taxol is one of the most effective chemotherapeutic agents for the treatment of patients with breast cancer. Despite impressive clinical responses initially, the majority of patients eventually develop resistance to Taxol. Lactate dehydrogenase-A (LDH-A) is one of the predominant isoforms of LDH expressed in breast tissue, which controls the conversion of pyruvate to lactate and plays an important role in glucose metabolism. In this study we investigated the role of LDH-A in mediating Taxol resistance in human breast cancer cells. Results Taxol-resistant subclones, derived from the cancer cell line MDA-MB-435, sustained continuous growth in high concentrations of Taxol while the Taxol-sensitive cells could not. The increased expression and activity of LDH-A were detected in Taxol-resistant cells when compared with their parental cells. The downregulation of LDH-A by siRNA significantly increased the sensitivity of Taxol-resistant cells to Taxol. A higher sensitivity to the specific LDH inhibitor, oxamate, was found in the Taxol-resistant cells. Furthermore, treating cells with the combination of Taxol and oxamate showed a synergistical inhibitory effect on Taxol-resistant breast cancer cells by promoting apoptosis in these cells. Conclusion LDH-A plays an important role in Taxol resistance and inhibition of LDH-A re-sensitizes Taxol-resistant cells to Taxol. This supports that Warburg effect is a property of Taxol resistant cancer cells and may play an important role in the development of Taxol resistance. To our knowledge, this is the first report showing that the increased expression of LDH-A plays an important role in Taxol resistance of human breast cancer cells. This study provides valuable information for the future development and use of targeted therapies, such as oxamate, for the treatment of patients with Taxol-resistant breast cancer. PMID:20144215

  4. 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

  5. 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

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

    PubMed Central

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

    2008-01-01

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

  7. Sirolimus- or paclitaxel-eluting stents to prevent coronary artery restenosis.

    PubMed

    Doggrell, Sheila A

    2004-11-01

    The restenosis rate is lower with stent implantation than with balloon angioplasty. Nevertheless, even with the use of stenting, restenosis still occurs in approximately one-third of patients with diabetes, small coronary vessels, and long lesions. The two drugs commonly used in eluting stents are sirolimus and paclitaxel. Systemically administered sirolimus decreased vascular proliferation in animal models. After preliminary trials showing benefit with sirolimus-eluting stents in de novo coronary lesions, the large-scale SIRIUS (Sirolomus-coated Bx Velocity balloon-expandable stent in the treatment of patients with de novo coronary artery lesions) trial was undertaken. SIRIUS showed that sirolimus reduced restenosis and target vessel revascularisation, compared to bare stents. These benefits were also apparent in the diabetic, and small- and long vessel subgroups. The RESEARCH (Rapamycin-eluting Stent Evaluated At Rotterdam Cardiology Hospital) registry have established that sirolimus-eluting stents are superior to bare stents in practice. Thus, the benefits of sirolimus-eluting stents over bare stents have been clearly established, and sirolimus can be considered the benchmark eluting agent for the prevention of coronary artery restenosis. Animal studies with paclitaxel-eluting stents, mainly in endothelium denuded normal vessels, have shown that paclitaxel reduces restenosis in the short-term, and that this may be a delay, rather than a prevention of restenosis. In clinical trials, stents eluting the paclitaxel derivative 7-hexanolytaxol, or paclitaxel without a polymer, delay rather than prevent restenosis. Slowing the release of paclitaxel with a polymer base in the TAXUS (Taxol(trade mark) [paclitaxel]-eluting stent) series of clinical trials reduced the revascularisation rate at 12 and 18 months, indicating that polymer-based paclitaxel is effective for longer. The results of the REALITY trial comparing the sirolimus- and paclitaxel-eluting stents in diabetics and other high-risk patients are eagerly awaited. PMID:15500367

  8. The anticancer efficacy of paclitaxel liposomes modified with mitochondrial targeting conjugate in resistant lung cancer.

    PubMed

    Zhou, Jia; Zhao, Wei-Yu; Ma, Xu; Ju, Rui-Jun; Li, Xiu-Ying; Li, Nan; Sun, Meng-Ge; Shi, Ji-Feng; Zhang, Cheng-Xiang; Lu, Wan-Liang

    2013-05-01

    Lung cancer is the leading cause of cancer-related death in humans and the multidrug resistance (MDR) is the major obstacle to successful chemotherapy of lung cancer. In this study, a d-?-tocopheryl polyethylene glycol 1000 succinate-triphenylphosphine conjugate (TPGS1000-TPP) was synthesized as the mitochondrial targeting molecule, and was incorporated onto the surface of paclitaxel liposomes to treat the drug-resistant lung cancer. Evaluations were performed on the human lung cancer A549 cells, the drug-resistant lung cancer A549/cDDP cells, and the drug-resistant lung cancer A549/cDDP cells xenografted nude mice. The yield of TPGS1000-TPP conjugate synthesized was about 50% and the particle size of targeting paclitaxel liposomes developed was approximately 80 nm. In comparison with taxol and regular paclitaxel liposomes, the targeting paclitaxel liposomes exhibited the strongest anticancer efficacy in vitro and in the drug-resistant A549/cDDP xenografted tumor model. The targeting paclitaxel liposomes could significantly enhance the cellular uptake, be selectively accumulated into the mitochondria, and cause the release of cytochrome C. This targeting delivery of drug initiated a cascade of caspase 9 and 3 reactions, activated the pro-apoptotic Bax and Bid proteins and suppressed the anti-apoptotic Bcl-2 protein, thereby enhancing the apoptosis by acting on the mitochondrial signaling pathways. In conclusion, the targeting paclitaxel liposomes have the potential to treat drug-resistant lung cancer. PMID:23422592

  9. Inhibition of glycogen synthase kinase 3beta activity with lithium prevents and attenuates paclitaxel-induced neuropathic pain

    PubMed Central

    Gao, Mei; Yan, Xisheng; Weng, Han-Rong

    2013-01-01

    Paclitaxel (taxol) is a first-line chemotherapy-drug used to treat many types of cancers. Neuropathic pain and sensory dysfunction are the major toxicities, which are dose-limiting and significantly reduce the quality of life in patients. Two known critical spinal mechanisms underlying taxol-induced neuropathic pain are an increased production of pro-inflammatory cytokines including interleukin-1? (IL-1?) and suppressed glial glutamate transporter activities. In this study, we uncovered that increased activation of glycogen synthase kinase 3beta (GSK3?) in the spinal dorsal horn was concurrently associated with increased protein expressions of GFAP, IL-1? and a decreased protein expression of glial glutamate transporter 1 (GLT-1), as well as the development and maintenance of taxol-induced neuropathic pain. The enhanced GSK3? activities were supported by the concurrently decreased AKT and mTOR activities. The changes of all these biomarkers were basically prevented when animals received pre-emptive lithium (a GSK3? inhibitor) treatment, which also prevented the development of taxol-induced neuropathic pain. Further, chronic lithium treatment, which began on day 11 after the first taxol injection, reversed the existing mechanical and thermal allodynia induced by taxol. The taxol-induced increased GSK3? activities and decreased AKT and mTOR activities in the spinal dorsal horn were also reversed by lithium. Meanwhile, protein expressions of GLT-1, GFAP and IL-1? in the spinal dorsal horn were improved. Hence, suppression of spinal GSK3? activities is a key mechanism used by lithium to reduce taxol-induced neuropathic pain, and targeting spinal GSK3? is an effective approach to ameliorate GLT-1 expression and suppress activation of astrocytes and IL-1? over-production in the spinal dorsal horn. PMID:24070631

  10. The current state of paclitaxel and radiation in the combined-modality therapy of non-small cell lung cancer

    Microsoft Academic Search

    Hak Choy; Rob MacRae

    2001-01-01

    The results of randomized trials have prompted an evolution in the treatment approach to inoperable locally advanced non-small cell lung cancer, from radio-therapy alone to sequential chemoradiotherapy and now to concurrent chemoradiotherapy. The improvement in outcome seen with a concurrent chemoradio-therapy approach may be because of spatial cooperation, enhanced radiosensitization, and\\/or enhanced cytotoxicity. The taxanes, specifically paclitaxel (Taxol; Bristol-Myers Squibb

  11. Paclitaxel in the treatment of carcinoma of the esophagus.

    PubMed

    Ajani, J A; Ilson, D H; Daugherty, K; Kelsen, D P

    1995-06-01

    Systemic chemotherapeutic agents, given either singly or in combination, have not affected the dismal prognosis of patients with metastatic or locoregional unresectable carcinoma of the esophagus. New active agents are needed to improve the outcome for these patients. A phase II study evaluated paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) administered by 24-hour intravenous infusion with granulocyte colony-stimulating factor support to patients with unresectable locoregional or metastatic carcinoma of the esophagus. Response rate, duration of response, and toxicity were assessed. No prior chemotherapy or biologic therapy was allowed, but radiotherapy to a limited field that did not compromise signal lesion evaluation could have been given. The starting paclitaxel dose was 250 mg/m2 repeated every 21 days. The study group included 44 men and seven women with a median age of 57 years and a median Zubrod performance status of I. Among 51 evaluable patients, one complete response and 15 partial responses (PRs) occurred, for a total response rate of 31%. In addition, 11 (22%) achieved a minor response. Among 33 patients with adenocarcinoma, 12 achieved either a complete response (one patient) or a PR (11 patients), and six patients had a minor response. Four of 18 patients with squamous cell carcinoma had a PR and five (28%) had a minor response. The median duration of PR was 17 weeks (range, 7 to 58 weeks). At a median follow-up of 12+ months, 28 patients are alive, with an actuarial median survival duration of 10.2 months (range, 2 to 20+ months). Paclitaxel was well tolerated. Granulocytopenia was frequent, resulting in 11 hospitalizations in nine patients. Grade 3 neuropathy was observed in three patients. Our data suggest that paclitaxel is active against both adenocarcinoma and squamous cell carcinoma of the esophagus. Plans to study paclitaxel in combination with cisplatin and 5-fluorouracil in this group of patients are under way. PMID:7541155

  12. 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.

  13. Paclitaxel formulations: challenges and novel delivery options.

    PubMed

    Nehate, Chetan; Jain, Sharad; Saneja, Ankit; Khare, Vaibhav; Alam, Noor; Dubey, Ravindra Dhar; Gupta, Prem N

    2014-01-01

    Paclitaxel (PTX), a taxane plant product, is one of the most effective broad-spectrum anti-cancer agents and approved for the treatment of a variety of cancers including ovarian, breast, lung, head and neck as well as Kaposi's sarcoma. Poor aqueous solubility and serious side effects associated with commercial preparation of PTX (Taxol®) triggered the development of alternative PTX formulations. Over past three decades, plethora of research work has been published towards the development of cremophor free and efficient formulations. Various nanocarrier systems including nanoparticles, liposomes, micelles, bioconjugates and dendrimers have been employed in order to improve PTX solubility and eliminate undesired side effects. These nanocarriers offer the advantage of high degree of encapsulation and cellular uptake, escape from elimination by P-glycoprotein (P-gp) mediated efflux, and can be explored for targeted drug delivery. The potential of these nanocarriers is reflected by the fact that various nanocarriers of PTX are in different stages of clinical trials and a few have already been commercialized including Abraxane®, Lipusu and Genexol PM®. This review focuses on the various challenges associated with PTX formulation development, limitations of existing formulations and novel approaches for the development of alternative formulations for PTX and also highlights the development of novel formulations in clinical settings. PMID:24909147

  14. 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

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

    PubMed

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

    2015-04-01

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

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

    SciTech Connect

    Werner, Michael E.; Cummings, Natalie D.; Sethi, Manish; Wang, Edina C.; Sukumar, Rohit [Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina (United States) [Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina (United States); Carolina Center for Cancer Nanotechnology Excellence, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina (United States); Moore, Dominic T. [Division of Biostatistics and Data Management, Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina (United States)] [Division of Biostatistics and Data Management, Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina (United States); Wang, Andrew Z., E-mail: zawang@med.unc.edu [Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina (United States); Carolina Center for Cancer Nanotechnology Excellence, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina (United States)

    2013-07-01

    Purpose: A key research objective in radiation oncology is to identify agents that can improve chemoradiation therapy. Nanoparticle (NP) chemotherapeutics possess several properties, such as preferential accumulation in tumors, that are uniquely suited for chemoradiation therapy. To facilitate the clinical translation of NP chemotherapeutics in chemoradiation therapy, we conducted preclinical evaluation of Genexol-PM, the only clinically approved NP chemotherapeutic with a controlled drug release profile, as a radiosensitizer using non-small cell lung cancer (NSCLC) as a model disease. Methods and Materials: The physical characteristics and drug release profile of Genexol-PM were characterized. Genexol-PM's efficacy as a radiosensitizer was evaluated in vitro using NSCLC cell lines and in vivo using mouse xenograft models of NSCLC. Paclitaxel dose to normal lung and liver after Genexol-PM administration were quantified and compared with that after Taxol administration. Results: Genexol-PM has a size of 23.91 ± 0.41 nm and surface charge of ?8.1 ± 3.1 mV. It releases paclitaxel in a controlled release profile. In vitro evaluation of Genexol-PM as a radiosensitizer showed it is an effective radiosensitizer and is more effective than Taxol, its small molecule counterpart, at the half maximal inhibitory concentration. In vivo study of Genexol-PM as a radiosensitizer demonstrated that it is more effective as a radiosensitizer than Taxol. We also found that Genexol-PM leads to lower paclitaxel exposure to normal lung tissue than Taxol at 6 hours postadministration. Conclusions: We have demonstrated that Genexol-PM is more effective than Taxol as a radiosensitizer in the preclinical setting and holds high potential for clinical translation. Our data support the clinical evaluation of Genexol-PM in chemoradiation therapy for NSCLC.

  17. Synthesis and characterization of polymeric nanospheres loaded with the anticancer drug paclitaxel and magnetic particles

    NASA Astrophysics Data System (ADS)

    Závišová, Vlasta; Koneracká, Martina; Mú?ková, Marta; Kop?anský, Peter; Tomašovi?ová, Natália; Lancz, Gábor; Timko, Milan; Pätoprstá, Božena; Bartoš, Peter; Fabián, Martin

    2009-05-01

    We describe the preparation (by nanoprecipitation) and characterization of nanospheres (NPs) for magnetic drug targeting made of a magnetic fluid with poly(ethylene glycol), poly( D, L-lactic- co-glycolic acid) (PLGA), and the anticancer drug paclitaxel (Taxol ®). Infrared spectroscopy confirmed the incorporation of the drug in the PLGA NPs, which were also characterized in terms of morphology, size (typical diameter 200-250 nm) and colloidal stability in aqueous solutions of NaCl. Drug release and in vivo toxicity experiments of the prepared samples were performed. Their stability, magnetic properties (superparamagnetism), and lethal dose were found to be acceptable for the proposed application in cancer therapy.

  18. Synergistic cytotoxicity of cisplatin and Taxol in overcoming Taxol resistance through the inhibition of LDHA in oral squamous cell carcinoma

    PubMed Central

    FENG, LIN; E, LING-LING; SOLOVEIV, MICHAIL MICHAILOVICH; WANG, DONG-SHENG; ZHANG, BO; DONG, YU WAN; LIU, HONG-CHEN

    2015-01-01

    The development of chemoresistance in patients represents a major challenge in cancer treatment. Lactate dehydrogenase-A (LDHA) is one of the principle isoforms of LDH that is expressed in breast tissue, controlling the conversion of pyruvate to lactate and also playing a significant role in the metabolism of glucose. The aim of this study was to identify whether LDHA was involved in oral cancer cell resistance to Taxol and whether the downregulation of LDHA, as a result of cisplatin treatment, may overcome Taxol resistance in human oral squamous cells. The OECM-1 oral epidermal carcinoma cell line was used, which has been widely used as a model of oral cancer in previous studies. The role of LDHA in Taxol and cisplatin resistance were investigated and the synergistic cytotoxicity of cisplatin and/or Taxol in oral squamous cells was analyzed. Cell viability was analyzed by MTT assay, LDHA expression was analyzed by western blot analysis and siRNA tranfection was performed to knock down LDHA expression. The present study results showed that decreased levels of LDHA were responsible for the resistance of oral cancer cells to cisplatin (CDDP). CDDP treatments downregulated LDHA expression, and lower levels of LDHA were detected in the CDDP-resistant oral cancer cells compared with the CDDP-sensitive cells. By contrast, the Taxol-resistant cancer cells showed elevated LDHA expression levels. In addition, small interfering RNA-knockdown of LDHA sensitized the cells to Taxol, but desensitized them to CDDP treatment, while exogenous expression of LDHA sensitized the cells to CDDP, but desensitized them to Taxol. The present study also revealed the synergistic cytotoxicity of CDDP and Taxol for killing oral cancer cells through the inhibition of LDHA. This study highlights LDHA as a novel therapeutic target for overcoming Taxol resistance in oral cancer patients using the combined treatments of Taxol and CDDP.

  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. Paclitaxel and immune system

    Microsoft Academic Search

    Aqeel Javeed; Muhammad Ashraf; Amjad Riaz; Aamir Ghafoor; Sheryar Afzal; Muhammad Mahmood Mukhtar

    2009-01-01

    Chemotherapy remains the mainstay of treatment for both early stage as well as metastatic tumors. Paclitaxel (PTX), a novel anticancer drug, is a prominent taxane which is active against a broad range of tumors that are generally considered to be refractory to conventional chemotherapy, with benefits gained in terms of overall survival and disease-free survival. PTX is initially characterized as

  1. 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

  2. Pharmacologic sensitivity of Paclitaxel to its delivery vehicles drives distinct clinical outcomes of Paclitaxel formulations.

    PubMed

    Li, Yan; Chen, Nianhang; Palmisano, Maria; Zhou, Simon

    2015-04-01

    Paclitaxel, an effective antitumor agent, is formulated in various vehicles serving as carriers to deliver the hydrophobic paclitaxel to tissue. The approved formulations in the U.S. are paclitaxel formulated in Cremophor EL (currently known as Kolliphor EL) and nanoparticle albumin-bound paclitaxel (nab-paclitaxel). Despite having the same active ingredient (paclitaxel), different formulations produce distinct products with unique efficacy and safety profiles. A semimechanistic model was developed to describe the pharmacologic sensitivity of paclitaxel under different formulations. Circulating paclitaxel concentration data from patients treated with nab-paclitaxel or Cremophor EL-paclitaxel were analyzed in NONMEM using a semimechanistic model with simultaneous disposition of paclitaxel-carrier complexes and the total paclitaxel released from the complexes. The key factors driving paclitaxel exposure in circulation and peripheral tissues were explored via sensitivity analysis. The rapid decline of total paclitaxel concentration following intravenous administration of nab-paclitaxel and Cremophor EL-paclitaxel was attributed to rapid tissue distribution of the paclitaxel-carrier complexes, with minor contribution of free and protein-bound paclitaxel. Distribution of nab-paclitaxel to peripheral tissue was 4-fold faster and 10-fold more extensive than that of Cremophor EL-paclitaxel micelles, resulting in distinct tissue paclitaxel profiles. Sensitivity analyses showed the plasma paclitaxel-time profile was insensitive to the rapid rates of tissue distribution and decomposition of paclitaxel-carrier complexes but that the tissue distribution profile of paclitaxel was highly sensitive. Tissue distribution of paclitaxel is carrier complex system-dependent. Different delivery systems result in distinct tissue paclitaxel profiles but similar paclitaxel concentration-time profiles in plasma or blood, rendering the paclitaxel plasma profile a poor surrogate for its clinical outcome. PMID:25714793

  3. Tumor-targeted delivery of Paclitaxel using low density lipoprotein-mimetic solid lipid nanoparticles.

    PubMed

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

    2015-04-01

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

  4. 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

  5. Possible Side Effects of Paclitaxel

    Cancer.gov

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

  6. Taxol, a microtubule stabilizer, prevents ischemic ventricular arrhythmias in rats

    PubMed Central

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

    2011-01-01

    Abstract Microtubule integrity is important in cardio-protection, and microtubule disruption has been implicated in the response to ischemia in cardiac myocytes. However, the effects of Taxol, a common microtubule stabilizer, are still unknown in ischemic ventricular arrhythmias. The arrhythmia model was established in isolated rat hearts by regional ischemia, and myocardial infarction model by ischemia/reperfusion. Microtubule structure was immunohistochemically measured. The potential mechanisms were studied by measuring reactive oxygen species (ROS), activities of oxidative enzymes, intracellular calcium concentration ([Ca2+]i) and Ca2+ transients by using fluorometric determination, spectrophotometric assays and Fura-2-AM and Fluo-3-AM, respectively. The expression and activity of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) was also examined using real-time polymerase chain reaction, Western blot and pyruvate/Nicotinamide adenine dinucleotide-coupled reaction. Our data showed that Taxol (0.1, 0.3 and 1 ?M) effectively reduced the number of ventricular premature beats and the incidence and duration of ventricular tachycardia. The infarct size was also significantly reduced by Taxol (1 ?M). At the same time, Taxol preserved the microtubule structure, increased the activity of mitochondrial electron transport chain complexes I and III, reduced ROS levels, decreased the rise in [Ca2+]i and preserved the amplitude and decay times of Ca2+ transients during ischemia. In addition, SERCA2a activity was preserved by Taxol during ischemia. In summary, Taxol prevents ischemic ventricular arrhythmias likely through ameliorating abnormal calcium homeostasis and decreasing the level of ROS. This study presents evidence that Taxol may be a potential novel therapy for ischemic ventricular arrhythmias. PMID:20561109

  7. Identification and expression analysis of methyl jasmonate responsive ESTs in paclitaxel producing Taxus cuspidata suspension culture cells

    PubMed Central

    2012-01-01

    Background Taxol® (paclitaxel) promotes microtubule assembly and stabilization and therefore is a potent chemotherapeutic agent against wide range of cancers. Methyl jasmonate (MJ) elicited Taxus cell cultures provide a sustainable option to meet the growing market demand for paclitaxel. Despite its increasing pharmaceutical importance, the molecular genetics of paclitaxel biosynthesis is not fully elucidated. This study focuses on identification of MJ responsive transcripts in cultured Taxus cells using PCR-based suppression subtractive hybridization (SSH) to identify genes involved in global pathway control. Results Six separate SSH cDNA libraries of paclitaxel-accumulating Taxus cuspidata P991 cell lines were constructed at three different post-elicitation time points (6h, 18h and 5 day) to identify genes that are either induced or suppressed in response to MJ. Sequencing of 576 differentially screened clones from the SSH libraries resulted in 331 unigenes. Functional annotation and Gene Ontology (GO) analysis of up-regulated EST libraries showed enrichment of several known paclitaxel biosynthetic genes and novel transcripts that may be involved in MJ-signaling, taxane transport, or taxane degradation. Macroarray analysis of these identified genes unravelled global regulatory expression of these transcripts. Semi-quantitative RT-PCR analysis of a set of 12 candidate genes further confirmed the MJ-induced gene expression in a high paclitaxel accumulating Taxus cuspidata P93AF cell line. Conclusions This study elucidates the global temporal expression kinetics of MJ responsive genes in Taxus suspension cell culture. Functional characterization of the novel genes identified in this study will further enhance the understanding of paclitaxel biosynthesis, taxane transport and degradation. PMID:22530557

  8. The In vitro Subcellular Localization and In vivo Efficacy of Novel Chitosan\\/GMO Nanostructures containing Paclitaxel

    Microsoft Academic Search

    W. J. Trickler; A. A. Nagvekar; A. K. Dash

    2009-01-01

    Purpose  To determine the in vitro sub-cellular localization and in vivo efficacy of chitosan\\/GMO nanostructures containing paclitaxel (PTX) compared to a conventional PTX treatment (Taxol®).\\u000a \\u000a \\u000a \\u000a Methods  The sub-cellular localization of coumarin-6 labeled chitosan\\/GMO nanostructures was determined by confocal microscopy in MDA-MB-231\\u000a cells. The antitumor efficacy was evaluated in two separate studies using FOX-Chase (CB17) SCID Female-Mice MDA-MB-231 xenograph\\u000a model. Treatments consisted of

  9. Taxol and Taxane Production by Taxomyces andreanae, an Endophytic Fungus of Pacific Yew

    Microsoft Academic Search

    Andrea Stierle; Gary Strobel; Donald Stierle

    1993-01-01

    Taxomyces andreanae, a fungal endophyte, was isolated from the phloem (inner bark) of the Pacific yew, Taxus brevifolia. The fungus is hyphomyceteous and, when grown in a semi-synthetic liquid medium, produced taxol and related compounds. Taxol was identified by mass spectrometry, chromatography, and reactivity with monoclonal antibodies specific for taxol. Both [1-14C]acetic acid and L-[U-14C]phenylalanine served as precursors of [14C]taxol

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

    PubMed Central

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

    2015-01-01

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

  11. 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.

  12. Low-dose paclitaxel ameliorates fibrosis in the remnant kidney model by down-regulating miR-192.

    PubMed

    Sun, Lin; Zhang, Dongshan; Liu, Fuyou; Xiang, Xudong; Ling, Guanghui; Xiao, Li; Liu, Yinghong; Zhu, Xuejing; Zhan, Ming; Yang, Yeyi; Kondeti, Vinay K; Kanwar, Yashpal S

    2011-11-01

    Transforming growth factor (TGF)-? has been shown to play a central role in the development of tubulointerstitial fibrosis, which can be corrected via treatment with paclitaxel. The biology of microRNA (miR) can be modulated by paclitaxel. We hypothesized that paclitaxel may attenuate renal fibrosis in a rat model of remnant kidney disease by inhibiting TGF-? induced-miRs. Rats in groups of 12 were subjected to 5/6 nephrectomy and received low-dose intraperitoneal injection of paclitaxel. Renal functions were assessed at 8 weeks. The TGF-? signalling cascade and ECM proteins were evaluated by real-time polymerase chain reaction (TRT-PCR) and immunofluorescence microscopy. Animals with remnant kidneys developed hypertension, which was not relieved with paclitaxel treatment. However, paclitaxel treatment resulted in dampening the proteinuric response, reduction in serum BUN, creatinine levels and urine protein : creatinine ratio and normalization of creatinine clearance. These effects were accompanied by the inhibition of Smad2/3 activation, attenuation of renal fibrosis and normalization of integrin-linked kinase (ILK), COL(I)A1, COL(IV)A2 and ?-SMA expression. Also, paclitaxel down-regulated the expression of miR-192, miR-217 and miR -377, while miR-15 was up-regulated in the remnant kidney. In vitro, in tubular epithelial cells (NRK-52E), paclitaxel also inhibited TGF-?1-induced Smad2/3 activation and normalized ILK, COL(I)A1, COL(IV)A2 and ?-SMA expression. Furthermore, ChIP analyses indicated that Taxol suppressed Smad3-mediated miR-192 transcriptional activity. Over-expression of miR-192 in NRK-52E mimicked the changes seen in the remnant kidney, while inclusion of miR-192 inhibitor in the culture medium blocked TGF-?1-induced COL(I)A1 and COL(IV)A2 expression, while ILK and ?-SMA were unaffected. These data suggest that low-dose paclitaxel ameliorates renal fibrosis via modulating miR-192 pathobiology and TGF-?/Smad signalling. PMID:21984124

  13. Polyelectrolyte multilayer nanoshells with hydrophobic nanodomains for delivery of Paclitaxel

    PubMed Central

    Jing, Jing; Guillot, Raphael; Paintrand, Isabelle; Auzely-Velty, Rachel; Picart, Catherine

    2014-01-01

    Efficient and effective delivery of poorly water-soluble drug molecules, which constitute a large part of commercially available drugs, is a major challenge in the field of drug delivery. Several drugs including paclitaxel (PTX) which are used for cancer treatment are hydrophobic, exhibit poor aqueous solubility and need to be delivered using an appropriate carrier. In the present work, we engineered Taxol-loaded polyelectrolyte films and microcapsules by pre-complexing PTX with chemically modified derivative of hyaluronic acid (alkylamino hydrazide) containing hydrophobic nanocavities, and subsequent assembly with either poly(L-lysine) (PLL) or quaternized chitosan (QCHI) as polycations. The PTX loading capacity of the films was found to be dependent on number of layers in the films as well as on the initial concentration of PTX pre-complexed to hydrophobic HA, with a loading capacity up to 5000-fold the initial PTX concentration. The films were stable in physiological medium and were degraded in the presence of hyaluronidase. The PTX-loaded microcapsules were found to decrease the viability and proliferation of MDA MB 231 breast cancer cells, while unloaded microcapsules did not impact cell viability. All together, our results highlight the potential of hyaluronan-based assemblies containing hydrophobic nanodomains for hydrophobic drug delivery. PMID:22300622

  14. 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

  15. Kinetics of mitotic arrest and apoptosis in murine mammary and ovarian tumors treated with taxol

    Microsoft Academic Search

    Luka Milas; Nancy R. Hunter; Belma Kurdoglu; Kathryn A. Mason; Raymond E. Meyn; L. C. Stephens; Lester J. Peters

    1995-01-01

    The kinetics of taxol-induced mitotic arrest and apoptosis in murine mammary carcinoma MCA-4 and ovarian carcinoma OCA-I tumors were determined to establish a possible causative relationship between mitotic arrest and apoptosis and to see whether these cellular effects of taxol would correlate with the extent of its antitumor efficacy. Mice bearing 8-mm tumors in a hind leg were given taxol

  16. 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

  17. 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

  18. Engineering Isoprenoid Biosynthesis in Artemisia annua L. for the Production of Taxadiene: A Key Intermediate of Taxol

    PubMed Central

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

    2015-01-01

    Taxadiene is the first committed precursor to paclitaxel, marketed as Taxol, arguably the most important anticancer agent against ovarian and breast cancer. In Taxus, taxadiene is directly synthesized from geranylgeranyl diphosphate (GGPP) that is the common precursor for diterpenoids and is found in most plants and microbes. In this study, Artemisia annua L., a Chinese medicinal herb that grows fast and is rich in terpenoids, was used as a genetic engineering host to produce taxadiene. The TXS (taxadiene synthase) gene, cloned from Taxus and inserted into pCAMBIA1304, was transformed into Artemisia annua L. using the Agrobacterium tumefaciens-mediated method. Thirty independent transgenic plants were obtained, and GC-MS analysis was used to confirm that taxadiene was produced and accumulated up to 129.7??g/g dry mass. However, the high expression of TXS did not affect plant growth or photosynthesis in transgenic Artemisia annua L. It is notable that artemisinin is produced and stored in leaves and most taxadiene accumulated in the stem of transgenic Artemisia annua L., suggesting a new way to produce two important compounds in one transgenic plant: leaves for artemisinin and stem for taxadiene. Overall, this study demonstrates that genetic engineering of the taxane biosynthetic pathway in Artemisia annua L. for the production of taxadiene is feasible. PMID:25705665

  19. Engineering Isoprenoid Biosynthesis in Artemisia annua L. for the Production of Taxadiene: A Key Intermediate of Taxol.

    PubMed

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

    2015-01-01

    Taxadiene is the first committed precursor to paclitaxel, marketed as Taxol, arguably the most important anticancer agent against ovarian and breast cancer. In Taxus, taxadiene is directly synthesized from geranylgeranyl diphosphate (GGPP) that is the common precursor for diterpenoids and is found in most plants and microbes. In this study, Artemisia annua L., a Chinese medicinal herb that grows fast and is rich in terpenoids, was used as a genetic engineering host to produce taxadiene. The TXS (taxadiene synthase) gene, cloned from Taxus and inserted into pCAMBIA1304, was transformed into Artemisia annua L. using the Agrobacterium tumefaciens-mediated method. Thirty independent transgenic plants were obtained, and GC-MS analysis was used to confirm that taxadiene was produced and accumulated up to 129.7??g/g dry mass. However, the high expression of TXS did not affect plant growth or photosynthesis in transgenic Artemisia annua L. It is notable that artemisinin is produced and stored in leaves and most taxadiene accumulated in the stem of transgenic Artemisia annua L., suggesting a new way to produce two important compounds in one transgenic plant: leaves for artemisinin and stem for taxadiene. Overall, this study demonstrates that genetic engineering of the taxane biosynthetic pathway in Artemisia annua L. for the production of taxadiene is feasible. PMID:25705665

  20. Biological assessment of triazine dendrimer: toxicological profiles, solution behavior, biodistribution, drug release and efficacy in a PEGylated, paclitaxel construct.

    PubMed

    Lo, Su-Tang; Stern, Stephan; Clogston, Jeffrey D; Zheng, Jiwen; Adiseshaiah, Pavan P; Dobrovolskaia, Marina; Lim, Jongdoo; Patri, Anil K; Sun, Xiankai; Simanek, Eric E

    2010-08-01

    The physicochemical characteristics, in vitro properties, and in vivo toxicity and efficacy of a third generation triazine dendrimer bearing approximately nine 2 kDa polyethylene glycol chains and twelve ester linked paclitaxel groups are reported. The hydrodynamic diameter of the neutral construct varies slightly with aqueous solvent ranging from 15.6 to 19.4 nm. Mass spectrometry and light scattering suggest radically different molecular weights with the former approximately 40 kDa mass consistent with expectation, and the latter 400 kDa mass consistent with a decameric structure and the observed hydrodynamic radii. HPLC can be used to assess purity as well as paclitaxel release, which is insignificant in organic solvents or aqueous solutions at neutral and low pH. Paclitaxel release occurs in vitro in human, rat, and mouse plasma and is nonlinear, ranging from 7 to 20% cumulative release over a 48 h incubation period. The construct is 2-3 orders of magnitude less toxic than Taxol by weight in human hepatocarcinoma (Hep G2), porcine renal proximal tubule (LLC-PK1), and human colon carcinoma (LS174T) cells, but shows similar cytotoxicity to Abraxane in LS174T cells. Both Taxol and the construct appear to induce caspase 3-dependent apoptosis. The construct shows a low level of endotoxin, is not hemolytic and does not induce platelet aggregation in vitro, but does appear to reduce collagen-induced platelet aggregation in vitro. Furthermore, the dendrimer formulation slightly activates the complement system in vitro due most likely to the presence of trace amounts (<1%) of free paclitaxel. An animal study provided insight into the maximum tolerated dose (MTD) wherein 10, 25, 50, and 100 mg of paclitaxel/kg of construct or Abraxane were administered once per week for three consecutive weeks to non tumor bearing athymic nude mice. The construct showed in vivo toxicity comparable to that of Abraxane. Both formulations were found to be nontoxic at the administered doses, and the dendrimer had an acute MTD greater than the highest dose administered. In a prostate tumor model (PC-3-h-luc), efficacy was observed over 70 days with an arrest of tumor growth and lack of luciferase activity observed in the twice treated cohort. PMID:20481608

  1. Pseudoneoplastic proliferation of histiocytes with paclitaxel-induced ultrastructural changes in a mastectomy specimen.

    PubMed

    Lemos, Luciano B; Qu, Zhenhong; Garg, Karuna; Papasozomenos, Sozos

    2004-10-01

    A 49-year-old Hispanic woman with a T4N1M0 infiltrating duct carcinoma of the left breast underwent four courses of FAC (doxorubicin 86 mg, 5-fluorouracil 860 mg, cyclophosphamide 86 mg, and dexamethasone 10 mg) adjuvant chemotherapy plus four courses of paclitaxel (Taxol; Bristol-Myers Squibb Oncology, Princeton, NJ) and subsequent mastectomy. The tumor shrunk from 6.5 cm to 2.5 cm after the treatment. The residual tumor in the surgical specimen measured 1.5 cm with eight positive out of 24 axillary lymph nodes. The tumor showed typical chemotherapy changes and a massive proliferation of histiocytes that mimicked a neoplasm. A nodular proliferation of the same cells in one axillary node raised the impression of a second malignant tumor in the breast spreading to the node. The histiocytic cells contained lamellar and coarse periodic acid-Schiff-positive material distending their cytoplasm and they were strongly positive for CD68 and negative for CD1a, pan keratin, and S-100. These findings ruled out histiocytoid carcinoma, granular cell tumor, and Erdheim-Chester disease. The proliferating histiocytes had ultrastructural findings of paclitaxel-induced cytotoxicity with disorganized stacks of intermediate filaments positive for vimentin by immunostains and fewer masses of tubulin. The treated breast carcinoma cells were tubulin-positive but the proliferating histiocytes were tubulin-negative. PMID:15494938

  2. Taxol produced from endophytic fungi induces apoptosis in human breast, cervical and ovarian cancer cells.

    PubMed

    Wang, Xin; Wang, Chao; Sun, Yu-Ting; Sun, Chuan-Zhen; Zhang, Yue; Wang, Xiao-Hua; Zhao, Kai

    2015-01-01

    Currently, taxol is mainly extracted from the bark of yews; however, this method can not meet its increasing demand on the market because yews grow very slowly and are a rare and endangered species belonging to first- level conservation plants. Recently, increasing efforts have been made to develop alternative means of taxol production; microbe fermentation would be a very promising method to increase the production scale of taxol. To determine the activities of the taxol extracted from endophytic fungus N. sylviforme HDFS4-26 in inhibiting the growth and causing the apoptosis of cancer cells, on comparison with the taxol extracted from the bark of yew, we used cellular morphology, cell counting kit (CCK-8) assay, staining (HO33258/PI and Giemsa), DNA agarose gel electrophoresis and flow cytometry (FCM) analyses to determine the apoptosis status of breast cancer MCF-7 cells, cervical cancer HeLa cells and ovarian cancer HO8910 cells. Our results showed that the fungal taxol inhibited the growth of MCF-7, HeLa and HO8910 cells in a dose-and time-dependent manner. IC50 values of fungal taxol for HeLa, MCF-7 and HO8910 cells were 0.1-1.0 ?g/ml, 0.001-0.01 ?g/ml and 0.01- 0.1 ?g/ml, respectively. The fungal taxol induced these tumor cells to undergo apoptosis with typical apoptotic characteristics, including morphological changes for chromatin condensation, chromatin crescent formation, nucleus fragmentation, apoptotic body formation and G2/M cell cycle arrest. The fungal taxol at the 0.01-1.0 ?g/ ml had significant effects of inducing apoptosis between 24-48 h, which was the same as that of taxol extracted from yews. This study offers important information and a new resource for the production of an important anticancer drug by endofungus fermentation. PMID:25640339

  3. Proteomic investigation of taxol and taxotere resistance and invasiveness in a squamous lung carcinoma cell line.

    PubMed

    Murphy, L; Henry, M; Meleady, P; Clynes, M; Keenan, J

    2008-09-01

    Pulse selections on a chemotherapy naive squamous lung carcinoma cell line, SKMES-1, with clinically relevant concentrations of taxanes (taxol or taxotere) resulted in the development of a stable taxotere-resistant variant, SKMES-1-Taxotere and an unstable taxol-resistant variant, SKMES-1-Taxol. Both variants exhibited increased invasiveness in vitro. The unstable nature of SKMES-1-Taxol facilitated looking at factors involved in loss of taxol resistance and increased invasion. The taxotere and taxol-resistant cell lines were 5.9-fold and 12.5-fold resistant to taxotere and taxol respectively. Alterations in expression of/or point mutations in tubulin, the main target of taxanes, is a major mechanism or resistance. However, alterations in expression of beta tubulin were not consistent in the taxane-selected variants. Cross-resistance to adriamycin, vincristine and etoposide (VP-16) was consistent with overexpression of P-glycoprotein (P-gp). However, P-gp alone is not sufficient to confer the complete multiple drug resistance phenotype as all cell lines exhibited cross-resistance to 5-Fluorouracil (5-FU) and more than one mechanism has been linked to taxane resistance. There was no correlation between the fall of taxol resistance in SKMES-1-Taxol and P-gp expression indicating the loss in resistance to be independent of P-gp expression. Furthermore, resistance to the other drugs was not unstable in SKMES-1-Taxol suggesting some parallel mechanisms of resistance. Two-dimensional electrophoresis coupled with matrix assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry was used to identify alterations in expression of specific proteins associated with taxane resistance. A large number of differentially regulated proteins were identified in the resistant and invasive variants affecting cellular processes including stress response, protein turnover and cytoskeleton proteins. PMID:18503785

  4. Possible Side Effects of Carboplatin and Paclitaxel

    Cancer.gov

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

  5. "OA02" peptide facilitates the precise targeting of paclitaxel-loaded micellar nanoparticles to ovarian cancer in vivo.

    PubMed

    Xiao, Kai; Li, Yuanpei; Lee, Joyce S; Gonik, Abby M; Dong, Tiffany; Fung, Gabriel; Sanchez, Eduardo; Xing, Li; Cheng, Holland R; Luo, Juntao; Lam, Kit S

    2012-04-15

    Micellar nanoparticles based on linear polyethylene glycol (PEG) block dendritic cholic acids (CA) copolymers (telodendrimers), for the targeted delivery of chemotherapeutic drugs in the treatment of cancers, are reported. The micellar nanoparticles have been decorated with a high-affinity "OA02" peptide against ?-3 integrin receptor to improve the tumor-targeting specificity which is overexpressed on the surface of ovarian cancer cells. "Click chemistry" was used to conjugate alkyne-containing OA02 peptide to the azide group at the distal terminus of the PEG chain in a representative PEG(5k)-CA(8) telodendrimer (micelle-forming unit). The conjugation of OA02 peptide had negligible influence on the physicochemical properties of PEG(5k)-CA(8) nanoparticles and as hypothesized, OA02 peptide dramatically enhanced the uptake efficiency of PEG(5k)-CA(8) nanoparticles (NP) in SKOV-3 and ES-2 ovarian cancer cells via receptor-mediated endocytosis, but not in ?-3 integrin-negative K562 leukemia cells. When loaded with paclitaxel, OA02-NPs had significantly higher in vitro cytotoxicity against both SKOV-3 and ES-2 ovarian cancer cells as compared with nontargeted nanoparticles. Furthermore, the in vivo biodistribution study showed OA02 peptide greatly facilitated tumor localization and the intracellular uptake of PEG(5k)-CA(8) nanoparticles into ovarian cancer cells as validated in SKOV3-luc tumor-bearing mice. Finally, paclitaxel (PTX)-loaded OA02-NPs exhibited superior antitumor efficacy and lower systemic toxicity profile in nude mice bearing SKOV-3 tumor xenografts, when compared with equivalent doses of nontargeted PTX-NPs as well as clinical paclitaxel formulation (Taxol). Therefore, OA02-targeted telodendrimers loaded with paclitaxel have great potential as a new therapeutic approach for patients with ovarian cancer. PMID:22396491

  6. Resveratrol confers resistance against taxol via induction of cell cycle arrest in human cancer cell lines.

    PubMed

    Mao, Qi-Qi; Bai, Yu; Lin, Yi-Wei; Zheng, Xiang-Yi; Qin, Jie; Yang, Kai; Xie, Li-Ping

    2010-11-01

    Resveratrol, which is highly concentrated in the skin of grapes and is abundant in red wine, has been demonstrated to account for several beneficial properties, including antioxidant, anticoagulant, anti-inflammatory and anticancer effects. Taxol is a microtubule-stabilizing drug that has been extensively used as effective chemotherapeutic agents in the treatment of solid tumors. Here, we investigated whether the combination of the two compounds would yield increased antitumor efficacy in human cancer cells. Unexpectedly, resveratrol effectively prevented tumor cell death induced by taxol in 5637 bladder cancer cells. This pronounced antagonistic function of resveratrol against taxol was associated with changes in multiple signal transduction pathways, but not with tubulin polymerization. Importantly, cell cycle analysis showed that resveratrol prevented the cells from entering into mitosis, the phase in which taxol exerts its action. Furthermore, resveratrol blocked the cytotoxic effects of vinblastine but not cisplatin in 5637 cells. Interestingly, resveratrol pre-treatment followed by taxol resulted in synergistic cytotoxicity. Finally, we extended our studies to various human cancer cell lines. Taken together, our results indicate that resveratrol may have the potential to negate the therapeutic efficacy of taxol and suggest that consumption of resveratrol-related products may be contraindicated during cancer therapy with taxol. PMID:20521268

  7. 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

  8. Linear-Dendritic Copolymer Composed of Polyethylene Glycol and All-trans-Retinoic Acid as Drug Delivery Platform for Paclitaxel against Breast Cancer.

    PubMed

    Li, Jianfeng; Jiang, Xutao; Guo, Yubo; An, Sai; Kuang, Yuyang; Ma, Haojun; He, Xi; Jiang, Chen

    2015-03-18

    A new linear-dendritic copolymer composed of poly(ethylene glycol) (PEG) and all-trans-retinoic acid (ATRA) was synthesized as the anticancer drug delivery platform (PEG-G3-RA8). It can self-assemble into core-shell micelles with a low critical micelle concentration (CMC) at 3.48 mg/L. Paclitaxel (PTX) was encapsulated into PEG-G3-RA8 to form PEG-G3-RA8/PTX micelles for breast cancer treatment. The optimized formulation had high drug loading efficacy (20% w/w of drug copolymer ratio), nanosized diameter (27.6 nm), and narrow distribution (PDI = 0.103). Compared with Taxol, PEG-G3-RA8/PTX remained highly stable in the serum-containing cell medium and exhibited 4-fold higher cellular uptake. Besides, near-infrared fluorescence (NIR) optical imaging results indicated that fluorescent probe loaded micelle had a preferential accumulation in breast tumors. Pharmacokinetics and biodistribution studies (10 mg/kg) showed the area under the plasma concentration-time curve (AUC0-?) and mean residence time (MRT0-?) for PEG-G3-RA8/PTX and Taxol were 12.006 ± 0.605 mg/L h, 2.264 ± 0.041 h and 15.966 ± 1.614 mg/L h, 1.726 ± 0.097 h, respectively. The tumor accumulation of PEG-G3-RA8/PTX group was 1.89-fold higher than that of Taxol group 24 h postinjection. With the advantages like efficient cellular uptake and preferential tumor accumulation, PEG-G3-RA8/PTX showed superior therapeutic efficacy on MCF-7 tumor bearing mice compared to Taxol. PMID:25675244

  9. Amphiphilic carboxymethyl chitosan-quercetin conjugate with P-gp inhibitory properties for oral delivery of paclitaxel.

    PubMed

    Wang, Xiaoying; Chen, Yihang; Dahmani, Fatima Zohra; Yin, Lifang; Zhou, Jianping; Yao, Jing

    2014-08-01

    An amphiphilic carboxymethyl chitosan-quercetin (CQ) conjugate was designed and synthesized for oral delivery of paclitaxel (PTX) to improve its oral bioavailability by increasing its water solubility and bypassing the P-gp drug efflux pumps. CQ conjugate had low critical micelle concentration (55.14 ?g/mL), and could self assemble in aqueous condition to form polymeric micelles (PMs). PTX-loaded CQ PMs displayed a particle size of 185.8 ± 4.6 nm and polydispersity index (PDI) of 0.134 ± 0.056. The drug-loading content (DL) and entrapment efficiency (EE) were 33.62 ± 1.34% and 85.63 ± 1.26%, respectively. Moreover, PTX-loaded CQ PMs displayed similar sustained-release profile in simulated gastrointestinal fluids (pH 1.2/pH 6.8) and PBS (pH 7.4). In situ intestinal absorption experiment showed that PTX-loaded CQ PMs significantly improved the effective permeability of PTX as compared to verapamil (P < 0.01). Likewise, PTX-loaded CQ PMs significantly enhanced the oral bioavailability of PTX, resulting in strong antitumor efficacy against tumor xenograft models with better safety profile as compared to Taxol(®) and Taxol(®) with verapamil. Overall, the results implicate that CQ PMs are promising vehicles for the oral delivery of water-insoluble anticancer drugs. PMID:24927684

  10. Efficacy of taxol in the orpk mouse model of polycystic kidney disease

    Microsoft Academic Search

    Carla S. Sommardahl; Richard P. Woychik; William E. Sweeney; Ellis D. Avner; J. Erby Wilkinson

    1997-01-01

    .   Polycystic kidney disease (PKD) a is common disease in the human population that can lead to renal failure and death. Taxol\\u000a has recently been reported to be of therapeutic benefit in the cpk mouse model of PKD. To determine whether these results also apply to other models of PKD, we studied the effects of taxol\\u000a treatment on the development

  11. 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

  12. Paclitaxel-loaded PCL-TPGS nanoparticles: in vitro and in vivo performance compared with Abraxane®.

    PubMed

    Bernabeu, Ezequiel; Helguera, Gustavo; Legaspi, Maria J; Gonzalez, Lorena; Hocht, Christian; Taira, Carlos; Chiappetta, Diego A

    2014-01-01

    The purpose of this work was to develop Cremophor(®) EL-free nanoparticles (NPs) loaded with Paclitaxel (PTX) in order to improve the drug i.v. pharmacokinetic profile and to evaluate its activity against commercially available formulations such as Taxol(®) and Abraxane(®). PTX-loaded poly(?-caprolactone)-alpha tocopheryl polyethylene glycol 1000 succinate (PCL-TPGS) NPs were prepared using three different techniques: (i) by nanoprecipitation (NPr-method), (ii) by emulsion-solvent evaporation homogenized with an Ultra-Turrax(®) (UT-method) and (iii) by emulsion-solvent evaporation homogenized with an ultrasonicator (US-method). The NPs prepared by US-method showed the smallest size and the highest drug content. The NPs exhibited a slow and continuous release of PTX. The in vitro anti-tumoral activity was assessed using two human breast cancer cell lines (MCF-7 and MDA-MB-231) with the WTS assay. Cytotoxicity studies with both cell lines showed that PTX-loaded PCL-TPGS NPs exhibited better anti-cancer activity compared to PTX solution and the commercial formulation Abraxane(®) at different concentrations. Importantly, in the case of triple negative MDA-MB-231 breast cancer cells, the IC50 value for PTX-loaded PCL-TPGS NPs was 7.8 times lower than Abraxane(®). Finally, in vivo studies demonstrated that PTX-loaded PCL-TPGS NPs exhibited longer systemic circulation time and slower plasma elimination rate than Taxol(®) and Abraxane(®). Therefore, the novel NPs investigated might be an alternative nanotechnological platform for PTX delivery system in cancer chemotherapy. PMID:24060929

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

    PubMed Central

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

    2015-01-01

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

  14. [A patient with paclitaxel hypersensitivity treated with nab-paclitaxel].

    PubMed

    Ouchi, Akira; Ouchi, Akira; Asano, Masahiko; Aono, Keiya; Watanabe, Tetsuya; Kato, Takehiro

    2014-07-01

    A 63-year-old man with multiple liver metastases from gastric cancer was treated with S-1 plus cisplatin; however, the number of multiple liver metastases increased. The patient received paclitaxel(PTX)treatment, but a hypersensitivity reaction occurred after administering the second dose; therefore, he received docetaxel treatment. A hypersensitivity reaction occurred after administering the first dose of docetaxel; therefore, he received irinotecan treatment. However, irinotecan administration was stopped because of severe diarrhea and weight reduction. Subsequently, at the patient's request, nab-PTX treatment was initiated by administering a premedication regimen of dexamethasone(8mg)and chlorpheniramine(10mg); no hypersensitivity reactions were reported thereafter. Nab-PTX is a contraindication; however, it might be possible to use nab-PTX for treating patients with PTX hypersensitivity. PMID:25131878

  15. 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.

  16. Human mutations that confer paclitaxel resistance.

    PubMed

    Yin, Shanghua; Bhattacharya, Rajat; Cabral, Fernando

    2010-02-01

    The involvement of tubulin mutations as a cause of clinical drug resistance has been intensely debated in recent years. In the studies described here, we used transfection to test whether beta1-tubulin mutations and polymorphisms found in cancer patients are able to confer resistance to drugs that target microtubules. Three of four mutations (A185T, A248V, R306C, but not G437S) that we tested caused paclitaxel resistance, as indicated by the following observations: (a) essentially 100% of cells selected in paclitaxel contained transfected mutant tubulin; (b) paclitaxel resistance could be turned off using tetracycline to turn off transgene expression; (c) paclitaxel resistance increased as mutant tubulin production increased. All the paclitaxel resistance mutations disrupted microtubule assembly, conferred increased sensitivity to microtubule-disruptive drugs, and produced defects in mitosis. The results are consistent with a mechanism in which tubulin mutations alter microtubule stability in a way that counteracts drug action. These studies show that human tumor cells can acquire spontaneous mutations in beta1-tubulin that cause resistance to paclitaxel, and suggest that patients with some polymorphisms in beta1-tubulin may require higher drug concentrations for effective therapy. PMID:20103599

  17. Src family kinases and paclitaxel sensitivity

    PubMed Central

    2011-01-01

    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 and 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 and neck cancers. Identification and validation of predictive biomarkers could also permit personalization of the therapy. PMID:21646863

  18. Preparation, characterization, and in vitro targeted delivery of folate-decorated paclitaxel-loaded bovine serum albumin nanoparticles

    PubMed Central

    Zhao, Dongmei; Zhao, Xiuhua; Zu, Yuangang; Li, Jialei; Zhang, Yu; Jiang, Ru; Zhang, Zhonghua

    2010-01-01

    Paclitaxel (Taxol®) is an important anticancer drug in clinical use for treatment of a variety of cancers. Because of its low solubility, it is formulated in high concentration in Cremophor EL® which induces hypersensitivity reactions. In this study, targeted delivery of paclitaxel-loaded nanoparticles was prepared by a desolvation procedure, crosslinked on the wall material of bovine serum albumin, and subsequently decorated by folic acid. The characteristics of the nanoparticles, such as amount of folate conjugation, surface morphology, drug entrapment efficiency, drug loading efficiency, and release kinetics were investigated in vitro. The targeting effect was investigated in vitro by cancer cell uptake of fluorescein isothiocyanate-labeled nanoparticles. The spherical nanoparticles obtained were negatively charged with a zeta potential of about ?30 mV, and characterized around 210 nm with a narrow size distribution. Drug entrapment efficiency and drug loading efficiency were approximately 95.3% and 27.2%, respectively. The amount of folate conjugation was 9.22 ?g/mg of bovine serum albumin. The folate-decorated nanoparticles targeted a human prostate cancer cell line effectively. PMID:20957218

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

    Cancer.gov

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

  20. Taxol and Taurine Protect the Renal Tissue of Rats after Unilateral Ureteral Obstruction: A Stereological Survey

    PubMed Central

    Karbalay-Doust, Saied; Pourshahid, Seyed-Mohammad

    2012-01-01

    Purpose Blockage of the urinary tract induces changes in renal structure including tubular dilatation or atrophy, tubular cell death, inflammatory processes, and progressive interstitial fibrosis with the loss of renal parenchyma. The present study was conducted to survey the protective effects of Taxol and taurine on the renal structure after unilateral ureteral obstruction (UUO). Materials and Methods UUO was induced in three groups of rats (n=6) who then received distilled water, Taxol (0.3 mg/kg/d), or taurine (7.5 mg/kg/d). Stereological methods were used to gather quantitative as well as comparative data. Results Less than -8% of the volume of the glomeruli, proximal convoluted tubules (PCT), distal convoluted tubules (DCT), Henle's loop, and collecting ducts were preserved after UUO. After treatment of the UUO rats with Taxol, between -32% and 88% of the parameters mentioned above remained intact, and after treatment of the UUO rats with taurine, between -16% and 46% of the parameters remained intact (p<0.01). Compared with the untreated UUO animals, the volume of necrotic and fibrotic tissues decreased -53% and -63% in the UUO rats treated with Taxol and taurine, respectively (p<0.01). Less than -3% of the lengths of the renal tubules (PCT, DCT, Henle's loop, and collecting) were preserved in the UUO rats. After treatment with Taxol and taurine, -61% to 70% and -43% to 53% of the length of the renal tubules were preserved, respectively (p<0.01). Conclusions Taurine and Taxol are effective in preventing some structural renal damage in a direct ureteral obstruction model. Taxol was more effective in renal protection. PMID:22670197

  1. Insulin-Like Growth Factor 2 Silencing Restores Taxol Sensitivity in Drug Resistant Ovarian Cancer

    PubMed Central

    Brouwer-Visser, Jurriaan; Lee, Jiyeon; McCullagh, KellyAnne; Cossio, Maria J.; Wang, Yanhua; Huang, Gloria S.

    2014-01-01

    Drug resistance is an obstacle to the effective treatment of ovarian cancer. We and others have shown that the insulin-like growth factor (IGF) signaling pathway is a novel potential target to overcome drug resistance. The purpose of this study was to validate IGF2 as a potential therapeutic target in drug resistant ovarian cancer and to determine the efficacy of targeting IGF2 in vivo. An analysis of The Cancer Genome Atlas (TCGA) data in the serous ovarian cancer cohort showed that high IGF2 mRNA expression is significantly associated with shortened interval to disease progression and death, clinical indicators of drug resistance. In a genetically diverse panel of ovarian cancer cell lines, the IGF2 mRNA levels measured in cell lines resistant to various microtubule-stabilizing agents including Taxol were found to be significantly elevated compared to the drug sensitive cell lines. The effect of IGF2 knockdown on Taxol resistance was investigated in vitro and in vivo. Transient IGF2 knockdown significantly sensitized drug resistant cells to Taxol treatment. A Taxol-resistant ovarian cancer xenograft model, developed from HEY-T30 cells, exhibited extreme drug resistance, wherein the maximal tolerated dose of Taxol did not delay tumor growth in mice. Blocking the IGF1R (a transmembrane receptor that transmits signals from IGF1 and IGF2) using a monoclonal antibody did not alter the response to Taxol. However, stable IGF2 knockdown using short-hairpin RNA in HEY-T30 effectively restored Taxol sensitivity. These findings validate IGF2 as a potential therapeutic target in drug resistant ovarian cancer and show that directly targeting IGF2 may be a preferable strategy compared with targeting IGF1R alone. PMID:24932685

  2. Taxol: an important new drug in the management of epithelial ovarian cancer.

    PubMed Central

    Markman, M.

    1991-01-01

    Taxol, an antineoplastic agent isolated from the Pacific yew, has been demonstrated in three phase 2 clinical trials to have major activity (30 percent overall response rate) in patients with ovarian cancer refractory to cisplatin. The major toxicities associated with the agent are neutropenia (dose-limiting), hypersensitivity reactions, peripheral sensory neuropathy, and cardiac arrhythmias. A recently reported phase 1 trial of the combination of cisplatin and taxol has defined acceptable doses for the two-drug combination to be tested against cisplatin and cyclophosphamide as frontline therapy of advanced ovarian cancer. Taxol has also been examined for intraperitoneal administration in patients with ovarian cancer, with a major pharmacokinetic advantage for peritoneal cavity exposure being demonstrated. Unfortunately, any future development of taxol as an antineoplastic agent in the management of ovarian cancer will be dependent on the finding of an alternative source of the drug, as the current method of obtaining taxol from the bark of the Pacific yew provides insufficient quantities for large-scale clinical use. PMID:1687343

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2007-01-01

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

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

    PubMed

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

    2014-12-01

    Chemotherapy-induced peripheral neuropathy accompanied by chronic neuropathic pain is the major dose-limiting toxicity of several anticancer agents including the taxane paclitaxel (Taxol). A critical mechanism underlying paclitaxel-induced neuropathic pain is the increased production of peroxynitrite in spinal cord generated in response to activation of the superoxide-generating enzyme, NADPH oxidase. Peroxynitrite in turn contributes to the development of neuropathic pain by modulating several redox-dependent events in spinal cord. We recently reported that activation of the Gi/Gq-coupled A3 adenosine receptor (A3AR) with selective A3AR agonists (ie, IB-MECA) blocked the development of chemotherapy induced-neuropathic pain evoked by distinct agents, including paclitaxel, without interfering with anticancer effects. The mechanism or mechanisms of action underlying these beneficial effects has yet to be explored. We now demonstrate that IB-MECA attenuates the development of paclitaxel-induced neuropathic pain by inhibiting the activation of spinal NADPH oxidase and two downstream redox-dependent systems. The first relies on inhibition of the redox-sensitive transcription factor (NF?B) and mitogen activated protein kinases (ERK and p38) resulting in decreased production of neuroexcitatory/proinflammatory cytokines (TNF-?, IL-1?) and increased formation of the neuroprotective/anti-inflammatory IL-10. The second involves inhibition of redox-mediated posttranslational tyrosine nitration and modification (inactivation) of glia-restricted proteins known to play key roles in regulating synaptic glutamate homeostasis: the glutamate transporter GLT-1 and glutamine synthetase. Our results unravel a mechanistic link into biomolecular signaling pathways employed by A3AR activation in neuropathic pain while providing the foundation to consider use of A3AR agonists as therapeutic agents in patients with chemotherapy-induced peripheral neuropathy. PMID:25242567

  6. Tumor Angiogenesis Therapy Using Targeted Delivery of Paclitaxel to the Vasculature of Breast Cancer Metastases

    PubMed Central

    Kisiel, Walter; Lu, Yang J.; Petersen, Lars C.; Ndungu, John M.; Moore, Terry W.; Parker, Ernest T.; Sun, Aiming; Liotta, Dennis C.; El-Rayes, Bassel F.; Brat, Daniel J.; Snyder, James P.; Shoji, Mamoru

    2014-01-01

    Breast cancer aberrantly expresses tissue factor (TF) in cancer tissues and cancer vascular endothelial cells (VECs). TF plays a central role in cancer angiogenesis, growth, and metastasis and, as such, is a target for therapy and drug delivery. TF is the cognate receptor of factor VIIa (fVIIa). We have coupled PTX (paclitaxel, also named Taxol) with a tripeptide, phenylalanine-phenylalanine-arginine chloromethyl ketone (FFRck) and conjugated it with fVIIa. The key aim of the work is to evaluate the antiangiogenic effects of PTX-FFRck-fVIIa against a PTX-resistant breast cancer cell line. Matrigel mixed with VEGF and MDA-231 was injected subcutaneously into the flank of athymic nude mice. Animals were treated by tail vein injection of the PTX-FFRck-fVIIa conjugate, unconjugated PTX, or PBS. The PTX-FFRck-fVIIa conjugate significantly reduces microvessel density in matrigel (p < 0.01–0.05) compared to PBS and unconjugated PTX. The breast cancer lung metastasis model in athymic nude mice was developed by intravenous injection of MDA-231 cells expressing luciferase. Animals were similarly treated intravenously with the PTX-FFRck-fVIIa conjugate or PBS. The conjugate significantly inhibits lung metastasis as compared to the control, highlighting its potential to antagonize angiogenesis in metastatic carcinoma. In conclusion, PTX conjugated to fVIIa is a promising therapeutic approach for improving selective drug delivery and inhibiting angiogenesis. PMID:25574399

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

    PubMed

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

    2015-02-01

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

  8. Folate-polyethyleneimine functionalized mesoporous carbon nanoparticles for enhancing oral bioavailability of paclitaxel.

    PubMed

    Wan, Long; Wang, Xiaofan; Zhu, Wenquan; Zhang, Chen; Song, Aihua; Sun, Changshan; Jiang, Tongying; Wang, Siling

    2015-04-30

    Polymer-functionalized carbon nanoparticles hold great promise for their use in enhancing the oral absorption of drugs with poor oral bioavailability. And since the abundant expression of folate receptors in intestinal tract, folic acid (FA) modified uniform mesoporous carbon spheres (UMCS) was used to improve oral absorption of paclitaxel, a chemotherapeutic drug with poor oral bioavailability. In this research, folate-polyethyleneimine (FA-PEI) was grafted onto acid-treated uniform mesoporous carbon spheres through one-step electrostatic attraction. PTX was loaded into mesopores of nanoparticles through solvent evaporation, present as amorphous. The release of PTX from the FA-PEI-UMCS nanoparticles exhibited an initial rapid release, followed by a sustained release. And release rate could be regulated by changing amount of FA-PEI complex on the UMCS. The uptake of PTX-encapsulated nanoparticles was studied exploiting Caco-2 cells as an in vitro model. The results of confocal microscopy and flow cytometry demonstrated that folate functionalization enhanced internalization of nanoparticles by the cells. Moreover, PTX loaded in FA-PEI-UMCS nanoparticles resulted in a 5.37-fold increase in apparent permeability (Papp) across Caco-2 cell monolayers compared to Taxol(®). And the in vivo results showed that FA-PEI-UMCS nanoparticles did not only improve the oral bioavailability of PTX, but also decrease the gastrointestinal toxicity of PTX. In conclusion, the FA-PEI-UMCS nanoparticles might be a potentially applicable system to improve oral absorption of drugs with poor oral bioavailability. PMID:25724138

  9. Solid lipid nanoparticles of paclitaxel strengthened by hydroxypropyl-?-cyclodextrin as an oral delivery system.

    PubMed

    Baek, Jong-Suep; So, Jae-Woo; Shin, Sang-Chul; Cho, Cheong-Weon

    2012-10-01

    The objective of this study was to evaluate the potential of surface-modified paclitaxel (PTX)-incorporated solid lipid nanoparticles with hydroxypropyl-?-cyclodextrin (smPSH). The smPSH released 89.70 ± 3.99% of its entrapped PTX within 24 h when placed in dissolution medium containing sodium lauryl sulfate. The cellular uptake of PTX from smPSH in Caco-2 cells was 5.3-fold increased compared to a PTX solution based on a Taxol formulation. Moreover, smPSH showed an increased cytotoxicity compared to PTX solution. In addition, AUC (5.43 µg•h/ml) and Cmax (1.44 µg/ml) of smPSH were higher than those (1.81 µg•h/ml and 0.73 µg/ml) of PTX solution. The drug concentration of smPSH (11.12 ± 4.45 ng/mg of lymph tissue) in lymph nodes was higher than that of the PTX solution (0.89 ± 0.75 ng/mg of lymph tissue), suggesting that more PTX was transported to the lymphatic vessels in the form of smPSH. In conclusion, smPSH have a potential as an alternative delivery system for oral administration of PTX. PMID:22859311

  10. 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

  11. Effects of combining Taxol and cyclooxygenase inhibitors on the angiogenesis and apoptosis in human ovarian cancer xenografts

    PubMed Central

    LI, WEI; TANG, YUN-XIAN; WAN, LIANG; CAI, JIA-HUI; ZHANG, JUN

    2013-01-01

    The present study aimed to investigate the combined effects of Taxol and cyclooxygenase (COX) inhibitors on angiogenesis and cell apoptosis of SKOV-3 human ovarian carcinoma cell xenograft-bearing mice. The experiments were continued for 28 days. Animals were treated with 3 mg/kg SC-560 (a COX-1-selective inhibitor) alone, 100 mg/kg celecoxib (a COX-2-selective inhibitor) alone or SC-560/celecoxib by gavage twice a day, 20 mg/kg Taxol alone intraperitoneally once a week or in combination with SC-560 or celecoxib or SC-560/celecoxib/Taxol for three weeks. The mRNA levels of vascular endothelial growth factor (VEGF) was determined by reverse transcription-polymerase chain reaction (RT-PCR). The microvessel density (MVD) of ovarian carcinoma was determined by immunohistochemistry with anti-CD34 as the label. The apoptotic index was detected by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) method. The MVD value and apoptotic index in the SC-560/Taxol group were notably inhibited compared with the Taxol group (P<0.001). Moreover, the VEGF mRNA levels, MVD value and apoptotic index in the SC-560/Taxol group were significantly different from the celecoxib/Taxol group (P<0.05, P<0.05 and P<0.001, respectively). The present study demonstrated that SC-560 enhances the anti-angiogenic and pro-apoptotic effects of Taxol and these effects are better than with celecoxib. PMID:23426648

  12. Anti-miR-155 oligonucleotide enhances chemosensitivity of U251 cell to taxol by inducing apoptosis.

    PubMed

    Meng, Wei; Jiang, Ling; Lu, Lin; Hu, Haiyan; Yu, Hailang; Ding, Dapeng; Xiao, Kun; Zheng, Wenling; Guo, Hongbo; Ma, Wenli

    2012-07-01

    The oncogene, microRNA-155, is significantly elevated in GBM (glioblastoma multiforme), regulating multiple genes associated with cancer cell proliferation, apoptosis and invasiveness. Thus, miR-155 can theoretically become a target for enhancement of the chemotherapy in cancer. Down-regulating miR-155 to enhance the effect of taxol has not been studied in human GBM. Human GBM U251 cells were treated with taxol and the miR-155 inhibitor alone or in combination. IC50 values were dramatically decreased in cells treated with miR-155 inhibitor combined with taxol, to a greater extent than those treated with taxol alone. Furthermore, the miR-155 inhibitor significantly enhanced apoptosis in U251 cells. The data suggest that miR-155 blockage increased the chemosensitivity to taxol in GBM cells, making combined treatment an effective therapeutic strategy for controlling the growth by inhibiting EAG1 expression. PMID:22276743

  13. Paclitaxel plus carboplatin–induced peripheral neuropathy

    Microsoft Academic Search

    Andreas A. Argyriou; Panagiotis Polychronopoulos; Gregoris Iconomou; Angelos Koutras; Haralabos P. Kalofonos; Elisabeth Chroni

    2005-01-01

    Objective  The current study intended to determine the incidence, severity and reversibility of paclitaxel plus carboplatin (CP)–induced\\u000a peripheral neuropathy (CPPN) and to describe its clinical and electrophysiological features.\\u000a \\u000a \\u000a \\u000a Patients and methods  We prospectively studied 21 adult patients scheduled to be treated with 6 courses of cumulative carboplatin plus paclitaxel\\u000a (CP) regimens for a non–myeloid malignancy. They were followed–up by neurological examination and

  14. Improved taxol yield by aromatic carboxylic acid and amino acid feeding to cell cultures of taxus cuspidata.

    PubMed

    Fett-Neto, A G; Melanson, S J; Nicholson, S A; Pennington, J J; Dicosmo, F

    1994-10-01

    Cell culture of Taxus cuspidata represents an alternative to whole plant extraction as a source of taxol and related taxanes. Feeding phenylalanine to callus cultures was previously shown to result in increased taxol yields, probably due to the involvement of this amino acid as a precursor for the N-benzoylphenylisoserine side chain of taxol. Inthis study, we have examined the effect of various concentrations of phenylalanine, benzoic acid, N-benzoylglycine, serine, glycine, alanine, and 3-amino-3-phenyl-propionic acid on taxol accumulation in 2-year-old cell suspensions of Taxus cuspidata, cell line FCL1F, and in developing callus cultures of T. cuspidata. All compounds tested were included in media at stationary phase (suspensions) or after the period of fastest growth (calli). Alanine and 3-amino-3-phenyl-propionicacid were tested only in callus cultures and did not affect taxol accumulation. Significant increases or trends toward increases in taxol accumulationin callus and suspensions were observed in the presence of phenylalanine, benzoic acid, N-benzoylglycine, serine, and glycine. The greatest increases in taxol accumulation were observed in the presence of various concentrations of phenylalanine (1 mM for callus; 0.05, 0.1, and 0.2 mM for suspensions) and benzoic acid (0.2 and 1 mM for callus and 0.05, 0.1, and 0.2 mM for suspensions). Increases in taxol yields of cell suspensions in the presence of the most effective precursors brought taxol amounts at stationary phase from 2 mug . g(-1) to approximately 10 mug . g(-1) of the extracted dry weight. The results are discussed in termsof possible implications to taxol biosynthesis and in terms of practical applications to large-scale cell culture systems for the production ofthis drug. (c) 1994 John Wiley & Sons, Inc. PMID:18618915

  15. Overcoming drug-resistant lung cancer by paclitaxel loaded dual-functional liposomes with mitochondria targeting and pH-response.

    PubMed

    Jiang, Lei; Li, Li; He, Xiaodan; Yi, Qiangying; He, Bin; Cao, Jun; Pan, Weisan; Gu, Zhongwei

    2015-06-01

    Mitochondrion-orientated transportation of smart liposomes has been developed as a promising strategy to deliver anticancer drugs directly to tumor sites, and these have a tremendous potential for killing cancer cells, especially those with multidrug resistance (MDR). Herein we report a novel dual-functional liposome system possessing both extracellular pH response and mitochondrial targeting properties to enhance drug accumulation in mitochondria and trigger apoptosis of drug-resistant cancer cells. Briefly, peptide D[KLAKLAK]2 (KLA) was modified with 2, 3-dimethylmaleic anhydride (DMA) and combined with 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) to yield a DSPE-KLA-DMA (DKD) lipid. This dual-functional DKD was then mixed with other commercially available lipids to fabricate liposomes. In vitro anticancer efficacy of this liposome system was evaluated in human lung cancer A549 cells and drug-resistant lung cancer A549/Taxol cells. At tumor extracellular pH (?6.8), liposomes could reverse their surface charge (negative to positive), facilitating liposome internalization. After cellular uptake, KLA peptide directed delivery-enabled selective accumulation of these liposomes into mitochondria and favored release of their cargo paclitaxel (PTX) into desired sites. Specifically, enhanced apoptosis of MDR cancer cells through mitochondrial signaling pathways was evidenced by release of cytochrome c and increased activity of caspase-9 and -3. These dual-functional liposomes had the greatest efficacy for treating A549 cells and A549/Taxol cells in vitro, and in treating drug-resistant lung cancer A549/Taxol cells xenografted onto nude mice (tumor growth inhibition 86.7%). In conclusion, dual-functional liposomes provide a novel and versatile approach for overcoming MDR in cancer treatment. PMID:25818419

  16. Biological characteristics of Taxol?resistant ovarian cancer cells and reversal of Taxol resistance by adenovirus expressing p53.

    PubMed

    Liu, Qun; Sui, Rui; Li, Ruirui; Miao, Jinwei; Liu, Jian

    2015-02-01

    The development of acquired drug resistance is the primary cause of chemotherapy failure in the treatment of ovarian cancer. To examine the mechanism underlying Taxol (TAX) resistance in ovarian cancer and attempt to reverse it, the present study induced a TAX?resistant ovarian cancer cell line SKOV3/TAX using a gradient concentration increment method. The properties of the resistant cell line were initially investigated by proliferation, colony formation, adhesion and cell cycle analysis compared with control SKOV3 cells. To examine the mechanism, the expression of p53 upregulated modulator of apoptosis (PUMA) was compared between SKOV3/TAX and SKOV3 cells by western blot analysis. An adenovirus expressing p53 (Ad?p53), alone or in combination with TAX, was used to treat the drug?resistant ovarian cancer cells SKOV3/TAX. The effects of Ad?p53 on pro?apoptosis and the reversal of drug resistance were evaluated using flow cytometric analysis, cleaved?poly ADP?ribose polymerase detection, microscopic observation and MTT measurement. Compared with the control cells, the TAX?resistant ovarian cancer cell line SKOV3/TAX was characterized by reduced sensitivity to TAX treatment, a significantly slower proliferation rate, higher colony?forming efficiency and higher adhesion ability. However, no significant difference in cell cycle distribution was identified. PUMA, a potent pro?apoptotic protein, was markedly suppressed in the SKOV3/TAX cells. Ad?p53 infection stimulated the upregulation of PUMA and re?sensitized the resistant ovarian cancer cells to TAX by an apoptotic mechanism. Therefore, Ad?p53 infection is an effective gene therapy method to re?sensitize the resistant ovarian cancer cells to TAX by restoring the expression of PUMA. PMID:25351378

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

    PubMed

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

    2015-04-10

    Tumor-targeted drug delivery and microenvironment-responsive drug release are attractive strategies in cancer treatment. Our previous study demonstrated that redox-sensitive micelles based on hyaluronic acid-deoxycholic acid (HA-ss-DOCA) conjugates exhibited excellent drug-loading capacities (34.1%) for paclitaxel (PTX) and rapid drug release in response to reducing agent, glutathione. In the present study, the physicochemical and biological properties of PTX-loaded HA-ss-DOCA (PTX-HA-ss-DOCA) micelles were investigated further. The micelles have an average size of about 120nm and a zeta potential of about -36mV. Transmission electron microscopy and wide-angle X-ray diffraction analysis demonstrated redox-sensitive degradation of micelles in the presence of glutathione. Moreover, the encapsulated payload was effectively released from HA-ss-DOCA micelles into cytoplasm and then rapidly transported into nuclei. In vitro cytotoxicity and cell apoptosis assay further revealed that HA significantly improved the tumor-specific drug delivery of HA-ss-DOCA micelles via receptor-mediated endocytosis, while efficient intracellular drug release and transportation lead to marked inhibition of tumor cell growth, as compared to Taxol(®) and insensitive micelles. More importantly, PTX-HA-ss-DOCA micelles demonstrated superior in vivo antitumor activity compared with Taxol(®) and insensitive control, and decreased systemic toxicity. Herein we present data which provide valuable insight into the design and development of tumor-specific drug delivery systems. PMID:25655715

  18. Paclitaxel resistance by random mutagenesis of ?-tubulin.

    PubMed

    Yin, Shanghua; Zeng, Changqing; Hari, Malathi; Cabral, Fernando

    2013-12-01

    Many mammalian ?-tubulin mutations that confer paclitaxel resistance have been characterized, but little is currently known about the role of ?-tubulin mutations in drug resistance. Previous studies using two-dimensional gel electrophoresis showed that ?-tubulin mutations occur with a frequency equal to ?-tubulin mutations among CHO cells selected for resistance to paclitaxel but the identities of those mutations are largely unknown. We have now sequenced the major ?-tubulin gene in several paclitaxel resistant CHO cell lines with lesions in genomic DNA and identified five mutations that predominately affect the amino terminal part of the protein. We also used random mutagenesis and transfection of ?-tubulin cDNA to select further paclitaxel resistant mutants in an effort to remove genomic constraints that may limit the diversity of mutations. This approach led to the identification of 16 additional mutations that were distributed throughout the ?-tubulin sequence. The mutations were confirmed as sufficient to confer resistance by site-directed mutagenesis, and they acted by a mechanism that involved reductions in microtubule assembly. One mutation prevented the acetylation of ?-tubulin but otherwise produced a phenotype similar to the other mutations. A scan of the literature revealed that a significant number of drug resistance mutations overlap or lie close to lesions that have been reported in patients with brain disorders suggesting that alterations in microtubule assembly underlie both cellular resistance and developmental defects. PMID:24155014

  19. Defining the role of APC in the mitotic spindle checkpoint in vivo: APC-deficient cells are resistant to Taxol.

    PubMed

    Radulescu, S; Ridgway, R A; Appleton, P; Kroboth, K; Patel, S; Woodgett, J; Taylor, S; Nathke, I S; Sansom, O J

    2010-12-01

    Mutations in the adenomatous polyposis coli (APC) tumour suppressor are the key initiating event of colorectal cancer. Although the control of WNT signalling is well established as a central tumour-suppressive function, the significance of APC in regulating chromosome instability is less well established. In this study, we test whether APC-deficient cells have a functional spindle assembly checkpoint (SAC) in vivo by examining the response of these cells to Taxol and Vinorelbine. We also show for the first time that APC deficiency compromises the arrest response to Taxol in vivo. This effect is independent of the role that APC has in WNT signalling. At higher levels of Taxol, APC-deficient cells arrest as efficiently as wild-type cells. Importantly, this dose of Taxol strongly suppresses intestinal tumourigenesis in models of benign (APC(Min/+) mouse) and invasive (AhCreER(+)APC(fl/+)PTEN(fl/fl)) cancer. In contrast to intestinal enterocytes with a general SAC defect because of Bub1 (budding uninhibited by benzimidazole 1) deletion, APC-deficient enterocytes arrest equivalently to wild type when treated with Vinorelbine. This suggests that the failed arrest in response to Taxol is because of a specific defect in microtubule stabilization following Taxol treatment rather than a general role of the APC protein in the mitotic spindle checkpoint. In summary, this study clarifies the role of APC as a mitotic spindle checkpoint protein in vivo and shows that APC-deficient cells have a compromised response to Taxol. PMID:20729907

  20. Subcutaneous study on the controlled release of Etanidazole and Taxol for the treatment of Glioma

    E-print Network

    Naraharisetti, Pavan Kumar

    BALB/c nude mice 6 weeks old were inoculated with glioma C6 cell-line and the efficacy of the different amount of Etanidazole-discs and Taxol-microspheres was investigated. Poly (D,L-lactic-co-glycolic acid) (PLGA) was ...

  1. Paclitaxel chemotherapy for the treatment of gastric cancer

    Microsoft Academic Search

    Junichi Sakamoto; Takanori Matsui; Yasuhiro Kodera

    2009-01-01

    A comprehensive review of phase I and phase II clinical trials of paclitaxel and paclitaxel-containing chemotherapy regimens\\u000a for advanced gastric cancer was performed. Response rates, median progression-free survivals, and median overall survivals\\u000a were examined, together with the treatment regimens and the numbers of patients registered in each trial. Although paclitaxel\\u000a monotherapy produced considerable improvement in tumor response and prognosis, combination

  2. 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

  3. Effects of amino acids, nitrate, and ammonium on the growth and taxol production in cell cultures of Taxus yunnanensis

    Microsoft Academic Search

    Yong-Qin Chen; Fei Yi; Min Cai; Jian-Xin Luo

    2003-01-01

    The effects of concentration of amino acids, nitrate, and ammonium on the growth and taxol production in cultures of cell line TY-21 of Taxus yunnanensis were investigated. Addition of 20 different amino acids each at 15–20 mg l-1 to B5 medium significantly improved callus growth but inhibited taxol formation in the cultures. The optimum nitrate concentration was 20–30 mM for

  4. Second-line treatment of advanced non-small cell lung cancer with paclitaxel and gemcitabine: a preliminary report on an active regimen.

    PubMed

    Georgoulias, V; Kourousis, C; Kakolyris, S; Androulakis, N; Dimopoulos, M A; Papadakis, E; Kotsakis, T; Vardakis, N; Kalbakis, K; Merambeliotakis, N; Hatzidaki, D

    1997-08-01

    A phase II study of combination paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ)/gemcitabine was conducted in patients with non-small cell lung cancer (NSCLC) who had failed first-line docetaxel- or cisplatin-based chemotherapy. Eligibility criteria included histologically confirmed measurable stage IIIB or IV NSCLC and previous exposure to docetaxel- or cisplatin-based regimens, World Health Organization performance status between 0 and 2, adequate hematologic parameters, and adequate hepatic, renal, and cardiac function. Gemcitabine (900 mg/m2) was given on days 1 and 8 as a 30-minute infusion; paclitaxel (175 mg/m2) was administered on day 8 as a 3-hour infusion after appropriate premedication. Granulocyte colony-stimulating factor (150 microg/m2 subcutaneously) was given on days 9 to 15. Treatment was repeated every 3 weeks until patients experienced disease progression. From October 1995 to December 1996, 26 patients with advanced NSCLC were enrolled (three stage IIIB, 23 stage IV). All 26 patients were assessable for toxicity, and 24 were evaluable for response. Two complete (8%) and five partial (21%) responses were observed, for an overall response rate of 29% (95% confidence interval, 11% to 47%). The median duration of response was 2.5 months and the median survival was 8 months. A median of three courses per patient was administered, and the median interval between courses was 21 days. The median delivered dose was 579 mg/m2/wk gemcitabine and 54.5 mg/m2/wk paclitaxel, corresponding to a relative dose intensity of 0.97 and 0.96, respectively. Grade 3/4 neutropenia occurred in two patients (8%). Grade 3 conjunctivitis occurred in one (4%) patient and grade 2/3 neurotoxicity in eight (31%) patients. Grade 3/4 and grade 2 fatigue occurred in four (15%) and eight (31%) patients, respectively. Other toxicities were mild to moderate. These preliminary results suggest that the paclitaxel/gemcitabine combination is an active and well-tolerated salvage regimen in patients with NSCLC previously treated with docetaxel- or cisplatin-based chemotherapy. The paclitaxel/gemcitabine combination merits further evaluation as first-line treatment. PMID:9331124

  5. Effects of SC-560 in Combination with Cisplatin or Taxol on Angiogenesis in Human Ovarian Cancer Xenografts

    PubMed Central

    Li, Wei; Wan, Liang; Zhai, Ling-Yun; Wang, Jane

    2014-01-01

    This study was designed to evaluate the effect of cyclooxygenase-1 (COX-1) inhibitor, SC-560, combined with cisplatin or taxol, on angiogenesis in human ovarian cancer xenografts. Mice were treated with intraperitoneal (i.p.) injections of SC-560 6 mg/kg/day, i.p. injections of cisplatin 3 mg/kg every other day and i.p. injections of taxol 20 mg/kg once a week for 21 days. Vascular endothelial growth factor (VEGF) mRNA levels were detected by reverse transcription-polymerase chain reaction (RT-PCR); microvessel density (MVD) was determined by immunohistochemistry; and prostaglandin E2 (PGE2) levels were determined using ELISA. Expression levels of VEGF mRNA and MVD in treatment groups were inhibited significantly when compared with the control group (p < 0.05 for all), and SC-560 combined with cisplatin displayed a greater reduction in the expression of VEGF and MVD than SC-560 or cisplatin alone (p < 0.05). SC-560 combined with taxol showed a greater inhibition on VEGF mRNA expression than SC-560 or taxol alone (p < 0.05). The level of PGE2 in treatment groups was significantly reduced when compared with the control group (p < 0.01 for all). These findings may indicate that cisplatin or taxol supplemented by SC-560 in human ovarian cancer xenografts enhances the inhibition effect of cisplatin or taxol alone on angiogenesis. PMID:25342321

  6. Electrochemical determination of the anticancer drug taxol at a ds-DNA modified pencil-graphite electrode and its application as a label-free electrochemical biosensor.

    PubMed

    Tajik, Somayeh; Taher, Mohammad Ali; Beitollahi, Hadi; Torkzadeh-Mahani, Mosoud

    2015-03-01

    In this study a novel biosensor for determination of taxol is described. The interaction of taxol with salmon-sperm double-stranded DNA (ds-DNA) based on the decreasing of the oxidation signals of guanine and adenine bases was studied electrochemically with a pencil-graphite electrode (PGE) using a differential pulse voltammetry (DPV) method. The decreases in the intensity of the guanine and adenine oxidation signals after interaction with taxol were used as indicator signals for the sensitive determination of taxol. DPV exhibits a linear dynamic range of 2.0×10(-7)-1.0×10(-5) M for taxol with a detection limit of 8.0×10(-8) M. Finally, this modified electrode was used for determination of taxol in some real samples. PMID:25618641

  7. Effective desensitization protocol to paclitaxel following hypersensitivity reaction.

    PubMed

    Fishman, A.; Gold, T.; Goldberg, A.; Confino-Cohen, R.; Beyth, Y.; Menczer, J.; Altaras, M.

    1999-03-01

    The objective of this paper is to describe our experience with a desensitization protocol to paclitaxel using the original paclitaxel solution in patients following severe hypersensitivity reactions. A retrospective review of 75 consecutive patients with ovarian cancer who received intravenous paclitaxel-based chemotherapy between January 1996 and May 1998 at the Gynecologic Oncology Unit at Meir Hospital-Sapir Medical Center, Kfar-Saba, Israel. All patients who developed a hypersensitivity reaction to paclitaxel were treated with a desensitization protocol. The protocol included serial 10-fold dilutions (up to 1:100,000) of the actual paclitaxel infusate, delivered in successive volumes of 1, 2, 4, and 8 ml. These escalating doses of paclitaxel were given intravenously at 15-min intervals for each dilution. Following administration of the last diluted dose, the patient received a 1-ml dose of the undiluted solution. If no side effects were recorded, the rest of the actual dose was delivered at a 3-h infusion rate. Vital signs were monitored and recorded throughout the course of treatment. Six patients with a previous paclitaxel-associated hypersensitivity reaction were successfully treated with the desensitization protocol. In conclusion, we demonstrate that the desensitization protocol is feasible and safe without compromising cytotoxic activity. Our results show that this strategy is a reasonable choice in this clinical setting and potentially avoids paclitaxel-based regimen interruption. PMID:11240758

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

    Cancer.gov

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

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

    Cancer.gov

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

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

    Cancer.gov

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

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

    PubMed

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

    2012-11-01

    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. PMID:22889832

  12. Development of a fluorescence polarization immunoassay (FPIA) for the quantitative determination of paclitaxel

    Microsoft Academic Search

    C. Bicamumpaka; M. Pagé

    1998-01-01

    We have developed a fluorescence polarization immunoassay (FPIA) for the quantitative determination of paclitaxel in serum, crude Taxus extracts and Erwinia taxi culture medium. To achieve this, we used an antipaclitaxel monoclonal antibody and an FITC-labeled paclitaxel. Paclitaxel was chemically modified by introducing an amino function to enable coupling with fluorescein isothiocyanate. Paclitaxel competitively inhibited the binding of the monoclonal

  13. Enhanced Oral Bioavailability of Paclitaxel by Coadministration of the P-Glycoprotein Inhibitor KR30031

    Microsoft Academic Search

    Jong Soo Woo; Chang Hyun Lee; Chang Koo Shim; Sung-Joo Hwang

    2003-01-01

    Purpose. In an attempt to improve the oral bioavailability of paclitaxel, a novel P-glycoprotein inhibitor, KR30031, which is verapamil analog with fewer cardiovascular effects, was coadministered with paclitaxel, and to elucidate other possible causes of the low oral bioavailability of paclitaxel, an inhibitor of hepatic metabolism, ketoconazole, was also coadministered with paclitaxel.

  14. Formal total synthesis of (-)-taxol through Pd-catalyzed eight-membered carbocyclic ring formation.

    PubMed

    Hirai, Sho; Utsugi, Masayuki; Iwamoto, Mitsuhiro; Nakada, Masahisa

    2015-01-01

    A formal total synthesis of (-)-taxol by a convergent approach utilizing Pd-catalyzed intramolecular alkenylation is described. Formation of the eight-membered carbocyclic ring has been a problem in the convergent total synthesis of taxol but it was solved by the Pd-catalyzed intramolecular alkenylation of a methyl ketone affording the cyclized product in excellent yield (97?%), indicating the high efficiency of the Pd-catalyzed intramolecular alkenylation. Rearrangement of the epoxy benzyl ether through a 1,5-hydride shift, generating the C3 stereogenic center and subsequently forming the C1-C2 benzylidene, was discovered and utilized in the preparation of a substrate for the Pd-catalyzed reaction. PMID:25346263

  15. 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

  16. In vitro and in vivo evaluation of taxol release from poly(lactic-co-glycolic acid) microspheres containing isopropyl myristate and degradation of the microspheres

    Microsoft Academic Search

    Ya Min Wang; Hitoshi Sato; Isamu Horikoshi

    1997-01-01

    This study describes the release and degradation profiles of taxol-loaded poly(lactic-co-glycolic acid) microspheres containing isopropyl myristate (IPM), namely, Taxol-IPM-PLGA-MS, in vitro and in vivo. Incorporation of IPM into the PLGA microspheres effectively increased the release of taxol from the microspheres in vitro. The molecular weight (Mol. Wt.) and copolymer ratio of lactic acid (LA) and glycolic acid (GA) displayed obvious

  17. Enhancement of the Therapeutic Efficacy of Taxol by the Mitogen-Activated Protein Kinase Kinase Inhibitor CI1040 in Nude Mice Bearing Human Heterotransplants

    Microsoft Academic Search

    Hayley M. McDaid; Lluis Lopez-Barcons; Aaron Grossman; Marie Lia; Steven Keller; Susan Band Horwitz

    2005-01-01

    Taxol may contribute to intrinsic chemoresistance by activat- ing the mitogen-activated protein kinase kinase (MEK)\\/ extracellular signal-regulated kinase (ERK) cytoprotective pathway in human cancer cell lines and tumors. We have previously shown additivity between Taxol and the MEK inhibitor, U0126 in human cancer cell lines. Here, the combination of Taxol with an orally bioavailable MEK inhibitor, CI-1040, was evaluated in

  18. Survivin is required for stable checkpoint activation in taxol-treated HeLa cells

    Microsoft Academic Search

    Ana Carvalho; Mar Carmena; Clara Sambade; William C. Earnshaw; Sally P. Wheatley

    2003-01-01

    gradual increase in the percentage of multinucleated cells in the culture. Time-lapse imaging of synchronized cultures revealed that control and Survivin-depleted cells arrested in mitosis in the presence of nocodazole; however, the latter failed to arrest in mitosis when treated with taxol. Immunofluorescence studies revealed that Survivin- depleted cells were unable to stably maintain BubR1 at the kinetochores in the

  19. 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

  20. Biodistribution and Bioimaging Studies of Hybrid Paclitaxel Nanocrystals: Lessons Learned of the EPR Effect and Image-Guided Drug Delivery

    PubMed Central

    Hollis, Christin P.; Weiss, Heidi L.; Leggas, Markos; Evers, B. Mark; Gemeinhart, Richard A.; Li, Tonglei

    2013-01-01

    Paclitaxel (PTX) nanocrystals (200 nm) were produced by crystallization from solution. Antitumor efficacy and toxicity were examined through a survival study in a human HT-29 colon cancer xenograft murine model. The antitumor activity of the nanocrystal treatments was comparable with that by the conventional solubilization formulation (Taxol®), but yielded less toxicity as indicated by the result of survival study. Tritium-labeled PTX nanocrystals were further produced with a near infrared (NIR) fluorescent dye physically integrated in the crystal lattice. Biodistribution and tumor accumulation of the tritium-labeled PTX nanocrystals were determined immediately after intravenous administration and up to 48 hours by scintillation counting. Whole-body optical imaging of animals was concurrently carried out; fluorescent intensities were also measured from excised tumors and major organs of euthanized animals. It was found that drug accumulation in the tumor was less than 1% of 20 mg/kg intravenous dose. Qualitatively correlation was identified between the biodistribution determined by using tritium-labeled particles and that using optical imaging, but quantitative divergence existed. The divergent results suggest possible ways to improve the design of hybrid nanocrystals for cancer therapy and diagnosis. The study also raises questions of the general role of the enhanced permeability and retention (EPR) effect in tumor targeting and the effectiveness of bioimaging, specifically for hybrid nanocrystals, in tracking drug distribution and pharmacokinetics. PMID:23920039

  1. Preparation and characterization of paclitaxel-loaded DSPE-PEG-liquid crystalline nanoparticles (LCNPs) for improved bioavailability.

    PubMed

    Zeng, Ni; Hu, Quanyin; Liu, Zhongyang; Gao, Xiaoling; Hu, Rongkuan; Song, Qingxiang; Gu, Guangzhi; Xia, Huimin; Yao, Lei; Pang, Zhiqing; Jiang, Xinguo; Chen, Jun; Fang, Liang

    2012-03-15

    Lipid-based liquid crystalline nanoparticles (LCNPs) have attracted growing interest as a new drug nanocarrier system for improving bioavailability for both hydrophilic and hydrophobic drugs. In this study, self-assembled LCNPs based on soy phosphatidyl choline and glycerol dioleate, which was known possessing low toxicity and negligible hemolysis, were prepared using poly(ethylene glycol)-grafted 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine (DSPE-PEG) as the dispersing agent. Paclitaxel (PTX) was used as a model hydrophobic drug. The particle size of the optimized DSPE-PEG-LCNPs and PTX-loaded DSPE-PEG-LCNPs were around 70nm. Crossed polarized light microscopy was used to characterize the phase behavior of liquid crystalline (LC) matrices, which showed a fan-like birefringent texture in dark background indicating the coexistence of reversed cubic and hexagonal phase in the optimized LC matrix. Transmission electron microscopy and cryo-field emission scanning electron microscopy revealed its internal water channel and "twig-like" surface morphology. PTX-loaded DSPE-PEG-LCNPs exhibited a biphasic drug sustained release pattern with a relatively fast release at the initial stage and a sustained release afterwards. PTX-loaded DSPE-PEG-LCNPs presented higher AUC (410.942±72.522?g/Lh) when compared with commercial product Taxol (212.670±41.396?g/Lh). These results indicated that DSPE-PEG-LCNPs might serve as a potential sustained release system for poorly water-soluble agents. PMID:22240390

  2. Paclitaxel induces acute pain via directly activating toll like receptor 4.

    PubMed

    Yan, Xisheng; Maixner, Dylan W; Yadav, Ruchi; Gao, Mei; Li, Pei; Bartlett, Michael G; Weng, Han-Rong

    2015-12-01

    Paclitaxel, a powerful anti-neoplastic drug, often causes pathological pain, which significantly reduces the quality of life in patients. Paclitaxel-induced pain includes pain that occurs immediately after paclitaxel treatment (paclitaxel-associated acute pain syndrome, P-APS) and pain that persists for weeks to years after cessation of paclitaxel treatment (paclitaxel induced chronic neuropathic pain). Mechanisms underlying P-APS remain unknown. In this study, we found that paclitaxel causes acute pain in rodents in a dose-dependent manner. The paclitaxel-induced acute pain occurs within 2 hrs after a single intravenous injection of paclitaxel. This is accompanied by low levels of paclitaxel penetrating into the cerebral spinal fluid and spinal dorsal horn. We demonstrated that an intrathecal injection of paclitaxel induces mechanical allodynia in a dose-dependent manner. Paclitaxel causes activation of toll like receptor 4 (TLR4) in the spinal dorsal horn and dorsal root ganglions. Through activating TLR4, paclitaxel increases glutamatergic synaptic activities and reduces glial glutamate transporter activities in the dorsal horn. Activations of TLR4 are necessary in the genesis of paclitaxel-induced acute pain. The cellular and molecular signaling pathways revealed in this study could provide rationales for the development of analgesics and management strategies for P-APS in patients. PMID:25775962

  3. Paclitaxel, cisplatin, and 5-fluorouracil in patients with advanced or recurrent squamous cell carcinoma of the head and neck: a preliminary report.

    PubMed

    Hussain, M; Salwen, W; Kucuk, O; Ensley, J

    1997-12-01

    The combination of 5-fluorouracil (5-FU) and cisplatin is considered the most active chemotherapy for patients with recurrent squamous cell carcinoma of the head and neck (SCCHN), with an overall response rate of 30%. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has demonstrated activity in SCCHN and synergy with cisplatin. To augment the activity of the combination of 5-FU and cisplatin, a pilot study was designed to determine the feasibility of combining 3-hour infusional paclitaxel with 5-FU and cisplatin. To be eligible, patients had to have recurrent or advanced SCCHN with measurable or evaluable disease and no prior chemotherapy. A minimum of three courses had to be delivered to determine cumulative toxicity. The starting dose level consisted of paclitaxel 135 mg/m2 on day 1, cisplatin 75 mg/m2 on day 2, and 5-FU 1 g/m2 on days 2 through 6. The first treated patient developed grade 4 mucositis, which resulted in reducing dose level 1 of 5-FU to 800 mg/m2/d on days 2 through 6 (seven patients); subsequently, the 5-FU dose was adjusted to 1 g/m2/d on days 2 through 5 (nine patients). To date, 17 patients have been enrolled, with a median age of 62 years (range, 48 to 75 years). Of the 17 patients, nine had recurrent disease following prior surgery and/or radiotherapy and eight had previously untreated advanced SCCHN. Major toxicities were neutropenia and mucositis. There were four early deaths (two treatment-related and two cancer-related). Forty-seven courses of therapy were delivered, with a median of two (range, one to five). The overall response rate in 14 response-evaluable patients was 71% (10 of 14 patients; eight partial and two complete responses). Five of seven response-evaluable patients with recurrent disease had major responses (one complete and four partial responses). At the current dose, the combination of paclitaxel/5-FU/cisplatin is feasible and shows very encouraging activity, particularly in patients with recurrent SCCHN. PMID:9427265

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

    PubMed

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

    2015-03-01

    Cladosporium oxysporum a new taxol producing endophytic fungus was identified and production of taxol were characterized using UV-visible spectroscopy (UV-vis), high-performance liquid chromatography (HPLC), infrared (IR) nuclear magnetic resonance spectroscopy (NMR ((13)C and (1)H)) and liquid chromatography-mass spectrometry (LC-MS). The taxol biosynthetic gene (dbat) was evaluated for new taxol producing fungus. Antibacterial activity against six different human pathogenic bacteria was done by agar well diffusion method. The anticancer efficacy of isolated fungal taxol were also evaluated in human colon cancer cell HCT 15 by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), cytotoxicity and nuclear morphology analysis. The isolated fungal taxol showed positive towards biosynthetic gene (dbat) and effective against both Gram positive as well as Gram negative. The fungal taxol suppress growth of cancer cell line HCT 15 with an IC50 value of 3.5?M concentration by 24h treatment. Thus, the result reveals that C. oxysporum could be a potential alternative source for production of taxol and have antibacterial as well as anticancer properties with possible clinical applications. PMID:25544183

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

    PubMed

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

    2008-01-01

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

  6. Preparation and evaluation of paclitaxel-loaded PEGylated immunoliposome

    Microsoft Academic Search

    Tao Yang; Min-Koo Choi; Fu-De Cui; Jung Sun Kim; Suk-Jae Chung; Chang-Koo Shim; Dae-Duk Kim

    2007-01-01

    A sterically stabilized paclitaxel-loaded liposome tailored to target human breast cancer cells was developed, thereby promoting the efficiency of intracellular delivery of paclitaxel through receptor-mediated endocytosis. Results indicated that the targeting moiety (thiolated Herceptin) was successfully coupled to the distal reactive maleimide terminus of the poly (ethylene glycol)-phospholipid conjugate as well as being incorporated in the liposomal bilayers. The particle

  7. Paclitaxel release from micro-porous PLGA disks

    Microsoft Academic Search

    Lai Yeng Lee; Sudhir Hulikal Ranganath; Yilong Fu; Jasmine Limin Zheng; How Sung Lee; Chi-Hwa Wang; Kenneth A. Smith

    2009-01-01

    Micro-porous biodegradable polymeric foams have potential applications in tissue engineering and drug delivery systems. A two-stage fabrication process combining spray drying and supercritical gas foaming is presented for the encapsulation of paclitaxel in micro-porous PLGA (poly lactic glycolic acid) foams. Encapsulation of paclitaxel in the PLGA polymer matrix was achieved and these foams have potential application as a new type

  8. Effect of Ethyl Pyruvate on Paclitaxel-Induced Neuropathic Pain in Rats

    PubMed Central

    Choi, Seong Soo; Koh, Won Uk; Nam, Jae Sik; Shin, Jin Woo; Leem, Jeong Gill

    2013-01-01

    Background Although paclitaxel is a widely used chemotherapeutic agent for the treatment of solid cancers, side effects such as neuropathic pain lead to poor compliance and discontinuation of the therapy. Ethyl pyruvate (EP) is known to have analgesic effects in several pain models and may inhibit apoptosis. The present study was designed to investigate the analgesic effects of EP on mechanical allodynia and apoptosis in dorsal root ganglion (DRG) cells after paclitaxel administration. Methods Rats were randomly divided into 3 groups: 1) a control group, which received only vehicle; 2) a paclitaxel group, which received paclitaxel; and 3) an EP group, which received EP after paclitaxel administration. Mechanical allodynia was tested before and at 7 and 14 days after final paclitaxel administration. Fourteen days after paclitaxel treatment, DRG apoptosis was determined by activated caspase-3 immunoreactivity (IR). Results Post-treatment with EP did not significantly affect paclitaxel-induced allodynia, although it tended to slightly reduce sensitivities to mechanical stimuli after paclitaxel administration. After paclitaxel administration, an increase in caspase-3 IR in DRG cells was observed, which was co-localized with NF200-positive myelinated neurons. Post-treatment with EP decreased the paclitaxel-induced caspase-3 IR. Paclitaxel administration or post-treatment with EP did not alter the glial fibrillary acidic protein IRs in DRG cells. Conclusions Inhibition of apoptosis in DRG neurons by EP may not be critical in paclitaxel-induced mechanical allodynia. PMID:23614074

  9. Radial Compression of Microtubules and the Mechanism of Action of Taxol and Associated Proteins

    PubMed Central

    Needleman, Daniel J.; Ojeda-Lopez, Miguel A.; Raviv, Uri; Ewert, Kai; Miller, Herbert P.; Wilson, Leslie; Safinya, Cyrus R.

    2005-01-01

    Microtubules (MTs) are hollow cylindrical polymers composed of ??-tubulin heterodimers that align head-to-tail in the MT wall, forming linear protofilaments that interact laterally. We introduce a probe of the interprotofilament interactions within MTs and show that this technique gives insight into the mechanisms by which MT-associated proteins (MAPs) and taxol stabilize MTs. In addition, we present further measurements of the mechanical properties of MT walls, MT-MT interactions, and the entry of polymers into the MT lumen. These results are obtained from a synchrotron small angle x-ray diffraction (SAXRD) study of MTs under osmotic stress. Above a critical osmotic pressure, Pcr, we observe rectangular bundles of MTs whose cross sections have buckled to a noncircular shape; further increases in pressure continue to distort MTs elastically. The Pcr of ?600 Pa provides, for the first time, a measure of the bending modulus of the interprotofilament bond within an MT. The presence of neuronal MAPs greatly increases Pcr, whereas surprisingly, the cancer chemotherapeutic drug taxol, which suppresses MT dynamics and inhibits MT depolymerization, does not affect the interprotofilament interactions. This SAXRD-osmotic stress technique, which has enabled measurements of the mechanical properties of MTs, should find broad application for studying interactions between MTs and of MTs with MAPs and MT-associated drugs. PMID:16100275

  10. 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

  11. [An oligopeptide improves solubility of paclitaxel by non-covalent interaction].

    PubMed

    Liu, Wei; Guo, Tao; Ge, Jing-Wen; Li, Hai-Yan; Xu, Xue-Jun; Sun, Li-Xin; Zhang, Ji-Wen

    2012-07-01

    Based on the principle of non-covalent interactions between oligopeptides and paclitaxel for improving the solubility of paclitaxel, an oligopeptide, N terminal-W(L)-FFGREKD-C terminal (W8), was designed and the solubilization effect of W8 on paclitaxel was detected through experiments. The binding efficiency and the possible optimal conformation were optimized by molecular docking program. The solubilization effect of W8 on paclitaxel was determined by RP-HPLC. And the solubilization mechanism of oligopeptide to paclitaxel was proposed at molecular level. It was indicated from the docking result that there existed pi-pi interactions and several hydrogen-bond interactions between the oligopeptide and paclitaxel. After being solubilized by the oligopeptide, the aqueous solubility of paclitaxel was increased to 28 times. This study provided basis for further research of the solubilization of paclitaxel by oligopeptide and confirmed a novel approach for the design of safe oligopeptide solubilizing excipient. PMID:22993863

  12. A Phase I Study of Paclitaxel and Cyclophosphamide in Recurrent Adenocarcinoma of the Ovary

    Microsoft Academic Search

    Eddie Reed; Gisele Sarosy; Elise Kohn; Michaele Christian; Barry Goldspiel; Patricia Davis; Joan Jacob; Martha Maher

    1996-01-01

    We have conducted a disease specific phase I study of paclitaxel and cyclophosphamide in recurrent adenocarcinoma of the ovary. This was done to take advantage of the cellular and molecular synergism between paclitaxel and DNA-damaging agents, with the hope of avoiding paclitaxel–cisplatin toxicities. Paclitaxel was given as a 24-hr CIVI, after which cyclophosphamide was given as a 60-min infusion. Cycles

  13. Synergistic dual-targeting hydrogel improves targeting and anticancer effect of Taxol in vitro and in vivo.

    PubMed

    Shu, Chang; Li, Ruixin; Yin, Yajun; Yin, Deyan; Gu, Yueqing; Ding, Li; Zhong, Wenying

    2014-12-18

    A synergistic dual-targeting molecular self-assembly hydrogel was designed with estrone (Et) and Arg-Gly-Asp (RGD) peptide. Confocal imaging in vitro and real-time visualization in vivo researches were carried out to evidence enhanced targeted delivery and anticancer effect of Taxol. PMID:25349928

  14. 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

  15. Choroidal neovascularization reduced by targeted drug delivery with cationic liposome-encapsulated paclitaxel or targeted photodynamic therapy with verteporfin encapsulated in cationic liposomes

    PubMed Central

    Gross, Nikolai; Ranjbar, Mahdy; Evers, Charlotte; Hua, Jing; Martin, Gottfried; Schulze, Brita; Michaelis, Uwe; Hansen, Lutz L.

    2013-01-01

    Purpose Intravitreal antivascular endothelial growth factor (anti-VEGF) application has revolutionized the treatment of choroidal neovascularization (CNV), a hallmark of wet age-related macular degeneration. However, additional treatment options are desirable as not all CNV lesions respond to anti-VEGF injections. Here, we assessed the feasibility of targeted delivery of cationic liposome-encapsulated paclitaxel (EndoTAG-1) in treating CNV. Furthermore, we investigated whether a new formulation of verteporfin encapsulated in cationic liposomes (CL-VTP) enhances the effect of photodynamic therapy (PDT). Methods EndoTAG-1, LipoSPA, and CL-VTP were produced by encapsulating paclitaxel, succinyl-paclitaxel, or verteporfin in cationic liposomes (CL). Mice underwent argon laser coagulations at day 0 (D0) to induce CNV. EndoTAG-1 and LipoSPA were injected into the tail vein at D1, D3, D5, D7, and D9. Taxol, CL, or trehalose buffer alone was injected in control animals. At D10, all animals were perfused with fluorescein isothiocyanate (FITC)-dextran. Flatmounts comprising the retinal pigment epithelium, choroid, and sclera were prepared for quantifying the CNV by measuring the area of lesions perfused with FITC-dextran. For PDT, mice received an injection with CL-VTP or Visudyne at D10. One eye was treated with PDT while the other served as a control. Evaluation of RPE-choroid-scleral and retinal flatmounts was performed at D12, D14, or D17. Perfusion with FITC-dextran and tetramethylrhodamine-5-(and 6)-isothiocyanate-lectin staining was used to distinguish between perfused and non-perfused choroidal vessels. Results EndoTAG-1 or LipoSPA significantly reduced CNV size to 15% compared to trehalose controls. The mean CNV area of mice treated with CL was reduced (though not significantly) to about one-half of the value of the trehalose control group. The same was observed for paclitaxel. Thus, the reduction in the CNV size between treatment with CL and treatment with EndoTAG-1 or LipoSPA was 40%, which was not significant. PDT using either CL-VTP or Visudyne reduced CNV size to 65% (D17) of trehalose control size. CNV size was further diminished to 56% with Visudyne and 53% with CL-VTP when PDT was repeated twice. Most importantly, PDT-associated retinal damage was less pronounced using CL-VTP compared to Visudyne. Conclusions Systemic intravenous injection of paclitaxel (EndoTAG-1)- or succinyl-paclitaxel (LipoSPA)-loaded CL had a significant antiangiogenic effect in a CNV mouse model. PDT with CL-VTP was as effective as Visudyne in neovascular obliteration but induced less tissue damage. Our data suggest that systemic application of cationic liposome formulations may serve to treat ocular neovascular diseases. This approach may reduce the need for intraocular injections and may benefit patients with neovascular lesions irresponsive to anti-VEGF treatment. PMID:23335851

  16. Potential biomarkers for paclitaxel sensitivity in hypopharynx cancer cell.

    PubMed

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

    2013-01-01

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

  17. Potential biomarkers for paclitaxel sensitivity in hypopharynx cancer cell

    PubMed Central

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

    2013-01-01

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

  18. Phase 1 and pharmacokinetic study of weekly docosahexaenoic acid-paclitaxel, Taxoprexin ® , in resistant solid tumor malignancies

    Microsoft Academic Search

    Paula M. Fracasso; Joel Picus; Jonathan D. Wildi; Sherry A. Goodner; Allison N. Creekmore; Feng Gao; Ramaswamy Govindan; Matthew J. Ellis; Benjamin R. Tan; Gerald P. Linette; ChauHwei J. Fu; Helen S. Pentikis; Stephen C. Zumbrun; Merrill J. Egorin; Robert E. Bellet

    2009-01-01

    Purpose  To determine the maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics of weekly docosahexaenoic acid-paclitaxel\\u000a (DHA-paclitaxel), a taxane fatty acid conjugate.\\u000a \\u000a \\u000a \\u000a Experimental design  Docosahexaenoic acid-paclitaxel was administered by 2-hour i.v. infusion weekly for three out of four weeks. DHA-paclitaxel\\u000a 200 mg\\/m2 was dose escalated by 100 mg\\/m2 per cohort to 600 mg\\/m2. Blood samples for pharmacokinetics of DHA-paclitaxel and paclitaxel derived from DHA-paclitaxel were

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

    PubMed Central

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

    2013-01-01

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

  20. Intraperitoneal delivery of paclitaxel by poly(ether-anhydride) microspheres effectively suppresses tumor growth in a murine metastatic ovarian cancer model.

    PubMed

    Yang, Ming; Yu, Tao; Wood, Joseph; Wang, Ying-Ying; Tang, Benjamin C; Zeng, Qi; Simons, Brian W; Fu, Jie; Chuang, Chi-Mu; Lai, Samuel K; Wu, T-C; Hung, Chien-Fu; Hanes, Justin

    2014-04-01

    Intraperitoneal (IP) chemotherapy is more effective than systemic chemotherapy for treating advanced ovarian cancer, but is typically associated with severe complications due to high dose, frequent administration schedule, and use of non-biocompatible excipients/delivery vehicles. Here, we developed paclitaxel (PTX)-loaded microspheres composed of di-block copolymers of poly(ethylene glycol) and poly(sebacic acid) (PEG-PSA) for safe and sustained IP chemotherapy. PEG-PSA microspheres provided efficient loading (~ 13% w/w) and prolonged release (~ 13 days) of PTX. In a murine ovarian cancer model, a single dose of IP PTX/PEG-PSA particles effectively suppressed tumor growth for more than 40 days and extended the median survival time to 75 days compared to treatments with Taxol(®) (47 days) or IP placebo particles (34 days). IP PTX/PEG-PSA was well tolerated, with only minimal to mild inflammation. Our findings support PTX/PEG-PSA microspheres as a promising drug delivery platform for IP therapy of ovarian cancer, and potentially other metastatic peritoneal cancers. PMID:24816829

  1. Intraperitoneal delivery of paclitaxel by poly(ether-anhydride) microspheres effectively suppresses tumor growth in a murine metastatic ovarian cancer model

    PubMed Central

    Yang, Ming; Yu, Tao; Wood, Joseph; Wang, Ying-Ying; Tang, Benjamin C.; Zeng, Qi; Simons, Brian W.; Fu, Jie; Chuang, Chi-Mu; Lai, Samuel K.; Wu, T.-C.; Hung, Chien-Fu; Hanes, Justin

    2014-01-01

    Intraperitoneal (IP) chemotherapy is more effective than systemic chemotherapy for treating advanced ovarian cancer, but is typically associated with severe complications due to high dose, frequent administration schedule, and use of non-biocompatible excipients/delivery vehicles. Here, we developed paclitaxel (PTX)-loaded microspheres composed of di-block copolymers of poly(ethylene glycol) and poly(sebacic acid) (PEG-PSA) for safe and sustained IP chemotherapy. PEG-PSA microspheres provided efficient loading (~ 13% w/w) and prolonged release (~ 13 days) of PTX. In a murine ovarian cancer model, a single dose of IP PTX/PEG-PSA particles effectively suppressed tumor growth for more than 40 days and extended the median survival time to 75 days compared to treatments with Taxol® (47 days) or IP placebo particles (34 days). IP PTX/PEG-PSA was well tolerated, with only minimal to mild inflammation. Our findings support PTX/PEG–PSA microspheres as a promising drug delivery platform for IP therapy of ovarian cancer, and potentially other metastatic peritoneal cancers. PMID:24816829

  2. Improved high-performance liquid chromatographic detection of paclitaxel in patient's plasma using solid-phase extraction, and semi-micro-bore C18 separation and UV detection.

    PubMed

    Suno, Manabu; Ono, Takashi; Iida, Shinya; Umetsu, Noriko; Ohtaki, Ko-ichi; Yamada, Takehiro; Awaya, Toshio; Satomi, Machiko; Tasaki, Yoshikazu; Shimizu, Keiko; Matsubara, Kazuo

    2007-12-01

    Although a number of analytical methods for taxanes have been published, none of them are sufficiently suitable for use in a medical setting. In this study, we established an improved analytical HPLC/UV detection method using a Sep-Pak C18 cartridge for extraction and a semi-micro-borecolumn for separation. This method employed here reduced chromatographic background signals, and allowed a more sensitive analysis of taxanes in human blood sample. The recovery of taxanes after the solid-phase extraction procedure was over 90%. Chromatographic separation of paclitaxel and docetaxel was achieved within 30 min with no interference peak by a semi-micro-bore column, packed either with C18 (Wakosil 5C18 RS) or pentafluorophenyl (Curosil/Taxol) materials. The method was reproducible with coefficients of variation less than 6%. This analytical procedure was simple and sensitive with lower quantification limit of 3 ng/ml. The improved sensitivity achieved by the popular HPLC/UV apparatus, which is available in hospitals, would vouch safer and more efficient therapy with taxane. PMID:18210665

  3. Targeting cyclin B1 inhibits proliferation and sensitizes breast cancer cells to taxol

    PubMed Central

    Androic, Ilija; Krämer, Andrea; Yan, Ruilan; Rödel, Franz; Gätje, Regine; Kaufmann, Manfred; Strebhardt, Klaus; Yuan, Juping

    2008-01-01

    Background Cyclin B1, the regulatory subunit of cyclin-dependent kinase 1 (Cdk1), is essential for the transition from G2 phase to mitosis. Cyclin B1 is very often found to be overexpressed in primary breast and cervical cancer cells as well as in cancer cell lines. Its expression is correlated with the malignancy of gynecological cancers. Methods In order to explore cyclin B1 as a potential target for gynecological cancer therapy, we studied the effect of small interfering RNA (siRNA) on different gynecological cancer cell lines by monitoring their proliferation rate, cell cycle profile, protein expression and activity, apoptosis induction and colony formation. Tumor formation in vivo was examined using mouse xenograft models. Results Downregulation of cyclin B1 inhibited proliferation of several breast and cervical cancer cell lines including MCF-7, BT-474, SK-BR-3, MDA-MB-231 and HeLa. After combining cyclin B1 siRNA with taxol, we observed an increased apoptotic rate accompanied by an enhanced antiproliferative effect in breast cancer cells. Furthermore, control HeLa cells were progressively growing, whereas the tumor growth of HeLa cells pre-treated with cyclin B1 siRNA was strongly inhibited in nude mice, indicating that cyclin B1 is indispensable for tumor growth in vivo. Conclusion Our data support the notion of cyclin B1 being essential for survival and proliferation of gynecological cancer cells. Concordantly, knockdown of cyclin B1 inhibits proliferation in vitro as well as in vivo. Moreover, targeting cyclin B1 sensitizes breast cancer cells to taxol, suggesting that specific cyclin B1 targeting is an attractive strategy for the combination with conventionally used agents in gynecological cancer therapy. PMID:19113992

  4. Paclitaxel resistance in untransformed human mammary epithelial cells is associated with an aneuploidy-prone phenotype

    PubMed Central

    Bouchet, B P; Bertholon, J; Falette, N; Audoynaud, C; Lamblot, C; Puisieux, A; Galmarini, C M

    2007-01-01

    Despite its increasing clinical use, almost no data are currently available about paclitaxel effects on non-cancerous mammary epithelial cells. We have previously established paclitaxel-resistant sub-cell lines (paclitaxel-surviving populations, PSPs; n=20), and sensitive controls (control clones, CCs; n=10), from the untransformed human mammary epithelial cell line HME1. In this study, we aimed to establish whether paclitaxel resistance was associated with a modified sensitivity to paclitaxel-induced aneuploidy. For this purpose, we analysed basal and paclitaxel-induced chromosome missegregation, apoptosis and aberrant spindle multipolarisation as well as microtubular network composition for each subline. PSP sublines showed higher basal and paclitaxel-induced chromosome missegregation than the CC sublines. This phenomenon was associated with resistance to paclitaxel-induced apoptosis. No significant difference in paclitaxel-induced spindle pole abnormalities between CC and PSP sublines was found. Besides, we showed that a majority of PSPs display a constitutively disrupted microtubular network composition due to aberrant tubulin expression and post-translational modifications. These results clearly indicate that paclitaxel resistance in untransformed human mammary epithelial cells is related to an increased susceptibility to acquire aneuploidy in response to this agent. The consequences of these paclitaxel-associated alterations could be deleterious as they can potentially trigger tumorigenesis. PMID:17968427

  5. Gemcitabine Plus Paclitaxel Versus Carboplatin Plus Either Gemcitabine or Paclitaxel in Advanced Non-small-cell Lung Cancer: A Literature-based Meta-analysis

    Microsoft Academic Search

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

    2010-01-01

    The combination of gemcitabine plus paclitaxel has been proposed as an alternative to the platinum-based combinations for\\u000a treatment of advanced non-small-cell lung cancer (NSCLC). However, conflicting results have been reported. This meta-analysis\\u000a was performed to compare the activity, efficacy, and toxicity of gemcitabine plus paclitaxel versus carboplatin plus either\\u000a gemcitabine or paclitaxel in patients with untreated advanced NSCLC. Randomized phase

  6. nab-paclitaxel for the management of patients with advanced non-small-cell lung cancer.

    PubMed

    Hirsh, Vera

    2014-02-01

    The 130 nm albumin-bound form of paclitaxel, nab-paclitaxel (Abraxane(®)), was recently approved by the US FDA for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer (NSCLC) in combination with carboplatin in patients who are not candidates for curative surgery or radiation therapy. In a Phase III registrational trial, nab-paclitaxel plus carboplatin demonstrated a significantly improved overall response rate, the primary endpoint, and a trend toward improved survival compared with solvent-based paclitaxel plus carboplatin in patients with advanced NSCLC. Significantly less neutropenia, neuropathy, arthralgia, and myalgia were observed with the nab-paclitaxel regimen, but the solvent-based paclitaxel regimen produced less thrombocytopenia and anemia. The clinical experience with nab-paclitaxel to date and the role of this newly approved therapy in the management of NSCLC will be summarized in this article. PMID:24467217

  7. Preclinical evaluation of nanoparticle albumin-bound paclitaxel for treatment of pediatric bone sarcoma.

    PubMed

    Wagner, Lars M; Yin, Hong; Eaves, David; Currier, Mark; Cripe, Timothy P

    2014-11-01

    The combination of docetaxel and gemcitabine is frequently used to treat recurrent bone sarcoma. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is less toxic and more active than docetaxel or paclitaxel for breast cancer patients. The combination of nab-paclitaxel and gemcitabine has preclinical synergy and is approved to treat pancreatic cancer. We observed growth inhibition and improved survival with nab-paclitaxel in a Ewing sarcoma xenograft, and activity was additive with gemcitabine in an osteosarcoma model. Primary Ewing sarcoma tumors expressed the transport protein SPARC, previously associated with nab-paclitaxel activity. These findings provide rationale for further evaluation of nab-paclitaxel with gemcitabine for bone sarcoma. PMID:24753077

  8. Effects of Cyclooxygenase Inhibitors in Combination with Taxol on Expression of Cyclin D1 and Ki-67 in a Xenograft Model of Ovarian Carcinoma

    PubMed Central

    Li, Wei; Cai, Jia-Hui; Zhang, Jun; Tang, Yun-Xian; Wan, Liang

    2012-01-01

    The present study was designed to investigate the effects of cyclooxygenase (COX) inhibitors in combination with taxol on the expression of cyclin D1 and Ki-67 in human ovarian SKOV-3 carcinoma cells xenograft-bearing mice. The animals were treated with 100 mg/kg celecoxib (a COX-2 selective inhibitor) alone, 3 mg/kg SC-560 (a COX-1 selective inhibitor) alone by gavage twice a day, 20 mg/kg taxol alone by intraperitoneally (i.p.) once a week, or celecoxib/taxol, SC-560/celecoxib, SC-560/taxol or SC-560/celecoxib/taxol, for three weeks. To test the mechanism of the combination treatment, the index of cell proliferation and expression of cyclin D1 in tumor tissues were determined by immunohistochemistry. The mean tumor volume in the treated groups was significantly lower than control (p < 0.05), and in the three-drug combination group, tumor volume was reduced by 58.27% (p < 0.01); downregulated cell proliferation and cyclin D1 expression were statistically significant compared with those of the control group (both p < 0.01). This study suggests that the effects of COX selective inhibitors on the growth of tumors and decreased cell proliferation in a SKOV-3 cells mouse xenograft model were similar to taxol. The three-drug combination showing a better decreasing tendency in growth-inhibitory effect during the experiment may have been caused by suppressing cyclin D1 expression. PMID:22949827

  9. 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

  10. Functionalized nanospheres for targeted delivery of paclitaxel.

    PubMed

    Bushman, Jared; Vaughan, Asa; Sheihet, Larisa; Zhang, Zheng; Costache, Marius; Kohn, Joachim

    2013-11-10

    Targeted delivery of anti-cancer agents to cancer cells is a mature line of investigation that has yet to realize its full potential. In this study we report on the development of a delivery platform with the future goal of merging two thus far parallel methods for selective elimination of cancer cells: targeted nanospheres and pretargeted radioimmunotherapy. Several clinical trials have shown the promise of pretargeted radioimmunotherapy, which leverages the specificity of antibodies for targeted cell populations and delivers a localized dose of a biotinylated radionuclide that is most often administered following binding of a biotinylated antibody and streptavidin (StA) to the target cells. The work presented here describes the development of biotinylated nanospheres based on an ABA-type copolymer comprised of a tyrosine-derived oligomer as the B-block and poly(ethylene glycol) (PEG) A-blocks. The biotinylated nanospheres encapsulate paclitaxel (PTX) to the same extent as unbiotinylated nanospheres. Efficacy of targeting was shown on CD44 positive cells in the SUM159 breast cancer cell line by incubating the cells sequentially with a biotinylated anti-CD44 antibody, StA and the biotinylated nanospheres encapsulating PTX. Targeted nanospheres achieved the half maximal inhibitory concentration of PTX on SUM159 cells at a 5-10 fold lower concentration than that of PTX applied in either non-targeted nanospheres or free drug approaches. Moreover, targeted nanospheres selectively eliminated CD44 positive SUM159 cells compared to free PTX and untargeted nanospheres. This new generation of nano-sized carrier offers a versatile platform that can be adopted for a wide variety of drug and target specific applications and has the potential to be combined with the clinically emerging method of pretargeted radioimmunotherapy. PMID:23792807

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

    E-print Network

    Prevention of local tumor growth with paclitaxel- loaded microspheres Solomon M. Azouz, MS,a Joseph. The primary aim of this study was to assess the feasibility of a microsphere drug delivery system to locally resection margin. Methods: Poly-(D,L-lactic-co-glycolic acid) (PLGA) microspheres loaded

  12. Chemotherapy with paclitaxel plus carboplatin for relapsed advanced thymic carcinoma

    PubMed Central

    2014-01-01

    Objective For rarity of thymic carcinoma, no definitive chemotherapeutic regimen has been established in second- or further-line settings. The aim of this study was to evaluate the feasibility and safety of paclitaxel plus carboplatin in advanced thymic carcinoma as second- or further-line treatment in our institute. Methods We evaluated the efficacy and toxicity of paclitaxel plus carboplatin as salvage therapy in 12 patients with previously treated advanced thymic carcinoma from 2005 to 2012 in Zhejiang Cancer Hospital. Survival analysis was evaluated by Kaplan-Meier method. Results Twelve patients were included in current study. Four patients achieved stable disease (SD), and three achieved partial response (PR), representing a response rate of 25.0% and disease control rate (DCR) of 58.3%. Median progression-free survival (PFS) and overall survival (OS) were 3.5 and 24.0 months, respectively. The toxicities associated with the paclitaxel plus carboplatin was generally acceptable. Conclusions Paclitaxel plus carboplatin appears to have some activity against thymic carcinoma as second-line or later chemotherapy in advanced thymic carcinoma. PMID:25589977

  13. Masitinib antagonizes ATP-binding cassette subfamily C member 10-mediated paclitaxel resistance: a preclinical study.

    PubMed

    Kathawala, Rishil J; Sodani, Kamlesh; Chen, Kang; Patel, Atish; Abuznait, Alaa H; Anreddy, Nagaraju; Sun, Yue-Li; Kaddoumi, Amal; Ashby, Charles R; Chen, Zhe-Sheng

    2014-03-01

    Paclitaxel displays 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 multidrug resistance protein 7 (MRP7) efflux transporter, is a major mediator of paclitaxel resistance. In this study, we show that masitinib, a small molecule stem-cell growth factor receptor (c-Kit) tyrosine kinase inhibitor, at nontoxic concentrations, significantly attenuates paclitaxel resistance in HEK293 cells transfected with ABCC10. Our in vitro studies indicated that masitinib (2.5 ?mol/L) enhanced the intracellular accumulation and decreased the efflux of paclitaxel by inhibiting the ABCC10 transport activity without altering the expression level of ABCC10 protein. Furthermore, masitinib, in combination with paclitaxel, significantly inhibited the growth of ABCC10-expressing tumors in nude athymic mice in vivo. Masitinib administration also resulted in a significant increase in the levels of paclitaxel in the plasma, tumors, and lungs compared with paclitaxel alone. In conclusion, the combination of paclitaxel and masitinib could serve as a novel and useful therapeutic strategy to reverse paclitaxel resistance mediated by ABCC10. PMID:24431074

  14. Synergy of Taxol and rhein lysinate associated with the downregulation of ERK activation in lung carcinoma cells

    PubMed Central

    ZHEN, YONG-ZHAN; HU, GANG; ZHAO, YU-FANG; YAN, FENG; LI, RAN; GAO, JUN-LING; LIN, YA-JUN

    2013-01-01

    In previous studies we observed that rhein lysinate (RHL), a salt of rhein and lysine that is easily dissolved in water, inhibited the growth of tumor cells in breast cancer, ovarian cancer, hepatocellular carcinoma and cervical cancer. The present study aimed to investigate the effects of RHL on H460 and A549 non-small cell lung cancer (NSCLC) cells using a combination of RHL and Taxol. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay was used to determine the growth inhibition effect of the drugs in the H460 and A549 cells. Cell apoptosis was analyzed by flow cytometry combined with fluorescein-isothiocyanate-Annexin V/propidium iodide (PI) staining. The expression levels of proteins were detected by western blotting. There was a significant reduction in the proliferation of the NSCLC cell lines treated with a combination of Taxol and RHL. The overall growth inhibition was directly correlated with apoptotic cell death. RHL potentiated Taxol-induced cell killing by reducing extracellular signal-regulated kinase (ERK) activity and increasing the levels of cleaved poly(ADP-ribose) polymerase (PARP) and caspase-3. Notably, the results for the Bcl-2 and NF-?B proteins also showed downregulation in the combined treatment group compared with the single-agent treatment and the untreated control groups. The present results showed that RHL potentiates the growth inhibition induced by Taxol in NSCLC cells and showed that this synergy may be associated with the downregulation of ERK activation. PMID:24137360

  15. Human cancer cell line microRNAs associated with in vitro sensitivity to paclitaxel

    PubMed Central

    CHEN, NING; CHON, HYE SOOK; XIONG, YIN; MARCHION, DOUGLAS C.; JUDSON, PATRICIA L.; HAKAM, ARDESHIR; GONZALEZ-BOSQUET, JESUS; PERMUTH-WEY, JENNIFER; WENHAM, ROBERT M.; APTE, SACHIN M.; CHENG, JIN Q.; SELLERS, THOMAS A.; LANCASTER, JOHNATHAN M.

    2014-01-01

    Paclitaxel is a mainstay of treatment for many solid tumors, and frequently, clinical outcome is influenced by paclitaxel sensitivity. Despite this, our understanding of the molecular basis of paclitaxel response is incomplete. Recently, it has been shown that microRNAs (miRNAs) influence messenger RNA (mRNA) transcriptional control and can contribute to human carcinogenesis. In the present study, our objective was to identify miRNAs associated with cancer cell line response to paclitaxel and to evaluate these miRNAs as therapeutic targets to increase paclitaxel sensitivity. We measured the expression of 335 unique miRNAs in 40 human cancer cell lines selected from the NCI panel. We then integrated miRNA expression data with publicly available paclitaxel-sensitivity (GI50) data for each of the 40 cell lines to identify miRNAs associated with paclitaxel sensitivity. Ovarian cancer cell lines with differential miRNA expression and paclitaxel sensitivity were transiently transfected with miRNA precursors and inhibitors, and the effects on in vitro cell paclitaxel sensitivity were evaluated. Pearson’s correlation identified 2 miRNAs (miR-367 and miR-30a-5p) associated with the NCI40 cell line in vitro paclitaxel response (P<0.0003). Ovarian cancer cells were selected based on the association between paclitaxel sensitivity and miR-367/miR-30a-5p expression. Overexpression of miR-367 in the paclitaxel-sensitive cells [PA1; IC50, 1.69 nM, high miR-367 (2.997), low miR-30a-5p (?0.323)] further increased paclitaxel sensitivity, whereas miR-367 depletion decreased paclitaxel sensitivity. In contrast, overexpression and depletion of miR-30a-5p in the paclitaxel-resistant cells [OVCAR4; IC50, 17.8 nM, low miR-367 (?0.640), high miR-30a-5p (3.270)] decreased and increased paclitaxel sensitivity, respectively. We identified and successfully targeted miRNAs associated with human cancer cell line response to paclitaxel. Our strategy of integrating in vitro miRNA expression and drug sensitivity data may not only aid in the characterization of determinants of drug response but also in the identification of novel therapeutic targets to increase activity of existing therapeutics. PMID:24220856

  16. Evaluating the role of nab-paclitaxel (Abraxane) in women with aggressive metastatic breast cancer.

    PubMed

    Ciruelos, Eva; Jackisch, Christian

    2014-05-01

    Nab-paclitaxel (Abraxane(®)) is an albumin-bound form of paclitaxel that utilizes the natural properties of albumin to improve paclitaxel delivery to the tumor. It is licensed for use in metastatic breast cancer (MBC) at a dose of 260 mg/m(2) Q3W based on its superior therapeutic index versus conventional paclitaxel 175 mg/m(2) Q3W demonstrated in a Phase III study. In a post-hoc analysis, nab-paclitaxel treatment was associated with rapid and dramatic tumor responses in patients with poor prognostic factors (visceral dominant disease, ?3 metastatic lesions), suggesting it may be a preferred treatment for these patients. Moreover, significant efficacy has been seen with nab-paclitaxel 100 and 150 mg/m(2) QW 3/4, suggesting it may be possible to tailor use of this agent in the future. PMID:24575935

  17. Overexpression of Tyro3 receptor tyrosine kinase leads to the acquisition of taxol resistance in ovarian cancer cells.

    PubMed

    Lee, Chuhee

    2015-07-01

    The majority of patients with ovarian cancer are diagnosed at the advanced stages (III/IV) and their 5?year?survival rate is relatively low. One of the major causes of the poor prognosis of ovarian cancer is the development of resistance to first?line chemotherapy, including platinum and taxol. Therefore, improvements in current understanding of chemoresistance is required for the successful treatment of ovarian cancer. In the present study, taxol?resistant ovarian cancer cells, SKOV3/TR, were established by exposing parental SKOV3 cells to increasing concentrations of taxol. . Briefly, cells were treated with 1.5 nM (for 4 weeks), 3 nM (for 4 weeks), 6 nM (for 5 weeks), 12 nM (for 5 weeks) and 24 nM taxol (for 8 weeks) over 6 months. The SKOV3/TR cells were found to be smaller in size and rounder in shape compared with their parental cells. Cell viability and colony formation assays demonstrated an increase in the population doubling time of the SKOV3/TR cells, indicating a reduction in the proliferative capacity of these cells. Reverse transcription?polymerase chain reaction and western blot analysis revealed that, among the TAM receptor tyrosine kinases (RTKs), the mRNA and protein expression levels of Tyro3 RTK were increased, while those of Axl and Mer RTK were decreased in the SKOV3/TR cells. In addition, restoration of the level of Tyro3 by transfecting Tyro3?specific small interfering RNA into the SKOV3/TR cells reduced the proliferative capacity of the cells, indicating that upregulation of the expression of Tyro3 in SKOV3/TR cells may promote survival in the presence of taxol, which eventually resulted in the acquisition of resistance upon taxol treatment. The present study subsequently found that, in the SKOV3/TR cells, the level of intracellular reactive oxygen species (ROS) was elevated, and antioxidant treatment with N?acetyl cysteine (NAC) exerted more profound antiproliferative effects compared with the parental cells. The western blot analysis demonstrated that treatment of the SKOV3/TR cells with NAC reduced the protein expression of Tyro3, and the inhibitory effect of NAC on the phosphorylation of Akt was increased, which may have had a positive effect on the proliferation of the SKOV3/TR cells. The levels of phosphorylation and protein expression of signal transducers and activators of transcription 3 (STAT3) were not affected by NAC treatment, indicating that the phosphorylation of Akt, but not expression or phosphorylation of STAT3, was associated with the increased intracellular ROS level in the SKOV3/TR cells. Taken together, the results of the present study demonstrated that the acquired taxol resistance of ovarian cancer cells was associated with ROS?dependent upregulation in the expression of Tyro3 RTK and the subsequent activation of Akt. PMID:25815442

  18. Combined Delivery of Paclitaxel and Tanespimycin via Micellar Nanocarriers: Pharmacokinetics, Efficacy and Metabolomic Analysis

    PubMed Central

    Wang, Yingzhe; Teng, Quincy; Tan, Chalet

    2013-01-01

    Background Despite the promising anticancer efficacy observed in preclinical studies, paclitaxel and tanespimycin (17-AAG) combination therapy has yielded meager responses in a phase I clinical trial. One serious problem associated with paclitaxel/17-AAG combination therapy is the employment of large quantities of toxic organic surfactants and solvents for drug solubilization. The goal of this study was to evaluate a micellar formulation for the concurrent delivery of paclitaxel and 17-AAG in vivo. Methodology/Principal Findings Paclitaxel/17-AAG-loaded micelles were assessed in mice bearing human ovarian tumor xenografts. Compared with the free drugs at equivalent doses, intravenous administration of paclitaxel/17-AAG-loaded micelles led to 3.5- and 1.7-fold increase in the tumor concentrations of paclitaxel and 17-AAG, respectively, without significant altering drug levels in normal organs. The enhanced tumor accumulation of the micellar drugs was further confirmed by the whole-body near infrared imaging using indocyanine green-labeled micelles. Subsequently, the anticancer efficacy of paclitaxel/17-AAG-loaded micelles was examined in comparison with the free drugs (weekly 20 mg/kg paclitaxel, twice-weekly 37.5 mg/kg 17-AAG). We found that paclitaxel/17-AAG-loaded micelles caused near-complete arrest of tumor growth, whereas the free drug-treated tumors experienced rapid growth shortly after the 3-week treatment period ended. Furthermore, comparative metabolomic profiling by proton nuclear magnetic resonance revealed significant decrease in glucose, lactate and alanine with simultaneous increase in glutamine, glutamate, aspartate, choline, creatine and acetate levels in the tumors of mice treated with paclitaxel/17-AAG-loaded micelles. Conclusions/Significance We have demonstrated in the current wok a safe and efficacious nano-sized formulation for the combined delivery of paclitaxel and 17-AAG, and uncovered unique metabolomic signatures in the tumor that correlate with the favorable therapeutic response to paclitaxel/17-AAG combination therapy. PMID:23505544

  19. A Retrospective Review of Paclitaxel-Associated Gastrointestinal Necrosis in Patients with Epithelial Ovarian Cancer

    Microsoft Academic Search

    Victoria L. Seewaldt; Joanna M. Cain; Barbara A. Goff; Hisham Tamimi; Benjamin Greer; David Figge

    1997-01-01

    Seven patients with gastrointestinal necrosis following paclitaxel chemotherapy are reported. Four of seven patients had platinum refractory disease, while 3\\/7 patients received primary paclitaxel therapy. Complications occurred 5 to 16 days following paclitaxel therapy. The most common clinical presentation was fever (7\\/7 patients), neutropenia (6\\/7 patients), and abdominal pain (6\\/7 patients). All seven patients developed gastrointestinal necrosis following the first

  20. miR-135a contributes to paclitaxel resistance in tumor cells both in vitro and in vivo

    PubMed Central

    Holleman, Amy; Chung, Ivy; Olsen, Rachelle R.; Kwak, Brian; Mizokami, Atsushi; Saijo, Nagahiro; Parissenti, Amadeo; Duan, Zhenfeng; Voest, Emile E.; Zetter, Bruce R.

    2013-01-01

    Cancer cell resistance to paclitaxel continues to be a major clinical problem. In this study, we utilized miRNA arrays to screen for differentially expressed miRNAs in paclitaxel-resistant cell lines established in vitro. We observed concordant upregulation of miR-135a in paclitaxel-resistant cell lines representing three human malignancies. Subsequently, the role of miRNA-135a was evaluated in an in vivo model of paclitaxel resistance. In this model, mice were inoculated subcutaneously with a non-small cell lung carcinoma cell line and treated with paclitaxel for a prolonged period. In paclitaxel-resistant cell lines, established either in vitro or in vivo, blockage of miR-135a sensitized resistant cell lines to paclitaxel-induced cell death. We further demonstrated a correlation between paclitaxel response and miR-135a expression in paclitaxel-resistant subclones that were established in vivo. The paclitaxel-resistant phenotype of these subclones was maintained upon retransplantation in new mice as shown by decreased tumor response upon paclitaxel treatment compared to controls. Upregulation of miR-135a was associated with reduced expression of the adenomatous polyposis coli gene (APC). APC knockdown increased paclitaxel resistance in parental cell lines. Our results indicate that paclitaxel resistance is associated with upregulation of miR-135a both in vitro and in vivo, and is in part mediated by miR-135a-mediated downregulation of APC. PMID:21552288

  1. Treatment of ovarian cancer with paclitaxel- or carboplatin-based intraperitoneal hyperthermic chemotherapy during secondary surgery

    Microsoft Academic Search

    Jeong Hoon Bae; Joon Mo Lee; Ki Sung Ryu; Yong Seok Lee; Yong Gyu Park; Soo Young Hur; Woong Shik Ahn; Seong Eun Namkoong

    2007-01-01

    ObjectiveWe aimed to evaluate the efficacy and feasibility of treating advanced ovarian cancer with paclitaxel or carboplatin in intraperitoneal hyperthermic chemotherapy (IPHC) during secondary surgery.

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

    NASA Astrophysics Data System (ADS)

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

    2013-03-01

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

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

    PubMed

    Sun, Nian-Kang; Huang, Shang-Lang; Chang, Pu-Yuan; Lu, Hsing-Pang; Chao, Chuck C-K

    2014-12-15

    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

  5. A mucoadhesive in situ gel delivery system for paclitaxel

    Microsoft Academic Search

    Saurabh Jauhari; Alekha K. Dash

    2006-01-01

    MUC1 gene encodes a transmembrane mucin glycoprotein that is overexpressed in human breast cancer and colon cancer. The objective\\u000a of this study was to develop an in situ gel delivery system containing paclitaxel (PTX) and mucoadhesives for sustained and\\u000a targeted delivery of anticancer drugs. The delivery system consisted of chitosan and glyceryl monooleate (GMO) in 0.33M citric\\u000a acid containing PTX.

  6. 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

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

    PubMed Central

    Pan, Zhi; Avila, Andrew; Gollahon, Lauren

    2014-01-01

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

  8. Chemical inhibitors suggest endophytic fungal paclitaxel is derived from both mevalonate and non-mevalonate-like pathways.

    PubMed

    Soliman, Sameh S M; Tsao, Rong; Raizada, Manish N

    2011-12-27

    Taxus trees possess fungal endophytes reported to produce paclitaxel. Inhibitors that block early steps in plant paclitaxel biosynthesis were applied to a paclitaxel-producing fungus to determine whether these steps are shared. The plant paclitaxel backbone is reportedly derived from the non-mevalonate terpenoid pathway, while the side chain is phenylalanine-derived. Evidence that the shikimate pathway contributes to fungal paclitaxel was shown by decreased paclitaxel accumulation following inhibition of phenylalanine ammonia lyase. Expression of another shikimate pathway enzyme, 3-dehydroquinate synthase, coincided with paclitaxel production. The importance of the mevalonate pathway in fungal paclitaxel biosynthesis was shown by inhibition of fungal paclitaxel accumulation using compactin, a specific inhibitor of 3-hydroxy-3-methyl-glutaryl-CoA reductase. Expression of another mevalonate pathway enzyme, 3-hydroxy-3-methyl-glutaryl-CoA synthase, coincided with fungal paclitaxel accumulation. Unexpectedly, results from using fosmidomycin suggested that fungal paclitaxel requires 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR), an enzyme in the 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway normally found in bacteria/plants. Additional lines of evidence support this finding; first, a plant DXR antibody recognized a fungal peptide of the correct size; second, expression of an apparent fungal DXR ortholog correlated to changes in paclitaxel production; finally, BLAST searching identified a gene putatively encoding 1-deoxy-D-xylulose-5-phosphate synthase, the first enzyme in the MEP pathway in Aspergillus. PMID:22103292

  9. Albumin-bound paclitaxel: a review of its use for the first-line combination treatment of metastatic pancreatic cancer.

    PubMed

    Hoy, Sheridan M

    2014-10-01

    Nanoparticle albumin-bound paclitaxel (Abraxane(®)) [hereafter referred to as nab-paclitaxel] is an intravenously administered microtubule inhibitor. It was developed to avoid the toxicities associated with the polyoxyethylated castor oil solvent (Cremophor) and ethanol vehicles used to overcome paclitaxel's poor aqueous solubility. Nab-paclitaxel is indicated in the EU and the USA as first-line combination therapy with gemcitabine in adults with metastatic adenocarcinoma of the pancreas. Compared with gemcitabine alone, nab-paclitaxel plus gemcitabine significantly prolonged median overall survival, reflecting a 28 % reduction in the risk of death, in adults with metastatic pancreatic cancer participating in a multinational phase III study. In addition, median progression-free survival was significantly prolonged and the objective response rate was significantly higher with nab-paclitaxel plus gemcitabine than with gemcitabine therapy. Nab-paclitaxel plus gemcitabine had a manageable tolerability profile; in general, adverse events in the phase III study were grade 3 or lower and resolved without specific therapy. Neutropenia and peripheral neuropathy were the most frequently reported adverse reactions leading to nab-paclitaxel dose reductions, or to delays in or the withholding of nab-paclitaxel dosing. Peripheral neuropathy was rapidly reversible in the majority of patients following interruptions in nab-paclitaxel administration and a subsequent reduction in the nab-paclitaxel dose. Current evidence indicates that nab-paclitaxel plus gemcitabine is a valuable option for the treatment of metastatic pancreatic cancer. PMID:25260887

  10. 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

  11. Agrobacterium tumefaciens-mediated genetic transformation of the Taxol-producing endophytic fungus Ozonium sp EFY21.

    PubMed

    Liu, L; Wei, Y M; Zhou, X W; Lin, J; Sun, X F; Tang, K X

    2013-01-01

    An efficient Agrobacterium tumefaciens-mediated genetic transformation method was successfully established for a newly isolated Taxol-producing fungus, Ozonium sp EFY21. A specific hygromycin B resistance expression vector, pCAMBIA1304'AN7-1, was constructed for fungal transformation. Key factors affecting transformation efficiency were thoroughly investigated and optimized. PCR amplification and Southern hybridization were used to verify the transformation events. This study should pave the way for future genetic modification studies of Ozonium sp EFY21. PMID:24065647

  12. Combination of Nab-Paclitaxel and Gemcitabine Improves Survival in Patients with Metastatic Pancreatic Cancer

    Cancer.gov

    In an international randomized phase III trial, patients with metastatic pancreatic cancer who were treated with a combination of albumin-bound paclitaxel (nab-paclitaxel [Abraxane®]) and gemcitabine (Gemzar®) lived longer than patients who were treated with gemcitabine alone. Patients who received both drugs also lived longer without their disease getting worse (progression-free survival).

  13. Localized delivery of paclitaxel using elastic liposomes: formulation development and evaluation.

    PubMed

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

    2011-07-01

    In the present study an elastic liposomes-based paclitaxel formulation was developed with the objective to remove Cremophor EL. Cremophor EL is currently used for solubilizing paclitaxel in the marketed formulation and is known to produce toxic effects. Elastic liposomal paclitaxel formulation was extensively characterized in vitro, ex-vivo, and in vivo. The results obtained were compared against the marketed paclitaxel formulation. The maximum amount of paclitaxel loaded in the elastic liposomal formulation was found to be 6.0 mg/ml, which is similar to the commercial strength of marketed paclitaxel formulation. In vitro skin permeation and deposition studies showed 10.8-fold enhanced steady state transdermal flux and 15.0-fold enhanced drug deposition in comparison to drug solution. These results further confirmed with the vesicle-skin interaction study using FTIR technique. Results of the hemolytic toxicity assay indicate that elastic liposomal formulation induced only 11.2 ± 0.2% hemolysis in comparison to the commercial formulation which showed 38 ± 3.0%. Further, results of the Draize test showed no skin irritation of paclitaxel elastic liposomal formulation. Findings of the study demonstrate that elastic liposomes as a carrier is an attractive approach for localized delivery of paclitaxel. PMID:21428706

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

    E-print Network

    Park, Jong-Sang

    have remained a problem. To achieve controlled drug release, paclitaxel (Ptx)-loaded poly(lactic-co- glycolic acid) (PLGA) nanoparticles (Ptx-PLGA-NPs) were prepared by the emulsion-solvent evaporation methodA Novel Technique for Loading of Paclitaxel-PLGA Nanoparticles onto ePTFE Vascular Grafts Hyun Jung

  15. Screening the endophytic flora of Wollemia nobilis for alternative paclitaxel sources

    Microsoft Academic Search

    Agata Staniek; Herman J. Woerdenbag; Oliver Kayser

    2010-01-01

    The endophytic flora of Wollemia nobilis was investigated in search for alternative paclitaxel producers. On one hand, metabolic profiling of the obtained specimens using an immunoenzymatic technique was carried out. On the other, we aimed at revealing the genetic background of presumed paclitaxel biosynthesis in the isolates.We found an indication of endophytic taxane production in the extracts of two strains,

  16. nab-Paclitaxel in combination with biologically targeted agents for early and metastatic breast cancer.

    PubMed

    Megerdichian, Christine; Olimpiadi, Yuliya; Hurvitz, Sara A

    2014-06-01

    Taxanes are highly active chemotherapeutic agents used 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 biologically interactive, solvent-free, 130-nm-sized albumin-bound paclitaxel, developed to avoid the Cremophor vehicle used in solvent-based paclitaxel. Based on a pivotal phase 3 study, nab-paclitaxel was shown to be safely infused at a significantly higher dose of paclitaxel than the doses used with standard paclitaxel therapy, and had a shorter infusion time, no premedication, and higher response rates. It is now approved in the United States for treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant therapy, and has demonstrated promising efficacy and favorable tolerability. Recently, several phase 2 and 3 studies have suggested a role for nab-paclitaxel in combination with biologically targeted agents for the treatment of early- and late-stage breast cancer. This review will discuss the findings of clinical trials evaluating nab-paclitaxel in combination with biologically targeted therapeutic agents for breast cancer in the neoadjuvant, adjuvant, and metastatic settings. PMID:24560997

  17. 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

  18. 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

  19. 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.

  20. 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

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

    PubMed Central

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

    2014-01-01

    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/m2. 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?

  2. 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

  3. Orally Bioavailable Tubulin Antagonists for Paclitaxel-Refractory Cancer

    PubMed Central

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

    2013-01-01

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

  4. A Novel Nanoparticle Formulation for Sustained Paclitaxel Delivery

    Microsoft Academic Search

    W. J. Trickler; A. A. Nagvekar; A. K. Dash

    2008-01-01

    Purpose  To develop a novel nanoparticle drug delivery system consisting of chitosan and glyceryl monooleate (GMO) for the delivery\\u000a of a wide variety of therapeutics including paclitaxel.\\u000a \\u000a \\u000a \\u000a Methods  Chitosan\\/GMO nanoparticles were prepared by multiple emulsion (o\\/w\\/o) solvent evaporation methods. Particle size and surface\\u000a charge were determined. The morphological characteristics and cellular adhesion were evaluated with surface or transmission\\u000a electron microscopy methods. The

  5. 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

  6. Nanoparticle albumin-bound-paclitaxel: a limited improvement under the current therapeutic paradigm of pancreatic cancer.

    PubMed

    Hoffman, Robert M; Bouvet, Michael

    2015-05-01

    Nanoparticle albumin-bound (nab)-paclitaxel is paclitaxel linked to albumin nanoparticles, which makes it soluble and is an example of an application of nanotechnology for cancer treatment. The development of nanotechnology as a delivery system for nab-paclitaxel has improved the pharmacokinetics and pharmacodynamics of paclitaxel, in part by decreasing its hydrophobicity. Nab-paclitaxel in combination with gemcitabine has slightly improved survival in pancreatic cancer, compared to gemcitabine alone, as demonstrated in Phase III clinical trials. Cell cycle phase-specific drugs, such as nab-paclitaxel, which target cells in the G2/M phase of the cell cycle, can only have limited efficacy since the vast majority of cells in a tumor are quiescent in G0/G1 phase. Recent advances in our laboratory on how to decoy cancer cells to cycle and then trap them in a sensitive phase of the cell cycle, can, in the hopefully near future, allow drugs such as nab-paclitaxel to have high efficacy, even in a treatment-resistant tumor such as pancreatic cancer. PMID:25887245

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

    PubMed Central

    Thangamani, Dhandapani; Edafiogho, Ivan Ogheneochuko

    2013-01-01

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

  8. 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

  9. Effect of ?-conotoxin MVIIA and Ph?1? on paclitaxel-induced acute and chronic pain.

    PubMed

    Rigo, Flávia K; Dalmolin, Gerusa D; Trevisan, Gabriela; Tonello, Raquel; Silva, Mariane A; Rossato, Mateus F; Klafke, Jonatas Z; Cordeiro, Marta do N; Castro Junior, Célio J; Montijo, Danuza; Gomez, Marcus V; Ferreira, Juliano

    2013-12-01

    The treatment with the chemotherapeutic agent paclitaxel produces a painful peripheral neuropathy, and is associated with an acute pain syndrome in a clinically significant number of patients. However, no standard therapy has been established to manage the acute pain or the chronic neuropathic pain related to paclitaxel. In the present study, we evaluated the analgesic potential of two N-type voltage-gated calcium channel (VGCC) blockers, ?-conotoxin MVIIA and Ph?1?, on acute and chronic pain induced by paclitaxel. Adult male rats were treated with four intraperitoneal injections of paclitaxel (1+1+1+1mg/kg, in alternate days) and the development of mechanical hyperalgesia was evaluated 24h (acute painful stage) or 15days (chronic painful stage) after the first paclitaxel injection. Not all animals showed mechanical hyperalgesia 24h after the first paclitaxel injection, but those that showed developed a more intense mechanical hyperalgesia at the chronic painful stage. Intrathecal administration (i.t.) of ?-conotoxin MVIIA (3-300pmol/site) or Ph?1? (10-300pmol/site) reduced the mechanical hyperalgesia either at the acute or at the chronic painful stage induced by paclitaxel. When administered at the acute painful stage, ?-conotoxin MVIIA (300pmol/site, i.t.) and Ph?1? (300pmol/site, i.t.) prevented the worsening of chronic mechanical hyperalgesia. Furthermore, Ph?1? (30-300pmol/site, i.t.) elicited less adverse effects than ?-conotoxin MVIIA (10-300 pmol/site, i.t.). Taken together, our data evidence the involvement of N-type VGCC in pain sensitization induced by paclitaxel and point out the potential of Ph?1? as a safer alternative than ?-conotoxin MVIIA to treat the pain related to paclitaxel. PMID:24148893

  10. 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

  11. 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

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

    PubMed

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

    2012-10-01

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

  13. 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

  14. 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

  15. Polyether–polyester diblock copolymers for the preparation of paclitaxel loaded polymeric micelle formulations

    Microsoft Academic Search

    R. T. Liggins; H. M. Burt

    2002-01-01

    A number of hypersensitivity reactions have been attributed to the presence of Cremophor® EL in the current formulation for paclitaxel. This has led to the development of formulations for paclitaxel employing polyether–polyester diblock copolymers as micelle forming carriers. Diblock copolymers of methoxypolyethylene glycol-block-poly(d,l-lactide) (MePEG:PDLLA) were synthesized from monomers of d,l-lactide and MePEG by a ring opening bulk polymerization in the

  16. Paclitaxel Stent Coating Inhibits Neointimal Hyperplasia at 4 Weeks in a Porcine Model of Coronary Restenosis

    Microsoft Academic Search

    Alan W. Heldman; Linda Cheng; G. Mark Jenkins; Phillip F. Heller; Dong-Woon Kim; Melvin Ware; Cynthia Nater; Ralph H. Hruban; Banafsheh Rezai; Benjamin S. Abella; Katherine E. Bunge; James L. Kinsella; Steven J. Sollott; Edward G. Lakatta; Jeffrey A. Brinker; William L. Hunter; Jeffrey P. Froehlich

    2010-01-01

    Background—Despite limiting elastic recoil and late vascular remodeling after angioplasty, coronary stents remain vulnerable to restenosis, caused primarily by neointimal hyperplasia. Paclitaxel, a microtubule-stabilizing drug, has been shown to inhibit vascular smooth muscle cell migration and proliferation contributing to neointimal hyperplasia. We tested whether paclitaxel-coated coronary stents are effective at preventing neointimal proliferation in a porcine model of restenosis. Methods

  17. Local Intracerebral Administration of Paclitaxel with the Paclimer ® Delivery System: Toxicity Study in a Canine Model

    Microsoft Academic Search

    Gustavo Pradilla; Paul P. Wang; Patrik Gabikian; Khan Li; Carolyn A. Magee; Kevin A. Walter; Henry Brem

    2006-01-01

    Summary  Introduction: Paclitaxel, a microtubule binding agent with potent anti-glioma activity in vitro, exhibits poor penetrance to the CNS when delivered systemically. To minimize toxicity and reach therapeutic concentrations\\u000a in the CNS, paclitaxel was previously incorporated into biodegradable microspheres (Paclimer®), and the efficacy of Paclimer® was determined in a rat model of malignant glioma. In this study we report the safety

  18. Antiangiogenic Activity of Sterically Stabilized Liposomes Containing Paclitaxel (SSL-PTX): In Vitro and In Vivo

    Microsoft Academic Search

    Yue Huang; Xiao-Mei Chen; Bing-Xiang Zhao; Xi-Yu Ke; Bo-Jun Zhao; Xin Zhao; Ying Wang; Xuan Zhang; Qiang Zhang

    2010-01-01

    The purpose of this present study was to evaluate the antiangiogenic activity of sterically stabilized liposomes containing\\u000a paclitaxel (SSL-PTX). The SSL-PTX was prepared by the thin-film method. The release of paclitaxel from SSL-PTX was analyzed\\u000a using a dialysis method. The effect of SSL-PTX on endothelial cell proliferation and migration was investigated in vitro. The antitumor and antiangiogenic activity of SSL-PTX

  19. 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,

  20. Paclitaxel-hyaluronic nanoconjugates prolong overall survival in a preclinical brain metastases of breast cancer model.

    PubMed

    Mittapalli, Rajendar K; Liu, Xinli; Adkins, Chris E; Nounou, Mohamed I; Bohn, Kaci A; Terrell, Tori B; Qhattal, Hussaini S; Geldenhuys, Werner J; Palmieri, Diane; Steeg, Patricia S; Smith, Quentin R; Lockman, Paul R

    2013-11-01

    Brain (central nervous system; CNS) metastases pose a life-threatening problem for women with advanced metastatic breast cancer. It has recently been shown that the vasculature within preclinical brain metastasis model markedly restricts paclitaxel delivery in approximately 90% of CNS lesions. Therefore to improve efficacy, we have developed an ultra-small hyaluronic acid (HA) paclitaxel nanoconjugate (?5 kDa) that can passively diffuse across the leaky blood-tumor barrier and then be taken up into cancer cells (MDA-MB-231Br) via CD44 receptor-mediated endocytocis. Using CD44 receptor-mediated endocytosis as an uptake mechanism, HA-paclitaxel was able to bypass p-glycoprotein-mediated efflux on the surface of the cancer cells. In vitro cytoxicity of the conjugate and free paclitaxel were similar in that they (i) both caused cell-cycle arrest in the G2-M phase, (ii) showed similar degrees of apoptosis induction (cleaved caspase), and (iii) had similar IC50 values when compared with paclitaxel in MTT assay. A preclinical model of brain metastases of breast cancer using intracardiac injections of Luc-2 transfected MDA-MB-231Br cells was used to evaluate in vivo efficacy of the nanoconjugate. The animals administered with HA-paclitaxel nanoconjugate had significantly longer overall survival compared with the control and the paclitaxel-treated group (P < 0.05). This study suggests that the small molecular weight HA-paclitaxel nanoconjugates can improve standard chemotherapeutic drug efficacy in a preclinical model of brain metastases of breast cancer. PMID:24002934

  1. Nanoparticles of biodegradable polymers for clinical administration of paclitaxel.

    PubMed

    Feng, Si-Shen; Mu, Li; Win, Khin Yin; Huang, Guofeng

    2004-02-01

    Paclitaxel is one of the best antineoplastic drugs found from nature in the past decades, which has been found effective against a wide spectrum of cancers including ovarian cancer, breast cancer, small and non small cell lung cancer, colon cancer, head and neck cancer, multiple myeloma, melanoma, and Kaposi's sarcoma. Like many other anticancer drugs, it has difficulties in clinical administration due to its poor solubility in water and most pharmaceutical reagents. In its current clinical application, an adjuvant called Cremophor EL has to be employed, which has been found to be responsible for many serious side effects. Nanoparticles of biodegradable polymers can provide an ideal solution to such an adjuvant problem and realize a controlled and targeted delivery of the drug with better efficacy and less side effects. With further development, such as particle size optimization and surface coating, nanoparticle formulation of paclitaxel can promote a new concept of chemotherapy to realize its full efficacy and to improve quality of life of the patients, which includes personalized chemotherapy, local chemotherapy, sustained chemotherapy, oral chemotherapy, chemotherapy across the blood-brain barrier, chemotherapy across the microcirculation barrier, etc. The present research proposes a novel formulation for fabrication of nanoparticles of poly(lactic-co-glycolic acid) (PLGA) by a modified solvent extraction/evaporation technique, in which natural emulsifiers, such as phospholipids, cholesterol and vitamin E TPGS are creatively applied to achieve high drug encapsulation efficiency, desired drug released kinetics, high cell uptake and high cytotoxicity. The nanoparticles composed of various recipes and manufactured under various conditions were characterized by laser light scattering (LLS) for size and size distribution, scanning electron microscopy (SEM) and atomic force microscopy (AFM) for morphological properties, X-ray photoelectron spectroscopy (XPS) and Fourier Transformation Infrared Spectroscopy (FTIR) for surface chemistry, zeta-potential for surface charge, and differential scanning calorimetry (DSC) for the thermogram properties. The drug encapsulation efficiency and the drug release kinetics under in vitro conditions were measured by high performance liquid chromatography (HPLC). It was found that these natural emulsifiers have great advantages for nanoparticle formulation of paclitaxel over the traditional macromolecular emulsifiers, such as polyvinyl alcohol (PVA). Nanoparticles of desired small size and narrow size distribution can be obtained. The drug encapsulation efficiency can be achieved as high as 100 %. The released kinetics can be made under control. The HT-29 cancer cell line experiment showed that after 24 hours of incubation, the cell mortality caused by the drug administered by such nanoparticle formulation could be more than 13 times higher than that caused by the free drug under similar conditions. PMID:14965222

  2. 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.

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

    NASA Astrophysics Data System (ADS)

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

    2014-04-01

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

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

    PubMed Central

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

    2011-01-01

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

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

    PubMed Central

    2014-01-01

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

  6. nab-Paclitaxel: novel clinical and experimental evidence in pancreatic cancer.

    PubMed

    Neesse, A; Michl, P; Tuveson, D A; Ellenrieder, V

    2014-04-01

    The past few decades have seen virtually no treatment advances for patients with metastatic pancreatic cancer. Clinical hallmark features of pancreatic ductal adenocarcinoma (PDA) include late symptom onset, invasive growth, early liver and lymph node metastasis, and resistance to available chemotherapies. nab-Paclitaxel (Abraxane®) is generated through high-pressure homogenization of human albumin and conventional paclitaxel resulting in non-covalently bound, water-soluble albumin-paclitaxel particles with an approximate diameter of 130?nm. Results from the recently completed Metastatic Pancreatic Adenocarcinoma Trial (MPACT) (phase III trial) showed a significant survival benefit for patients treated with nab-paclitaxel in combination with gemcitabine, and this treatment regimen is currently being implemented in national and international guidelines for PDA patients. Therefore, this regimen provides a much needed vantage point of attack for this recalcitrant tumor offering potential new hope for our patients. Mechanisms such as stromal depletion, selective intratumoral accumulation, synergism with gemcitabine metabolism and secreted protein acidic and rich in cysteine (SPARC) mediated anti-tumor activity have been suggested for nab-paclitaxel. This review discusses the clinical and experimental advances of nab-paclitaxel in pancreatic cancer. PMID:24687799

  7. Nab-paclitaxel: potential for the treatment of advanced pancreatic cancer.

    PubMed

    Al-Hajeili, Marwan; Azmi, Asfar S; Choi, Minsig

    2014-01-01

    Advanced pancreatic adenocarcinoma is a deadly disease and is considered incurable. For the past two decades, gemcitabine remained the major chemotherapeutic drug with modest clinical benefit. Many chemotherapy and targeted agents were combined with gemcitabine but failed to demonstrate improvement in pancreatic cancer (PC) survival. Taxanes (paclitaxel, docetaxel) were introduced in the clinic as anti-microtubule agents and showed activity against PC cells in vitro; however, clinical efficacy was limited. Nab-paclitaxel (Abraxane) is an albumin-bound paclitaxel that has shown clinical activity in advanced breast and lung cancer. Recently, nab-paclitaxel was tested in a large Phase III clinical trial in combination with gemcitabine for the treatment of advanced PC. The data showed that the addition of nab-paclitaxel improved the response rate (7% in gemcitabine alone versus 23% in combination), progression-free survival (from 3.7 months to 5.5 months), and overall survival from 6.7 months to 8.5 months, compared to single agent gemcitabine. Through this review, we provide the preclinical and clinical progress in the development of nab-paclitaxel for the treatment of metastatic PC. PMID:24523592

  8. [Nanoparticle albumin-bound Paclitaxel for unresectable or recurrent gastric cancer].

    PubMed

    Egawa, Tomohisa; Kemmochi, Takeshi; Nishiya, Shin; Mihara, Koki; Ito, Yasuhiro; Nagashima, Atsushi

    2014-11-01

    The efficacy and safety of nanoparticle albumin-bound paclitaxel(nab-paclitaxel)administered every 3 weeks for unresectable or recurrent gastric cancer was evaluated retrospectively. Nab-paclitaxel was intravenously administered at 260 mg/ m² on day 1 of each 21-day course without anti-allergic premedication until disease progression or discontinuation. Nine patients received nab-paclitaxel. The overall response rate was 11.1%, and the disease control rate was 55.6%. Grade 3/4 toxicities included neutropenia(44.4%), leukopenia(33.3%), and peripheral sensory neuropathy (33.3%). It is important to manage both neutropenia and peripheral neuropathy. Although only few cases were analyzed, therapeutic effect can be obtained even with the starting dose of 180 mg/m² suggesting management of toxicities will be feasible. In view of the toxicities observed, a reduced starting dose of 180 mg/m² should be considered in the case of poor performance status patients. Nab-paclitaxel is a promising drug because of its convenience and may replace weekly paclitaxel for unresectable or recurrent gastric cancer. PMID:25731486

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

    PubMed

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

    2014-07-01

    Local delivery of chemotherapeutics in the cervicovaginal tract using nanoparticles may reduce adverse side effects associated with systemic chemotherapy, while improving outcomes for early-stage cervical cancer. It is hypothesized here that drug-loaded nanoparticles that rapidly penetrate cervicovaginal mucus (CVM) lining the female reproductive tract will more effectively deliver their payload to underlying diseased tissues in a uniform and sustained manner compared with nanoparticles that do not efficiently penetrate CVM. Paclitaxel-loaded nanoparticles are developed, composed entirely of polymers used in FDA-approved products, which rapidly penetrate human CVM and provide sustained drug release with minimal burst effect. A mouse model is further employed with aggressive cervical tumors established in the cervicovaginal tract to compare paclitaxel-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (conventional particles, or CP) and similar particles coated with Pluronic F127 (mucus-penetrating particles, or MPP). CP are mucoadhesive and, thus, aggregated in mucus, while MPP achieve more uniform distribution and close proximity to cervical tumors. Paclitaxel-MPP suppress tumor growth more effectively and prolong median survival of mice compared with unencapsulated paclitaxel or paclitaxel-CP. Histopathological studies demonstrate minimal toxicity to the cervicovaginal epithelia, suggesting paclitaxel-MPP may be safe for intravaginal use. These results demonstrate the in vivo advantages of polymer-based MPP for treatment of tumors localized to a mucosal surface. PMID:24339398

  10. Mechanism of synergy of BH3 mimetics and paclitaxel in chronic myeloid leukemia cells: Mcl-1 inhibition.

    PubMed

    Song, Ting; Chai, Gaobo; Liu, Yubo; Xie, Mingzhou; Chen, Qingbin; Yu, Xiaoyan; Sheng, Hongkun; Zhang, Zhichao

    2015-04-01

    Paclitaxel is an alternative chemotherapeutic agent for chronic myelogenous leukemia (CML) when primary or secondary resistance of tyrosine kinase inhibitors (TKI) is emerging, because paclitaxel could bypass the apoptotic deficiencies linked to p53 and fas ligand pathways in CML. However, high levels of Bcl-2 family proteins in CML could resist paclitaxel-induced apoptosis. Herein, we utilized two BH3 mimetics ABT-737 and S1 to study the potential of BH3 mimetics in combination with paclitaxel in treatment of CML cells and illustrated the mechanism by which BH3 mimetics synergize with paclitaxel. As a single agent, S1 could induce apoptosis in CML-derived cell line K562, whereas ABT-737 was largely ineffective. However, both of the two agents could efficiently synergize with paclitaxel through intrinsic apoptosis pathway. By using Bcl-2 siRNA, Bcl-XL siRNA or Mcl-1 siRNA, we found although each of the three members exhibited activities to block paclitaxel-induced apoptosis, Mcl-1 was the determinant for the synergistic effect between paclitaxel and ABT-737 or S1. Furthermore, paclitaxel/ABT737 synergized to drastically upregulate Bim to displace Bak from Mcl-1, whereas S1 directly binds Mcl-1 to release both Bim and Bak. As such, ABT-737 and S1 sensitized CML to paclitaxel by Mcl-1 inhibition, indirect inhibition through Bim antagonizing Mcl-1, or direct inhibition through binding to Mcl-1 itself. Finally, activation of JNK/Bim pathway was identified as the apical mechanism for ABT-737/paclitaxel synergism. Together, our results demonstrated potent synergy between BH3 mimetics and paclitaxel in the killing of CML cells and revealed an important role for Mcl-1 in mediating synergism by these agents. PMID:25596561

  11. Is a reduction in radiation lung volume and dose necessary with paclitaxel chemotherapy for node-positive breast cancer?

    SciTech Connect

    Taghian, Alphonse G. [Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (United States)]. E-mail: ataghian@partners.org; Assaad, Sherif I. [Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (United States); Niemierko, Andrzej [Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (United States); Floyd, Scott R. [Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (United States); Powell, Simon N. [Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (United States)

    2005-06-01

    Purpose: To evaluate and quantify the effect of irradiated lung volume, radiation dose, and paclitaxel chemotherapy on the development of radiation pneumonitis (RP) in breast cancer patients with positive lymph nodes. Methods and Materials: We previously reported the incidence of RP among 41 patients with breast cancer treated with radiotherapy (RT) and adjuvant paclitaxel-containing chemotherapy. We recorded the central lung distance, a measure of the extent of lung included in the RT volume, in these patients. We used this measure and the historical and observed rates of RP in our series to model the lung tolerance to RT in patients receiving chemotherapy (CHT) both with and without paclitaxel. To evaluate the risk factors for the development of RP, we performed a case-control study comparing paclitaxel-treated patients who developed RP with those who did not, and a second case-control study comparing patients receiving paclitaxel in addition to standard CHT/RT (n = 41) and controls receiving standard CHT/RT alone (n 192). Results: The actuarial rate of RP in the paclitaxel-treated group was 15.4% compared with 0.9% among breast cancer patients treated with RT and non-paclitaxel-containing CHT. Our mathematical model found that the effective lung tolerance for patients treated with paclitaxel was reduced by approximately 24%. No statistically significant difference was found with regard to the dose delivered to specific radiation fields, dose per fraction, central lung distance, or percentage of lung irradiated in the case-control study of paclitaxel-treated patients who developed RP compared with those who did not. In the comparison of 41 patients receiving RT and CHT with paclitaxel and 192 matched controls receiving RT and CHT without paclitaxel, the only significant differences identified were the more frequent use of a supraclavicular radiation field and a decrease in the RT lung dose among the paclitaxel-treated patients. This finding indicates that the major factor associated with development of RP was paclitaxel treatment. Conclusions: The use of paclitaxel chemotherapy and RT in the primary treatment of node-positive breast cancer is likely to increase the incidence of RP. In patients treated with paclitaxel, reducing the percentage of lung irradiated by 24% should reduce the risk of RP to 1%, according to our calculations of lung tolerance. Future clinical trials using combination CHT that includes paclitaxel and RT should carefully evaluate the incidence and severity of RP and should also accurately monitor the extent of lung included within the RT volume to develop safe guidelines for the delivery of what is becoming standard therapy for node-positive breast cancer.

  12. Resistance mechanisms determining the in vitro sensitivity to paclitaxel of tumour cells cultured from patients with ovarian cancer.

    PubMed

    Baguley, B C; Marshall, E S; Whittaker, J R; Dotchin, M C; Nixon, J; McCrystal, M R; Finlay, G J; Matthews, J H; Holdaway, K M; van Zijl, P

    1995-01-01

    Paclitaxel, a drug which stabilises microtubules, demonstrates marked activity against ovarian cancer. We investigated the sensitivity to paclitaxel of tumour cells from disaggregated solid tumours or tumour-bearing ascites from 7 ovarian cancer patients, and 21 established tumour cell lines (ovarian, melanoma and lung). Response was quantitated by [3H]-thymidine incorporation in 96-well plates or by colony growth. Dose-response curves to paclitaxel were biphasic with a dose-dependent phase providing an IC50 value (50% reduction in incorporation) and dose-dependent "plateau" phase where the effect was independent of paclitaxel concentration. IC50 values ranged from 2.5 to 110 nM with evidence of multidrug resistance in the two most resistant cell lines. The "plateau" killing values varied from 0.1 log10 to > 3.4 log10 units reduction, and were found to be significantly correlated (r = 0.86; P < 0.0001) with logarithmic culture doubling times of the cell lines. Cellular glutathione levels were measured and found not to be significantly associated with response to paclitaxel. The results suggest that the ratio of paclitaxel exposure time to the culture doubling time is a major factor in paclitaxel cytotoxicity. The relationship between tumour cell cytokinetics and paclitaxel pharmacokinetics in vivo may therefore be crucial in determining clinical paclitaxel response. PMID:7718330

  13. Paclitaxel-induced hyposensitivity to nociceptive chemical stimulation in mice can be prevented by treatment with minocycline

    PubMed Central

    Masocha, Willias

    2014-01-01

    Development of peripheral neuropathy, which can present as painful neuropathy or loss of sensation, sometimes limit the use of paclitaxel in the treatment of solid tumors such as breast cancer. Previous studies reported development of thermal hyperalgesia in mice treated with paclitaxel. In this study an automated flinch detection system for the formalin test (20??l of 5% formalin injected subcutaneously into the paw dorsum) was used to evaluate chemical nociception in BALB/c mice treated with paclitaxel 2?mg/kg alone or coadministered with minocycline 50?mg/kg, intraperitoneally for 5 consecutive days. Reaction latency to thermal stimuli (hot-plate) was also measured. Injection of formalin resulted in biphasic paw flinches; phase 1 (1–9 minutes) and phase 2 (10–40 minutes). Treatment with paclitaxel reduced cumulative flinches in both phases 1 and 2 by 28% and 43%, respectively at day 7. However, treatment with paclitaxel also induced thermal hyperalgesia. Co-administration of paclitaxel with minocycline prevented development of both paclitaxel-induced hyposensitivity to chemical nociception and thermal hyperalgesia. In conclusion, the results indicate paclitaxel induces chemical hyposensitivity and thermal hyperalgesia in mice. Minocycline protected against paclitaxel-induced chemical hyposensitivity and thermal hyperalgesia, thus, providing further support of the usefulness of the drug in prevention of chemotherapy-induced neuropathy. PMID:25335491

  14. Disposition of docosahexaenoic acid-paclitaxel, a novel taxane, in blood: in vitro and clinical pharmacokinetic studies

    Microsoft Academic Search

    A. Sparreboom; A. C. Wolff; J. Verweij; Y. Zabelina; Zomeren van D. M; G. L. McIntire; C. S. Swindell; R. C. Donehower; S. D. Baker

    2003-01-01

    PURPOSE: Docosahexaenoic acid-paclitaxel is as an inert prodrug composed\\u000a of the natural fatty acid DHA covalently linked to the C2'-position of\\u000a paclitaxel (M. O. Bradley et al., Clin. Cancer Res., 7: 3229-3238, 2001).\\u000a Here, we examined the role of protein binding as a determinant of the\\u000a pharmacokinetic behavior of DHA-paclitaxel. EXPERIMENTAL DESIGN: The blood\\u000a distribution of DHA-paclitaxel was studied in

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

    PubMed Central

    2012-01-01

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

  16. A mucoadhesive in situ gel delivery system for paclitaxel.

    PubMed

    Jauhari, Saurabh; Dash, Alekha K

    2006-01-01

    MUC1 gene encodes a transmembrane mucin glycoprotein that is overexpressed in human breast cancer and colon cancer. The objective of this study was to develop an in situ gel delivery system containing paclitaxel (PTX) and mucoadhesives for sustained and targeted delivery of anticancer drugs. The delivery system consisted of chitosan and glyceryl monooleate (GMO) in 0.33M citric acid containing PTX. The in vitro release of PTX from the gel was performed in presence and absence of Tween 80 at drug loads of 0.18%, 0.30%, and 0.54% (wt/wt), in Sorensen's phosphate buffer (pH 7.4) at 37 degrees C. Different mucin-producing cell lines (Calu-3>Caco-2) were selected for PTX transport studies. Transport of PTX from solution and gel delivery system was performed in side by side diffusion chambers from apical to basal (A-B) and basal to apical (B-A) directions. In vitro release studies revealed that within 4 hours, only 7.61% +/- 0.19%, 12.0% +/- 0.98%, 31.7% +/- 0.40% of PTX were released from 0.18%, 0.30%, and 0.54% drug-loaded gel formulation, respectively, in absence of Tween 80. However, in presence of surfactant (0.05% wt/vol) in the dissolution medium, percentages of PTX released were 28.1% +/- 4.35%, 44.2% +/- 6.35%, and 97.1% +/- 1.22%, respectively. Paclitaxel has shown a polarized transport in all the cell monolayers with B-A transport 2 to 4 times higher than in the A-B direction. The highest mucin-producing cell line (Calu-3) has shown the lowest percentage of PTX transport from gels as compared with Caco-2 cells. Transport of PTX from mucoadhesive gels was shown to be influenced by the mucin-producing capability of cell. PMID:16796370

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

    PubMed Central

    Khan, Shadab Ali; Gambhir, Sanjay

    2014-01-01

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

  18. 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

  19. Effect of Wuzhi tablet (Schisandra sphenanthera extract) on the pharmacokinetics of paclitaxel in rats.

    PubMed

    Jin, Jing; Bi, Huichang; Hu, Jinqing; Zeng, Hang; Zhong, Guoping; Zhao, Lizi; Huang, Zhiying; Huang, Min

    2011-08-01

    Wuzhi tablet (WZ, registration no. in China: Z20025766) is a preparation of an ethanol herb extract of Wuweizi (Schisandra sphenanthera) containing 7.5?mg Schisantherin A per tablet. It was reported recently that WZ could significantly increase the blood concentrations of tacrolimus, which might be due to the inhibitory effect of WZ and its ingredients on P-gp and/or CYP450 activity. Paclitaxel is a substrate of the efflux transporter P-gp, and is mainly metabolized by CYP450 enzymes in the liver. Therefore, the purpose of this study was to investigate whether and how WZ affects the pharmacokinetics of paclitaxel in rats. After pretreatment with WZ, there were significant increases in the AUC(0-24h) of oral paclitaxel (from 280.8 ± 97.3 to 543.5?± 115.2?h ng/mL; p?paclitaxel with WZ showed a relatively small (when compared against oral paclitaxel) but still significant increase in AUC(0-24h) (from 163.6?±?22.1 to 212.7?±?17.7?h ng/mL; p?paclitaxel in rats. The herb-drug interaction between WZ and paclitaxel should be taken into consideration in clinical use. PMID:21796700

  20. CD133-targeted paclitaxel delivery inhibits local tumor recurrence in a mouse model of breast cancer.

    PubMed

    Swaminathan, Suresh Kumar; Roger, Emilie; Toti, Udaya; Niu, Lin; Ohlfest, John R; Panyam, Jayanth

    2013-11-10

    Expression of the membrane protein CD133 marks a subset of cancer cells with drug resistant phenotype and enhanced tumor initiating ability in xenotransplantation assays. Because drug resistance and tumor relapse are significant problems, approaches to eliminate these cells are urgently needed. As a step towards achieving this goal, we developed polymeric nanoparticles targeting CD133 by conjugating an anti-CD133 monoclonal antibody to nanoparticles formulated using poly(D,L lactide-co-glycolide) polymer. Nanoparticles were loaded with paclitaxel, a microtubule-stabilizing anticancer agent, as well as with 6-coumarin, a fluorescent probe. CD133-targeted nanoparticles (CD133NPs) were efficiently internalized by Caco-2 cells, which abundantly express CD133 (>9-fold higher uptake than non-targeted control nanoparticles). The effectiveness of CD133NPs in reducing tumor initiating cell (TIC) fraction was investigated using mammosphere formation and soft-agar colony formation assays. Free paclitaxel treatment was not effective in decreasing the TIC population relative to untreated control, whereas CD133NPs effectively decreased the number of mammospheres and colonies formed. In vivo studies in the MDA-MB-231 xenograft model showed that free paclitaxel was initially effective in inhibiting tumor growth but the tumors rebounded rapidly once the treatment was stopped. Tumor regrowth was significantly lower when paclitaxel was delivered through CD133NPs (tumor volume was 518.6±228 vs. 1370.9±295mm(3) for free paclitaxel at 63days; P<0.05). Our studies thus show that encapsulation of paclitaxel in CD133NPs results in a significant decrease in the TIC population and improved therapeutic efficacy compared to that with free paclitaxel treatment. These results indicate the potential of targeting anticancer therapeutics to CD133+ cells for reducing tumor recurrence. PMID:23871962

  1. 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

  2. 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

  3. 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

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

    PubMed

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

    2015-01-01

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

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

    NASA Technical Reports Server (NTRS)

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

    2000-01-01

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

  6. Increased chemoresistance to paclitaxel in the MCF10AT series of human breast epithelial cancer cells.

    PubMed

    Lim, Soo-Jeong; Choi, Hyeon Gyeom; Jeon, Chae Kyung; Kim, So Hee

    2015-04-01

    The MCF10AT cell series of human breast epithelial cancer cells includes normal MCF10A (10A), premalignant MCF10AT (10AT) and MCF10ATG3B (10ATG3B), and fully malignant MCF10CA1a (10CA1a) cells. The series is a unique model system showing progressive tumorigenic potential with the same origin. The effects of paclitaxel, a microtubule inhibitor, were evaluated in this cell system. Paclitaxel inhibited cell proliferation in a time-dependent (24, 48 and 72 h) and concentration-dependent (0-10 nM) manners with less sensitivity in 10CA1a cells. Treatment with paclitaxel (10 nM) for 24 h induced apoptosis in 10A, 10AT, 10ATG3B and 10CA1a cells, with 23.6, 26.1, 25.2 and 8.96%, respectively, in the sub-G1 phase. Treatment with paclitaxel (0-10 nM) for 24 h, resulted in the appearance of DNA fragmentation (a hallmark of apoptosis) with less sensitivity in the 10CA1a tumor cells. Paclitaxel increased p53 protein expression in 10A, 10AT, 10ATG3B and 10CA1a cells, by 87, 102, 812 and 84%, respectively. The p21Waf1/Cip1 protein expression increased by 2.57-, 1.53- and 2.48-fold in 10A, 10AT and 10ATG3B cells, respectively, with negligible detection in the 10CA1a cells. Activation of the Akt signaling pathway was observed in the MCF10AT cell lineage and the protein expression of phospho-Akt (Ser473 and Thr308). The downstream targets of this pathway, phospho-p70S6K and phospho-S6RP, were also inhibited by paclitaxel in 10A, 10AT and 10ATG3B cells, but minimally inhibited in 10CA1a cells, suggestive of chemoresistance in 10CA1a cells. The effects of paclitaxel on the multidrug resistance 1 (MDR1), MRP1 and breast cancer resistance protein (BCRP) gene expression were not significant in the MCF10AT cell lineage. These results collectively indicated that paclitaxel inhibited cell proliferation and induced apoptosis in the MCF10AT cell lineage, with chemoresistance in 10CA1a tumor cells. The decreased responsiveness to paclitaxel observed in 10CA1a tumor cells was likely due, in part, to activation of the Akt signaling pathway and a high expression of wild-type p53 with lack of p21Waf1/Cip1. PMID:25647149

  7. Independent Review of E2100: A Phase III Trial of Bevacizumab Plus Paclitaxel Versus Paclitaxel in Women With Metastatic Breast Cancer

    PubMed Central

    Gray, Robert; Bhattacharya, Suman; Bowden, Christopher; Miller, Kathy; Comis, Robert L.

    2009-01-01

    Purpose E2100, an open-label, randomized, phase III trial conducted by the Eastern Cooperative Oncology Group (ECOG), demonstrated a significant improvement in progression-free survival (PFS) and overall response rate (ORR) with paclitaxel plus bevacizumab compared with paclitaxel alone as initial chemotherapy for patients with HER2-negative metastatic breast cancer. Methods An independent, blinded review of radiologic and clinical data was performed, assessing progression and response according to Response Evaluation Criteria in Solid Tumors. In addition, ECOG's investigator assessments were reanalyzed using the same methods applied to the independent review. The primary end point was PFS as assessed by an independent review facility (IRF). Results The addition of bevacizumab to paclitaxel resulted in a statistically significant improvement in PFS using both the IRF and investigator assessments. Hazard ratios for PFS (0.48, 95% CI, 0.385 to 0.607; P < .0001 for the IRF v 0.42, 95% CI, 0.34 to 0.52; P < .0001 for ECOG investigators) and the improvement in median PFS (11.3 v 5.8 months for the IRF v 11.4 v 5.8 months for ECOG investigators) were similar. Among patients with measurable disease at baseline, the IRF-assessed ORR was significantly higher in patients treated with paclitaxel and bevacizumab (48.9% v 22.2%; P < .0001). Conclusion The risk of progression was reduced by more than half and the ORR more than doubled with the addition of bevacizumab to weekly paclitaxel in both analyses, confirming a substantial and robust bevacizumab treatment effect. The consistency between the IRF and ECOG analyses validates the original data previously reported by ECOG in this open-label trial. PMID:19720913

  8. Materials Science and Engineering A 438440 (2006) 11191123 Surface characteristics and biological properties of paclitaxel-embedding

    E-print Network

    Zheng, Yufeng

    2006-01-01

    ). The biodegradable polymer poly(lactide-co-glycoliade) (PLGA) degrades into lactic and glycolic acids which both can Surface characteristics and biological properties of paclitaxel-embedding poly]. Jackson [7] used PLGA blending with other polymers for the forma- tion of paclitaxel loaded films

  9. Contribution of taxane biosynthetic pathway gene expression to observed variability in paclitaxel accumulation in Taxus suspension cultures

    PubMed Central

    Patil, Rohan A.; Kolewe, Martin E.; Normanly, Jennifer; Walker, Elsbeth L.; Roberts, Susan C.

    2012-01-01

    Variability in product accumulation is one of the major obstacles limiting the widespread commercialization of plant cell culture technology to supply natural product pharmaceuticals. Despite extensive process engineering efforts, which have led to increased yields, plant cells exhibit variability in productivity that is poorly understood. Elicitation of Taxus cultures with methyl jasmonate (MeJA) induces paclitaxel accumulation, but to varying extents in different cultures. In this work, cultures with different aggregation profiles were established to create predictable differences in paclitaxel accumulation upon MeJA elicitation. Expression of known paclitaxel biosynthetic genes in MeJA-elicited cultures exhibiting both substantial (15-fold) and moderate (2-fold) differences in paclitaxel accumulation was analyzed using qRT-PCR. Each population exhibited the characteristic large increase in paclitaxel pathway gene expression following MeJA elicitation; however, differences in expression between populations were minor, and only observed for the cultures with the 15-fold variation in paclitaxel content. These data suggest that although upregulation of biosynthetic pathway gene expression contributes to observed increases in paclitaxel synthesis upon elicitation with MeJA, there are additional factors that need to be uncovered before paclitaxel productivity can be fully optimized. PMID:22095859

  10. Efficacy of poly(sebacic acid-co-ricinoleic acid) biodegradable delivery system for intratumoral delivery of paclitaxel.

    PubMed

    Shikanov, Ariella; Vaisman, Boris; Shikanov, Sergey; Domb, Abraham J

    2010-03-15

    The effectiveness of an injectable polymeric formulation, based on poly(sebacic acid-co-ricinoleic acid) and paclitaxel against a heterotopic tumor model was studied. An injectable pasty polymer that releases an incorporated drug over a period of weeks was used. The degradation rate of formulations with paclitaxel was examined in vitro and in vivo. The effectiveness of the polymeric carrier of paclitaxel was investigated using a melanoma heterotopic model in C57BL/6 mice. Tumor bearing animals were injected intratumorally with 0.1 ml of formulations containing 5%, 10%, 15%, and 20% paclitaxel. Formulations with 5% and 10% paclitaxel content degraded faster in vivo then in vitro. Changes in tumor progression, survival time, and body weight were observed over a period of 77 days. The highest tumor size was reported for the control groups that did not receive paclitaxel in their treatment regiment: 3.6 g on day 20, while in all groups treated with polymer loaded with paclitaxel the tumor size was much smaller than that in the blank polymer or non treatment groups and ranged from 1.3 g to 0.3 g. Intratumoral injection of paclitaxel loaded in the polymer was found to be an effective treatment for localized tumors. PMID:19343769

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

    PubMed

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

    2012-09-01

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

  12. Acetaminophen Enhances Cisplatin- and Paclitaxel-mediated Cytotoxicity to SKOV3 Human Ovarian Carcinoma

    PubMed Central

    Wu, Y. Jeffrey; Neuwelt, Alexander J.; Muldoon, Leslie L.; Neuwelt, Edward A.

    2013-01-01

    Background Ovarian cancer is commonly treated with cisplatin/paclitaxel but many tumors become resistant. Acetaminophen reduced glutathione and enhanced chemotherapy efficacy in treating hepatic cancer. The objective of this study was to examine if acetaminophen enhances the cytotoxicity of cisplatin/paclitaxel in ovarian cancer. Materials and Methods SKOV3 human ovarian carcinoma cells in vitro and a subcutaneous tumor nude rat model were used and treated with cisplatin/paclitaxel with or without acetaminophen. Results In vitro, acetaminophen enhanced apoptosis induced by cisplatin and paclitaxel with similar effects on glutathione, reactive oxygen species and mitochondrial membrane potential but different effects on nuclear factor erythroid 2-related factor 2 (NRF2) translocation. In vivo, acetaminophen was uniformly distributed in tissue and significantly reduced hepatic glutathione. Acetaminophen enhanced cisplatin chemotherapeutic effect by reducing tumor recurrence Conclusion Our results suggest that acetaminophen as a chemoenhancing adjuvant could improve the efficacy of cisplatin and paclitaxel in treating patients with ovarian carcinoma and other tumor types. PMID:23749887

  13. 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

  14. 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

  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. 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

  17. In vitro and in vivo conditional sensitization of hepatocellular carcinoma cells to TNF-induced apoptosis by Taxol.

    PubMed

    Minero, V G; De Stefanis, D; Costelli, P; Baccino, F M; Bonelli, G

    2015-04-01

    High mortality among hepatocellular carcinoma (HCC) patients reflects both late diagnosis and low curability, due to pharmacoresistance. Taxol (TAX) is toxic for many human HCC-derived cell lines, yet its clinical efficacy on HCCs is poor. Combining TAX with other drugs appears a promising possibility to overcome such refractoriness. We analyzed whether combining tumor necrosis factor (TNF) with TAX would improve their toxicity. Human HCC-derived cell lines were treated with TAX or TNF, alone or combined. Apoptosis was assessed by morphology and flow-cytometry. Several pro- and anti-apoptotic molecules were evaluated by western blotting and/or enzymatic assay. After a 24 hour treatment, TNF was ineffective and TAX modestly cytotoxic, whereas HCC cells were conditionally sensitized to TNF by TAX. Indeed some relevant parameters were shifted to a prodeath setting: TNF-receptor 1 was increased, SOCS3, c-FLIP and pSTAT3 were markedly downregulated. These observations provide a significant clue to critically improve the drug susceptibility of HCC cells by combining 2 agents, TAX and TNF. The sequential application of TAX at a low dosage followed by TNF for only a short time triggered a strong apoptotic response. Of interest, prior TAX administration could also sensitize to TNF-induced apoptosis in the Yoshida AH-130 hepatoma transplanted in mice. Therefore, scrutinizing the possibility to develop similar combination drug regimens in suitable preclinical models seems highly advisable. PMID:25564714

  18. 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

  19. Praziquantel Synergistically Enhances Paclitaxel Efficacy to Inhibit Cancer Cell Growth

    PubMed Central

    Wu, Zhen Hua; Lu, Ming-ke; Hu, Long Yu; Li, Xiaotong

    2012-01-01

    The major challenges we are facing in cancer therapy with paclitaxel (PTX) are the drug resistance and severe side effects. Massive efforts have been made to overcome these clinical challenges by combining PTX with other drugs. In this study, we reported the first preclinical data that praziquantel (PZQ), an anti-parasite agent, could greatly enhance the anticancer efficacy of PTX in various cancer cell lines, including PTX-resistant cell lines. Based on the combination index value, we demonstrated that PZQ synergistically enhanced PTX-induced cell growth inhibition. The co-treatment of PZQ and PTX also induced significant mitotic arrest and activated the apoptotic cascade. Moreover, PZQ combined with PTX resulted in a more pronounced inhibition of tumor growth compared with either drug alone in a mouse xenograft model. We tried to investigate the possible mechanisms of this synergistic efficacy induced by PZQ and PTX, and we found that the co-treatment of the two drugs could markedly decrease expression of X-linked inhibitor of apoptosis protein (XIAP), an anti-apoptotic protein. Our data further demonstrated that down-regulation of XIAP was required for the synergistic interaction between PZQ and PTX. Together, this study suggested that the combination of PZQ and PTX may represent a novel and effective anticancer strategy for optimizing PTX therapy. PMID:23251610

  20. Delivery of paclitaxel using PEGylated graphene oxide as a nanocarrier.

    PubMed

    Xu, Zhiyuan; Zhu, Shaojia; Wang, Mingwei; Li, Yongjun; Shi, Ping; Huang, Xiaoyu

    2015-01-21

    Paclitaxel (PTX) is an extensively used potent chemotherapy drug; however, low water solubility, poor bioavailability, and emergence of drug resistance in patients limited its biological application. In this report, we proposed a new drug delivery system for cancer therapy based on graphene oxide (GO), a novel 2D nanomaterial obtained from the oxidation of natural graphite, to improve the utilization rate of PTX. PTX was first connected to biocompatible 6-armed poly(ethylene glycol), followed by covalent introduction into the surface of GO sheets via a facile amidation process under mild conditions, affording the drug delivery system, GO-PEG-PTX (size 50-200 nm). GO-PEG nanosized carrier could quickly enter into human lung cancer A549 and human breast cancer MCF-7 cells verified by inverted fluorescence microscope using fluorescein isothiocyanate as probe. This nanocarrier was nontoxic to A549 and MCF-7 cells without linking with PTX. Nevertheless, GO-PEG-PTX showed remarkably high cytotoxicity to A549 and MCF-7 cells in a broad range of concentration of PTX and time compared to free PTX. This kind of nanoscale drug delivery system based on PEGylated GO may find widespread application in biomedicine. PMID:25546399

  1. Chemotherapy in Metastatic NSCLC – New Regimens (Pemetrexed, Nab-Paclitaxel)

    PubMed Central

    Blais, Normand; Hirsh, Vera

    2014-01-01

    Platinum-based chemotherapy doublets have been the standard approach to first-line therapy for more than a decade. Many randomized trials testing new combinations have not been able to produce significant gains in patient outcomes when these studies have looked at an unselected patient population. The recognition of the biologic importance of histology and molecular features of lung cancer has dramatically impacted on patient care, as can be easily recognized by the advent of targeted therapy for molecularly defined lung cancers. Similarly, for lung cancers without recognized driver mutations, subgroup evaluations of trials-based histology has identified that some chemotherapy regimens offer greater benefit in the squamous cell or the non-squamous cell groups. Two such examples are nab-paclitaxel and pemetrexed. These have shown improved anti-tumor activity and a decreased toxicity profile compared to standard combinations. Preferential activity in histologic divided patient subgroups can allow the clinician to personalize his approach to care. The role of these two agents in the management of NSCLC will be described in this article. PMID:25101242

  2. [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

  3. Quasi-Complete Response of Classic Kaposi's Sarcoma Treated with Weekly Paclitaxel.

    PubMed

    Benbrahim, Zineb; Arifi, Samia; Benhammane, Hafida; Inani, Kaoutar; Gallouj, Salim; Meziane, Meriem; Mernissi, Fatima Zahra; Mellas, Nawfel; El Mesbahi, Omar

    2013-01-01

    Classic Kaposi's sarcoma (CKS) is a subtype that traditionally occurs in elderly HIV-negative males of Mediterranean origin. Patients with CKS characteristically present with skin lesions in the distal extremities. Involvement of the viscera is uncommon but may occur in the late stages of the disease. Patients with extensive KS can be treated with systemic chemotherapy. A number of drugs approved for treatment of AIDS-associated KS, especially Paclitaxel, have activity against CKS after failure of prior therapy. We report a patient treated with weekly Paclitaxel, as initial chemotherapy, for CKS presenting with multiple visceral involvement and having a contraindication for Bleomycin. The patient had quasi-complete response after three months of chemotherapy suggesting that weekly Paclitaxel might be effective as a first-line therapy for classical type KS with visceral involvement. PMID:23476845

  4. Quasi-Complete Response of Classic Kaposi's Sarcoma Treated with Weekly Paclitaxel

    PubMed Central

    Benbrahim, Zineb; Arifi, Samia; Benhammane, Hafida; Inani, Kaoutar; Gallouj, Salim; Meziane, Meriem; Mernissi, Fatima Zahra; Mellas, Nawfel; El Mesbahi, Omar

    2013-01-01

    Classic Kaposi's sarcoma (CKS) is a subtype that traditionally occurs in elderly HIV-negative males of Mediterranean origin. Patients with CKS characteristically present with skin lesions in the distal extremities. Involvement of the viscera is uncommon but may occur in the late stages of the disease. Patients with extensive KS can be treated with systemic chemotherapy. A number of drugs approved for treatment of AIDS-associated KS, especially Paclitaxel, have activity against CKS after failure of prior therapy. We report a patient treated with weekly Paclitaxel, as initial chemotherapy, for CKS presenting with multiple visceral involvement and having a contraindication for Bleomycin. The patient had quasi-complete response after three months of chemotherapy suggesting that weekly Paclitaxel might be effective as a first-line therapy for classical type KS with visceral involvement. PMID:23476845

  5. Cellular and clinical pharmacology of the taxanes docetaxel and paclitaxel--a review.

    PubMed

    de Weger, Vincent A; Beijnen, Jos H; Schellens, Jan H M

    2014-05-01

    Paclitaxel and docetaxel are active against a range of human cancers. Their antitumor activity is based on stabilization of the microtubule dynamics and thereby disruption of the cell cycle. The taxanes are administered as intravenous solutions in a short administration schedule. Distribution of both taxanes is rapid, with large volumes of distribution and significant binding to plasma proteins. The metabolism of paclitaxel is mediated primarily by the P450 cytochrome enzymes CYP2C8 and CYP3A, whereas docetaxel is only metabolized by CYP3A4. The most common toxicities after intravenous administration are neutropenia, hypersensitivity reactions, neurotoxicity, and alopecia. Several new administration forms are in development; albumin-bound paclitaxel (Abraxane) has recently been registered. Oral formulations of taxanes have been developed, and several are now undergoing phase I trials. New formulations might improve efficacy and safety and could be easier to use. PMID:24637579

  6. Nab-paclitaxel for metastatic pancreatic cancer: clinical outcomes and potential mechanisms of action.

    PubMed

    Al-Batran, Salah-Eddin; Geissler, Michael; Seufferlein, Thomas; Oettle, Helmut

    2014-01-01

    For almost 15 years there has been stagnation in the systemic treatment of patients with pancreatic ductal adenocarcinoma (PDAC). Recently, several developments seem to indicate clinically relevant improvements in the treatment of patients with metastatic disease. One of these developments is the introduction of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) into the firstline treatment of metastatic disease. In this review, underlying preclinical and clinical data are discussed, with a special focus on mechanisms of action, the potential interaction with albumin and calcium-binding matricellular glycoproteins, such as the secreted protein acidic and rich in cysteine (SPARC), as well as the clinical outcome associated with the use of nab-paclitaxel. PMID:24685917

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

    PubMed

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

    2004-01-26

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

  8. High-dose paclitaxel in combination with doxorubicin, cyclophosphamide and peripheral blood progenitor cell rescue in patients with high-risk primary and responding metastatic breast carcinoma: toxicity profile, relationship to paclitaxel pharmacokinetics and short-term outcome

    PubMed Central

    Somlo, G; Doroshow, J H; Synold, T; Longmate, J; Reardon, D; Chow, W; Forman, S J; Leong, L A; Margolin, K A; Jr, R J Morgan; Raschko, J W; Shibata, S I; Tetef, M L; Yen, Y; Kogut, N; Schriber, J; Alvarnas, J

    2001-01-01

    We assessed the feasibility and pharmacokinetics of high-dose infusional paclitaxel in combination with doxorubicin, cyclophosphamide, and peripheral blood progenitor cell rescue. Between October 1995 and June 1998, 63 patients with high-risk primary [stage II with ? 10 axillary nodes involved, stage IIIA or stage IIIB inflammatory carcinoma (n = 53)] or with stage IV responsive breast cancer (n = 10) received paclitaxel 150–775?mg/m2infused over 24 hours, doxorubicin 165?mg/m2as a continuous infusion over 96 hours, and cyclophosphamide 100?mg kg–1. There were no treatment-related deaths. Dose-limiting toxicity was reversible, predominantly sensory neuropathy following administration of paclitaxel at the 775?mg/m2dose level. Paclitaxel pharmacokinetics were non-linear at higher dose levels; higher paclitaxel dose level, AUC, and peak concentrations were associated with increased incidence of paraesthesias. No correlation between stomatitis, haematopoietic toxicities, and paclitaxel dose or pharmacokinetics was found. Kaplan–Meier estimates of 30-month event-free and overall survival for patients with primary breast carcinoma are 65% (95% CI; 51–83%) and 77% (95% CI; 64–93%). Paclitaxel up to 725?mg/m2infused over 24 hours in combination with with doxorubicin 165?mg/m2and cyclophosphamide 100?mg kg–1is tolerable. A randomized study testing this regimen against high-dose carboplatin, thiotepa and cyclophosphamide (STAMP V) is currently ongoing. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11401310

  9. A phase I study with an expanded cohort to assess the feasibility of intravenous paclitaxel, intraperitoneal carboplatin and intraperitoneal paclitaxel in patients with untreated ovarian, fallopian tube or primary peritoneal carcinoma: A Gynecologic Oncology Group study?,??,?

    PubMed Central

    Gould, Natalie; Sill, Michael W.; Mannel, Robert S.; Thaker, P.H.; DiSilvestro, Paul; Waggoner, Steve; Yamada, S. Diane; Armstrong, Deborah K.; Wenzel, Lari; Huang, Helen; Fracasso, Paula M.; Walker, Joan L.

    2013-01-01

    Objective To define the maximum tolerated dose (MTD) and assess the feasibility of intravenous (IV) paclitaxel, intraperitoneal (IP) carboplatin, and IP paclitaxel in women with newly diagnosed Stages II–IV ovarian, fallopian tube, or primary peritoneal carcinoma. Methods Patients received escalating doses of paclitaxel IV and carboplatin IP on day 1 and paclitaxel IP 60 mg/m2 on day 8. A standard 3+3 design was used in the escalation phase. A two-stage group sequential design with 20 patients at the MTD was used in the feasibility phase. Patient-reported neurotoxicity was assessed pre and post treatment. Results Patients were treated with paclitaxel 175 mg/m2 IV and carboplatin IP from AUC 5–7 on day 1 and paclitaxel 60 mg/m2 IP on day 8. The MTD was estimated at carboplatin AUC 6 IP and 25 patients enrolled at this dose level. Within the first 4 cycles, seven (35%) of twenty evaluable patients had dose-limiting toxicities (DLTs) including grade 4 thrombocytopenia (1), grade 3 neutropenic fever (3), >2 week delay due to ANC recovery (1), grade 3 LFT (1), and grade 3 infection (1). De-escalation to paclitaxel 135 mg/m2 IV was given to improve the safety. After six evaluable patients completed 4 cycles without a DLT, bevacizumab was added and six evaluable patients completed 4 cycles with one DLT (grade 3 hyponatremia). Conclusions Paclitaxel at 175 mg/m2 IV, carboplatin AUC 6 IP day 1 and paclitaxel 60 mg/m2 IP day 8 yield 18–56% patients with DLTs. The tolerability of the regimen in combination with bevacizumab was indicated in a small cohort. PMID:22155262

  10. Luteolin enhances paclitaxel-induced apoptosis in human breast cancer MDA-MB-231 cells by blocking STAT3.

    PubMed

    Yang, Mon-Yuan; Wang, Chau-Jong; Chen, Nai-Fang; Ho, Wen-Hsin; Lu, Fung-Jou; Tseng, Tsui-Hwa

    2014-04-25

    The potential use of low-dose chemotherapy has been appealing because lower dosages are more attainable during cancer therapy and cause less toxicity in patients. Combination therapy of paclitaxel, a promising frontline chemotherapy agent, with natural anti-tumor agents that are considerably less toxic and possess the capability of activating additional apoptotic signals may provide a rational molecular basis for novel chemotherapeutic strategies. Luteolin, a natural flavone, possesses multiple biological activities, including anti-tumor potential. In the present study, the effects of concomitant administration of luteolin and paclitaxel were investigated in human breast cancer MDA-MB-231 cells. Luteolin alone demonstrated an anti-proliferative effect. Co-administration of luteolin and paclitaxel resulted in an increase in apoptosis compared with the treatment of paclitaxel alone as evidenced by the results of a diamidino-2-phenylindole (DAPI) stain and Annexin-V-based assay. Moreover, immunoblotting analysis also showed that the co-administration of luteolin and paclitaxel activated caspase-8 and caspase-3 and increased the expression of Fas. Furthermore, the increased expression of Fas due to co-administration was shown to be due to the blocking of signal transducer and activator of transcription 3 (STAT3). Finally, combination therapy with luteolin and paclitaxel significantly reduced tumor size and tumor weight in an orthotopic tumor model of MDA-MB-231 cells in nude mice. These results suggest that the luteolin-paclitaxel combination could be a novel strategy for the treatment of breast cancer. PMID:24525192

  11. [Interest of studying the in vitro genotoxicity of an antineoplastic drug on healthy human cells: paclitaxel example].

    PubMed

    Digue, Laurence; Orsière, Thierry; Baciuchka-Palmaro, Marjorie; Duffaud, Florence; Pompili, Jocelyne; Favre, Roger; Botta, Alain

    2002-10-01

    Paclitaxel is often used as an adjuvant antineoplastic agent. However, very little data is available in literature on its potential genotoxicity on healthy human cells. Our objective is to study the potential in vitro genotoxicity of paclitaxel, by using the cytokinesis-blocked micronucleus assay in combination with fluorescent in situ hybridization of nonspecific centromeric probes on human T-lymphocytes. Paclitaxel was found to significantly increase the micronucleated lymphocyte rates with a concentration-dependant manner. This increase is observed as early as with the weakest concentration tested (2,5 nM). Over 85% of those micronuclei contained one or more whole chromosomes, indicating that paclitaxel is a strong aneugenic drug. Paclitaxel induces the formation of aneuploid daughter cells, as a consequence of abnormalities in the distribution of chromosomes during the cell division. However, aneuploidy is probably one of the first events in the oncogenesis process, and it often seems to be linked to a dysfunction of the centrosome. An interaction between paclitaxel and centrosome could explain a considerable amount of the centromere-positive micronuclei due to multipolar mitosis. Paclitaxel, whose influence is being questioned in clinical practice in the occurrence of secondary acute myeloid leukemia, is therefore an in vitro aneugenic drug, which could be carcinogenic. PMID:12441280

  12. Combination therapy of albumin-bound Paclitaxel and Carboplatin as first line therapy in a patient with ovarian cancer.

    PubMed

    Srinivasan, K N; Rauthan, Amit; Gopal, R

    2014-01-01

    Background. Ovarian cancer is the ninth most common cancer among women and causes more deaths than any other type of female reproductive cancer. Albumin-bound paclitaxel is known to increase intratumoral concentration of the paclitaxel by a receptor-mediated transport process across the endothelial cell wall, thereby breaching the blood/tumor interface. We present below three cases in which nab-paclitaxel based chemotherapy has been used in different settings for patients with ovarian cancer. Case Presentation. In the first case nab-paclitaxel was used along with carboplatin in adjuvant setting, in the second case, nab-paclitaxel was used along with carboplatin and bevacizumab as second line chemotherapy in a relapsed ovarian cancer case, and the third case delineates the use of nab-paclitaxel along with cisplatin as third line chemotherapy. Conclusion. In all the three scenarios, patients tolerated the chemotherapy well, as well as responding well to nab-paclitaxel based chemotherapy. The patients are currently on long-term follow-up and have been having an uneventful postchemotherapy. PMID:24804130

  13. Simultaneous determination of gemcitabine, taxol, cyclophosphamide and ifosfamide in wipe samples by high-performance liquid chromatography/tandem mass spectrometry: protocol of validation and uncertainty of measurement.

    PubMed

    Sottani, Cristina; Turci, Roberta; Schierl, Rudolf; Gaggeri, Raffaella; Barbieri, Anna; Violante, Francesco Saverio; Minoia, Claudio

    2007-01-01

    Measurable levels of anticancer agents are still detected on work surfaces in health-care settings. However, application of recent guidelines for the protection of workers' safety and health has resulted in lowered contamination levels. To assess occupational exposure to antineoplastic agents, very sensitive and specific procedures for environmental sampling and analysis are therefore needed. In the present study an assay for simultaneous determination of gemcitabine, taxol, cyclophosphamide, and ifosfamide in wipe samples, using two internal standards (trofosfamide and cephalomannine), was developed and validated by high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS). Solid-phase extraction (SPE) was used for sample concentration and cleanup. The assay was found to be linear up to 1000 ng/wipe, with limits of quantitation of 25.0 ng/wipe for gemcitabine and taxol, and 12.5 ng/wipe for cyclophosphamide and ifosfamide. In order to investigate the effectiveness of the surface sampling, removal efficiency tests were repeated on different types of surfaces. Recovery rates of between 62 and 81% were obtained at two contamination levels (50.0 and 250 ng/100 cm2). Precision and trueness were determined on three different days. The within-day precision was found to be always less than 12.1% for all the analytes. The overall precision, expressed as relative standard deviation (RSD), was always less than 9.4%. Recoveries varying from 75.0 (gemcitabine) to 95.0% (taxol) were obtained at three levels. In order to obtain a quantitative indication of the quality of the result, the overall uncertainty of measurement (UOM) was evaluated according to the EURACHEM/CITAC guide. The relative combined uncertainty was found to be always less than 9.5%. The relative expanded uncertainty was also calculated, at three contamination levels. PMID:17340557

  14. Phenotypic modifications in ovarian cancer stem cells following Paclitaxel treatment

    PubMed Central

    Craveiro, Vinicius; Yang-Hartwich, Yang; Holmberg, Jennie C; Sumi, Natalia J; Pizzonia, John; Griffin, Brian; Gill, Sabrina K; Silasi, Dan-Arin; Azodi, Masoud; Rutherford, Thomas; Alvero, Ayesha B; Mor, Gil

    2013-01-01

    Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Despite initial responsiveness, 80% of EOC patients recur and present with chemoresistant and a more aggressive disease. This suggests an underlying biology that results in a modified recurrent disease, which is distinct from the primary tumor. Unfortunately, the management of recurrent EOC is similar to primary disease and does not parallel the molecular changes that may have occurred during the process of rebuilding the tumor. We describe the characterization of unique in vitro and in vivo ovarian cancer models to study the process of recurrence. The in vitro model consists of GFP+/CD44+/MyD88+ EOC stem cells and mCherry+/CD44?/MyD88? EOC cells. The in vivo model consists of mCherry+/CD44+/MyD88+ EOC cells injected intraperitoneally. Animals received four doses of Paclitaxel and response to treatment was monitored by in vivo imaging. Phenotype of primary and recurrent disease was characterized by quantitative polymerase chain reaction (qPCR) and Western blot analysis. Using the in vivo and in vitro models, we confirmed that chemotherapy enriched for CD44+/MyD88+ EOC stem cells. However, we observed that the surviving CD44+/MyD88+ EOC stem cells acquire a more aggressive phenotype characterized by chemoresistance and migratory potential. Our results highlight the mechanisms that may explain the phenotypic heterogeneity of recurrent EOC and emphasize the significant plasticity of ovarian cancer stem cells. The significance of our findings is the possibility of developing new venues to target the surviving CD44+/MyD88+ EOC stem cells as part of maintenance therapy and therefore preventing recurrence and metastasis, which are the main causes of mortality in patients with ovarian cancer. PMID:24403249

  15. Development of an indirect competitive enzyme-linked immunosorbent assay (icELISA) using highly specific monoclonal antibody against paclitaxel.

    PubMed

    Chao, Zhi; Tan, Mingming; Paudel, Madan Kumar; Sakamoto, Seiichi; Ma, Liling; Sasaki-Tabata, Kaori; Tanaka, Hiroyuki; Shoyama, Yukihiro; Xuan, Lijiang; Morimoto, Satoshi

    2013-07-01

    Paclitaxel, the major active component of the yew tree, is used as an important anti-cancer agent. To obtain the monoclonal antibody (MAb) against paclitaxel for paclitaxel determination using immunoassay, 7-xylosyltaxol was conjugated to the carrier protein bovine serum albumin (BSA) to construct the immunogen, and the ratio of hapten in XylTax-BSA conjugate was determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. After immunization of mice with this conjugate, hybridomas secreting MAbs against paclitaxel were obtained by fusing the splenocytes with the mouse myeloma cell line SP2/0. After hybridoma screening, the anti-paclitaxel MAb 3A3 was obtained, which showed a relatively high specificity to paclitaxel (cross-reactivities against other naturally occurred taxanes: 7-xylosyltaxol, 31.8%; cephalomannine, 6.17%; baccatin III, 10-deacetyl-baccatin III, 1-hydroxybaccatin I, 13-acetyl-9-dihydrobaccatin III and 1-acetoxyl-5-deacetyl-baccatin I, <0.11%). Using the MAb 3A3, we established an indirect competitive enzyme-linked immunosorbent assay (icELISA) for paclitaxel determination with a detection range of 0.098-312.5 ?g ml(-1). Determination of paclitaxel contents in various yew tree samples with this icELISA resulted in recovery rates ranging from 92 to 94.8%, and intra- and inter-assay variations of 3.6 and 4.7%, respectively. This icELISA provides a valuable method of paclitaxel determination for various purposes. PMID:23007175

  16. A randomized phase II trial comparing every 3-weeks carboplatin\\/paclitaxel with every 3-weeks carboplatin and weekly paclitaxel in advanced non-small cell lung cancer

    Microsoft Academic Search

    M. A. Socinski; A. Ivanova; K. Bakri; J. Wall; M. Q. Baggstrom; T. A. Hensing; A. Mears; M. Tynan; J. Beaumont; A. H. Peterman; H. B. Niell

    2005-01-01

    Background: The optimal schedule of taxane administration has been an area of active interest in several recent clinical trials. Methods: To address a pure schedule question, we randomized 161 patients with advanced stage IIIB or IV non-small-cell lung cancer (NSCLC) to either paclitaxel 225 mg\\/m2 every 3 weeks · 4 cycles or 75 mg\\/m2\\/week · 12 (cumulative dose on each

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

    PubMed

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

    2013-11-01

    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

  18. Phase II trial of weekly nab-paclitaxel and carboplatin treatment with or without trastuzumab as nonanthracycline neoadjuvant chemotherapy for locally advanced breast cancer

    PubMed Central

    Huang, Liang; Chen, Sheng; Yao, Ling; Liu, Guangyu; Wu, Jiong; Shao, Zhiming

    2015-01-01

    Background Neoadjuvant chemotherapy has become standard treatment for women with locally advanced breast cancer. The aim of this study was to compare the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) versus paclitaxel combined with carboplatin. Methods Thirty patients were treated with neoadjuvant nab-paclitaxel (125 mg/m2, days 1, 8, and 15) and carboplatin (area under the curve =2; days 1, 8, and 15) every 21 days for four cycles. Ninety matched patients received paclitaxel (80 mg/m2, days 1, 8, and 15) and carboplatin every 21 days for four cycles. Weekly trastuzumab is recommended for overexpression of human epidermal receptor-2. The primary endpoint was pathologic complete response (defined as ypT0/is ypN0). Matching was conducted according to six variables: body mass index, clinical tumor stage, clinical lymph node status, estrogen receptor status, HER2 status, and trastuzumab receiving rate. Results Ninety percent of patients in the nab-paclitaxel group and 80% of patients in the paclitaxel group experienced a clinical objective response (complete response or partial response; P=0.450). Eight patients in the nab-paclitaxel group and 23 patients in the paclitaxel group had a pathologic complete response in the breast and axillary nodes (26.7% versus 25.6%; P=0.904). Nab-paclitaxel showed a beneficial effective trend on clinical tumor stage II (36.8% versus 15.8%; P=0.051). When trastuzumab was added to nab-paclitaxel, the pathologic complete response rate was not significantly improved more than with trastuzumab and paclitaxel (43.6% versus 39.6%; P=0.769). Carboplatin plus nab-paclitaxel or paclitaxel had similarly low pathologic complete response rates (7.7% versus 10.5%) for the luminal molecular subtype. One (50%) triple-negative patient achieved a pathologic complete response. The nab-paclitaxel regimen caused more grade 4 neutropenia than the paclitaxel regimen (56.7% versus 21.1%; P<0.001). Conclusion Our study shows that weekly nab-paclitaxel and carboplatin with or without trastuzumab resulted in a pathologic complete response rate that was not superior to the matched cohorts. Future, larger trials are needed to validate that nab-paclitaxel is beneficial for clinical tumor stage II and the triple-negative subgroup. PMID:25792830

  19. Paclitaxel-Conjugated PAMAM Dendrimers Adversely Affect Microtubule Structure through Two Independent Modes of Action

    E-print Network

    Walter, Nils G.

    in cultured cancer cells. Mechanisms of action responsible for this cytotoxicity are unknown, that is, whether is poorly water-soluble, it is currently solubilized in a mixture of polyethoxylated castor oil and ethanol cancer drug,1 making the design of a targeted delivery strategy using a water-soluble form of paclitaxel

  20. Molecular Mechanisms of Paclitaxel Resistance and Resveratrol Sensitivity in MDA-MB-231 Breast Cancer Cells

    E-print Network

    Zhou, Yaoqi

    Molecular Mechanisms of Paclitaxel Resistance and Resveratrol Sensitivity in MDA-MB-231 Breast to the parent line. It has been suggested that the polyphenol natural compound, resveratrol, which has been sensitive to resveratrol treatment. We observed that treatment with 10-100 µM concentrations of resveratrol

  1. The Use of Paclitaxel and Platinum-Based Chemotherapy in Uterine Papillary Serous Carcinoma

    Microsoft Academic Search

    Kristine M. Zanotti; Jerome L. Belinson; Alexander W. Kennedy; Kenneth D. Webster; Maurie Markman

    1999-01-01

    Objective. Uterine papillary serous carcinoma (UPSC) is an aggressive malignancy with a histologic appearance and pattern of spread that resembles that of papillary serous adenocarcinoma of the ovary. The current standard therapy for advanced ovarian cancer, cisplatin or carboplatin plus paclitaxel, results in high objective response rates for that tumor. This regimen has thus far not been evaluated in UPSC.Methods.

  2. Comparison of 1Hour and 3Hours Paclitaxel Infusion Pharmacokinetics: Results from a Randomized Trial

    Microsoft Academic Search

    K. Mross; B. Häring; N. Holländer; S. Mielke; D. Behringer; U. Massing; C. Unger

    2002-01-01

    SummaryPurpose: Aim of this study was to characterize the difference in pharmacokinetics (PK) of paclitaxel (PAC) after 1-h and 3-h infusion in humans and to define a pharmacodynamic relationship between PAC PK and myelotoxicity. Patients and Methods: PAC PK were studied during the first PAC application in the first treatment cycle (1 treatment cycle = 6 PAC applications) in 25

  3. Application of coherent anti-Stokes Raman scattering microscopy to image the changes in a paclitaxel

    E-print Network

    Cheng, Ji-Xin

    in a paclitaxel­ poly(styrene-b-isobutylene-b-styrene) matrix pre- and post-drug elution Eunah Kang,1 Haifeng Wang, and noninvasiveness of the technology. Additionally, the morphological changes of poly(styrene-b-isobutylene(styrene-b- isobutylene-b-styrene) (SIBS); coherent anti-Stokes Raman scattering (CARS); microscopy INTRODUCTION Drug

  4. Improved paclitaxel and baccatin III production in suspension cultures of Taxus media.

    PubMed

    Cusidó, Rosa M; Palazón, Javier; Bonfill, Mercedes; Navia-Osorio, Alberto; Morales, Carmen; Piñol, M Teresa

    2002-01-01

    A cell suspension culture of Taxus media was established from a stable callus line of this species. The growth rate and production of paclitaxel and baccatin III of this cell suspension were significantly increased during the shake flask culture in its respective optimum media for cell growth and product formation, which were selected after assaying 24 different culture media. The highest yields of paclitaxel (2.09 mg L(-1)) and baccatin III (2.56 mg L(-1)) in the production medium rose (factors of 7.0 and 3.0, respectively) in the presence of methyljasmonate (220 microg g(-1) FW). When the elicitor was added together with mevalonate (0.38 mM) and N-benzoylglycine (0.2 mM), the increase in the yields of paclitaxel and baccatin III was even higher (factors of 8.3 and 4.0, respectively). Thereafter, a two-stage culture for cell suspension was carried out using a 5-l stirred bioreactor running for 36 days, the first stage being in the cell growth medium until cells entered their stationary growth phase (12 days) and the second stage being in the production medium supplemented with the elicitor and two putative precursors in the concentrations indicated above. Under these conditions, 21.12 mg L(-1) of paclitaxel and 56.03 mg L(-1) of baccatin III were obtained after 8 days of culture in the production medium. PMID:12052053

  5. 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

  6. Bioadhesive Drug Delivery System Using Glyceryl Monooleate for the Intravesical Administration of Paclitaxel

    Microsoft Academic Search

    Seung-Ju Lee; Sae Woong Kim; Hesson Chung; Yeong Taek Park; Young Wook Choi; Yong-Hyun Cho; Moon Soo Yoon

    2005-01-01

    Background: Many reports have shown that the efficacy of intravesical therapy for bladder cancer is in part limited by the poor penetration of drugs into the urothelium. The present study evaluated the effect of glyceryl monooleate (GMO) on the absorption of intravesically administered paclitaxel in a rabbit model of bladder cancer. Methods: Urine, plasma, and tissue pharmacokinetics were determined in

  7. NK105, a paclitaxel-incorporating micellar nanoparticle, is a more potent radiosensitising agent compared to free paclitaxel

    PubMed Central

    Negishi, T; Koizumi, F; Uchino, H; Kuroda, J; Kawaguchi, T; Naito, S; Matsumura, Y

    2006-01-01

    NK105 is a micellar nanoparticle formulation designed to enhance the delivery of paclitaxel (PTX) to solid tumours. It has been reported to exert antitumour activity in vivo and to have reduced neurotoxicity as compared to that of free PTX. The purpose of this study was to investigate the radiosensitising effect of NK105 in comparison with that of PTX. Lewis lung carcinoma (LLC)-bearing mice were administered a single intravenous (i.v.) injection of PTX or NK105; 24?h after the drug administration, a proportion of the mice received radiation to the tumour site or lung fields. Then, the antitumour activity and lung toxicity were evaluated. In one subset of mice, the tumours were excised and specimens were prepared for analysis of the cell cycle distribution by flow cytometry. Combined NK105 treatment with radiation yielded significant superior antitumour activity as compared to combined PTX treatment with radiation (P=0.0277). On the other hand, a histopathological study of lung sections revealed no significant difference in histopathological changes between mice treated with PTX and radiation and those treated with NK105 and radiation. Flow-cytometric analysis showed that NK105-treated LLC tumour cells showed more severe arrest at the G2/M phase as compared to PTX-treated tumour cells. The superior radiosensitising activity of NK105 was thus considered to be attributable to the more severe cell cycle arrest at the G2/M phase induced by NK105 as compared to that induced by free PTX. The present study results suggest that further clinical trials are warranted to determine the efficacy and feasibility of combined NK105 therapy with radiation. PMID:16909136

  8. Genetic inactivation and pharmacological blockade of sigma-1 receptors prevent paclitaxel-induced sensory-nerve mitochondrial abnormalities and neuropathic pain in mice

    PubMed Central

    2014-01-01

    Background Paclitaxel, a widely-used antineoplastic drug, produces a painful peripheral neuropathy that in rodents is associated with peripheral-nerve mitochondrial alterations. The sigma-1 receptor (?1R) is a ligand-regulated molecular chaperone involved in mitochondrial calcium homeostasis and pain hypersensitivity. This receptor plays a key role in paclitaxel-induced neuropathic pain, but it is not known whether it also modulates mitochondrial abnormalities. In this study, we used a mouse model of paclitaxel-induced neuropathic pain to test the involvement of the ?1R in the mitochondrial abnormalities associated with paclitaxel, by using genetic (?1R knockout mice) and pharmacological (?1R antagonist) approaches. Results Paclitaxel administration to wild-type (WT) mice produced cold- and mechanical-allodynia, and an increase in the frequency of swollen and vacuolated mitochondria in myelinated A-fibers, but not in C-fibers, of the saphenous nerve. Behavioral and mitochondrial alterations were marked at 10 days after paclitaxel-administration and had resolved at day 28. In contrast, paclitaxel treatment did not induce allodynia or mitochondrial abnormalities in ?1R knockout mice. Moreover, the prophylactic treatment of WT mice with BD-1063 also prevented the neuropathic pain and mitochondrial abnormalities induced by paclitaxel. Conclusions These results suggest that activation of the ?1R is necessary for development of the sensory nerve mitochondrial damage and neuropathic pain produced by paclitaxel. Therefore, ?1R antagonists might have therapeutic value for the prevention of paclitaxel-induced neuropathy. PMID:24517272

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

    NASA Astrophysics Data System (ADS)

    Zubris, Kimberly Ann Veronica

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

  10. Curcumin improves the paclitaxel-induced apoptosis of HPV-positive human cervical cancer cells via the NF-?B-p53-caspase-3 pathway

    PubMed Central

    DANG, YU-PING; YUAN, XIAO-YING; TIAN, RONG; LI, DONG-GUANG; LIU, WEI

    2015-01-01

    Paclitaxel, isolated from Taxus brevifolia, is considered to be an efficacious agent against a wide spectrum of human cancers, including human cervical cancer. However, dose-limiting toxicity and high cost limit its clinical application. Curcumin, a nontoxic food additive, has been reported to improve paclitaxel chemotherapy in mouse models of cervical cancer. However, the underlying mechanisms remain unclear. In this study, two human cervical cancer cell lines, CaSki [human papilloma virus (HPV)16-positive] and HeLa (HPV18-positive), were selected in which to investigate the effect of curcumin on the anticancer action of paclitaxel and further clarify the mechanisms. Flow cytometry and MTT analysis demonstrated that curcumin significantly promoted paclitaxel-induced apoptosis and cytotoxicity in the two cervical cell lines compared with that observed with paclitaxel alone (P<0.05). Reverse transcription-polymerase chain reaction indicated that the decline of HPV E6 and E7 gene expression induced by paclitaxel was also assisted by curcumin. The expression levels of p53 protein and cleaved caspase-3 were increased significantly in the curcumin plus paclitaxel-treated HeLa and CaSki cells compared with those in the cells treated with paclitaxel alone (P<0.01). Significant reductions in the levels of phosphorylation of I?B? and the p65-NF-?B subunit in CaSki cells treated with curcumin and paclitaxel were observed compared with those in cells treated with paclitaxel alone (P<0.05). This suggests that the combined effect of curcumin and paclitaxel was associated with the NF-?B-p53-caspase-3 pathway. In conclusion, curcumin has the ability to improve the paclitaxel-induced apoptosis of HPV-positive human cervical cancer cell lines via the NF-?B-p53-caspase-3 pathway. Curcumin in combination with paclitaxel may provide a superior therapeutic effect on human cervical cancer. PMID:25780454

  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. C-MYC modulation induces responsiveness to paclitaxel in adrenocortical cancer cell lines.

    PubMed

    Cerquetti, Lidia; Sampaoli, Camilla; De Salvo, Maria; Bucci, Barbara; Argese, Nicola; Chimento, Adele; Vottari, Sebastiano; Marchese, Rodolfo; Pezzi, Vincenzo; Toscano, Vincenzo; Stigliano, Antonio

    2015-05-01

    C-MYC is overexpressed in many types of cancer linked to poor prognosis. We examined the c-Myc protein expression in adrenocortical cancer (ACC) cells to investigate the role of this protein in the neoplasm, its involvement in chemotherapy and finally to determine whether c-Myc could be considered a prognostic factor in patients with ACC. H295R and SW13 cell lines were treated with paclitaxel. c-Myc overexpressing cell clones were achieved by transfecting the H295R cell line with the pcDNA3-hMYC plasmid expressing the full-lengh C-MYC coding sequence. The SW13 cell line was transfected with siRNA oligonucleotides for C-MYC. Cell cycle analysis was evaluated by flow cytometry. c-Myc, cyclin B1 and pro caspase expression levels were evaluated by western blot analysis. We found that expression of c-Myc was highly expressed in the SW13 cells, whereas the protein was undetectable in the H295R cells. Different doses of paclitaxel were required in the two ACC cell line to induce a block in the G2 phase, characterized by increased cyclin B1 levels and to induce apoptosis by pro-caspase-3 activation. Interestingly, the silencing of C-MYC mRNA prevented paclitaxel induced apoptosis in SW13 cells, whereas in the H295R cells the overexpression of C-MYC rendered the cells more prone to growth inhibition after paclitaxel exposure. The present study directly demonstrates that C-MYC plays a central role in controlling proliferation in ACC cells after paclitaxel treatment and that c-Myc could be considered as a marker for predicting response to chemotherapeutic agents in ACC cell lines. PMID:25708932

  13. Cisplatin improves antitumor activity of weekly nab-paclitaxel in patients with metastatic breast cancer.

    PubMed

    Sun, Si; Tang, Lichen; Zhang, Jian; Lv, Fangfang; Wang, Zhonghua; Wang, Leiping; Zhang, Qunling; Zheng, Chunlei; Qiu, Lixin; Jia, Zhen; Lu, Yunhua; Liu, Guangyu; Shao, Zhimin; Wang, Biyun; Hu, Xichun

    2014-01-01

    Although nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is approved to be given every 3 weeks, weekly use of this drug is becoming a new standard of care in patients with metastatic breast cancer (MBC). This prospective Phase II study was conducted to improve the efficacy of weekly nab-paclitaxel with cisplatin in MBC patients. Seventy-three women with recurrent or MBC were eligible for participation. Nab-paclitaxel was administered weekly at a dose of 125 mg/m(2) on day 1, day 8, and day 15, followed by cisplatin 75 mg/m(2) on day 1, repeated every 28 days with a maximum of 6 cycles. The primary objective was investigator-assessed overall response rate (ORR). A high ORR of 67.1% was obtained, with rates of 80.6% for the first-line patients and 80% for patients not pretreated with taxanes. Among those who had objective responses, a large percentage of patients (83.7%) showed quickly remarkable tumor shrinkage during the first two cycles. The median progression-free and overall survival times were 9.8 and 26.9 months, respectively. For the patients receiving first-, second-, and third-line therapy or beyond, median progression-free survival was 11.7, 7.7, and 7.6 months, respectively (P=0.005). Molecular subtype was not significantly associated with ORR or disease progression. Grade 4 neutropenia occurred in 46 patients (63.0%), with febrile neutropenia found in 9 patients (12.3%). Grade 3 peripheral neuropathy was an accumulated dose-limiting toxicity occurring in 19 patients (26.0%). Efficacy of weekly nab-paclitaxel can be improved by adding cisplatin. The doublet is highly effective, with quick response, manageable toxicity, and possible equivalence across molecular subtypes in MBC patients. PMID:24672237

  14. MyD88 predicts chemoresistance to paclitaxel in epithelial ovarian cancer

    PubMed Central

    Silasi, Dan-Arin; Alvero, Ayesha B.; Illuzzi, Jessica; Kelly, Michael; Chen, Rui; Fu, Han-Hsuan; Schwartz, Peter; Rutherford, Thomas; Azodi, Masoud; Mor, Gil

    2007-01-01

    Introduction: Early identification of chemoresistance in patients with ovarian cancer is of utmost importance in order to provide them with the most appropriate therapy. Recently, we described the expression of MyD88 in ovarian cancer cells that were resistant to the cytotoxic agent paclitaxel. In addition to chemoresistance, in MyD88 positive ovarian cancer cells, paclitaxel stimulates growth and production of proinflammatory cytokines. The objective of this study was to determine the correlation of MyD88 expression in primary and recurrent epithelial ovarian cancers with the response to carboplatin and paclitaxel combination chemotherapy. Methods: Tumors are heterogeneous structures that contain different cell populations, thus rendering the identification of specific tumor markers difficult. Using laser capture microdissection, pure cancer cells were isolated from ovarian malignant tumors that were obtained from 20 patients at the time of surgery. The microdissected cells were evaluated for the expression of MyD88, FasL, and XIAP by western blot analysis. Results: Protein expression was observed in samples containing as low as 500 cells. The results were correlated with the clinical course of those patients. It was evident that MyD88 expression in ovarian cancer cells accurately predicts a poor response to paclitaxel chemotherapy as shown by a short progression-free interval and overall survival. Conclusion: We describe for the first time a molecular approach to identify paclitaxel chemoresistance. Toxicity from agents without therapeutic benefit can be avoided by identifying those patients who will not respond to a specific agent. Molecular markers will enable us to design individualized treatments and improve overall survival. PMID:17940625

  15. Royal jelly protects from taxol-induced testicular damages via improvement of antioxidant status and up-regulation of E2f1.

    PubMed

    Delkhoshe-Kasmaie, Fatemeh; Malekinejad, Hassan; Khoramjouy, Mona; Rezaei-Golmisheh, Ali; Janbaze-Acyabar, Hamed

    2014-04-01

    This study was carried out to evaluate the protective effects of royal jelly (RJ) on taxol (TXL)-induced damage of the testis. Wistar rats were divided into control and test groups. The test group was divided into five subgroups; the first four groups along with TXL administration (7.5?mg/kg body weight (bw), weekly), received various doses of RJ (0, 50, 100, and 150?mg/kg bw). The last group received only RJ at 100?mg/kg. Royal jelly lowered the TXL-induced malondialdehyde and nitric oxide levels and enhanced the total thiol molecules in the testis. Remarkably RJ reduced the TXL-induced pathological injuries such as cellular shrinkage and seminiferous tubule depletion. Taxol-reduced sperm viability (27.5?±?2.98 % vs. 85.0?±?8.6% in the control group) was recovered by RJ administration as 80.5?±?10.6% of the sperm were found alive in the group of animals which received 150?mg/kg RJ. The TXL-exposed and TXL plus RJ-administered animals showed a significant up-regulation of transcription factor E2f1 mRNA. Our data suggest that the TXL-induced histopathological and biochemical alterations could be protected by the administration of RJ. The RJ protective effects might be attributed to its antioxidant capacity and its capability in the regulation of E2f1 expression. PMID:24377747

  16. SPAG5 upregulation predicts poor prognosis in cervical cancer patients and alters sensitivity to taxol treatment via the mTOR signaling pathway

    PubMed Central

    Yuan, L-J; Li, J-D; Zhang, L; Wang, J-H; Wan, T; Zhou, Y; Tu, H; Yun, J-P; Luo, R-Z; Jia, W-H; Zheng, M

    2014-01-01

    Previously, we found that sperm-associated antigen 5 (SPAG5) was upregulated in pelvic lymph node metastasis–positive cervical cancer. The aim of this study is to examine the role of SPAG5 in the proliferation and tumorigenicity of cervical cancer and its clinical significance in tumor progression. In our study, SPAG5 expression in cervical cancer patients was detected using quantitative real-time polymerase chain reaction, western blotting, and immunohistochemistry; cervical cancer cell function with downregulated SPAG5 in vitro was explored using tetrazolium assay, flow cytometry, and colony formation and Transwell assays. SPAG5 was upregulated in tumor tissue compared with paired adjacent noncancerous tissues; SPAG5 upregulation in tumor tissues indicated poor disease-free survival, which was also an independent prognostic indicator for cervical cancer patients. In vitro study demonstrated that SPAG5 downregulation inhibited cell proliferation and growth significantly by G2/M arrest and induction of apoptosis, and hindered cell migration and invasion. Under SPAG5 downregulation, the sensitivity of cervical cancer cells differed according to taxol dose, which correlated with mammalian target of rapamycin (mTOR) signaling pathway activity. In general, SPAG5 upregulation relates to poor prognosis in cervical cancer patients, and SPAG5 is a regulator of mTOR activity during taxol treatment in cervical cancer. PMID:24853425

  17. Micro-porous Paclitaxel-Loaded PLGA Foams -- a New Implant Material for Controlled Release of Chemotherapeutic Agents

    E-print Network

    Lee, Lai Yeng

    Supercritical gas foaming using CO? was used to fabricate blank poly DL lactide-co-glycolide (PLGA) micro-porous foams. Paclitaxel-loaded PLGA foams were also produced for the first time using a modification of the ...

  18. Epirubicin and paclitaxel (EPI-TAX regimen) for advanced ovarian cancer after failure of platinum-containing regimens

    Microsoft Academic Search

    Isabelle Ray-Coquard; Thomas Bachelot; Jean-Paul Guastalla; Éric Levy; Jean-Dominique Tigaud; Pascal Vincent; Dominique Dramais; David Assouline; Eric Pujade-Lauraine

    2003-01-01

    BackgroundThe place of anthracyclines in the treatment of advanced ovarian cancer remains a matter of debate. We have assessed the feasibility and evaluated the tolerance of epirubicin (EPI) combined with paclitaxel (TAX) in heavily pretreated ovarian cancer patients.

  19. Nanoparticle albumin-bound-Paclitaxel in the treatment of metastatic urethral adenocarcinoma: the significance of molecular profiling and targeted therapy.

    PubMed

    Abaza, Yasmin M; Alemany, Carlos

    2014-01-01

    Primary urethral cancer is rare and accounts for only 0.003% of all malignancies arising from the female genitourinary tract. Due to the rarity of this disease, no consensus exists regarding the optimal therapeutic approach. Nanoparticle albumin-bound-paclitaxel has been shown to be effective in the treatment of a number of malignancies including metastatic breast, pancreatic, and bladder cancer. We present a 67-year-old woman with advanced metastatic urethral adenocarcinoma resistant to two lines of chemotherapy (ifosfamide/paclitaxel/cisplatin and irinotecan/5-fluorouracil/leucovorin) that showed a dramatic response to nanoparticle albumin-bound-paclitaxel. This is the first case report to document the use and efficacy of nanoparticle albumin-bound-paclitaxel in the treatment of unresectable metastatic urethral cancer. PMID:25202467

  20. Nanoparticle Albumin-Bound-Paclitaxel in the Treatment of Metastatic Urethral Adenocarcinoma: The Significance of Molecular Profiling and Targeted Therapy

    PubMed Central

    Abaza, Yasmin M.; Alemany, Carlos

    2014-01-01

    Primary urethral cancer is rare and accounts for only 0.003% of all malignancies arising from the female genitourinary tract. Due to the rarity of this disease, no consensus exists regarding the optimal therapeutic approach. Nanoparticle albumin-bound-paclitaxel has been shown to be effective in the treatment of a number of malignancies including metastatic breast, pancreatic, and bladder cancer. We present a 67-year-old woman with advanced metastatic urethral adenocarcinoma resistant to two lines of chemotherapy (ifosfamide/paclitaxel/cisplatin and irinotecan/5-fluorouracil/leucovorin) that showed a dramatic response to nanoparticle albumin-bound-paclitaxel. This is the first case report to document the use and efficacy of nanoparticle albumin-bound-paclitaxel in the treatment of unresectable metastatic urethral cancer. PMID:25202467

  1. 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

  2. Novel C-seco-taxoids possessing high potency against paclitaxel-resistant cancer cell lines overexpressing class III ?-tubulin

    Microsoft Academic Search

    Antonella Pepe; Liang Sun; Ilaria Zanardi; Xinyuan Wu; Cristiano Ferlini; Gabriele Fontana; Ezio Bombardelli; Iwao Ojima

    2009-01-01

    Novel C-seco-taxoids were synthesized from 10-deacetylbaccatin III and their potencies evaluated against drug-sensitive and drug-resistant cancer cell lines. The drug-resistant cell lines include ovarian cancer cell lines resistant to cisplatin, topotecan, adriamycin and paclitaxel overexpressing class III ?-tubulin, A2780TC1 and A2780TC3. The last two cell lines were selected through chronic exposure of A2780wt to paclitaxel and Pgp blocker cyclosporine. All

  3. Pilot phase II study of weekly chemotherapy with paclitaxel and carboplatin for refractory or relapsed small-cell lung cancer

    Microsoft Academic Search

    Kiyoshi Mori; Yukari Kamiyama; Tetsuro Kondo; Yasuhiko Kano; Tetsuro Kodama

    2006-01-01

    Purpose: The safety and efficacy of weekly chemotherapy with paclitaxel and carboplatin for the treatment of patients with refractory\\u000a or relapsed small-cell lung cancer (SCLC) were evaluated. Patients and methods: Paclitaxel (100 mg\\/m2) and carboplatin (with a target area under the concentration versus time curve of 2 mg min\\/ml using the Calvert formula)\\u000a were administered to patients with previously- treated SCLC on days

  4. Rescue of neurons from undergoing hallmark tau-induced Alzheimer's disease cell pathologies by the antimitotic drug paclitaxel

    Microsoft Academic Search

    A. Shemesh; Micha E. Spira

    2011-01-01

    Through the use of live confocal imaging, electron microscopy, and the novel cell biological platform of cultured Aplysia neurons we show that unfolding of the hallmark cell pathologies induced by mutant-human-tau (mt-human-tau) expression is rescued by 10 nM paclitaxel. At this concentration paclitaxel prevents mt-human-tau-induced swelling of axonal segments, translocation of tau and microtubules (MT) to submembrane domains, reduction in

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

    PubMed

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

    2008-07-01

    This article focuses on the recent findings by Marsh and colleagues, and also discusses recent findings with regards to breast cancer. Taxanes are amongst the most active agents in the treatment of breast cancer. However, many tumors are intrinsically resistant. Therefore, it would be an enormous progress, if factors could be identified that reliably differentiate between taxane-sensitive and -resistant patients. Marsh and colleagues analyzed the CYP1B1*3 (Val432Leu) polymorphism in patients with high-risk stage III and IV breast cancer, who received dose-intense paclitaxel in combination with doxorubicin and cyclophosphamide. They report for the first time that patients with two leucine alleles in codon 432 of CYP1B1 experience a longer progression-free survival compared with patients with the Val/Leu or Val/Val genotypes. If confirmed in independent cohorts CYP1B1*3 may prove to be an important factor that helps to differentiate between paclitaxel-sensitive and resistant breast cancer patients. However, the mechanism behind the association between CYP1B1*3 and prognosis of paclitaxel-treated patients remains unclear. Several studies provide strong evidence that CYP1B1 does not influence tumor progression independently from paclitaxel chemotherapy, and that CYP1B1 itself does not alter paclitaxel resistance. In addition, CYP1B1 mRNA expression does not correlate with paclitaxel sensitivity of primary tumor cells. Although still speculative, a possible explanation is an association between CYP1B1*3 with still unknown factors that, on their part, influence paclitaxel sensitivity. In the future, studies with SNP chips and studies on the transcriptome, proteome and metabolome level should be performed in order to identify signatures differentiating between paclitaxel-sensitive and -resistant patients. PMID:18597657

  6. The effect of 17-allylamino-17-demethoxygeldanamycin alone or in combination with paclitaxel on anaplastic thyroid carcinoma cells.

    PubMed

    Kim, Si Hyoung; Kang, Jun Goo; Kim, Chul Sik; Ihm, Sung-Hee; Choi, Moon Gi; Yoo, Hyung Joon; Lee, Seong Jin

    2015-04-01

    The effect of 17-allylamino-17-demethoxygeldanamycin (17-AAG), an hsp90 inhibitor, alone or in combination with paclitaxel on survival of anaplastic thyroid carcinoma (ATC) was evaluated. In 8505C and CAL62 cells, after treatment of 17-AAG, cell viability decreased, and the percentage of dead cells increased. 17-AAG did not cause cleavage of caspase-3 protein, and change expression of IAPs. Pretreatment of z-VAD-fmk did not alter cell viability and the percentage of dead cells. In 17-AAG-treated cells, knockdown of p53 rescued growth inhibition, while cycloheximide attenuated cell death. When cells were treated with both 17-AAG and paclitaxel, all of the combination index values were higher than 1, indicating antagonism between 17-AAG and paclitaxel. In 17-AAG- and paclitaxel-treated cells, compared with paclitaxel alone-treated cells, the protein levels of hsp90, hsp70, and hsc70 increased. In conclusion, our results suggest that 17-AAG induces non-apoptotic cell death requiring de novo protein synthesis in ATC cells. Moreover, these results demonstrate that 17-AAG antagonizes paclitaxel with concomitant alterations in hsp90 client proteins in ATC cells. PMID:25096912

  7. 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

  8. Preparation and characterization of poly(lactic acid)–poly(ethylene glycol)–poly(lactic acid) (PLA–PEG–PLA) microspheres for controlled release of paclitaxel

    Microsoft Academic Search

    Gang Ruan; Si-Shen Feng

    2003-01-01

    Microspheres of a new kind of copolymer, poly(lactic acid)–poly(ethylene glycol)–poly(lactic acid) (PLA–PEG–PLA), are proposed in the present work for clinical administration of an antineoplastic drug paclitaxel with hypothesis that incorporation of a hydrophilic PEG segment within the hydrophobic PLA might facilitate the paclitaxel release. Paclitaxel-loaded PLA–PEG–PLA microspheres of various compositions were prepared by the solvent extraction\\/evaporation method. Characterization of the

  9. 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 ...

  10. Reversal of P-glycoprotein-mediated paclitaxel resistance by new synthetic isoprenoids in human bladder cancer cell line.

    PubMed

    Enokida, Hideki; Gotanda, Takenari; Oku, Shoichi; Imazono, Yoshiharu; Kubo, Hiroyuki; Hanada, Toshikatsu; Suzuki, Shigenori; Inomata, Kouhei; Kishiye, Takao; Tahara, Yoshiyuki; Nishiyama, Kenryu; Nakagawa, Masayuki

    2002-09-01

    We isolated a paclitaxel-resistant cell line (KK47/TX30) from a human bladder cancer cell line (KK47/WT) in order to investigate the mechanism of and reversal agents for paclitaxel resistance. KK47/TX30 cells exhibited 700-fold resistance to paclitaxel and cross-resistance to vinca alkaloids and topoisomerase II inhibitors. Tubulin polymerization assay showed no significant difference in the ratio of polymerized alpha- and beta-tubulin between KK47/WT and KK47/TX30 cells. Western blot analysis demonstrated overexpression of P-glycoprotein (P-gp) and lung resistance-related protein (LRP) in KK47/TX30 cells. Drug accumulation and efflux studies showed that the decreased paclitaxel accumulation in KK47/TX30 cells was due to enhanced paclitaxel efflux. Cell survival assay revealed that verapamil and cepharanthine, conventional P-gp modulators, could completely overcome paclitaxel resistance. To investigate whether new synthetic isoprenoids could overcome paclitaxel resistance, we synthesized 31 isoprenoids based on the structure of N-solanesyl-N,N'-bis(3,4-dimethoxybenzyl)ethylenediamine (SDB), which could reverse multidrug resistance (MDR), as shown previously. Among those examined, trans-N,N'-bis(3,4-dimethoxybenzyl)-N-solanesyl-1,2-diaminocyclohexane (N-5228) could completely reverse paclitaxel resistance in KK47/TX30 cells. N-5228 inhibited photoaffinity labeling of P-gp by [(3)H]azidopine, suggesting that N-5228 could bind to P-gp directly and could be a substrate of P-gp. Next, we investigated structural features of these 31 isoprenoids in order to determine the structural requirements for the reversal of P-gp-mediated paclitaxel resistance, suggesting that the following structural features are important for overcoming paclitaxel resistance: (1) a basic structure of 8 to 10 isoprene units, (2) a cyclohexane ring or benzene ring within the framework, (3) two cationic sites in close proximity to each other, and (4) a benzyl group with 3,4-dimethoxy functionalities, which have moderate electron-donating ability. These findings may provide valuable information for the development of P-gp-mediated MDR-reversing agents. PMID:12359058

  11. Clinical pharmacokinetic and in vitro combination studies of nolatrexed dihydrochloride (AG337, ThymitaqTM) and paclitaxel

    PubMed Central

    Hughes, A N; Griffin, M J; Newell, D R; Calvert, A H; Johnston, A; Kerr, B; Lee, C; Liang, B; Boddy, A V

    2000-01-01

    A clinical study of nolatrexed dihydrochloride (AG337, ThymitaqTM) in combination with paclitaxel was performed. The aims were to optimize the schedule of administration and determine any pharmacokinetic (PK) interactions between the two drugs. In vitro combination studies were performed to assist with schedule optimization. Three patients were entered on each of three different schedules of administration of the two drugs: (1) paclitaxel 0–3 h, nolatrexed 24–144 h; (2) nolatrexed 0–120 h, paclitaxel 48–51 h; (3) nolatrexed 0–120 h, paclitaxel 126–129 h. Paclitaxel was administered at a dose of 80 mg m?2over 3 h and nolatrexed at a dose of 500 mg m?2day?1as a 120-h continuous intravenous infusion. Plasma concentrations of both drugs were determined by high performance liquid chromatography. In vitro growth inhibition studies using corresponding schedules were performed using two head and neck cancer cell lines. In both HNX14C and HNX22B cell lines, synergistic growth inhibition was observed on schedule 2, whereas schedules 1 and 3 demonstrated antagonistic effects. In the clinical study, there was no effect of schedule on the pharmacokinetics of nolatrexed. However, patients on schedules 1 and 3 had a higher clearance of paclitaxel (322–520 ml min?1m?2) than those on schedule 2 (165–238 ml min?1m?2). Peak plasma concentrations (1.66–1.93 vs 0.86–1.32 ?M) and areas under the curve (392–565 vs 180–291 ?M min?1) of paclitaxel were correspondingly higher on schedule 2. The pharmacokinetic interaction was confirmed by studies with human liver microsomes, nolatrexed being an inhibitor of the major routes of metabolism of paclitaxel. Toxicity was not schedule-dependent. Nolatrexed and paclitaxel may be safely given together when administered sequentially at the doses used in this study. Studies in vitro suggest some synergy, however, due to a pharmacokinetic interaction, paclitaxel doses should be reduced when administered during nolatrexed infusion. © 2000 Cancer Research Campaign PMID:10789718

  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. Detection of apoptosis caused by anticancer drug paclitaxel in MCF-7 cells by confocal Raman microscopy

    NASA Astrophysics Data System (ADS)

    Salehi, H.; Middendorp, E.; Végh, A.-G.; Ramakrishnan, S.-K.; Gergely, C.; Cuisinier, F. J. G.

    2013-02-01

    Confocal Raman Microscopy, a non-invasive, label free imaging technique is used to study apoptosis in living MCF-7 cells. The images are based on Raman spectra of cells components. K-mean clustering was used to determine mitochondria position in cells and cytochrome c distribution inside the cells was based on correlation analysis. Cell apoptosis is defined as cytochrome c diffusion in cytoplasm. Co-localization of cytochrome c is found within mitochondria after three hours of incubation with 10 ?M paclitaxel. Our results demonstrate that the presence of paclitaxel at this concentration in the culture media for 3 hours does not induce apoptosis of MCF7 cells via a caspase independent pathway.

  14. Development and evaluation of paclitaxel loaded PLGA:poloxamer blend nanoparticles for cancer chemotherapy.

    PubMed

    Gupta, Prem N; Jain, Sharad; Nehate, Chetan; Alam, Noor; Khare, Vaibhav; Dubey, Ravindra Dhar; Saneja, Ankit; Kour, Smit; Singh, Shashank K

    2014-08-01

    This investigation described the development of novel PLGA:poloxamer blend nanoparticles for intravenous administration of paclitaxel in order to limit the cremophor-associated adverse effects. The developed formulation was well-characterized using various techniques including scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy and differential scanning calorimetry. The nanoparticles had an average particle size around 180nm and zeta potential of -22.7mV. The in vitro release study of nanoparticles exhibited biphasic release pattern. The non-hemolytic potential of the nanoparticles indicated the suitability of the developed formulation for intravenous administration. The PLGA:poloxamer blend nanoparticles showed significantly improved cytotoxicity in cell lines (MCF-7 and Colo-205), as compared to free drug. Further, the developed formulation was stable under the accelerated storage conditions. In conclusion, the results indicated that the developed polymeric formulation is a novel and potential alternative for the paclitaxel delivery. PMID:24942992

  15. B7-H3 silencing increases paclitaxel sensitivity by abrogating Jak2/Stat3 phosphorylation

    PubMed Central

    Liu, Hao; Tekle, Christina; Chen, Yih-Wen; Kristian, Alexandr; Zhao, Yuhua; Zhou, Ming; Liu, Zixing; Ding, Yan; Wang, Bin; Mælandsmo, Gunhild Mari; Nesland, Jahn Marthin; Fodstad, Oystein; Tan, Ming

    2012-01-01

    In many types of cancer, the expression of the immunoregulatory protein B7-H3 has been associated with poor prognosis. Previously, we observed a link between B7-H3 and tumor cell migration and invasion, and in present work we have investigated the role of B7-H3 in chemoresistance in breast cancer. We observed that silencing of B7-H3, via stable shRNA or transient siRNA transfection, increased the sensitivity of multiple human breast cancer cell lines to paclitaxel as a result of enhanced drug-induced apoptosis. Overexpression of B7-H3 made the cancer cells more resistant to the drug. Next, we investigated the mechanisms behind B7-H3 mediated paclitaxel resistance, and found that the level of Stat3 Tyr705 phosphorylation was decreased in B7-H3 knockdown cells, along with the expression of its direct downstream targets Mcl-1 and Survivin. The phosphorylation of Jak2, an upstream molecule of Stat3, was also significantly decreased. In contrast, reexpression of B7-H3 in B7-H3 knockdown and low B7-H3- expressing cells increased the phosphorylation of Jak2 and Stat3. In vivo animal experiments showed that B7-H3 knock down tumors displayed a slower growth rate than the control xenografts. Importantly, paclitaxel treatment showed a strong anti-tumor activity in the mice with B7-H3 knockdown tumors, but only a marginal effect in the control group. Taken together, our data demonstrate that in breast cancer cells B7-H3 induces paclitaxel resistance, at least partially by interfering with Jak2/Stat3 pathway. These results provide novel insight into the function of B7-H3 and encourage the design and testing of approaches targeting this protein and its partners. PMID:21518725

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

    SciTech Connect

    Kelsey, Chris R. [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States)], E-mail: kelse003@mc.duke.edu; Chino, Junzo P.; Willett, Christopher G.; Clough, Robert W. [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Hurwitz, Herbert I.; Morse, Michael A.; Bendell, Johanna C. [Department of Internal Medicine, Division of Medical Oncology and Transplantation, Duke University Medical Center, Durham, NC (United States); D'Amico, Thomas A. [Department of General Surgery, Duke University Medical Center, Durham, NC (United States); Czito, Brian G. [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States)

    2007-11-01

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

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

    PubMed

    Musia?-Kulik, Monika; Kasperczyk, Janusz; Jelonek, Katarzyna; Dobrzy?ski, Piotr; Gebarowska, Katarzyna; Janeczek, Henryk; Libera, Marcin

    2010-01-01

    Biodegradable polymers have become common materials used in pharmacy and medicine due to their properties such as mechanical strength, biocompatibility and non-toxic degradation products. Different compositions of copolymers and also their chain microstructure may have an effect on matrices degradation and thus on the drug release profile. In our study, we aimed at the influence of paclitaxel content on hydrolytic degradation process of terpolymeric matrices. Hydrolytic degradation of three kinds of matrices (with 5 or 10% of paclitaxel and drug free matrices) prepared from three types of terpolymers was performed in vitro at 37 degrees C in phosphate buffer solution (PBS, pH 7,4). The 1H and 13C NMR spectra of terpolymers were recorded. Thermal properties were monitored by differential scanning calorimetry (DSC). Molecular weight dispersity (D) and molecular weight were determined using gel permeation chromatography (GPC). The surface morphology was studied by means of the scanning electron microscopy (SEM). The most significant degradation was observed in case of poly(L-lactide-co-glycolide-co-epsilon-caprolactone) 44:32:24. Weight loss and water uptake were similar in the event of the same type of matrices obtained from the two poly(L-lactide-co-glycolide-co-TMC). Decelerated paclitaxel release in case of matrices with 51:26:23 molar ratio was noticed and it can be connected with higher content of carbonate units. Knowledge of paclitaxel influence on hydrolytic degradation process may contribute to receive valuable information about its release mechanisms from biodegradable terpolymers. PMID:21229883

  18. Assessment of Paclitaxel Induced Sensory Polyneuropathy with “Catwalk” Automated Gait Analysis in Mice

    PubMed Central

    Endres, Matthias

    2013-01-01

    Neuropathic pain as a symptom of sensory nerve damage is a frequent side effect of chemotherapy. The most common behavioral observation in animal models of chemotherapy induced polyneuropathy is the development of mechanical allodynia, which is quantified with von Frey filaments. The data from one study, however, cannot be easily compared with other studies owing to influences of environmental factors, inter-rater variability and differences in test paradigms. To overcome these limitations, automated quantitative gait analysis was proposed as an alternative, but its usefulness for assessing animals suffering from polyneuropathy has remained unclear. In the present study, we used a novel mouse model of paclitaxel induced polyneuropathy to compare results from electrophysiology and the von Frey method to gait alterations measured with the Catwalk test. To mimic recently improved clinical treatment strategies of gynecological malignancies, we established a mouse model of dose-dense paclitaxel therapy on the common C57Bl/6 background. In this model paclitaxel treated animals developed mechanical allodynia as well as reduced caudal sensory nerve action potential amplitudes indicative of a sensory polyneuropathy. Gait analysis with the Catwalk method detected distinct alterations of gait parameters in animals suffering from sensory neuropathy, revealing a minimized contact of the hind paws with the floor. Treatment of mechanical allodynia with gabapentin improved altered dynamic gait parameters. This study establishes a novel mouse model for investigating the side effects of dose-dense paclitaxel therapy and underlines the usefulness of automated gait analysis as an additional easy-to-use objective test for evaluating painful sensory polyneuropathy. PMID:24143194

  19. 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

  20. Influence of drug formulation on OATP1B-mediated transport of paclitaxel.

    PubMed

    Nieuweboer, Annemieke J M; Hu, Shuiying; Gui, Chunshan; Hagenbuch, Bruno; Ghobadi Moghaddam-Helmantel, Inge M; Gibson, Alice A; de Bruijn, Peter; Mathijssen, Ron H J; Sparreboom, Alex

    2014-06-01

    Taxane antineoplastic agents are extensively taken up into hepatocytes by OATP1B-type transporters before metabolism and excretion. Because the biodistributional properties imposed upon these agents by different solubilizers drive clinically important pharmacodynamic endpoints, we tested the hypothesis that the in vitro and in vivo interaction of taxanes with OATP1B transporters is affected by the choice of drug delivery system. Transport of paclitaxel, docetaxel, and cabazitaxel was studied in vitro using various cell lines transfected with OATP1B1, OATP1B3, or the rodent equivalent OATP1B2. Pharmacokinetic studies were done in wild-type and OATP1B2-knockout mice in the presence or absence of polysorbate 80 (PS80) or Kolliphor EL (formerly Cremophor EL; CrEL). Paclitaxel and docetaxel, but not cabazitaxel, were transported substrates of OATP1B1, OATP1B3, and OATP1B2, and these in vitro transport processes were strongly reduced in the presence of clinically relevant concentrations of PS80 and CrEL. When paclitaxel was administered without any solubilizers, deficiency of OATP1B2 in mice was associated with a significantly decreased systemic clearance because of a liver distribution defect (P=0.000484). However, this genotype dependence of paclitaxel clearance was masked in the presence of PS80 or CrEL because of significant inhibition of OATP1B2-mediated hepatocellular uptake of the drug (P<0.05). Our findings confirm the importance of OATP1B-type transporters in the hepatic elimination of taxanes and indicate that this process can be inhibited by PS80 and CrEL. These results suggest that the likelihood of drug-drug interactions mediated by these transporters is strongly dependent on the selected taxane solubilizer. PMID:24755470

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

    PubMed Central

    De Placido, Sabino; De Angelis, Carmine

    2015-01-01

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

  2. The bisphosphonate, zoledronic acid, induces apoptosis of breast cancer cells: evidence for synergy with paclitaxel

    PubMed Central

    Jagdev, S P; Coleman, R E; Shipman, C M; Rostami-H, A; Croucher, P I

    2001-01-01

    Bisphosphonates are well established in the management of breast-cancer-induced bone disease. Recent studies have suggested that these compounds are effective in preventing the development of bone metastases. However, it is unclear whether this reflects an indirect effect via an inhibition of bone resorption or a direct anti-tumour effect. The breast cancer cell lines, MCF-7 and MDA-MB-231 cells were treated with increasing concentrations of the bisphosphonate, zoledronic acid, for varying time periods, in the presence or absence of paclitaxel. The effects of zoledronic acid were determined by assessing cell number and rate of apoptosis by evaluating changes in nuclear morphology and using a fluorescence nick translation assay. Zoledronic acid caused a dose- and time-dependent decrease in cell number (P< 0.001) and a concomitant increase in tumour cell apoptosis (P< 0.005). Short-term exposure to zoledronic acid was sufficient to cause a significant reduction in cell number and increase in apoptosis (P< 0.05). These effects could be prevented by incubation with geranyl geraniol, suggesting that zoledronic acid-induced apoptosis is mediated by inhibiting the mevalonate pathway. Treatment with zoledronic acid and clinically achievable concentrations of paclitaxel resulted in a 4–5-fold increase in tumour cell apoptosis (P< 0.02). Isobologram analysis revealed synergistic effects on tumour cell number and apoptosis when zoledronic acid and paclitaxel were combined. Short-term treatment with zoledronic acid, which closely resembles the clinical setting, has a clear anti-tumour effect on breast cancer cells. Importantly, the commonly used anti-neoplastic agent, paclitaxel, potentiates the anti-tumour effects of zoledronic acid. These data suggest that, in addition to inhibiting bone resorption, zoledronic acid has a direct anti-tumour activity on breast cancer cells in vitro. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11308265

  3. Electrospun Micro and Nanofibers for Sustained Delivery of Paclitaxel to Treat C6 Glioma in Vitro

    Microsoft Academic Search

    Jingwei Xie; Chi-Hwa Wang

    2006-01-01

    Purpose  The present study aims to develop electrospun PLGA-based micro- and nanofibers as implants for the sustained delivery of anticancer drug to treat C6 glioma in vitro.Methods  PLGA and an anticancer drug—paclitaxel-loaded PLGA micro- and nanofibers were fabricated by electrospinning and the key processing parameters were investigated. The physical and chemical properties of the micro- and nanofibers were characterized by various state-of-the-art

  4. 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

  5. A retrospective study of paclitaxel combining nedaplatin chemotherapy for esophageal cancer.

    PubMed

    Du, Jianping; Hu, Changlu; Zhang, Yuliu; Hu, Bing; Wang, Fen; Zhang, Yumei

    2015-01-01

    The aim of this study was to evaluate the efficacy and tolerability of the combination of paclitaxel and nedaplatin in patients with advanced esophageal cancer. Patients (n = 310) with recurrent or metastatic esophageal squamous cell carcinoma, who had a maximum of one previous chemotherapy regimen, were enrolled in this study. All patients had bidimensionally measurable disease. Patients received 175 mg/m of paclitaxel over a 3 h infusion, followed by nedaplatin 80 mg/m in a 1 h infusion on day 1 every 3 weeks for up to 6 treatment cycles. The overall response rate was 47.7%, with complete and partial response rates of 6.1 and 41.7%, respectively. The median time to progression for all patients was 6.8 months (95% confidence interval, 6.2-7.4 months) and the 3-year disease-free survival probability was 3 (15.8%). The major toxicity observed was cumulative neutropenia, with 29% patients developing grade 4 toxicity. There was no treatment-related death. The most common nonhematologic toxicity encountered with this regimen was pain and cumulative peripheral neuropathy, with 26% patients experiencing grade 2 or 3 toxicity. The combination of paclitaxel and nedaplatin shows significant antitumor activity and a favorable toxicity profile in patients with metastatic carcinoma of esophageal cancer. PMID:25222530

  6. The influence of P-glycoprotein on morphine transport in Caco-2 cells. Comparison with paclitaxel.

    PubMed

    Crowe, Andrew

    2002-04-01

    In vitro monolayer studies using Caco-2 cells were employed here to explore P-glycoprotein mediated transport of morphine. Bi-directional transport studies of 10-75 microM morphine showed efflux to be twofold higher than influx (4 x 10(-6) compared to 2 x 10(-6) cm/s) and cellular accumulation in the efflux direction was eightfold higher. The cyclosporin analogue (PSC-833) equilibrated morphine transport in both directions. Depletion of intracellular glutathione had a greater effect on increasing cellular morphine accumulation than P-glycoprotein inhibitors, suggesting a role for glutathione in morphine transport. P-glycoprotein had a substantially greater effect on paclitaxel accumulation, efflux and bi-directional transport than for morphine. Paclitaxel transport was below detection (<0.1 x 10(-6) cm/s) in the influx direction, yet efflux was very high (18.4 x 10(-6) cm/s) and P-glycoprotein inhibition increased accumulation >100-fold. These results reinforce the substantial role P-glycoprotein has in paclitaxel transport. Conversely, P-glycoprotein regulated morphine transport is weak. Nevertheless, morphine transport rates could be doubled when administered with P-glycoprotein substrates. Therefore, increased analgesia through P-glycoprotein inhibition should be possible. PMID:11959083

  7. 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

  8. 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

  9. 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

  10. TRPA1 and TRPV4 mediate paclitaxel-induced peripheral neuropathy in mice via a glutathione-sensitive mechanism.

    PubMed

    Materazzi, Serena; Fusi, Camilla; Benemei, Silvia; Pedretti, Pamela; Patacchini, Riccardo; Nilius, Bernd; Prenen, Jean; Creminon, Christophe; Geppetti, Pierangelo; Nassini, Romina

    2012-04-01

    Paclitaxel produces a sensory neuropathy, characterized by mechanical and cold hypersensitivity, which are abated by antioxidants. The transient receptor potential vanilloid 4 (TRPV4) channel has been reported to contribute to paclitaxel-evoked allodynia in rodents. We recently showed that TRP ankyrin 1 (TRPA1) channel mediates oxaliplatin-evoked cold and mechanical allodynia, and the drug targets TRPA1 via generation of oxidative stress. Here, we have explored whether TRPA1 activation contributes to paclitaxel-induced mechanical and cold hypersensitivity and whether this activation is mediated by oxidative stress generation. Paclitaxel-evoked mechanical allodynia was reduced partially by the TRPA1 antagonist, HC-030031, and the TRPV4 antagonist, HC-067047, and was completely abated by the combination of the two antagonists. The reduced paclitaxel-evoked mechanical allodynia, observed in TRPA1-deficient mice, was completely abolished when mice were treated with HC-067047. Cold allodynia was abated completely by HC-030031 and in TRPA1-deficient mice. Exposure to paclitaxel of slices of mouse esophagus released the sensory neuropeptide, calcitonin gene-related peptide (CGRP). This effect was abolished by capsaicin desensitization and in calcium-free medium (indicating neurosecretion from sensory nerve terminals), partially reduced by either HC-030031 or HC-067047, and completely abated in the presence of glutathione (GSH). Finally, the reduced CGRP release, observed in esophageal slices of TRPA1-deficient mice, was further inhibited by GSH. Paclitaxel via oxygen radical formation targets TRPA1 and TRPV4, and both channels are key for the delayed development of mechanical allodynia. Cold allodynia is, however, entirely dependent on TRPA1. PMID:22258694

  11. Synergy of Nab-paclitaxel and Bevacizumab in Eradicating Large Orthotopic Breast Tumors and Preexisting Metastases12

    PubMed Central

    Volk, Lisa D; Flister, Michael J; Chihade, Deena; Desai, Neil; Trieu, Vuong; Ran, Sophia

    2011-01-01

    Introduction Patients with metastatic disease are considered incurable. We previously showed that nabpaclitaxel (nanoparticle albumin-embedded paclitaxel) combined with anti-vascular endothelial growth factor A (VEGF-A) antibody, bevacizumab, eradicates orthotopic small-sized breast tumors and metastasis. Here, we assessed this therapy in two models of advanced (450–600 mm3) breast tumors and delineated VEGF-A-dependent mechanisms of tumor resistance. Methods Mice with luciferase-tagged advanced MDA-MB-231 and MDA-MB-435 tumors were treated with saline, nab-paclitaxel (10 or 30 mg/kg), bevacizumab (4 mg/kg), or combined drugs. Lymphatic and lung metastases were measured by luciferase assay. Proinflammatory and survival pathways were measured by ELISA, Western blot and immunohistochemistry. Results Nab-paclitaxel transiently suppressed primary tumors by 70% to 90% but had no effect on metastasis. Coadministration of bevacizumab increased the response rate to 99%, including 71% of complete responses in MDA-MB-231-bearing mice treated concurrently with 30 mg/kg of nab-paclitaxel. This combinatory regimen significantly reduced or eliminated preexisting lymphatic and distant metastases in MDA-MB-231 and MDA-MB-435 models. The mechanism involves paclitaxel-induced NF-?B pathway that upregulates VEGF-A and other tumor prosurvival proteins. Conclusions Bevacizumab prevents tumor recurrence and metastasis promoted by nab-paclitaxel activation of NF-?B pathway. Combination therapy with high-dosed nab-paclitaxel demonstrates the potential to eradicate advanced primary tumors and preexisting metastases. These findings strongly support translating this regimen into clinics. PMID:21472137

  12. Antiangiogenic Therapy with Human Apolipoprotein(a) Kringle V and Paclitaxel in a Human Ovarian Cancer Mouse Model12

    PubMed Central

    Yu, Hyun-Kyung; Lee, Ho-Jeong; Yun, Seok-Joong; Lee, Sun-Joo; Langley, Robert R.; Yoon, Yeup; Yi, Lee S.H.; Bae, Duk-Soo; Kim, Jang-Seong; Kim, Sun Jin

    2014-01-01

    INTRODUCTION: The present study compared the effect of combination therapy using human apolipoprotein(a) kringle V (rhLK8) to conventional chemotherapy with paclitaxel for human ovarian carcinoma producing high or low levels of vascular endothelial growth factor (VEGF). MATERIALS AND METHODS: Human ovarian carcinoma cells producing high (SKOV3ip1) or low (HeyA8) levels of VEGF were implanted into the peritoneal cavity of female nude mice. Seven days later, mice were randomized into four groups: control (vehicle), paclitaxel [5 mg/kg, weekly intraperitoneal (i.p.) injection], rhLK8 (50 mg/kg, daily i.p. injection), or the combination of paclitaxel and rhLK8. Mice were treated for 4 weeks and examined by necropsy. RESULTS: In mice implanted with SKOV3ip1 cells, rhLK8 treatment had no significant effect on tumor incidence or the volume of ascites but induced a significant decrease in tumor weight compared with control mice. Paclitaxel significantly reduced tumor weight and ascites volume, and combination treatment with paclitaxel and rhLK8 had an additive therapeutic effect. Similarly, in HeyA8 mice, the effect of combination treatment on tumor weight and tumor incidence was statistically significantly greater than that of paclitaxel or rhLK8 alone. Immunohistochemical analysis showed a significant decrease in microvessel density and a marked increase of apoptosis in tumor and tumor-associated endothelial cells in response to combination treatment with paclitaxel and rhLK8. CONCLUSION: Collectively, these results suggest that antiangiogenic therapy with rhLK8 in combination with taxane-based conventional chemotherapy could be effective for the treatment of ovarian carcinomas, regardless of VEGF status. PMID:25180060

  13. miR-17-5p Downregulation Contributes to Paclitaxel Resistance of Lung Cancer Cells through Altering Beclin1 Expression

    PubMed Central

    Chatterjee, Abhisek; Chattopadhyay, Dhrubajyoti; Chakrabarti, Gopal

    2014-01-01

    Non- small- cell lung cancer (NSCLC) is one of the most leading causes of cancer-related deaths worldwide. Paclitaxel based combination therapies have long been used as a standard treatment in aggressive NSCLCs. But paclitaxel resistance has emerged as a major clinical problem in combating non-small-cell lung cancer and autophagy is one of the important mechanisms involved in this phenomenon. In this study, we used microRNA (miRNA) arrays to screen differentially expressed miRNAs between paclitaxel sensitive lung cancer cells A549 and its paclitaxel-resistant cell variant (A549-T24). We identified miR-17-5p was one of most significantly downregulated miRNAs in paclitaxel-resistant lung cancer cells compared to paclitaxel sensitive parental cells. We found that overexpression of miR-17-5p sensitized paclitaxel resistant lung cancer cells to paclitaxel induced apoptotic cell death. Moreover, in this report we demonstrated that miR-17-5p directly binds to the 3?-UTR of beclin 1 gene, one of the most important autophagy modulator. Overexpression of miR-17-5p into paclitaxel resistant lung cancer cells reduced beclin1 expression and a concordant decease in cellular autophagy. We also observed similar results in another paclitaxel resistant lung adenosquamous carcinoma cells (H596-TxR). Our results indicated that paclitaxel resistance of lung cancer is associated with downregulation of miR-17-5p expression which might cause upregulation of BECN1 expression. PMID:24755562

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

    PubMed Central

    2014-01-01

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

  15. 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

  16. The Suppression of Human Prostate Tumor Growth in Mice by the Intratumoral Injection of a SlowRelease Polymeric Paste Formulation of Paclitaxel1

    Microsoft Academic Search

    John K. Jackson; Martin E. Gleave; Virginia Yago; Eliana Beraldi; William L. Hunter; Helen M. Burt

    2000-01-01

    Most patients that present in the clinic with prostate cancer have either localized or recurrent postradiotherapy therapy tumors that may be amenable to injectable treatments using slow-release cytotoxic drugs. The objective of this preclinical study was to design an injectable polymeric paste formulation of paclitaxel for intratumoral injection into nonmeta- static human prostate tumors grown s.c. in mice. Paclitaxel was

  17. Phase I\\/II Clinical Study of Pulsed Paclitaxel Radiosensitization for Thoracic Malignancy: A Therapeutic Approach on the Basis of Preclinical Research of Human Cancer Cell Lines1

    Microsoft Academic Search

    Yuhchyau Chen; Kishan Pandya; Peter C. Keng; David Johnstone; Jigang Li; Yi-Jang Lee; Therese Smudzin; Paul Okunieff

    2003-01-01

    Purpose: A Phase I\\/II clinical study using pulsed low- dose paclitaxel and radiation for thoracic malignancy was conducted. The study was based on preclinical research of the effects of paclitaxel on apoptosis and the cell cycle in human cancer cell lines. Experimental Design: Three human epithelial cancer cell lines were investigated for preclinical study. Cells were analyzed for apoptosis and

  18. Characterization of cell death events induced by anti-neoplastic drugs cisplatin, paclitaxel and 5-fluorouracil on human hepatoma cell lines: Possible mechanisms of cell resistance

    Microsoft Academic Search

    O. Brenes; F. Arce; O. Gätjens-Boniche; C. Díaz

    2007-01-01

    Two different hepatoma cell lines were incubated for 48h with chemotherapeutic drugs cisplatin, paclitaxel and 5-FU to determine their ability to induce cytotoxicity and DNA fragmentation as well as to modify the expression of some cell death-related genes that could be involved in the resistance to therapy. We observed that cisplatin and paclitaxel induced cytotoxicity, but significant differences between both

  19. Tumor stroma and differentiated cancer cells can be originated directly from polyploid giant cancer cells induced by paclitaxel.

    PubMed

    Zhang, Shiwu; Mercado-Uribe, Imelda; Liu, Jinsong

    2014-02-01

    Paclitaxel is widely used to treat cancer patients through the blocking of mitosis and result in formation of polyploidy giant cancer cells (PGCCs), which are generally believed to be nondividing cells or in mitotic catastrophe. Here, we showed that PGCCs following the treatment of paclitaxel of MCF-7 breast cancer cell line have capability to generate regular-sized progeny cells through budding. The PGCCs not only grew into well-differentiated cancer cells that formed cancer organotypic structures in vitro but also trans-differentiated into multiple tumor stromal cells including myoepithelial, endothelial and erythroid cells. PGCCs formed glandular and vessel-like cancer organotypic structures that expressed normal stem cell markers. These progeny cells generated from PGCCs showed decreased ability of proliferation, invasion and tumor growth and became more resistant to paclitaxel than parental MCF-7 cells. These results demonstrated that paclitaxel-induced PGCCs have properties of cancer stem cells that can generate both epithelial cancer cells and multilineage of stromal cells. PGCCs are not only the morphogenic determinant to tumor histogenesis and but also contribute to paclitaxel resistance. PMID:23754740

  20. Direct comparison of two albumin-based paclitaxel-loaded nanoparticle formulations: is the crosslinked version more advantageous?

    PubMed

    Li, Chunlei; Li, Yanhui; Gao, Yuqing; Wei, Na; Zhao, Xi; Wang, Caixia; Li, Yongfeng; Xiu, Xian; Cui, Jingxia

    2014-07-01

    Nanoparticles using albumin as particle matrix have entered the mainstream of drug delivery. It was reported that non-crosslinked albumin nanoparticles were unstable in circulation and could deliver drugs into tumor through gp60/SPARC pathway; in contrast, the delivery of drugs with stable nanoparticles was dependent on enhanced permeability and retention effect. Thus, it is questionable which kind of nanoparticles was more advantageous. Two versions of albumin-bound paclitaxel nanoparticles were prepared. In vitro, the non-crosslinked particles could rapidly disintegrate and the crosslinked was stable. The pharmacokinetics of both formulations was different especially at early time and the non-crosslinked particles were cleared rapidly. After non-crosslinked particle treatment paclitaxel had a tendency to accumulate into heart and kidney and following therapy with the crosslinked particles, paclitaxel was liable to be delivered into lung, spleen and liver. The delivery efficiency of paclitaxel into tumor following the non-crosslinked particle treatment was greater than that of the crosslinked (p<0.05), thus resulting in a considerably improved antineoplastic activity. Moreover, the non-crosslinked formulation was only slightly more toxic. It was concluded that the non-crosslinked formulation was more advantageous for the delivery of paclitaxel and our conclusion might be generalized to other lipophilic drugs delivered with albumin nanoparticles. PMID:24709221

  1. The telomere/telomerase binding factor PinX1 regulates paclitaxel sensitivity depending on spindle assembly checkpoint in human cervical squamous cell carcinomas.

    PubMed

    Tian, Xiao-Peng; Qian, Dong; He, Li-Ru; Huang, He; Mai, Shi-Juan; Li, Chang-Peng; Huang, Xiao-Xia; Cai, Mu-Yan; Liao, Yi-Ji; Kung, Hsiang-fu; Zeng, Yi-Xin; Xie, Dan

    2014-10-10

    Paclitaxel is a main ingredient in the combination chemotherapy treatment of advanced human cervical squamous cell carcinomas. We investigated the roles and underlying molecular mechanisms of PinX1 in cervical squamous cell carcinomas (CSCC) cells response to paclitaxel and its clinical significances. The expression dynamics of PinX1 was first examined by immunohistochemistry in 122 advanced CSCC patients treated with cisplatin/paclitaxel chemotherapy. The expression of PinX1 was significantly associated with the effects of cisplatin/paclitaxel chemotherapy in advanced CSCCs (P<0.05). High expression of PinX1 correlated with CSCC's response to cisplatin/paclitaxel chemotherapy, and was an independent predictor of shortened survival (P<0.05). A series of in vivo and in vitro assays were performed to elucidate the function of PinX1 on CSCC cells chemosensitivity to paclitaxel and underlying mechanisms. In CSCC cells, the levels of PinX1 were only associated with the cytotoxicity and sensitivity of paclitaxel, in which knockdown of PinX1 dramatically enhanced paclitaxel cytotoxicity, whereas the reestablishment of PinX1 levels substantially reduced the paclitaxel-induced killing effect. In addition, we identified that the ability of PinX1 to stabilize the tension between sister kinetochores and maintain the spindle assembly checkpoint was the main reason CSCC cells undergo apoptosis when treated with paclitaxel, and further studies demonstrated that shortened distance between sisters kinetochores by nocodazole confers upon PinX1-replenished cells a sensitivity to the death inducing paclitaxel effects. Furthermore, our study of CSCC cells xenografts in nude mice confirmed the role of PinX1 in paclitaxel sensitivity in vivo. Our data reveal that PinX1 could be used as a novel predictor for CSCC patient response to paclitaxel, and the role of PinX1-mediated paclitaxel sensitivity might represent a new direction for the development of a new generation of microtubule drugs. PMID:25045845

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

    PubMed Central

    Koizumi, Wasaburo; Morita, Satoshi; Sakata, Yuh

    2015-01-01

    Paclitaxel is an agent widely used in second-line chemotherapy for advanced gastric cancer. The aim of this trial is to evaluate the efficacy and safety of 3-weekly or weekly doses of nanoparticle albumin-bound-paclitaxel compared with weekly doses of Cremophor-based paclitaxel in patients with unresectable or recurrent gastric cancer refractory to first-line chemotherapy comprising fluoropyrimidines. A total of 730 patients will be enrolled from 72 institutions. The primary endpoint is the overall survival, and the secondary endpoints are progression-free survival, time to treatment failure, overall response rate, disease control rate, quality of life (by using the EQ-5D system) and safety. PMID:25516635

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

    PubMed

    Koizumi, Wasaburo; Morita, Satoshi; Sakata, Yuh

    2015-03-01

    Paclitaxel is an agent widely used in second-line chemotherapy for advanced gastric cancer. The aim of this trial is to evaluate the efficacy and safety of 3-weekly or weekly doses of nanoparticle albumin-bound-paclitaxel compared with weekly doses of Cremophor-based paclitaxel in patients with unresectable or recurrent gastric cancer refractory to first-line chemotherapy comprising fluoropyrimidines. A total of 730 patients will be enrolled from 72 institutions. The primary endpoint is the overall survival, and the secondary endpoints are progression-free survival, time to treatment failure, overall response rate, disease control rate, quality of life (by using the EQ-5D system) and safety. PMID:25516635

  4. 3,3'-Diindolylmethane potentiates paclitaxel-induced antitumor effects on gastric cancer cells through the Akt/FOXM1 signaling cascade.

    PubMed

    Jin, Hua; Park, Man Hee; Kim, Soo Mi

    2015-04-01

    Gastric cancer is the fourth most common cancer and is one of the leading causes of cancer-related mortality worldwide. Forkhead box M1 (FOXM1) is overexpressed in gastric cancer, suggesting that it is important in gastric cancer oncogenesis. However, no studies have investigated the role of 3,3'-diindolylmethane (DIM), a component of cruciferous vegetables, in the regulation of FOXM1 and its signaling pathway in gastric cancer. Here, we report for the first time that DIM effectively downregulated Akt/FOXM1 in gastric cancer cells. Combination treatment with DIM and paclitaxel significantly and dose-dependently inhibited the proliferation of SNU638 cells when compared to treatment with DIM or paclitaxel alone. Colony formation of SNU638 cells was significantly attenuated by treatment with DIM and paclitaxel, and DIM potentiated the inhibition of colony formation in SNU638 cells by paclitaxel when compared to treatment with a single agent. Treatment with DIM plus paclitaxel substantially increased apoptosis as indicated by increased levels of cleaved polyADP-ribose polymerase (PARP) and cleaved caspase-9 protein. DIM dose-dependently sensitized gastric cancer cells through downregulation of FOXM1 and potentiated the effects of paclitaxel. FOXM1 effector genes such as CDK4, p53 and cyclin D1 were downregulated in gastric cancer cells by combination treatment with DIM and paclitaxel. In addition, DIM significantly and dose-dependently inhibited phosphorylation of Akt and potentiated paclitaxel-induced inhibition of Akt function in gastric cancer cells. Therefore, our results indicate that DIM effectively potentiates the efficacy of chemotherapeutic agents such as paclitaxel by downregulation of the Akt/FOXM1 signaling cascade in gastric cancer cells. Our findings suggest that DIM enhances the therapeutic efficacy of paclitaxel in gastric cancer and is a potential clinical anticancer agent for the prevention and/or treatment of gastric cancer. PMID:25633416

  5. Neoadjuvant and postoperative chemotherapy with paclitaxel plus cisplatin for the treatment of FIGO stage IB cervical cancer in pregnancy

    PubMed Central

    Kong, Tae-Wook; Lee, Eun Ju; Lee, Yonghee; Chang, Suk-Joon; Son, Joo Hyuk

    2014-01-01

    Cervical cancer is one of the most common malignancy diagnosed during pregnancy. The experience of the use of neoadjuvant chemotherapy (NACT) with paclitaxel plus cisplatin during pregnancy is limited. Three pregnant women with International Federation of Gynecology and Obstetrics (FIGO) stage IB cervical cancer received NACT with paclitaxel plus cisplatin until fetal lung maturity, and then underwent cesarean delivery and radical hysterectomy. Two of our patients had intermediate pathologic risk factors, and received adjuvant chemotherapy with the same regimen used in NACT. All patients did not have any evidence of disease recurrence for follow-up of 3, 4, and 8 years, respectively. NACT with paclitaxel plus cisplatin followed by radical hysterectomy and adjuvant chemotherapy could be considered as one of feasible alternatives to primary radical surgery or concurrent chemoradiation therapy with the termination of pregnancy in pregnant women with FIGO stage IB cervical cancer who have two or more intermediate pathologic-risk factors. PMID:25469346

  6. Successful Chemotherapy with Nab-Paclitaxel in a Heavily Treated Non-Small Cell Lung Cancer Patient: A Case Report

    PubMed Central

    Ishihara, Mikiko; Igawa, Satoshi; Maki, Sachiyo; Harada, Shinya; Kusuhara, Seiichiro; Niwa, Hideyuki; Otani, Sakiko; Sasaki, Jiichiro; Jiang, Shi-Xu; Masuda, Noriyuki

    2014-01-01

    Non-small cell lung cancer (NSCLC) accounts for the majority of all lung cancers. A 69-year-old female with postoperatively recurrent NSCLC was treated weekly with nanoparticle-albumin-bound paclitaxel (nab-paclitaxel) monotherapy every 4 weeks as a tenth line chemotherapy, and stable disease was achieved by seven cycles of this regimen. The patient developed grade 4 neutropenia and grade 3 leukopenia, but none of the other toxicities, including febrile neutropenia and peripheral neuropathy, were severe, and thus she was able to tolerate this salvage chemotherapy. To our knowledge this is the first report of the efficacy of nab-paclitaxel monotherapy in a heavily treated NSCLC patient. PMID:25076891

  7. Successful chemotherapy with nab-Paclitaxel in a heavily treated non-small cell lung cancer patient: a case report.

    PubMed

    Ishihara, Mikiko; Igawa, Satoshi; Maki, Sachiyo; Harada, Shinya; Kusuhara, Seiichiro; Niwa, Hideyuki; Otani, Sakiko; Sasaki, Jiichiro; Jiang, Shi-Xu; Masuda, Noriyuki

    2014-05-01

    Non-small cell lung cancer (NSCLC) accounts for the majority of all lung cancers. A 69-year-old female with postoperatively recurrent NSCLC was treated weekly with nanoparticle-albumin-bound paclitaxel (nab-paclitaxel) monotherapy every 4 weeks as a tenth line chemotherapy, and stable disease was achieved by seven cycles of this regimen. The patient developed grade 4 neutropenia and grade 3 leukopenia, but none of the other toxicities, including febrile neutropenia and peripheral neuropathy, were severe, and thus she was able to tolerate this salvage chemotherapy. To our knowledge this is the first report of the efficacy of nab-paclitaxel monotherapy in a heavily treated NSCLC patient. PMID:25076891

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

    PubMed Central

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

    2014-01-01

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

  9. 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.

  10. Adjuvant Paclitaxel and Trastuzumab for Node-Negative, HER2-Positive Breast Cancer

    PubMed Central

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

    2015-01-01

    BACKGROUND No single standard treatment exists for patients with small, node-negative, human epidermal growth factor receptor type 2 (HER2)–positive breast cancers, because most of these patients have been ineligible for the pivotal trials of adjuvant trastuzumab. METHODS We performed an uncontrolled, single-group, multicenter, investigator-initiated study of adjuvant paclitaxel and trastuzumab in 406 patients with tumors measuring up to 3 cm in greatest dimension. Patients received weekly treatment with paclitaxel and trastuzumab for 12 weeks, followed by 9 months of trastuzumab monotherapy. The primary end point was survival free from invasive disease. RESULTS The median follow-up period was 4.0 years. The 3-year rate of survival free from invasive disease was 98.7% (95% confidence interval [CI], 97.6 to 99.8). Among the 12 relapses seen, 2 were due to distant metastatic breast cancer. Excluding contra-lateral HER2-negative breast cancers and nonbreast cancers, 7 disease-specific events were noted. A total of 13 patients (3.2%; 95% CI, 1.7 to 5.4) reported at least one episode of grade 3 neuropathy, and 2 had symptomatic congestive heart failure (0.5%; 95% CI, 0.1 to 1.8), both of whom had normalization of the left ventricular ejection fraction after discontinuation of trastuzumab. A total of 13 patients had significant asymptomatic declines in ejection fraction (3.2%; 95% CI, 1.7 to 5.4), as defined by the study, but 11 of these patients were able to resume trastuzumab therapy after a brief interruption. CONCLUSIONS Among women with predominantly stage I HER2-positive breast cancer, treatment with adjuvant paclitaxel plus trastuzumab was associated with a risk of early recurrence of about 2%; 6% of patients withdrew from the study because of protocol-specified adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT00542451.) PMID:25564897

  11. Vinorelbine and paclitaxel for locoregional advanced or metastatic non-small-cell lung cancer.

    PubMed

    Pérez, Juan E; Machiavelli, Mario R; Romero, Alberto O; Romero Acuña, Luis A; Domínguez, María E; Fasce, Hebe; Flores Acosta, Luis; Marrone, Nora; Romero Acuña, Juan M; Langhi, Mario J; Amato, Sonia; Bologna, Fabrina; Ortiz, Eduardo H; Leone, Bernardo A; Lacava, Juan A; Vallejo, Carlos T

    2002-08-01

    A phase II trial was performed to evaluate the efficacy and toxicity of the novel combination of vinorelbine and paclitaxel as first-line chemotherapy in patients with stages IIIB and IV non-small-cell lung cancer. From January 1997 to September 1999, 34 patients (9 stage IIIB and 25 stage IV) received a regimen consisting of the following: vinorelbine 30 mg/m2 20 minutes intravenous (i.v.) infusion, days 1 and 8; and paclitaxel 135 mg/m2 3-hour i.v. (starting 1 hour after vinorelbine) on day 1. Cycles were repeated every 28 days until progression of disease or unacceptable toxicity development. The median age was 57 years (range 41-70 years); median performance status was 1. Histology was as follows: squamous cell in 24 (71%), large cell in 1 (3%), and adenocarcinoma in 9 (26%). All patients are evaluable for toxicity, whereas 30 are evaluable for response (4 patients refused treatment). Objective response was recorded in 4 of 30 patients (13%, 95% CI 1-25%). No complete response was observed. Partial response was recorded in 4 patients (13%), no change in 10 patients (34%), and progressive disease in 16 patients (53%). The median time to treatment failure was 4 months and median survival was 9 months. The limiting toxicity was myelosuppression: leukopenia in 23 patients (68%), whereas neutropenia was observed in 25 patients (78%). Peripheral neurotoxicity developed in 14 patients (41%) (without G3 or G4 episodes), and constipation (G1-G2: 10 patients), myalgia (G1-G2: 11 patients), diarrhea (G1-G2: 7 patients), and stomatitis were observed in 7 patients. Vinorelbine-paclitaxel combination showed only modest activity against locoregionally advanced or metastatic NSCLC. PMID:12151970

  12. Inherent and Acquired Resistance to Paclitaxel in Hepatocellular Carcinoma: Molecular Events Involved

    PubMed Central

    Meena, Avtar Singh; Sharma, Aanchal; Kumari, Ratna; Mohammad, Naoshad; Singh, Shivendra Vikram; Bhat, Manoj Kumar

    2013-01-01

    Hepatocellular carcinoma (HCC) is a primary malignancy of the liver and is a major cause of cancer related deaths worldwide. Only 10 to 20% of HCC can be surgically excised. Therefore, chemotherapeutic intervention and treatment is essential for achieving favorable prognosis. However, therapeutic outcome of chemotherapy is generally poor owing to inherent resistance of cancer cells to the treatment or due to development of acquired resistance. To differentiate and delineate the molecular events, we developed drug resistant Hep3B cells (DRC) by treating cells with the increasing concentration of paclitaxel. We also developed a unique single cell clone of Hep3B cells (SCC) by selecting single cell colonies and screening them for resistant phenotype. Interestingly, both DRC and SCC were resistant to paclitaxel in comparison to parental Hep3B cells. We analyzed the contributory factors that may be involved in the development of resistance. As expected, level of P-glycoprotein (P-gp) was elevated in DRC. In addition, Caveolin-1 (Cav-1), Fatty acid synthase (FASN) and Cytochrome P450 (CYP450) protein levels were elevated in DRC whereas in SCC, FASN and CYP450 levels were elevated. Downregulation of these molecules by respective siRNAs and/or by specific pharmacological inhibitors resensitized cells to paclitaxel. Interestingly, these drug resistant cells were also less sensitive to vinblastine, doxorubicin and methotrexate with the exception of cisplatin. Our results suggested that differential levels of P-gp, Cav-1 and FASN play a major role in acquired resistant phenotype whereas FASN level was associated with the presentation of inherent resistant phenotype in HCC. PMID:23613870

  13. Multifunctional liposomes loaded with paclitaxel and artemether for treatment of invasive brain glioma.

    PubMed

    Li, Xiu-Ying; Zhao, Yao; Sun, Meng-Ge; Shi, Ji-Feng; Ju, Rui-Jun; Zhang, Cheng-Xiang; Li, Xue-Tao; Zhao, Wei-Yu; Mu, Li-Min; Zeng, Fan; Lou, Jin-Ning; Lu, Wan-Liang

    2014-07-01

    Invasive brain glioma is the most lethal type of cancer and is highly infiltrating. This leads to an extremely poor prognosis and makes complete surgical removal of the tumor virtually impossible. Non-penetration of therapeutic drugs across the blood-brain barrier (BBB), brain cancer stem cells (CSCs), and brain cancer vasculogenic mimicry (VM) results in relapse after surgical and radio therapy. We developed a functional targeting chemotherapy for transporting drugs across the BBB, destroying VM channels, and eliminating CSCs and cancer cells in the brain. The studies were undertaken on brain glioma cells in vitro and in brain glioma-bearing rats. Using paclitaxel as the anticancer drug and artemether as the regulator of apoptosis and inhibitor of VM channels, a kind of functional targeting paclitaxel plus artemether liposomes was developed by modifying two new functional materials: a mannose-vitamin E derivative conjugate (MAN-TPGS1000) and a dequalinium-lipid derivative conjugate (DQA-PEG2000-DSPE). The transport mechanism across the BBB was associated with receptor-mediated endocytosis by MAN-TPGS1000 conjugate via glucose transporters and adsorptive-mediated endocytosis by DQA-PEG2000-DSPE conjugate via electric charge-based interactions. The efficacy was related to the destruction of VM channels by regulating VM indicators, as well as the induction of apoptosis in brain cancer cells and CSCs by activating apoptotic enzymes and pro-apoptotic proteins and inhibiting anti-apoptotic proteins. These data suggest that the chemotherapy using functional targeting paclitaxel plus artemether liposomes could provide a new strategy for treating invasive brain glioma. PMID:24726749

  14. Novel paclitaxel formulations for oral application: a phase I pharmacokinetic study in patients with solid tumours

    Microsoft Academic Search

    S. A. Veltkamp; H. Rosing; A. D. R. Huitema; M. R. Fetell; A. Nol; J. H. Beijnen; J. H. M. Schellens

    2007-01-01

    Purpose  To explore the pharmacokinetics (PKs) of paclitaxel and two major metabolites after three single oral administrations of a\\u000a novel drinking solution and two capsule formulations in combination with cyclosporin A (CsA) in patients with advanced cancer.\\u000a Moreover, the tolerability and safety of the formulations was studied. In addition, single nucleotide polymorphisms in the\\u000a multidrug resistance (MDR1) gene were determined.\\u000a \\u000a \\u000a \\u000a Patients

  15. Interleukin6 protects against paclitaxel, cisplatin and vincristine-induced neuropathies without impairing chemotherapeutic activity

    Microsoft Academic Search

    Noelle Callizot; Emile Andriambeloson; Jonathan Glass; Michel Revel; Pamela Ferro; Rocco Cirillo; Pierre-Alain Vitte; Michel Dreano

    2008-01-01

    Purpose  This study was conducted to investigate the potential neuroprotective effect of IL-6 on chemotherapy induced neuropathy (CIN).\\u000a IL-6 was compared to four-methylcatechol (4-MC)-a known inducer of NGF secretion previously shown to exhibit neuroprotective\\u000a effects in CIN models.\\u000a \\u000a \\u000a \\u000a Methods  \\u000a Three CIN models were used; two in rats (cisplatin and vincristine) and one in mice (paclitaxel). IL-6 was delivered in four different

  16. Prevention of paclitaxel-evoked painful peripheral neuropathy by acetyl-L-carnitine: Effects on axonal mitochondria, sensory nerve fiber terminal arbors, and cutaneous Langerhans cells

    PubMed Central

    Jin, Hai Wei; Flatters, Sarah J.L.; Xiao, Wen Hua; Mulhern, Howard L.; Bennett, Gary J.

    2008-01-01

    Prophylactic treatment with acetyl-L-carnitine (ALCAR) prevents the neuropathic pain syndrome that is evoked by the chemotherapeutic agent, paclitaxel. The paclitaxel-evoked pain syndrome is associated with degeneration of the intraepidermal terminal arbors of primary afferent neurons, with the activation of cutaneous Langerhans cells, and with an increased incidence of swollen and vacuolated axonal mitochondria in A-fibers and C-fibers. Previous work suggests that ALCAR is neuroprotective in other nerve injury models and that it improves mitochondrial dysfunction. Thus, we examined whether the prophylactic efficacy of ALCAR was associated with the prevention of intraepidermal terminal arbor degeneration, the inhibition of Langerhans cell activation, or the inhibition of swelling and vacuolation of axonal mitochondria. In animals with a confirmed ALCAR effect, we found no evidence of a neuroprotective effect on the paclitaxel-evoked degeneration of sensory terminal arbors or an inhibition of the paclitaxel-evoked activation of Langerhans cells. However, ALCAR treatment completely prevented the paclitaxel-evoked increase in the incidence of swollen and vacuolated C-fiber mitochondria, while having no effect on the paclitaxel-evoked changes in A-fiber mitochondria. Our results suggest that the efficacy of prophylactic ALCAR treatment against the paclitaxel-evoked pain may be related to a protective effect on C-fiber mitochondria. PMID:18078936

  17. Atractylenolide-I Sensitizes Human Ovarian Cancer Cells to Paclitaxel by Blocking Activation of TLR4/MyD88-dependent Pathway

    PubMed Central

    Huang, Jian-Ming; Zhang, Guo-Nan; Shi, Yu; Zha, Xiao; Zhu, Yi; Wang, Miao-Miao; Lin, Qing; Wang, Wen; Lu, Hai-Yan; Ma, Shi-Qi; Cheng, Jia; Deng, Bi-Fang

    2014-01-01

    Paclitaxel, a known TLR4 ligand, leads to activation of TLR4/MyD88-dependent pathway that mediates chemoresistance and tumor progression in epithelial ovarian carcinoma (EOC). Atractylenolide-I (AO-I), a novel TLR4-antagonizing agent, inhibits TLR4 signaling by interfering with the binding of LPS or paclitaxel to membrane TLR4 of human leukocytes. In this study, AO-I was found to attenuate paclitaxel-induced protein expression of IL-6, VEGF and survivin, and to enhance early apoptosis and growth inhibition in MyD88+ EOC cells; AO-I was shown to fit into the hydrophobic pocket of human MD-2 and to partially overlap with the binding site of paclitaxel by docking simulations, suggesting that AO-I may block the MD-2-mediated TLR4/MyD88-dependent paclitaxel signaling in MyD88+ EOC cells. Therefore, AO-I could significantly sensitize the response of MyD88+ EOC cells to paclitaxel by blocking MD-2-mediated TLR4/MyD88 signaling, and that AO-I-paclitaxel combination could be a promising strategy for the treatment of EOC with a functional TLR4/MyD88/NF-?B pathway. PMID:24452475

  18. Lin28 Mediates Paclitaxel Resistance by Modulating p21, Rb and Let-7a miRNA in Breast Cancer Cells

    PubMed Central

    Lv, Kezhen; Liu, Liqun; Wang, Linbo; Yu, Jiren; Liu, Xiaojiao; Cheng, Yongxia; Dong, Minjun; Teng, Rongyue; Wu, Linjiao; Fu, Peifen; Deng, Wuguo; Hu, Wenxian; Teng, Lisong

    2012-01-01

    Resistance to chemotherapy is a major obstacle for the effective treatment of cancers. Lin28 has been shown to contribute to tumor relapse after chemotherapy; however, the relationship between Lin28 and chemoresistance remained unknown. In this study, we investigated the association of Lin28 with paclitaxel resistance and identified the underlying mechanisms of action of Lin28 in human breast cancer cell lines and tumor tissues. We found that the expression level of Lin28 was closely associated with the resistance to paclitaxel treatment. The T47D cancer cell line, which highly expresses Lin28, is more resistant to paclitaxel than the MCF7, Bcap-37 or SK-BR-3 cancer cell lines, which had low-level expression of Lin28. Knocking down of Lin28 in Lin28 high expression T47D cells increased the sensitivity to paclitaxel treatment, while stable expression of Lin28 in breast cancer cells effectively attenuated the sensitivity to paclitaxel treatment, resulting in a significant increase of IC50 values of paclitaxel. Transfection with Lin28 also significantly inhibited paclitaxel-induced apoptosis. We also found that Lin28 expression was dramatically increased in tumor tissues after neoadjuvant chemotherapy or in local relapse or metastatic breast cancer tissues. Moreover, further studies showed that p21, Rb and Let-7 miRNA were the molecular targets of Lin28. Overexpression of Lin28 in breast cancer cells considerably induced p21 and Rb expression and inhibited Let-7 miRNA levels. Our results indicate that Lin28 expression might be one mechanism underlying paclitaxel resistance in breast cancer, and Lin28 could be a potential target for overcoming paclitaxel resistance in breast cancer. PMID:22808086

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

    SciTech Connect

    Burstein, Harold J. [Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA (United States)]. E-mail: hburstein@partners.org; Bellon, Jennifer R. [Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA (United States); Galper, Sharon [Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA (United States); Lu, H.-M. [Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA (United States); Kuter, Irene [Department of Hematology/Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (United States); Taghian, Alphonse G. [Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (United States); Wong, Julia [Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA (United States); Gelman, Rebecca [Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA (United States); Department of Biostatistics, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA (United States); Bunnell, Craig A. [Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA (United States); Parker, Leroy M.; Garber, Judy E. [Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA (United States); Winer, Eric P.; Harris, Jay R. [Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA (United States); Powell, Simon N. [Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (United States)

    2006-02-01

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

  20. Paclitaxel-loaded iron platinum stealth immunomicelles are potent MRI imaging agents that prevent prostate cancer growth in a PSMA-dependent manner

    PubMed Central

    Taylor, Robert M; Sillerud, Laurel O

    2012-01-01

    Background and methods: Problems with the clinical management of prostate cancer include the lack of both specific detection and efficient therapeutic intervention. We report the encapsulation of superparamagnetic iron platinum nanoparticles (SIPPs) and paclitaxel in a mixture of polyethyleneglycolated, fluorescent, and biotin-functionalized phospholipids to create multifunctional SIPP-PTX micelles (SPMs) that were conjugated to an antibody against prostate-specific membrane antigen (PSMA) for the specific targeting, magnetic resonance imaging (MRI), and treatment of human prostate cancer xenografts in mice. Results: SPMs were 45.4 ± 24.9 nm in diameter and composed of 160.7 ± 22.9 ?g/mL iron, 247.0 ± 33.4 ?g/mL platinum, and 702.6 ± 206.0 ?g/mL paclitaxel. Drug release measurements showed that, at 37°C, half of the paclitaxel was released in 30.2 hours in serum and two times faster in saline. Binding assays suggested that PSMA-targeted SPMs specifically bound to C4-2 human prostate cancer cells in vitro and released paclitaxel into the cells. In vitro, paclitaxel was 2.2 and 1.6 times more cytotoxic than SPMs to C4-2 cells at 24 and 48 hours of incubation, respectively. After 72 hours of incubation, paclitaxel and SPMs were equally cytotoxic. SPMs had MRI transverse relaxivities of 389 ± 15.5 Hz/mM iron, and SIPP micelles with and without drug caused MRI contrast enhancement in vivo. Conclusion: Only PSMA-targeted SPMs and paclitaxel significantly prevented growth of C4-2 prostate cancer xenografts in nude mice. Furthermore, mice injected with PSMA-targeted SPMs showed significantly more paclitaxel and platinum in tumors, compared with nontargeted SPM-injected and paclitaxel-injected mice. PMID:22915856

  1. The effect of seal oil on paclitaxel induced cytotoxicity and apoptosis in breast carcinoma MCF-7 and MDA-MB-231 cell lines.

    PubMed

    Wang, Zheyu; Butt, Krista; Wang, Lili; Liu, Hu

    2007-01-01

    Some studies have suggested that omega-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 omega-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 2 breast cancer cell lines, MCF-7 and MDA-MB-231, respectively. Cytotoxicity evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that the concentration of paclitaxel that is required for 50% inhibition of cell growth in the presence of seal oil was significantly lower than that of paclitaxel alone. Apoptosis assessment based on morphological changes and DNA fragmentation results indicated that more cells treated with paclitaxel in combination with seal oil underwent apoptosis than with paclitaxel alone. Western blot analysis showed that the expression of B cell lymphoma-2 (Bcl-2) protein, an apoptosis inhibitory protein, in both cell lines was decreased more significant by paclitaxel in combination with seal oil than by paclitaxel alone. In addition, seal oil alone was found to induce apoptosis in both cell lines tested, which appeared to be due to the increased intracellular lipid peroxides produced. It is therefore concluded that paclitaxel in combination with seal oil demonstrated enhanced cytotoxicity and apoptosis in MCF-7 and MDA-MB-231 cells compared to paclitaxel alone, and the use of seal oil may be beneficial in the treatment of breast cancer. PMID:17640170

  2. Paclitaxel Prodrugs with Sustained Release and High Solubility in Poly(ethylene glycol)- b -poly(?-caprolactone) Micelle Nanocarriers: Pharmacokinetic Disposition, Tolerability, and Cytotoxicity

    Microsoft Academic Search

    M. Laird Forrest; Jaime A. Yáñez; Connie M. Remsberg; Yusuke Ohgami; Glen S. Kwon; Neal M. Davies

    2008-01-01

    Purpose  Develop a Cremophor® and solvent free formulation of paclitaxel using amphiphilic block co-polymer micelles of poly(ethylene\\u000a glycol)-b-poly(?-caprolactone) (PEG-b-PCL) and characterize their release, solubility, cytotoxicity, tolerability, and disposition.\\u000a \\u000a \\u000a \\u000a Methods  Hydrophobic prodrugs of paclitaxel were synthesized via DCC\\/DMAP or anhydride chemistry to overcome the poor loading (<1%\\u000a w\\/w) of paclitaxel in micelles of PEG-b-PCL. Micelles were prepared by a co-solvent extraction technique. A

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

    PubMed Central

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

    2014-01-01

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

  4. Analgesic effect of magnetic stimulation on paclitaxel-induced peripheral neuropathic pain in mice.

    PubMed

    Ami, Nozomi; Okamoto, Kazuo; Oshima, Hidehiko

    2012-06-21

    Peripheral neuropathies are common side effects of chemotherapeutic drugs, including taxanes, platinum-based drugs, vinca alkaloids, and thalidomide. The most common symptoms are numbness, tingling and/or burning pain in a stocking-glove distribution. Severe peripheral neuropathies result in dose reductions, a change in chemotherapy regimen, or early cessation of chemotherapy. There are no proven interventions to prevent or treat chemotherapy-induced peripheral neuropathy. We designed and built a unique magnetic stimulator to clarify the effects of magnetic stimulation in the mouse paclitaxel-induced peripheral neuropathic pain model. Magnetic stimulation significantly reversed paclitaxel-induced mechanical hyperalgesia. The analgesic efficacy of magnetic stimulation was inhibited by naloxone, a ? opioid receptor antagonist. These findings indicate that the analgesic effect of magnetic stimulation is likely to be mediated by the endogenous opioid system. Furthermore, a combination of magnetic stimulation and pregabalin, a Ca(2+) channel blocker, induced a potent combinational analgesic effect, suggesting that analgesic drug dose reduction might be possible. These findings indicate that there is a potential therapeutic utility for magnetic stimulation in pain relief. PMID:22608074

  5. Amphiphilic N-(2,3-dihydroxypropyl)-chitosan-cholic acid micelles for paclitaxel delivery.

    PubMed

    Pan, Zheng; Gao, Yunling; Heng, Linseng; Liu, Yi; Yao, Gan; Wang, Yun; Liu, Yuping

    2013-04-15

    Self-assembled amphiphilic N-(2,3-dihydroxypropyl)-chitosan-cholic acid (DHP-CS-CHO) micelle was prepared as a carrier for paclitaxel. DHP-CS-CHO was synthesized by grafted small molecules cholic acid and glycidol onto primary amine group of chitosan, respectively. The DHP-CS-CHO formed uniform micelles (size=212.4±3.1 nm) with a low critical micelle concentration (0.024 mg/ml) in PBS. Hydrophobic anticancer drug, paclitaxel (PTX), was easily encapsulated into chitosan derivative micelles by a dialysis method with loading efficiency up to 80%. The PTX loaded micelles released the drug in a sustained manner more than a week in PBS containing 0.1% (w/v) Tween 80 at 37°C. In vitro antitumor experiment demonstrated that PTX loaded chitosan derivative micelles could inhibit MCF-7 cell growth and induce its apoptosis. These results suggested that DHP-CS-CHO may be a promising carrier for the anticancer drug PTX. PMID:23544554

  6. 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

  7. S-1 plus intravenous and intraperitoneal Paclitaxel for gastric cancer with peritoneal metastasis.

    PubMed

    Kitayama, Joji; Ishigami, Hironori; Yamaguchi, Hironori; Yamashita, Hiroharu; Emoto, Shigenobu; Kaisaki, Shoichi

    2012-05-01

    Peritoneal metastasis is the most frequent and life-threatening type of metastasis in patients with advanced gastric cancer. Despite recent advances in chemotherapeutic agents, any treatment, if administered only via the intravenous (IV) route, cannot satisfactorily control peritoneal metastasis in gastric cancer. Although intraperitoneal (IP) chemotherapy has been proposed as a treatment option, the clinical efficacy of IP chemotherapy for peritoneal lesions has not been examined in gastrointestinal cancer. One hundred patients with gastric cancer received combination chemotherapy of S-1 plus IV (50 mg/m(2)) and IP (20 mg/m(2)) paclitaxel (PTX) via a subcutaneously implanted peritoneal access port. S-1 was administered at 80 mg/m(2) per day for 14 consecutive days, followed by 7 days' rest. Radical gastrectomy was performed in a salvage setting when macroscopic curative resection was made feasible by the downstaging achieved by the combined chemotherapy. The median survival time (MST) of the patient sample was 23.6 months, with a 1-year survival of 80%. Combination chemotherapy of S-1 plus IV and IP PTX is well tolerated and very effective in patients with gastric cancer and peritoneal metastasis. Systemic chemotherapy combined with repeated IP administration of paclitaxel is a promising strategy for peritoneal carcinomatosis in gastrointestinal cancer. PMID:22876333

  8. Methylation of CHFR sensitizes esophageal squamous cell cancer to docetaxel and paclitaxel

    PubMed Central

    Gao, Dan; Linghu, Enqiang; Brock, Malcolm V.; Yin, Dongtao; Zhan, Qimin; Herman, James G.; Guo, Mingzhou

    2015-01-01

    Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide. Both genetic and epigenetic changes are involved in esophageal carcinogenesis. CHFR methylation has been found frequently in different cancers and is regarded as a marker of taxane sensitivity. CHFR methylation was found in 0% (0/16) of normal mucosa, 2.9% (1/34) of grade I dysplasia, 0% (0/8) of grade II dysplasia, 12.5% (1/8) of grade III dysplasia and 45% (49/109) of invasive cancer. When treated with docetaxel or paclitaxel, cell viability was lower in CHFR methylated esophageal cancer cells than in unmethylated cells (p<0.05). No difference was found with either cisplatin or VP16 treatment in either group (p>0.05). In CHFR methylated cells, treatment with docetaxel or paclitaxel resulted in almost all cells being suspended in G0/G1 phase of the cell cycle. After 5-AZ treatment, there was an increased fraction of CHFR-methylated cells in S and G2/M phases (p<0.05). In conclusion, CHFR is frequently methylated in ESCC and the expression of CHFR is regulated by promoter region methylation. CHFR methylation is a late stage event in ESCC. Methylation of CHFR sensitized ESCC cells to taxanes. 5-AZ may re-sensitize chemotherapy resistant in refractory tumors by inducing cell cycle phase re-distribution.

  9. Top-down and Bottom-up Approaches in Production of Aqueous Nanocolloids of Low Soluble Drug Paclitaxel

    PubMed Central

    Pattekari, P.; Zheng, Z.; Zhang, X.; Levchenko, T.; Torchilin, V.

    2015-01-01

    Nano-encapsulation of poorly soluble anticancer drug was developed with sonication assisted layer-by-layer polyelectrolyte coating (SLbL). We changed the strategy of LbL-encapsulation from making microcapsules with many layers in the walls for encasing highly soluble materials to using very thin polycation / polyanion coating on low soluble nanoparticles to provide their good colloidal stability. SLbL encapsulation of paclitaxel resulted in stable 100-200 nm diameter colloids with high electrical surface ?-potential (of -45 mV) and drug content in the nanoparticles of 90 wt %. In the top-down approach, nanocolloids were prepared by rupturing powder of paclitaxel using ultrasonication and simultaneous sequential adsorption of oppositely charged biocompatible polyelectrolytes. In the bottom-up approach paclitaxel was dissolved in organic solvent (ethanol or acetone), and drug nucleation was initiated by gradual worsening the solution with the addition of aqueous polyelectrolyte assisted by ultrasonication. Paclitaxel release rates from such nanocapsules were controlled by assembling multilayer shells with variable thicknesses and are in the range of 10-20 hours. PMID:21442095

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

    PubMed

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

    2014-12-01

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

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

    PubMed Central

    2013-01-01

    A system of novel nanoparticles of star-shaped cholic acid-core polylactide-d-?-tocopheryl polyethylene glycol 1000 succinate (CA-PLA-TPGS) block copolymer was developed for paclitaxel delivery for breast cancer treatment, which demonstrated superior in vitro and in vivo performance in comparison with paclitaxel-loaded poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles and linear PLA-TPGS nanoparticles. The paclitaxel- or couramin 6-loaded nanoparticles were fabricated by a modified nanoprecipitation method and then characterized in terms of size, surface charge, surface morphology, drug encapsulation efficiency, and in vitro drug release. The CA-PLA-TPGS nanoparticles were found to be spherical in shape with an average size of around 120 nm. The nanoparticles were found to be stable, showing no change in the particle size and surface charge during 90-day storage of the aqueous solution. The release profiles of the paclitaxel-loaded nanoparticles exhibited typically biphasic release patterns. The results also showed that the CA-PLA-TPGS nanoparticles have higher antitumor efficacy than the PLA-TPGS nanoparticles and PLGA nanoparticles in vitro and in vivo. In conclusion, such nanoparticles of star-shaped cholic acid-core PLA-TPGS block copolymer could be considered as a potentially promising and effective strategy for breast cancer treatment. PMID:24134303

  12. Molecular determinants of response to matuzumab in combination with paclitaxel for patients with advanced non-small cell lung cancer

    Microsoft Academic Search

    Marcus M. Schittenhelm; Christian Kollmannsberger; Karin Oechsle; Amy Harlow; Jason Morich; Friedemann Honecker; Raffael Kurek; Stephan Storkel; Lothar Kanz; Christopher L. Corless; Kwok-Kin Wong; Carsten Bokemeyer; Michael C. Heinrich

    2009-01-01

    Antibodies targeting epidermal growth factor receptor (EGFR) have proven to be effective in patients with non- small cell lung cancer (NSCLC) that express EGFR. We re- cently published a phase I study of weekly matuzumab plus paclitaxel. This therapy was well tolerated and showed clinical responses in the majority of patients. Although matu- zumab displays potent antitumor activity in some

  13. Determination of paclitaxel distribution in solid tumors by nano-particle assisted laser desorption ionization mass spectrometry imaging.

    PubMed

    Morosi, Lavinia; Spinelli, Pietro; Zucchetti, Massimo; Pretto, Francesca; Carrà, Andrea; D'Incalci, Maurizio; Giavazzi, Raffaella; Davoli, Enrico

    2013-01-01

    A sensitive, simple and reproducible protocol for nanoparticle-assisted laser desorption/ionization mass spectrometry imaging technique is described. The use of commercially available TiO2 nanoparticles abolishes heterogeneous crystallization, matrix background interferences and enhances signal detection, especially in the low mass range. Molecular image normalization was based on internal standard deposition on tissues, allowing direct comparison of drug penetration and distribution between different organs and tissues. The method was applied to analyze the distribution of the anticancer drug paclitaxel, inside normal and neoplastic mouse tissue sections. Spatial resolution was good, with a linear response between different in vivo treatments and molecular imaging intensity using therapeutic drug doses. This technique distinguishes the different intensity of paclitaxel distribution in control organs of mice, such as liver and kidney, in relation to the dose. Animals treated with 30 mg/kg of paclitaxel had half of the concentration of those treated with 60 mg/kg. We investigated the spatial distribution of paclitaxel in human melanoma mouse xenografts, following different dosage schedules and found a more homogeneous drug distribution in tumors of mice given repeated doses (5×8 mg/kg) plus a 60 mg/kg dose than in those assigned only a single 60 mg/kg dose. The protocol can be readily applied to investigate anticancer drug distribution in neoplastic lesions and to develop strategies to optimize and enhance drug penetration through different tumor tissues. PMID:23991120

  14. The Synergistic Combination of the Farnesyl Transferase Inhibitor Lonafarnib and Paclitaxel Enhances Tubulin Acetylation and Requires a Functional Tubulin Deacetylase

    Microsoft Academic Search

    Adam I. Marcus; Jun Zhou; Aurora O'Brate; Ernest Hamel; Jason Wong; Michael Nivens; Adel El-Naggar; Tso-Pang Yao; Fadlo R. Khuri; Paraskevi Giannakakou

    2005-01-01

    Farnesyl transferase (FT) inhibitors (FTI) are anticancer agents developed to target oncogenic Ras proteins by inhibiting Ras farnesylation. FTIs potently synergize with paclitaxel and other microtubule-stabilizing drugs; however, the mechanistic basis underlying this synergistic interaction remains elusive. Here we show that the FTI lonafarnib affects the microtubule cytoskeleton resulting in microtubule bundle formation, increased microtubule stabilization and acetyla- tion, and

  15. Prostate Cancer Prostatic Dis . Author manuscript Pilot trial of adjuvant paclitaxel plus androgen deprivation for patients with

    E-print Network

    Boyer, Edmond

    Prostate Cancer Prostatic Dis . Author manuscript Page /1 7 Pilot trial of adjuvant paclitaxel plus androgen deprivation for patients with high-risk prostate cancer after radical prostatectomy: results unclear with no clear consensus for men with high-risk prostate cancer after radical prostatectomy. We

  16. Bisphosphonates inhibit stellate cell activity and enhance antitumor effects of nanoparticle albumin-bound paclitaxel in pancreatic ductal adenocarcinoma.

    PubMed

    Gonzalez-Villasana, Vianey; Rodriguez-Aguayo, Cristian; Arumugam, Thiruvengadam; Cruz-Monserrate, Zobeida; Fuentes-Mattei, Enrique; Deng, Defeng; Hwang, Rosa F; Wang, Huamin; Ivan, Cristina; Garza, Raul Joshua; Cohen, Evan; Gao, Hui; Armaiz-Pena, Guillermo N; Del C Monroig-Bosque, Paloma; Philip, Bincy; Rashed, Mohammed H; Aslan, Burcu; Erdogan, Mumin Alper; Gutierrez-Puente, Yolanda; Ozpolat, Bulent; Reuben, James M; Sood, Anil K; Logsdon, Craig; Lopez-Berestein, Gabriel

    2014-11-01

    Pancreatic stellate cells (PSC) have been recognized as the principal cells responsible for the production of fibrosis in pancreatic ductal adenocarcinoma (PDAC). Recently, PSCs have been noted to share characteristics with cells of monocyte-macrophage lineage (MML cells). Thus, we tested whether PSCs could be targeted with the nitrogen-containing bisphosphonates (NBP; pamidronate or zoledronic acid), which are potent MML cell inhibitors. In addition, we tested NBPs treatment combination with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) to enhance antitumor activity. In vitro, we observed that PSCs possess ?-naphthyl butyrate esterase (ANBE) enzyme activity, a specific marker of MML cells. Moreover, NBPs inhibited PSCs proliferation, activation, release of macrophage chemoattractant protein-1 (MCP-1), and type I collagen expression. NBPs also induced PSCs apoptosis and cell-cycle arrest in the G1 phase. In vivo, NBPs inactivated PSCs; reduced fibrosis; inhibited tumor volume, tumor weight, peritoneal dissemination, angiogenesis, and cell proliferation; and increased apoptosis in an orthotopic murine model of PDAC. These in vivo antitumor effects were enhanced when NBPs were combined with nab-paclitaxel but not gemcitabine. Our study suggests that targeting PSCs and tumor cells with NBPs in combination with nab-paclitaxel may be a novel therapeutic approach to PDAC. PMID:25193509

  17. Determination of Paclitaxel Distribution in Solid Tumors by Nano-Particle Assisted Laser Desorption Ionization Mass Spectrometry Imaging

    PubMed Central

    Zucchetti, Massimo; Pretto, Francesca; Carrà, Andrea; D’Incalci, Maurizio; Giavazzi, Raffaella; Davoli, Enrico

    2013-01-01

    A sensitive, simple and reproducible protocol for nanoparticle-assisted laser desorption/ionization mass spectrometry imaging technique is described. The use of commercially available TiO2 nanoparticles abolishes heterogeneous crystallization, matrix background interferences and enhances signal detection, especially in the low mass range. Molecular image normalization was based on internal standard deposition on tissues, allowing direct comparison of drug penetration and distribution between different organs and tissues. The method was applied to analyze the distribution of the anticancer drug paclitaxel, inside normal and neoplastic mouse tissue sections. Spatial resolution was good, with a linear response between different in vivo treatments and molecular imaging intensity using therapeutic drug doses. This technique distinguishes the different intensity of paclitaxel distribution in control organs of mice, such as liver and kidney, in relation to the dose. Animals treated with 30 mg/kg of paclitaxel had half of the concentration of those treated with 60 mg/kg. We investigated the spatial distribution of paclitaxel in human melanoma mouse xenografts, following different dosage schedules and found a more homogeneous drug distribution in tumors of mice given repeated doses (5×8 mg/kg) plus a 60 mg/kg dose than in those assigned only a single 60 mg/kg dose. The protocol can be readily applied to investigate anticancer drug distribution in neoplastic lesions and to develop strategies to optimize and enhance drug penetration through different tumor tissues. PMID:23991120

  18. First total synthesis of (5Z,9Z)-(+/-)-2-methoxy-5,9-octadecadienoic acid, a marine derived methoxylated analog of taxoleic acid.

    PubMed

    Carballeira, Néstor M; O'Neill, Rosann; Silva, Diana

    2008-11-01

    The first total synthesis for the sponge derived (5Z,9Z)-(+/-)-2-methoxy-5,9-octadecadienoic acid, an analog of taxoleic acid, was accomplished in seven steps and in a 10% overall yield. It was again corroborated that the best strategy to prepare these cis,cis dimethylene interrupted double bonds is the double-alkyne bromide coupling reaction of 1,5-hexadiyne, which provides the advantage of achieving a 100% cis stereochemical purity for both double bonds after hydrogenation under Lindlar conditions. The alpha-methoxy functionality was best prepared via the Mukaiyama reaction of (4Z,8Z)-heptadecadienal with trimethylsilyl cyanide and triethylamine followed by acid hydrolysis. Selective methylation of the hydroxyl group of (5Z,9Z)-(+/-)-2-hydroxy-5,9-octadecadienoic acid was achieved with sodium hydride/methyl iodide when tetrahydrofuran was used as solvent. Complete spectral data is presented, for the first time, for this unusual marine alpha-methoxylated fatty acid. PMID:18761005

  19. Therapeutic targeting of erbB3 with MM-121/SAR256212 enhances antitumor activity of paclitaxel against erbB2-overexpressing breast cancer

    PubMed Central

    2013-01-01

    Introduction Elevated expression of erbB3 rendered erbB2-overexpressing breast cancer cells resistant to paclitaxel via PI-3 K/Akt-dependent upregulation of Survivin. It is unclear whether an erbB3-targeted therapy may abrogate erbB2-mediated paclitaxel resistance in breast cancer. Here, we study the antitumor activity of an anti-erbB3 antibody MM-121/SAR256212 in combination with paclitaxel against erbB2-overexpressing breast cancer. Methods Cell growth assays were used to determine cell viability. Cells undergoing apoptosis were quantified by a specific apoptotic ELISA. Western blot analyses were performed to assess the protein expression and activation. Lentiviral vector containing shRNA was used to specifically knockdown Survivin. Tumor xenografts were established by inoculation of BT474-HR20 cells into nude mice. The tumor-bearing mice were treated with paclitaxel and/or MM-121/SAR256212 to determine whether the antibody (Ab) enhances paclitaxel’s antitumor activity. Immunohistochemistry was carried out to study the combinatorial effects on tumor cell proliferation and induction of apoptosis in vivo. Results MM-121 significantly facilitated paclitaxel-mediated anti-proliferative/anti-survival effects on SKBR3 cells transfected with a control vector or erbB3 cDNA. It specifically downregulated Survivin associated with inactivation of erbB2, erbB3, and Akt. MM-121 enhances paclitaxel-induced poly(ADP-ribose) polymerase (PARP) cleavage, activation of caspase-8 and -3, and apoptosis in both paclitaxel-sensitive and -resistant cells. Specific knockdown of Survivin in the trastuzumab-resistant BT474-HR20 cells dramatically enhanced paclitaxel-induced apoptosis, suggesting that increased Survivin caused a cross-resistance to paclitaxel. Furthermore, the studies using a tumor xenograft model-established from BT474-HR20 cells revealed that either MM-121 (10 mg/kg) or low-dose (7.5 mg/kg) paclitaxel had no effect on tumor growth, their combinations significantly inhibited tumor growth in vivo. Immunohistochemical analysis showed that the combinations of MM-121 and paclitaxel significantly reduced the cells with positive staining for Ki-67 and Survivin, and increased the cells with cleaved caspase-3. Conclusions The combinations of MM-121 and paclitaxel not only inhibit tumor cell proliferation, but also promote erbB2-overexpressing breast cancer cells to undergo apoptosis via downregulation of Survivin in vitro and in vivo, suggesting that inactivation of erbB3 with MM-121 enhances paclitaxel-mediated antitumor activity against erbB2-overexpressing breast cancers. Our data supports further exploration of the combinatorial regimens consisting of MM-121 and paclitaxel in breast cancer patients with erbB2-overexpressing tumors, particularly those resistant to paclitaxel. PMID:24168763

  20. Paclitaxel-loaded polymeric microparticles: Quantitative relationships between in vitro drug release rate and in vivo pharmacodynamics

    PubMed Central

    Tsai, Max; Lu, Ze; Wientjes, M. Guillaume; Au, Jessie L.-S.

    2013-01-01

    Intraperitoneal therapy (IP) has demonstrated survival advantages in patients with peritoneal cancers, but has not become a widely practiced standard-of-care in part due to local toxicity and sub-optimal drug delivery. Paclitaxel-loaded, polymeric microparticles were developed to overcome these limitations. The present study evaluated the effects of microparticle properties on paclitaxel release (extent and rate) and in vivo pharmacodynamics. In vitro paclitaxel release from microparticles with varying physical characteristics (i.e., particle size, copolymer viscosity and composition) was evaluated. A method was developed to simulate the dosing rate and cumulative dose released in the peritoneal cavity based on the in vitro release data. The relationship between the simulated drug delivery and treatment outcomes of seven microparticle compositions was studied in mice bearing IP human pancreatic tumors, and compared to that of the intravenous Cremophor micellar paclitaxel solution used off-label in previous IP studies. Paclitaxel release from polymeric microparticles in vitro was multi-phasic; release was greater and more rapid from microparticles with lower polymer viscosities and smaller diameters (e.g., viscosity of 0.17 vs. 0.67 dl/g and diameter of 5–6 vs. 50–60 ?m). The simulated drug release in the peritoneal cavity linearly correlated with treatment efficacy in mice (r2>0.8, p<0.001). The smaller microparticles, which distribute more evenly in the peritoneal cavity compared to the large microparticles, showed greater dose efficiency. For single treatment, the microparticles demonstrated up to 2-times longer survival extension and 4-times higher dose efficiency, relative to the paclitaxel/Cremophor micellar solution. Upon repeated dosing, the paclitaxel/Cremophor micellar solution showed cumulative toxicity whereas the microparticle that yielded 2-times longer survival did not display cumulative toxicity. The efficacy of IP therapy depended on both temporal and spatial factors that were determined by the characteristics of the drug delivery system. A combination of fast- and slow-releasing microparticles with 5–6 ?m diameter provided favorable spatial distribution and optimal drug release for IP therapy. PMID:24056144

  1. 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

  2. Expression of thymidine phosphorylase in peripheral blood cells of breast cancer patients is not increased by paclitaxel

    PubMed Central

    Bartsch, Rupert; Steger, Guenther G; Forstner, Birgit; Wenzel, Catharina; Pluschnig, Ursula; Rizovski, Blanka; Altorjai, Gabriela; Zielinski, Christoph C; Mader, Robert M

    2007-01-01

    Background A synergistic cytotoxic effect has been hypothesized for taxanes and capecitabine, a prodrug of 5-fluorouracil. Based on preclinical studies, this synergism has been attributed to an up-regulation of the enzyme thymidine phosphorylase (TP). Beside tumour tissue, TP is highly expressed in white blood cells, possibly causing increased hematotoxicity, when taxanes are combined with capecitabine. So far, this hypothesis has not been investigated in humans. Methods A total of 128 consecutive blood samples were collected from eight patients with advanced breast cancer receiving paclitaxel weekly at a dose of 80 mg/m2. To assess the expression of TP in blood cells, samples were collected prior to first therapy, at the end of infusion, and up to 15 days thereafter. This procedure was repeated during the sixth application of paclitaxel. After isolation of the peripheral mononuclear blood cells, the expression of TP was assessed by ELISA. In parallel, paclitaxel level in plasma was evaluated at three selected time points as pharmacokinetic control parameter. Results Paclitaxel concentrations at the end of infusion did not change significantly from week 1 to week 6. The expression of TP in peripheral mononuclear blood cells decreased significantly after infusion below pretherapeutic values (p = 0.023; n = 8). After the nadir on day 3, the expression of TP increased moderately returning to baseline levels within one week. The overall picture in week 6 was similar to week 1. Using a trend analysis, neither a short-term nor a long-term induction of TP was observed. Conclusion TP in peripheral mononuclear blood cells was hardly regulated under therapy with paclitaxel. Therefore, no increased haematotoxicity due to TP upregulation is expected from the combination of taxanes and capecitabine. PMID:17640356

  3. Ultra-sensitive assay for paclitaxel in intracellular compartments of A549 cells using liquid chromatography-tandem mass spectrometry.

    PubMed

    Wang, Tingting; Ma, Wenxiao; Sun, Yantong; Yang, Yan; Zhang, Weiping; Fawcett, J Paul; Du, Hongwei; Gu, Jingkai

    2013-01-01

    A high-performance liquid chromatography-tandem mass spectrometric (LC-MS/MS) method for the determination of paclitaxel in intracellular compartments using docetaxel as internal standard (IS) has been developed and validated. A549 cancer cells (10(6)) were incubated with paclitaxel (2ng/mL) for up to 4h and then subjected to sequential extraction of cytosolic, membrane/organelle, nuclear and cytoskeleton soluble protein. Fractions were ultrasonicated to release protein bound paclitaxel after which drug was extracted using liquid-liquid extraction with diethyl ether:dichloromethane (2:1, v/v). Chromatographic separation was then carried out on an Ascentis Express C18 column (50mm×4.6mm, 2.7?m) with a mobile phase of acetonitrile:0.1% formic acid in water (50:50, v/v). Detection involved electrospray positive ionization followed by multiple reactions monitoring of the precursor-to-product ion transitions of paclitaxel at m/z 854.4?286.3 and docetaxel at m/z 808.6?226.1. Assay validation based on samples of total cell extract in the same buffer as protein fractions showed the assay was linear over the range 2-600pg/mL with intra- and inter-day precision (as relative standard deviation) and accuracy (as relative error) of <7% and <±12%, respectively. Recovery was approximately 70% and matrix effects were minimal. The distribution of paclitaxel in subcellular components of A549 cancer cells was mainly into the cytoskeletal compartment. PMID:23262197

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

    PubMed Central

    2012-01-01

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

  5. Enhanced Oral Absorption of Paclitaxel in a Novel Self-Microemulsifying Drug Delivery System with or Without Concomitant Use of P-Glycoprotein Inhibitors

    Microsoft Academic Search

    Shicheng Yang; R. Neslihan Gursoy; Gregory Lambert; Simon Benita

    2004-01-01

    Purpose. The objective of this study was to evaluate the pharmacokinetics of paclitaxel in a novel self-microemulsifying drug delivery system (SMEDDS) for improved oral administration with or without P-glycoprotein (P-gp) inhibitors.

  6. An Antimitotic and Antivascular Agent BPR0L075 Overcomes Multidrug Resistance and Induces Mitotic Catastrophe in Paclitaxel-Resistant Ovarian Cancer Cells

    PubMed Central

    Wang, Xiaolei; Wu, Erxi; Wu, Jun; Wang, Tian-Li; Hsieh, Hsing-Pang; Liu, Xinli

    2013-01-01

    Paclitaxel plays a major role in the treatment of ovarian cancer; however, resistance to paclitaxel is frequently observed. Thus, new therapy that can overcome paclitaxel resistance will be of significant clinical importance. We evaluated antiproliferative effects of an antimitotic and antivascular agent BPR0L075 in paclitaxel-resistant ovarian cancer cells. BPR0L075 displays potent and broad-spectrum cytotoxicity at low nanomolar concentrations (IC50?=?2–7 nM) against both parental ovarian cancer cells (OVCAR-3, SKOV-3, and A2780-1A9) and paclitaxel-resistant sublines (OVCAR-3-TR, SKOV-3-TR, 1A9-PTX10), regardless of the expression levels of the multidrug resistance transporter P-gp and class III ?-tubulin or mutation of ?-tubulin. BPR0L075 blocks cell cycle at the G2/M phase in paclitaxel-resistant cells while equal concentration of paclitaxel treatment was ineffective. BPR0L075 induces cell death by a dual mechanism in parental and paclitaxel-resistant ovarian cancer cells. In the parental cells (OVCAR-3 and SKOV-3), BPR0L075 induced apoptosis, evidenced by poly(ADP-ribose) polymerase (PARP) cleavage and DNA ladder formation. BPR0L075 induced cell death in paclitaxel-resistant ovarian cancer cells (OVCAR-3-TR and SKOV-3-TR) is primarily due to mitotic catastrophe, evidenced by formation of giant, multinucleated cells and absence of PARP cleavage. Immunoblotting analysis shows that BPR0L075 treatment induced up-regulation of cyclin B1, BubR1, MPM-2, and survivin protein levels and Bcl-XL phosphorylation in parental cells; however, in resistant cells, the endogenous expressions of BubR1 and survivin were depleted, BPR0L075 treatment failed to induce MPM-2 expression and phosphorylation of Bcl-XL. BPR0L075 induced cell death in both parental and paclitaxel-resistant ovarian cancer cells proceed through caspase-3 independent mechanisms. In conclusion, BPR0L075 displays potent cytotoxic effects in ovarian cancer cells with a potential to overcome paclitaxel resistance by bypassing efflux transporters and inducing mitotic catastrophe. BPR0L075 represents a novel microtubule therapeutic to overcome multidrug resistance and trigger alternative cell death by mitotic catastrophe in ovarian cancer cells that are apoptosis-resistant. PMID:23762410

  7. Liquid-Liquid Extraction for Recovery of Paclitaxel from Plant Cell Culture: Solvent Evaluation and Use of Extractants for Partitioning and Selectivity

    PubMed Central

    McPartland, Timothy J.; Patil, Rohan A.; Malone, Michael F.; Roberts, Susan C.

    2012-01-01

    A major challenge in the production of metabolites by plant cells is the separation and purification of a desired product from a number of impurities. An important application of plant cell culture is the biosynthesis of the anti-cancer agent paclitaxel. Liquid-liquid extraction plays a critical role in the recovery of paclitaxel and other valuable plant-derived products from culture broth. In this study, the extraction of paclitaxel and a major unwanted by-product, cephalomannine, from plant cell culture broth into organic solvents is quantified. Potential solvent mixtures show varying affinity and selectivity for paclitaxel over cephalomannine. The partition coefficient of paclitaxel is highest in ethyl acetate and dichloromethane, with measured values of 28 and 25, respectively; however selectivity coefficients are less than 1 for paclitaxel over cephalomannine for both solvents. Selectivity coefficient increases to 1.7 with extraction in n-hexane but the partition coefficient decreases to 1.9. Altering the pH of the aqueous phase results in an increase in both recovery and selectivity using n-hexane, but does not change the results for other solvents significantly. The addition of extractants trioctyl amine (TOA) or tributyl phosphate (TBP) to n-hexane gives significantly higher partition coefficients for paclitaxel (8.6 and 23.7, respectively), but no selectivity. Interestingly, when 20% hexafluorobenzene (HFB) is added to n-hexane, the partition coefficient remains approximately constant but the selectivity coefficient for paclitaxel over cephalomannine improves to 4.5. This significant increase in selectivity early in the purification process has the potential to simplify downstream processing steps and significantly reduce overall purification costs. PMID:22581674

  8. Apoptosis of non-small-cell lung cancer cell lines after paclitaxel treatment involves the BH3-only proapoptotic protein Bim

    Microsoft Academic Search

    R Li; T Moudgil; H J Ross; H-M Hu

    2005-01-01

    A significant variation in susceptibility to paclitaxel-mediated killing was observed among a panel of short-term cultured non-small-cell lung cancer (NSCLC) cell lines. Susceptibility to killing by paclitaxel correlated with expression of the BH3-only protein, Bim, but not with other members of Bcl-2 family. NSCLC cell lines with the highest level of Bim expression are most susceptible to apoptosis induction after

  9. Paclitaxel alters the expression and specific activity of deoxycytidine kinase and cytidine deaminase in non-small cell lung cancer cell lines

    Microsoft Academic Search

    Stacy S Shord; Shitalben R Patel

    2009-01-01

    BACKGROUND: We observed that paclitaxel altered the pharmacokinetic properties of gemcitabine in patients with non-small cell lung cancer (NSCLC) and limited the accumulation of gemcitabine and its metabolites in various primary and immortalized human cells. Therefore, we classified the drug-drug interaction and the effects of paclitaxel on deoxycytidine kinase (dCK) and cytidine deaminase (CDA) in three NSCLC cell lines. These

  10. 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

  11. A phase I safety and pharmacokinetic study of ABT-263 in combination with carboplatin/paclitaxel in the treatment of patients with solid tumors.

    PubMed

    Vlahovic, Gordana; Karantza, Vassiliki; Wang, Ding; Cosgrove, David; Rudersdorf, Nikita; Yang, Jianning; Xiong, Hao; Busman, Todd; Mabry, Mack

    2014-10-01

    Bcl-2 family proteins are the key regulators of the intrinsic apoptotic pathway, controlling the point-of no-return and setting the threshold to engage the death machinery in response to chemical damage. Bcl-2 proteins have emerged as attractive targets for anti-cancer drug development. Navitoclax is a selective, potent, orally bioavailable, small molecule Bcl-2 inhibitor. Primary endpoints assessed the safety and pharmacokinetic (PK) interactions between navitoclax in combination with carboplatin/paclitaxel or paclitaxel alone in patients with solid tumors The study comprised two arms, one a combination of navitoclax with paclitaxel and carboplatin, the second with navitoclax and paclitaxel alone. Nineteen patients were enrolled in this study. The most frequently reported treatment-emergent AEs were alopecia (57.9 %), anemia (52.6 %), nausea (52.6 %), constipation (42.1 %), diarrhea (42.1 %), fatigue (42.1 %), neutropenia (36.8 %), thrombocytopenia (36.8 %), vomiting (31.6 %), decreased appetite (31.6 %), dehydration (26.3 %), and hypomagnesaemia (26.3 %). In the light of significant hematological and non-hematological toxicity the study was ended before de-escalation of navitoclax. Only one partial response was obtained at any dose tested, thus lowering doses could not have increased efficacy. It is the combination of toxicity with modest efficacy that led to discontinuation. No apparent PK interaction was observed between navitoclax and carboplatin or paclitaxel and the combination of navitoclax and paclitaxel had modest anti-tumor activity. PMID:24894650

  12. Clinical experience with nanoparticle albumin-bound paclitaxel, a novel taxane anticancer agent, and management of adverse events in females with breast cancer

    PubMed Central

    TAKASHIMA, SEIKI; KIYOTO, SACHIKO; TAKAHASHI, MINA; HARA, FUMIKATA; AOGI, KENJIRO; OHSUMI, SHOZO; MUKAI, RYOKO; FUJITA, YORIKO

    2015-01-01

    Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is currently approved in Japan for treatment of breast cancer. However, apart from phase I clinical trials, data regarding Japanese patients are scant. In the present study, the efficacy and safety of nab-paclitaxel therapy were retrospectively analyzed in 22 patients with advanced or metastatic breast cancer who were treated at the National Hospital Organization Shikoku Cancer Center between November 2010 and June 2012. The nab-paclitaxel was administered once every three weeks. The median age of the patients was 59 years. The tumors were estrogen-receptor positive and/or progesterone-receptor positive in 63.6% patients. None of the patients had HER2-positive breast cancer. The median number of treatment cycles was six (range, two to 12). Six patients exhibited a partial response; the response rate was 27.3% and the clinical benefit rate was 31.8%. The response rate and clinical benefit rate were higher in patients who received nab-paclitaxel as first- or second-line treatment. The median time to treatment failure was 127 days (range, 27–257). Major adverse events were peripheral neuropathy (59%; Grade 3, 9%), myalgia (59%), rash (45%), and nausea and vomiting (50%). The results suggest that nab-paclitaxel is a well-tolerated and clinically useful anticancer preparation. PMID:25789050

  13. Synergistic co-delivery of doxorubicin and paclitaxel by porous PLGA microspheres for pulmonary inhalation treatment.

    PubMed

    Feng, Tianshi; Tian, Huayu; Xu, Caina; Lin, Lin; Xie, Zhigang; Lam, Michael Hon-Wah; Liang, Haojun; Chen, Xuesi

    2014-11-01

    PLGA porous microspheres loaded with doxorubicin (DOX) and paclitaxel (PTX) were developed for in situ treatment of metastatic lung cancer. The synergistic effect of the combined drugs was investigated against B16F10 cells to obtain the optimal prescription for in vivo studies. The combination therapy showed great synergism when DOX was the majority in the combination therapy, while they showed moderate antagonism when PTX is in major. The combination of DOX and PTX at a molar ratio of 5/1 showed the best synergistic therapeutic effect in the free form. However, the drugs exhibited more synergism in the PLGA microspheres at a molar ratio of 2/1, due to the difference in drug release rate. The in vivo study verified the synergism of DOX and PTX at the optimal molar ratio. These results suggested that dual encapsulation of DOX and PTX in porous PLGA microspheres would be a promising technology for long effective lung cancer treatment. PMID:25305583

  14. 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

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

    PubMed Central

    2015-01-01

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

  16. Naringin mitigates erythrocytes aging induced by paclitaxel: an in vitro study.

    PubMed

    Harisa, Gamaleldin I

    2014-03-01

    In this study, the protective role of naringin (NAR) against paclitaxel (PTX)-induced erythrocytes aging has been investigated using human erythrocyte as an in vitro model. Erythrocytes were incubated with PTX in the presence and absence of NAR. Incubation of erythrocytes with PTX resulted in increased protein carbonyl content and malondialdehyde and hemolysis percentage compared with control. Furthermore, a significant increase in the ratios of glutathione peroxidase/glutathione reductase, superoxide dismutase/glutathione peroxidase, and superoxide dismutase/catalase in PTX-treated cells was observed, compared with control cells. In contrast, reduced glutathione/oxidized glutathione ratio and glucose-6-phosphate dehydrogenase activity were decreased upon PTX treatment. The simultaneous incubation of erythrocytes with PTX and NAR restored these variables to values similar to those of control erythrocytes. These results suggest that NAR inhibited PTX-induced aging by lessening the PTX-induced oxidative stress. PMID:24375949

  17. Folate-mediated targeting of albumin conjugates of paclitaxel obtained through a heterogeneous phase system.

    PubMed

    Dosio, Franco; Arpicco, Silvia; Stella, Barbara; Brusa, Paola; Cattel, Luigi

    2009-12-01

    The study developed cytotoxic macromolecular conjugates that specifically target the folate receptor and deliver the drug into cell cytoplasm. The anticancer agent paclitaxel was conjugated to human serum albumin (HSA) and this drug-albumin conjugate was further equipped with folic acid, linked via an extended poly(ethylene glycol) spacer. Preparation was carried out in a heterogeneous phase system exploiting the binding ability of Cibacron Blue dye to HSA. Unreacted reagents were easily removed and, after purification by gel filtration, the conjugate was fully characterized. Binding and in vitro cytotoxicity studies on human nasopharyngeal epidermal carcinoma KB and colorectal carcinoma HT-29 cells (as negative control) demonstrated increased selectivity and anti-tumoral activity. PMID:19712735

  18. 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

  19. Enhancement of taxol, doxorubicin and zoledronate anti-proliferation action on triple-negative breast cancer cells by a PTHrP blocking monoclonal antibody

    PubMed Central

    Camirand, Anne; Fadhil, Ibtihal; Luco, Aimée-Lee; Ochietti, Benoît; Kremer, Richard B

    2013-01-01

    Triple-negative breast cancers (TNBCs) are heterogeneous cancers that present tumors without the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Because of the absence of these receptors, there are currently no known specific molecular targets for treatment, and although TNBC tumors are chemosensitive, prognosis is poor because this type of cancer relapses more frequently and more aggressively than hormone receptor-positive cancers. The mechanisms by which TNBCs escape control by chemotherapy are not clear, and it is crucial to identify novel molecular drivers that can be targeted in order to develop more efficient therapeutic approaches. We recently highlighted a pleiotropic role for parathyroid hormone-related protein (PTHrP) in all stages of breast cancer, and used our neutralizing anti-PTHrP monoclonal antibody (mAb M158) to efficiently inhibit progression and metastasis of human breast cancer xenografts in athymic mice. In the present study, we present evidence for a strong in vitro anti-proliferative effect of our blocking anti-PTHrP mAb M158 as a single agent on TNBC lines of various subtypes that are known to express PTHrP (MDA-MB-231, BT-549, MDA-MB-435). The same mAb is inactive in a TNBC line without detectable PTHrP expression (MDA-MB-468). In in vitro combination studies, the mAb enhances the effect of the chemotherapeutic drugs taxol and doxorubicin in PTHrP-positive TNBC cells in an additive manner. When combined with the bisphosphonate zoledronate, M158 can act in additive or antagonistic fashion in vitro depending on the cell line. Our observations identify PTHrP as a novel target against TNBC cell proliferation, and suggest that combination therapies that include an anti-PTHrP approach might increase treatment efficacy in patients with PTHrP-positive TNBC. PMID:24224127

  20. Aptamer conjugated paclitaxel and magnetic fluid loaded fluorescently tagged PLGA nanoparticles for targeted cancer therapy

    NASA Astrophysics Data System (ADS)

    Aravind, Athulya; Nair, Remya; Raveendran, Sreejith; Veeranarayanan, Srivani; Nagaoka, Yutaka; Fukuda, Takahiro; Hasumura, Takahashi; Morimoto, Hisao; Yoshida, Yasuhiko; Maekawa, Toru; Sakthi Kumar, D.

    2013-10-01

    Controlled and targeted drug delivery is an essential criterion in cancer therapy to reduce the side effects caused by non-specific drug release and toxicity. Targeted chemotherapy, sustained drug release and optical imaging have been achieved using a multifunctional nanocarrier constructed from poly (D, L-lactide-co-glycolide) nanoparticles (PLGA NPs), an anticancer drug paclitaxel (PTX), a fluorescent dye Nile red (NR), magnetic fluid (MF) and aptamers (Apt, AS1411, anti-nucleolin aptamer). The magnetic fluid and paclitaxel loaded fluorescently labeled PLGA NPs (MF-PTX-NR-PLGA NPs) were synthesized by a single-emulsion technique/solvent evaporation method using a chemical cross linker bis (sulfosuccinimidyl) suberate (BS3) to enable binding of aptamer on to the surface of the nanoparticles. Targeting aptamers were then introduced to the particles through the reaction with the cross linker to target the nucleolin receptors over expressed on the cancer cell surface. Specific binding and uptake of the aptamer conjugated magnetic fluid loaded fluorescently tagged PLGA NPs (Apt-MF-NR-PLGA NPs) to the target cancer cells induced by aptamers was observed using confocal microscopy. Cytotoxicity assay conducted in two cell lines (L929 and MCF-7) confirmed that targeted MCF-7 cancer cells were killed while control cells were unharmed. In addition, aptamer mediated delivery resulting in enhanced binding and uptake to the target cancer cells exhibited increased therapeutic effect of the drug. Moreover, these aptamer conjugated magnetic polymer vehicles apart from actively transporting drugs into specifically targeted tumor regions can also be used to induce hyperthermia or for facilitating magnetic guiding of particles to the tumor regions.

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

    PubMed Central

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

    2014-01-01

    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 PAT to attach these molecules directly to cobalt–chromium (Co–Cr) alloy, an ultra-thin stent strut material. Four different groups of drug coated specimens were prepared by directly adding PAT to Co–Cr alloy surfaces: Group-A (PAT coated, unheated, and ethanol cleaned); Group-B (PAT coated, heat treated, and ethanol cleaned); Group-C (PAT coated, unheated, and not ethanol cleaned); and Group-D (PAT coated, heat treated and not ethanol cleaned). In vitro drug release of these specimens was investigated using high performance liquid chromatography. Groups A and B showed sustained PAT release for up to 56 days. A simple ethanol cleaning procedure after PAT deposition can remove the loosely bound drug crystals from the alloy surfaces and thereby allowing the remaining strongly bound drug molecules to be released at a sustained rate. The heat treatment after PAT coating further improved the stability of PAT on Co–Cr alloy and allowed the drug to be delivered at a much slower rate, especially during the initial 7 days. The specimens which were not cleaned in ethanol, Groups C and D, showed burst release. PAT coated Co–Cr alloy specimens were thoroughly characterized using scanning electron microscopy, atomic force microscopy, and X-ray photoelectron spectroscopy. These techniques were collectively useful in studying the morphology, distribution, and attachment of PAT molecules on Co–Cr alloy surfaces. Thus, this study suggests the potential for delivering paclitaxel from Co–Cr alloy surfaces without using any carriers. PMID:20398928

  2. 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

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

    NASA Astrophysics Data System (ADS)

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

    2015-02-01

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

  4. Influence of Drug Formulation on OATP1B-Mediated Transport of Paclitaxel

    PubMed Central

    Nieuweboer, Annemieke J.M.; Hu, Shuiying; Hagenbuch, Bruno; Moghaddam-Helmantel, Inge Ghobadi; Gibson, Alice A.; de Bruijn, Peter; Mathijssen, Ron H. J.; Sparreboom, Alex

    2014-01-01

    Purpose Taxane antineoplastic agents are extensively taken up into hepatocytes by OATP1B-type transporters prior to metabolism and excretion. Because the biodistributional properties imposed upon these agents by different solubilizers drive clinically-important pharmacodynamic endpoints, we tested the hypothesis that the in vitro and in vivo interaction of taxanes with OATP1B transporters is affected by the choice of drug delivery system. Experimental Design Transport of paclitaxel, docetaxel, and cabazitaxel was studied in vitro using various cell lines transfected with OATP1B1, OATP1B3, or the rodent equivalent Oatp1b2. Pharmacokinetic studies were done in wildtype and Oatp1b2-knockout mice in the presence or absence of polysorbate 80 (PS80) or Kolliphor EL (formerly Cremophor EL; CrEL). Results Paclitaxel and docetaxel, but not cabazitaxel, were transported substrates of OATP1B1, OATP1B3, and Oatp1b2, and these transport processes were strongly reduced in the presence of clinically-relevant concentrations of PS80 and CrEL. In the absence of solubilizers, deficiency of Oatp1b2 in mice was associated with a significantly decreased taxane clearance due to a liver distribution defect (P<0.00001), but these kinetic changes were masked in the presence of PS80 or CrEL (P>0.05). Conclusions Our findings confirm the importance of OATP1B-type transporters in the hepatic elimination of taxanes, and that this process can be inhibited by PS80 and CrEL. These results suggest that the likelihood of drug-drug interactions mediated by these transporters is strongly dependent on the selected taxane solubilizer. PMID:24755470

  5. TLR4 is a novel determinant of the response to paclitaxel in breast cancer

    PubMed Central

    Rajput, Sandeep; Volk-Draper, Lisa D.; Ran, Sophia

    2013-01-01

    Overexpression of Toll-like Receptor-4 (TLR4) in human tumors often correlates with chemoresistance and metastasis. We found that TLR4 is overexpressed in the majority of clinical breast cancer (BC) samples and in 68% of the examined BC lines. TLR4 is activated by lipopolysaccharide (LPS) and other ligands including the widely-used drug paclitaxel (PXL). LPS is frequently used to show a tumor-promoting role of TLR4 although this bacterial component is unlikely to be found in BC environment. We reasoned that PXL-dependent activation of TLR4 is more relevant to BC chemoresistance that could be mediated by activation of the NF-?B pathway leading to upregulation of pro-survival genes. To test this hypothesis, we correlated TLR4 expression with resistance to PXL in two modified BC lines with either depleted or overexpressed TLR4 protein. Depletion of TLR4 in naturally overexpressing MDA-MB-231 cells downregulated pro-survival genes concomitant with 2–3 fold reduced IC50 to PXL in vitro and a 6-fold decrease in recurrence rate in vivo. Conversely, TLR4 overexpression in a negative cell line HCC1806 significantly increased expression of inflammatory and pro-survival genes along with a 3-fold increase of IC50 to PXL in vitro and enhanced tumor resistance to PXL therapy in vivo. Importantly, both tumor models showed that many PXL-upregulated inflammatory cytokines were co-induced with their receptors suggesting that this therapy induces autocrine tumor-promoting loops. Collectively, these results demonstrate that paclitaxel not only kills tumor cells but also enhances their survival by activating TLR4 pathway. These findings suggest that blocking TLR4 could significantly improve response to PXL therapy. PMID:23720768

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

    SciTech Connect

    Lupe, Krystine [Department of Radiation Oncology, University of Western Ontario and London Health Sciences Centre, London, Ontario (Canada); Kwon, Janice [Division of Gynecologic Oncology, University of Western Ontario and London Health Sciences Centre, London, Ontario (Canada)]. E-mail: Janice.kwon@lhsc.on.ca; D'Souza, David [Department of Radiation Oncology, University of Western Ontario and London Health Sciences Centre, London, Ontario (Canada); Gawlik, Christine [Department of Pharmacy, University of Western Ontario and London Health Sciences Centre, London, Ontario (Canada); Stitt, Larry [Department of Biostatistics and Epidemiology, University of Western Ontario and London Health Sciences Centre, London, Ontario (Canada); Whiston, Frances [Clinical Cancer Research Program, University of Western Ontario and London Health Sciences Centre, London, Ontario (Canada); Nascu, Patricia [Department of Obstetrics and Gynecology, University of Western Ontario and London Health Sciences Centre, London, Ontario (Canada); Wong, Eugene [Department of Radiation Oncology, University of Western Ontario and London Health Sciences Centre, London, Ontario (Canada); Carey, Mark S. [Division of Gynecologic Oncology, University of Western Ontario and London Health Sciences Centre, London, Ontario (Canada)

    2007-01-01

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

  7. 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

  8. Paclitaxel resistance in MCF-7/PTX cells is reversed by paeonol through suppression of the SET/phosphatidylinositol 3-kinase/Akt pathway.

    PubMed

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

    2015-07-01

    Breast cancer is one of the most prevalent types of malignant tumor. Paclitaxel is widely used in the treatment of breast cancer; however, the major problem contributing to the failure of chemotherapy in breast cancer is the development of drug resistance. Therefore, it is necessary to identify novel therapeutic targets and reversal agents for breast cancer. In the present study, the protein expression levels of SET, protein phosphatase 2A (PP2A) and phosphatidylinositol 3?kinase (PI3K)/Akt pathway were determined in MCF?7/PTX human breast carcinoma paclitaxel?resistant cells using western blot analysis. Small interference RNAs (siRNAs) were used to knock down the gene expression of SET in MCF?7/PTX cells and the cell viability was assessed following treatment with paclitaxel, using 3?(4,5?dimethylthiazol?2?yl)?2,5?diphenyl tetrazolium bromide assays and flow cytometry. In addition, western blot analysis was used to determined PI3K/Akt pathway activity following SET knockdown. Furthermore, the reversal effects of paeonol on paclitaxel, and its underlying mechanisms of action, were investigated using western blot analysis and reverse transcription?quantitative polymerase chain reaction. The results demonstrated that increased levels of SET and PI3K/Akt pathway proteins were present in the MCF?7/PTX cells, compared with normal MCF?7 cells. Knockdown of SET significantly sensitized MCF?7/PTX cells to paclitaxel and induced cell apoptosis. In addition, the expression levels of the adenosine triphosphate binding cassette (ABC) transporter proteins were significantly reduced in the MCF?7/PTX cells compared with the normal MCF?7 cells. SET?induced paclitaxel resistance was found to be associated with the activation of the PI3K/Akt pathway. Paeonol significantly reduced the mRNA and protein expression levels of SET in the MCF?7/PTX cells. Furthermore, paeonol significantly sensitized the MCF?7/PTX to paclitaxel via regulation of ABC transporters, B cell lymphoma?2 (Bcl?2) and Bcl?2?associated X protein. In addition, paeonol inhibited SET?mediated paclitaxel resistance by attenuating PI3K/Akt pathway activity in the MCF?7/PTX cells. In conclusion, the results of the present study demonstrated that SET was associated with paclitaxel resistance in MCF?7/PTX cells, and that paeonol reversed paclitaxel resistance in MCF?7/PTX cells by downregulating the activity of the SET/PP2A/Akt pathway. PMID:25760096

  9. 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

  10. 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

  11. [Long-term control of stage IV breast and gastric cancer with combination therapy of S-1 and paclitaxel].

    PubMed

    Yamada, Chizu; Ishikawa, Fumihiko; Nitta, Hiroshi; Fujita, Yoshihisa; Omoto, Hideyuki; Kamata, Shigeyuki; Ito, Hiroshi

    2014-11-01

    We here describe a case of Stage IV breast and gastric cancer in which S-1/paclitaxel therapy was effective in maintaining the patient's QOL. A 50-year-old woman visited our hospital with complaints of her right breast tumor and right brachialgia. She was diagnosed with breast cancer with multiple bone metastases including cervical vertebrae. Accordingly, local radiation therapy and tamoxifen(TAM)administration was started immediately. Gastrointestinal endoscopy revealed gastric cancer, but laparotomy disclosed the gastric cancer was unresectable. At that time, the complaints of pain, nausea, and fatigue had increased and S-1/paclitaxel therapy was started immediately. The treatment reduced the size of the lesions in the breast and stomach and improved the QOL without serious adverse events. We have been maintaining partial response(PR)in this patient for 28 months. PMID:25731389

  12. Poly(vinyl alcohol)-graft-poly(lactide-co-glycolide) nanoparticles for local delivery of paclitaxel for restenosis treatment

    Microsoft Academic Search

    Ulrich Westedt; Marc Kalinowski; Matthias Wittmar; Thomas Merdan; Florian Unger; Jutta Fuchs; Susann Schäller; Udo Bakowsky; Thomas Kissel

    2007-01-01

    Catheter-based local delivery of biodegradable nanoparticles (NP) with sustained release characteristics represents a therapeutic approach to reduce restenosis. Paclitaxel-loaded NP consisting of poly(vinyl alcohol)-graft-poly(lactide-co-glycolide) (PVA-g-PLGA) with varying PLGA chain length as well as poly(lactide-co-glycolide) (PLGA), were prepared by a solvent evaporation technique. NP of <180 nm in diameter characterized by photon correlation spectroscopy (PCS), scanning electron microscopy (SEM), and atomic force

  13. Potent Killing of Paclitaxel and Doxorubicin-resistant Breast Cancer Cells by Calphostin C Accompanied by Cytoplasmic Vacuolization

    Microsoft Academic Search

    Baoqing Guo; Stacey L. Hembruff; David J. Villeneuve; Angie F. Kirwan; Amadeo M. Parissenti

    2003-01-01

    Drug resistance is a major impediment to the successful treatment of breast cancer using chemotherapy. The photoactivatable drug calphostin C has shown promise in killing select drug-resistant tumor cells lines in vitro. To assess the effectiveness of this agent in killing doxorubicin- or paclitaxel-resistant breast tumor cells and to explore its mode of action, MCF-7 cells were exposed to increasing

  14. PEG-PE Micelles Loaded with Paclitaxel and Surface-Modified by a PBR-Ligand: Synergistic Anticancer Effect

    Microsoft Academic Search

    Tiziana Musacchio; Valentino Laquintana; Andrea Latrofa; Giuseppe Trapani; Vladimir P. Torchilin

    2009-01-01

    Selective ligands to the peripheral benzodiazepine receptor (PBR) may induce apoptosis and cell cycle arrest. An overexpression of PBR in certain cancers allowed us to consider the use of highly selective ligands to PBR for receptor-mediated drug targeting to tumors. With this in mind, we prepared PBR-targeted nanoparticulate drug delivery systems (PEG-PE micelles) loaded with the anticancer drug paclitaxel (PCL)

  15. Phase II trial of paclitaxel, carboplatin, and concurrent radiation therapy for locally advanced non-small-cell lung cancer

    Microsoft Academic Search

    Vorachai Ratanatharathorn; Vicharn Lorvidhaya; Savitree Maoleekoonpairoj; Pramook Phromratanapongse; Suwannee Sirilerttrakul; Puangthong Kraipiboon; Arkom Cheirsilpa; Saipin Tangkaratt; Vichien Srimuninnimit; Pitayapoon Pattaranutaporn

    2001-01-01

    We conducted a phase II trial to investigate the efficacy of concurrent chemoradiation in patients with stage III non-small-cell lung cancer (NSCLC). Thirty patients with inoperable NSCLC were enrolled onto a multicenter phase II trial of concurrent chemoradiation therapy. Patients received six weekly cycles of paclitaxel 45 mg\\/m2 over 1 h; carboplatin at (area under the curve) AUC 2; and

  16. A novel trans-lymphatic drug delivery system: Implantable gelatin sponge impregnated with PLGA–paclitaxel microspheres

    Microsoft Academic Search

    Jiang Liu; Dale Meisner; Elizabeth Kwong; Xiao Y. Wu; Michael R. Johnston

    2007-01-01

    A translymphatic drug delivery system which incorporates poly-lactide-co-glycolide–paclitaxel (PLGA–PTX) or PLGA–rhodamine microspheres into gelatin sponge matrix is described. The system combines the sustained release properties of PLGA–PTX with the structural advantages of gelatin matrix that can be implanted directly to the lymphatic site for both therapeutic and prophylactic purposes. The PLGA microspheres were prepared using spray drying technique. The particles

  17. Weekly paclitaxel-cisplatin administration with G-CSF support in advanced breast cancer. A phase II study

    Microsoft Academic Search

    Giuseppe Frasci; Pasquale Comella; Giuseppe D'Aiuto; Alfredo Budillon; Deborah Barbarulo; Renato Thomas; Immacolata Capasso; Rossana Casaretti; Antonio Daponte; Francesco Caponigro; Adriano Gravina; Luigi Maiorino; Giacomo Caratení; Alfonso Gentile; Giuseppe Comella

    1998-01-01

    Purpose: In a previous phase I study we found the MTDs of paclitaxel and cisplatin when given together weekly, with or without G-CSF support, in patients with advanced solid tumors. The present study was conducted to define the toxicity and efficacy of this regimen, when used with G-CSF support, in chemotherapy-naive or pretreated patients with advanced breast cancer, and to

  18. Comparison of Bare-Metal and Sirolimus- or Paclitaxel-Eluting Stents for Aorto-Ostial Coronary Disease

    Microsoft Academic Search

    Peter Barlis; Sahin Kaplan; Konstantinos Dimopoulos; Giuseppe Ferrante; Carlo Di Mario

    2008-01-01

    Objectives: Aorto-ostial lesions (AOL) are technically challenging, given their greater propensity to be calcific and associated with elastic recoil compared to non-ostial lesions. This study set out to assess angiographic and clinical outcomes in patients with AOL treated using either paclitaxel-eluting stents (PES) or sirolimus-eluting stents (SES) compared to bare-metal stent (BMS) implantation. Methods: We retrospectively identified 175 consecutive patients

  19. Phase II trial of nanoparticle albumin-bound paclitaxel as second-line chemotherapy for unresectable or recurrent gastric cancer.

    PubMed

    Sasaki, Yasutsuna; Nishina, Tomohiro; Yasui, Hirofumi; Goto, Masahiro; Muro, Kei; Tsuji, Akihito; Koizumi, Wasaburo; Toh, Yasushi; Hara, Takuo; Miyata, Yoshinori

    2014-07-01

    This multicenter phase II study first investigated the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) when given every 3 weeks to patients with unresectable or recurrent gastric cancer who had received a prior round of fluoropyrimidine-containing chemotherapy. Patients with unresectable or recurrent gastric cancer who experienced progression despite fluoropyrimidine-containing treatment were studied. Nab-paclitaxel was given i.v. at 260 mg/m(2) on day 1 of each 21-day cycle without anti-allergic premedication until disease progression or study discontinuation. The primary endpoint was the overall response rate. The secondary endpoints were the disease control rate, progression-free survival, overall survival, and safety. From April 2008 to July 2010, 56 patients were enrolled, 55 patients received the study treatment, and 54 patients were evaluable for responses. According to an independent review committee, the overall response rate was 27.8% (15/54; 95% confidence interval [CI], 16.5-41.6) and the disease control rate was 59.3% (32/54; 95% CI, 45.0-72.4). One patient had a complete response. The median progression-free survival and overall survival were 2.9 months (95% CI, 2.4-3.6) and 9.2 months (95% CI, 6.9-11.4), respectively. The most common grade 3/4 toxicities were neutropenia (49.1%), leucopenia (20.0%), lymphopenia (10.9%), and peripheral sensory neuropathy (23.6%). There were no treatment-related deaths. Nab-paclitaxel, given every 3 weeks, showed promising activity against previously treated unresectable or recurrent gastric cancers, with well-tolerated toxicities. (Trial registration, ClinicalTrials.gov: NCT00661167). PMID:24716542

  20. Comparative study of the antitumor activity of Nab-paclitaxel and intraperitoneal solvent-based paclitaxel regarding peritoneal metastasis in gastric cancer.

    PubMed

    Kinoshita, Jun; Fushida, Sachio; Tsukada, Tomoya; Oyama, Katsunobu; Watanabe, Toshihumi; Shoji, Masatoshi; Okamoto, Koichi; Nakanuma, Shinichi; Sakai, Seisho; Makino, Isamu; Furukawa, Hiroyuki; Hayashi, Hironori; Nakamura, Keishi; Inokuchi, Masahumi; Nakagawara, Hisatoshi; Miyashita, Tomoharu; Tajima, Hidehiro; Takamura, Hiroyuki; Ninomiya, Itasu; Fujimura, Takashi; Masakazu, Yashiro; Hirakawa, Kosei; Ohta, Tetsuo

    2014-07-01

    Intraperitoneal (i.p.) chemotherapy with paclitaxel (PTX) has been shown to be a promising treatment strategy for peritoneal metastasis. The present study focused on the comparative evaluation of the therapeutic efficacy of nanoparticle albumin-bound PTX (Nab-PTX) and i.p. administration of the conventional solvent-based PTX (Sb-PTX). We also investigated the difference in antitumor activity depending on the route of administration in the Nab-PTX treatment. Nab-PTX was administered i.p. or intravenously (i.v.) and Sb-PTX was administered i.p. at equitoxic and equal doses to nude mice bearing gastric cancer OCUM-2MD3 cell subcutaneous and peritoneal xenografts. Therapeutic efficacy of Sb-PTX and Nab-PTX was evaluated as inhibition of tumor growth using a peritoneal metastatic model with subcutaneous xenografts. The survival rate was also investigated using mouse peritoneal models. For assessment of subcutaneous tumors, the change in tumor volume was measured, and for assessment of peritoneal tumors, the weight of ascitic fluid and the total peritoneal tumor burden were measured for each individual mouse. At equitoxic doses, treatment with Nab-PTX resulted in a greater reduction in the size of subcutaneous tumors and the weight of ascites and peritoneal burden as compared with i.p. Sb-PTX (p<0.05). Treatment with i.p. and i.v. Nab-PTX also achieved greater survival benefit than i.p. Sb-PTX (p<0.05). In contrast, there was no significant difference in the degree of tumor reduction and the survival time between both drugs at equal doses. With regard to the route of administration, the antitumor efficacy of Nab-PTX after i.v. administration was equivalent to the efficacy after i.p. administration. These results suggest that i.v. Nab-PTX may be another encouraging treatment option that can target peritoneal dissemination in gastric cancer. PMID:24859429

  1. Preparation, characterization, cytotoxicity and drug release behavior of liposome-enveloped paclitaxel/Fe3O4 nanoparticles.

    PubMed

    Kim, Min-Jung; Jang, Dae-Hwan; Lee, Young-In; Jung, Hyun Sook; Lee, Hak-Jong; Choa, Yong-Ho

    2011-01-01

    Phospholipid vesicles encapsulating magnetic nanoparticles (liposome complexes) have been prepared for targeting a drug to a specific organ using a magnetic force, as well as for local hyperthermia therapy. Liposome complexes are also an ideal platform for use as contrast agents of magnetic resonance imaging (MRI). We describe the preparation and characterization of liposomes containing magnetite. These liposomes were obtained by thin film hydration method and Fe3O4 nanoparticles were synthesized by coprecipitation method. They were characterized by an electrophoretic light scattering spectrophotometer, the liposome complexes were subsequently coated using chitosan. We have further investigated the ability of the above formulation for drug delivery and MRI applications. We are specifically interested in evaluating our liposome complexes for drug therapy; hence, we selected paclitaxel for the combination study. The amount of paclitaxel was measured at 227 nm using a UV-Vis spectrophotometer. Cytotoxicity of liposome complexes was treated with the various concentrations of paclitaxel in PC3 cell lines. The structure and properties of liposome complexes were analyzed by FT-IR, XRD and VSM. The particle size was analyzed by TEM and DLS. PMID:21446568

  2. Efficacy and tolerability of paclitaxel, ifosfamide, and cisplatin as a neoadjuvant chemotherapy in locally advanced cervical carcinoma

    PubMed Central

    Scibilia, Giuseppe; Banna, Giuseppe Luigi; D'Agate, Gabriella; Lipari, Helga; Gieri, Stefania; Scollo, Paolo

    2015-01-01

    Objective To evaluate the efficacy and tolerability of a neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy in patients with locally advanced cervical carcinoma. Methods Patients with histologically confirmed locally advanced cervical carcinoma, aged ?18 years, were treated with intravenous ifosfamide 5,000 mg/m2 and mesna 5,000 mg/m2, on day 1; intravenous paclitaxel 175 mg/m2 and cisplatin 75 mg/m2, on day 2; every 3 weeks for three cycles. Following chemotherapy, operable patients underwent radical hysterectomy and pelvic lymphadenectomy, and, if necessary, adjuvant radiotherapy. Results One hundred fifty-two patients with median age 53 years (range, 24 to 79 years), FIGO stage IIB in 126 (89%), were treated with chemotherapy for median 3 cycles (range, 1 to 3). Treatment was delayed or withdrawn in 23 patients (15%). One hundred thirty-nine patients (91%) underwent surgery. Postchemotherapy pathological complete response rate was 18% (25 patients). Postoperative radiotherapy was administered in 100 patients (72%). The 5-year overall survival and progression-free survival were 87.3% (95% confidence interval [CI], 84.5 to 90.3) and 76.4% (95% CI, 73.5 to 79.5), respectively. Conclusion Neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy was feasible and effective in the treatment of locally advanced cervical carcinoma patients with older age and more advanced disease stage than reported in previous studies. Hematological and renal toxicity could be carefully prevented. PMID:25686397

  3. Synthetic Triterpenoids Can Protect Against Toxicity Without Reducing the Efficacy of Treatment with Carboplatin and Paclitaxel in Experimental Lung Cancer

    PubMed Central

    Liby, Karen T.

    2014-01-01

    Synthetic oleanane triterpenoids are multifunctional drugs being developed for the prevention and treatment of a variety of chronic diseases driven by inflammation and oxidative stress. Low nanomolar concentrations of triterpenoids inhibit the induction of inflammatory cytokines, and these drugs are potent activators of the Nrf2 cytoprotective pathway. In contrast, low micromolar concentrations of triterpenoids increased the production of ROS and induced apoptosis in a dose-dependent manner in malignant MCF10 CA1a breast cancer cells. Because cancer cells respond differently to ROS than normal cells, it should be possible to exploit these differences therapeutically. In an experimental model of lung cancer, the triterpenoids activated the Nrf2 pathway, as seen by induction of the cytoprotective enzyme NQO1, and reduced the toxicity of carboplatin and paclitaxel. The induction of the Nrf2 pathway in the lung did not suppress the efficacy of treatment with carboplatin and paclitaxel, as the average tumor burden in the group treated with the combination of CDDO-Me and carboplatin/paclitaxel decreased by 90% (P < 0.05 vs. the controls and both single treatment groups). Understanding the dose response of triterpenoids and related drugs will help provide the proper context for optimizing their potential clinical utility. PMID:24659938

  4. Delayed triggering of oestrogen induced apoptosis that contrasts with rapid paclitaxel-induced breast cancer cell death

    PubMed Central

    Obiorah, I; Sengupta, S; Fan, P; Jordan, V C

    2014-01-01

    Background: Oestrogen (E2) induces apoptosis in long-term E2-deprived MCF7 cells (MCF7:5C). Taxanes have been used extensively in the treatment of early and advanced breast cancer. We have interrogated the sequence of events that involve the apoptotic signalling pathway induced by E2 in comparison with paclitaxel. Methods: DNA quantification and cell cycle analysis were used to assess proliferation of cancer cells. Apoptosis was evaluated using annexin V and DNA staining methods. Regulation of apoptotic genes was determined by performing PCR-based arrays and RT–PCR. Results: E2-induced apoptosis is a delayed process, whereas paclitaxel immediately inhibits the growth and induces death of MCF7:5C cells. The cellular commitment for E2-triggered apoptosis occur after 24?h. Activation of the intrinsic pathway was observed by 36?h of E2 treatment with subsequent induction of the extrinsic apoptotic pathway by 48?h. Paclitaxel exclusively activated extramitochodrial apoptotic genes and caused rapid G2/M blockade by 12?h of treatment. By contrast, E2 causes an initial proliferation with elevated S phase of cell cycles followed by apoptosis of the MCF7:5C cells. Most importantly, we are the first to document that E2-induced apoptosis can be reversed after 24?h treatment. Conclusions: These data indicate that E2-induced apoptosis involves a novel, multidynamic process that is distinctly different from that of a classic cytotoxic chemotherapeutic drug used in breast cancer. PMID:24548860

  5. cDNA microarray gene expression profiling of hydroxyurea, paclitaxel, and p-anisidine, genotoxic compounds with differing tumorigenicity results.

    PubMed

    Lee, Michael; Kwon, Jung; Kim, Se Nyun; Kim, Ja Eun; Koh, Woo Suk; Kim, Eun-Joo; Chung, Moon-Koo; Han, Sang-Seop; Song, Chang Woo

    2003-01-01

    The potential application of toxicogenomics to predictive toxicology has been discussed widely, but the utility of the approach remains largely unproven. Using cDNA microarrays, we compared the gene expression profiles produced in mouse lymphoma cells by three genotoxic compounds, hydroxyurea (a carcinogen), p-anisidine (a noncarcinogen), and paclitaxel (carcinogenicity unknown). To minimize the effect of biological variability and technological limitations, quadruplicate observations were made for each compound and a subset of genes yielding reproducible induction/repression was selected for comparison. A method was applied to attach normalized expression data to genes with a low false-discovery rate (<0.1) to yield more confidence regarding differential expression. This analysis identified genotoxicity-specific gene expression. Seven genes were consistently upregulated and 12 downregulated more than 2-fold by the three genotoxic compounds. Using additional genes, the expression pattern induced by the genotoxic noncarcinogen, p-anisidine, was readily distinguished from that associated with the genotoxic carcinogen, hydroxyurea. Comparison of paclitaxel-induced expression data to data for p-anisidine and hydroxyurea suggested that paclitaxel's profile is more similar to the genotoxic noncarcinogen. With further supporting evidence it may be possible to perform large-scale monitoring of gene expression during drug and chemical development that can provide an early warning of potential toxicological responses. PMID:12929121

  6. 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

  7. Sequential combination therapy of ovarian cancer with degradable N-(2-hydroxypropyl)methacrylamide copolymer paclitaxel and gemcitabine conjugates

    PubMed Central

    Zhang, Rui; Yang, Jiyuan; Sima, Monika; Zhou, Yan; Kope?ek, Jind?ich

    2014-01-01

    For rapid and effective clinical translation, polymer-based anticancer therapeutics need long circulating conjugates that produce a sustained concentration gradient between the vasculature and solid tumor. To this end, we designed second-generation backbone-degradable diblock N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer carriers and evaluated sequential combination therapy of HPMA copolymer-paclitaxel and HPMA copolymer-gemcitabine conjugates against A2780 human ovarian carcinoma xenografts. First, extensive in vitro assessment of administration sequence impact on cell cycle, viability, apoptosis, migration, and invasion revealed that treatment with paclitaxel conjugate followed by gemcitabine conjugate was the most effective scheduling strategy. Second, in an in vivo comparison with first-generation (nondegradable, molecular weight below the renal threshold) conjugates and free drugs, the second-generation degradable high-molecular weight conjugates showed distinct advantages, such as favorable pharmacokinetics (three- to five-times half-life compared with the first generation), dramatically enhanced inhibition of tumor growth (complete tumor regression) by paclitaxel and gemcitabine conjugate combination, and absence of adverse effects. In addition, multimodality imaging studies of dual-labeled model conjugates confirmed the efficacy of second-generation conjugates by visualizing more than five-times enhanced tumor accumulation, rapid conjugate internalization, and effective intracellular release of payload. Taken together, the results indicate that the second-generation degradable HPMA copolymer carrier can provide an ideal platform for the delivery of a range of antitumor compounds, which makes it one of the most attractive candidates for potential clinical application. PMID:25092316

  8. Radiosensitizing effect of carboplatin and paclitaxel to carbon-ion beam irradiation in the non-small-cell lung cancer cell line H460

    PubMed Central

    Kubo, Nobuteru; Noda, Shin-ei; Takahashi, Akihisa; Yoshida, Yukari; Oike, Takahiro; Murata, Kazutoshi; Musha, Atsushi; Suzuki, Yoshiyuki; Ohno, Tatsuya; Takahashi, Takeo; Nakano, Takashi

    2015-01-01

    The present study investigated the ability of carboplatin and paclitaxel to sensitize human non-small-cell lung cancer (NSCLC) cells to carbon-ion beam irradiation. NSCLC H460 cells treated with carboplatin or paclitaxel were irradiated with X-rays or carbon-ion beams, and radiosensitivity was evaluated by clonogenic survival assay. Cell proliferation was determined by counting the number of viable cells using Trypan blue. Apoptosis and senescence were evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining and senescence-associated ?-galactosidase (SA-?-gal) staining, respectively. The expression of cleaved caspase-3, Bax, p53 and p21 was analyzed by western blotting. Clonogenic survival assays demonstrated a synergistic radiosensitizing effect of carboplatin and paclitaxel with carbon-ion beams; the sensitizer enhancement ratios (SERs) at the dose giving a 10% survival fraction (D10) were 1.21 and 1.22, respectively. Similarly, carboplatin and paclitaxel showed a radiosensitizing effect with X-rays; the SERs were 1.41 and 1.29, respectively. Cell proliferation assays validated the radiosensitizing effect of carboplatin and paclitaxel with both carbon-ion beam and X-ray irradiation. Carboplatin and paclitaxel treatment combined with carbon-ion beams increased TUNEL-positive cells and the expression of cleaved caspase-3 and Bax, indicating the enhancement of apoptosis. The combined treatment also increased SA-?-gal-positive cells and the expression of p53 and p21, indicating the enhancement of senescence. In summary, carboplatin and paclitaxel radiosensitized H460 cells to carbon-ion beam irradiation by enhancing irradiation-induced apoptosis and senescence. PMID:25599995

  9. Radiosensitizing effect of carboplatin and paclitaxel to carbon-ion beam irradiation in the non-small-cell lung cancer cell line H460.

    PubMed

    Kubo, Nobuteru; Noda, Shin-Ei; Takahashi, Akihisa; Yoshida, Yukari; Oike, Takahiro; Murata, Kazutoshi; Musha, Atsushi; Suzuki, Yoshiyuki; Ohno, Tatsuya; Takahashi, Takeo; Nakano, Takashi

    2015-03-01

    The present study investigated the ability of carboplatin and paclitaxel to sensitize human non-small-cell lung cancer (NSCLC) cells to carbon-ion beam irradiation. NSCLC H460 cells treated with carboplatin or paclitaxel were irradiated with X-rays or carbon-ion beams, and radiosensitivity was evaluated by clonogenic survival assay. Cell proliferation was determined by counting the number of viable cells using Trypan blue. Apoptosis and senescence were evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining and senescence-associated ?-galactosidase (SA-?-gal) staining, respectively. The expression of cleaved caspase-3, Bax, p53 and p21 was analyzed by western blotting. Clonogenic survival assays demonstrated a synergistic radiosensitizing effect of carboplatin and paclitaxel with carbon-ion beams; the sensitizer enhancement ratios (SERs) at the dose giving a 10% survival fraction (D10) were 1.21 and 1.22, respectively. Similarly, carboplatin and paclitaxel showed a radiosensitizing effect with X-rays; the SERs were 1.41 and 1.29, respectively. Cell proliferation assays validated the radiosensitizing effect of carboplatin and paclitaxel with both carbon-ion beam and X-ray irradiation. Carboplatin and paclitaxel treatment combined with carbon-ion beams increased TUNEL-positive cells and the expression of cleaved caspase-3 and Bax, indicating the enhancement of apoptosis. The combined treatment also increased SA-?-gal-positive cells and the expression of p53 and p21, indicating the enhancement of senescence. In summary, carboplatin and paclitaxel radiosensitized H460 cells to carbon-ion beam irradiation by enhancing irradiation-induced apoptosis and senescence. PMID:25599995

  10. MiR-16 targets Bcl-2 in paclitaxel-resistant lung cancer cells and overexpression of miR-16 along with miR-17 causes unprecedented sensitivity by simultaneously modulating autophagy and apoptosis.

    PubMed

    Chatterjee, Abhisek; Chattopadhyay, Dhrubajyoti; Chakrabarti, Gopal

    2015-02-01

    Non-small cell lung cancer is one of the most aggressive cancers as per as the mortality and occurrence is concerned. Paclitaxel based chemotherapeutic regimes are now used as an important option for the treatment of lung cancer. However, resistance of lung cancer cells to paclitaxel continues to be a major clinical problem nowadays. Despite impressive initial clinical response, most of the patients eventually develop some degree of paclitaxel resistance in the course of treatment. Previously, utilizing miRNA arrays we reported that downregulation of miR-17 is at least partly involved in the development of paclitaxel resistance in lung cancer cells by modulating Beclin-1 expression [1]. In this study, we showed that miR-16 was also significantly downregulated in paclitaxel resistant lung cancer cells. We demonstrated that anti-apoptotic protein Bcl-2 was directly targeted miR-16 in paclitaxel resistant lung cancer cells. Moreover, in this report we showed that the combined overexpression of miR-16 and miR-17 and subsequent paclitaxel treatment greatly sensitized paclitaxel resistant lung cancer cells to paclitaxel by inducing apoptosis via caspase-3 mediated pathway. Combined overexpression of miR-16 and miR-17 greatly reduced Beclin-1 and Bcl-2 expressions respectively. Our results indicated that though miR-17 and miR-16 had no common target, both miR-16 and miR-17 jointly played roles in the development of paclitaxel resistance in lung cancer. miR-17 overexpression reduced cytoprotective autophagy by targeting Beclin-1, whereas overexpression of miR-16 potentiated paclitaxel induced apoptotic cell death by inhibiting anti-apoptotic protein Bcl-2. PMID:25435430

  11. 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

  12. Application of coherent anti-Stokes Raman scattering microscopy to image the changes in a paclitaxel-poly(styrene-b-isobutylene-b-styrene) matrix pre- and post-drug elution.

    PubMed

    Kang, Eunah; Wang, Haifeng; Kwon, Il Keun; Song, Young-Ho; Kamath, Kalpana; Miller, Kathleen M; Barry, James; Cheng, Ji-Xin; Park, Kinam

    2008-12-15

    Mapping the drug distribution in a polymeric film and following the subsequent changes that result during and after drug release is important to better understand the mechanism of drug release. This understanding leads to more efficiently designed tailor-made release profiles for drug-containing biomedical devices. Coherent anti-Stokes Raman scattering (CARS) microscopy was used for in situ imaging of local drug distribution in polymeric films, taking advantage of the three-dimensional (3D) resolution, high speed, high sensitivity, and noninvasiveness of the technology. Additionally, the morphological changes of poly(styrene-b-isobutylene-b-styrene) (SIBS) films during paclitaxel release were characterized by scanning electron microscopy, and drug release was quantitatively determined by high performance liquid chromatography. The time-dependent changes in the 3D distribution of paclitaxel in the polymer film were visualized using CARS microscopy. CARS images showed that the paclitaxel was uniformly distributed throughout the SIBS matrix. Changes in the paclitaxel distribution during release were monitored using depth intensity profiles and showed that, upon exposure of the paclitaxel-loaded film to a release medium, the quantitative CARS intensity of paclitaxel decreased. These results indicate that paclitaxel was dissolved and depleted from the SIBS film during in vitro drug elution, supporting the use of CARS microscopy as an effective nondestructive technique for chemical imaging of paclitaxel elution dynamics in polymer films. PMID:18228250

  13. Identification of the first inhibitor of the GBP1:PIM1 interaction. Implications for the development of a new class of anticancer agents against paclitaxel resistant cancer cells.

    PubMed

    Andreoli, Mirko; Persico, Marco; Kumar, Ajay; Orteca, Nausicaa; Kumar, Vineet; Pepe, Antonella; Mahalingam, Sakkarapalayam; Alegria, Antonio E; Petrella, Lella; Sevciunaite, Laima; Camperchioli, Alessia; Mariani, Marisa; Di Dato, Antonio; Novellino, Ettore; Scambia, Giovanni; Malhotra, Sanjay V; Ferlini, Cristiano; Fattorusso, Caterina

    2014-10-01

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

  14. 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

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

    PubMed Central

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

    2011-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2015-02-01

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

  17. Poly(ethylene oxide)-block-polyphosphoester-graft-paclitaxel Conjugates with Acid-labile Linkages as a pH-Sensitive and Functional Nanoscopic Platform for Paclitaxel Delivery

    PubMed Central

    Zou, Jiong; Zhang, Fuwu; Zhang, Shiyi; Pollack, Stephanie F.; Elsabahy, Mahmoud; Fan, Jingwei; Wooley, Karen L.

    2013-01-01

    There has been an increasing interest to develop new types of stimuli-responsive drug delivery vehicles with high drug loading and controlled release properties for chemotherapeutics. An acid-labile, polyphosphoester-based degradable, polymeric paclitaxel (PTX) conjugate containing ultra-high levels of PTX loading has been improved significantly, in this second generation development, which involves connection of each PTX molecule to the polymer backbone via a pH-sensitive ?-thiopropionate linkage. The results for this system indicate that it has great potential as an effective anti-cancer agent. Poly(ethylene oxide)-block-polyphosphoester-graft-PTX drug conjugate (PEO-b-PPE-g-PTX G2) was synthesized by organocatalyst-promoted ring-opening polymerization of 2-(but-3-en-1-yloxy)-1,3,2-dioxaphospholane-2-oxide from a PEO macroinitiator, followed by thermo-promoted thiolene click conjugation of a thiol-functionalized PTX prodrug to the pendant alkene groups of the block copolymer. The PEO-b-PPE-g-PTX G2 formed well-defined nanoparticles in aqueous solution, by direct dissolution into water, with a number-averaged hydrodynamic diameter of 114 ± 31 nm. The conjugate had PTX loading capacity as high as 53 wt%, and a maximum PTX concentration of 0.68 mg/mL in water (vs. 1.7 ?g/mL for free PTX). Although the PTX concentration is ca. 10× less than for our first generation material, its accelerated release allowed for similar free PTX concentrations vs. time. The PEO-b-PPE-g-PTX G2 exhibited accelerated drug release under acidic conditions (~50 wt% PTX released in 8 d) compared to neutral conditions (~20 wt% PTX released in 8 d) and compared to the first generation analog that contained ester linkages between PTX and the polymer backbone (<5 wt% PTX released in 4 d), due to their acid-sensitive hydrolytically-labile ?-thiopropionate linkages between PTX molecules and the polymer backbone. The positive cell-killing activity of PEO-b-PPE-g-PTX G2 against two cancer cell lines was demonstrated, and the presence of pendant reactive functionality provides a powerful platform for future work to involve conjugation of multiple numbers and/or types of targeting ligands, other drugs and imaging agents to achieve chemotherapy and bioimaging. Compared to our previously reported polyphosphoester-based PTX drug conjugates, PEO-b-PPE-g-PTX G1 without the ?-thiopropionate linker, the PEO-b-PPE-g-PTX G2 showed pH-triggered drug release property and 5-to-8-fold enhanced in vitro cytotoxcity against two cancer cell lines. PMID:23997013

  18. 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

  19. Liposomes with high encapsulation capacity for paclitaxel: Preparation, characterisation and in vivo anticancer effect.

    PubMed

    Koudelka, Stepán; Turánek-Knötigová, Pavlína; Masek, Josef; Korvasová, Zina; Skrabalová, Michaela; Plocková, Jana; Bartheldyová, Eliska; Turánek, Jaroslav

    2010-05-01

    Paclitaxel (PTX) is approved for the treatment of ovarian and breast cancer. The commercially available preparation of PTX, Cremophor EL(R) is associated with hypersensitivity reactions in spite of a suitable premedication. In general, the developed liposomal PTX formulations are troubled with low PTX encapsulation capacity (maximal content, 3 mol%) and accompanied by PTX crystallisation. The application of "pocket-forming" lipids significantly increased the encapsulation capacity of PTX in the liposomes up to 10 mol%. Stable lyophilised preparation of PTX (7 mol%) encapsulated in the liposomes composed of SOPC/POPG/MOPC (molar ratio, 60:20:20) doped with 5 mol% vitamin E had the size distribution of 180-190 nm (PDI, 0.1) with zeta-potential of -31 mV. Sucrose was found to be a suitable cryoprotectant at the lipid:sugar molar ratios of 1:5-1:10. This liposomal formulation did not show any evidence of toxicity in C57BL/6 mice treated with the highest doses of PTX (100 mg/kg administered as a single dose and 150 mg/kg as a cumulative dose applied in three equivalent doses in 48-h intervals). A dose-dependent anticancer effect was found in both hollow fibre implants and syngenic B16F10 melanoma mouse tumour models. PMID:19904827

  20. Src inhibition potentiates antitumoral effect of paclitaxel by blocking tumor-induced angiogenesis.

    PubMed

    Delle Monache, Simona; Sanità, Patrizia; Calgani, Alessia; Schenone, Silvia; Botta, Lorenzo; Angelucci, Adriano

    2014-10-15

    The protein kinase Src is frequently over-activated in advanced cancers where it modulates the signaling transduction cascade of several growth factors. The feasibility of combination treatment of Src inhibitors with chemotherapy is currently under investigation. We evaluated the anti-tumoral effect of paclitaxel (PTX) in combination with S13, a tyrosine kinase inhibitor with a prevalent specificity for Src, in a hormone-insensible prostate cancer (PCa) cell model. In vivo, combination treatment with PTX and S13 reduced dramatically PCa tumor growth with a relevant difference in the density of new blood vessels with respect to control and single treatments. This reduction was determined by a concomitant impairment of endothelial cell migration and of VEGF release by cancer cells. In fact, S13, when used alone, was sufficient to reduce tubule formation in vivo, and to inhibit VEGFR2 activation and FAK expression in endothelial cells. In addition, the combination treatment determined a significant reduction in ROS production and HIF-1 stabilization in PCa cells respect to single treatments with S13 or PTX. In conclusion, Src-inhibition could be an effective therapeutic strategy aimed at supporting the anti-angiogenic action of PTX in aggressive PCa. PMID:25128812

  1. Paclitaxel and Gemcitabine Combinational Drug-loaded Mucoadhesive Delivery System in the Treatment of Colon Cancers.

    PubMed

    Guo, X-Y; Wang, P; Du, Q-G; Han, S; Zhu, S-M; Lv, Y-F; Liu, G-S; Hao, Z-M

    2015-04-01

    The combination of two different types of chemo-therapeutic drugs via nanocarriers is emerged as a promising strategy for treating multiple cancers. Such a co-delivery system will synchronize the drug exposure and synergize the therapeutic effects. Herein, we prepared a paclitaxel (PTX) and gemcitabine (GEM)-loaded N-succinyl chitosan nanoparticles (NSC NP) to target colon cancer. NSC NP showed a pH sensitive swelling at colonic pH and exhibited a sequential release pattern for both the drugs. Binary drug combination exhibited a synergistic cytotoxicity against HT-29 colon cancer cells with a remarkable G2/M phase arrest. Specifically, in vivo antitumor efficacy study showed that NSC NP prolonged the survival time of tumor-bearing mice up to 45 days wherein 50% of mice were still alive. Therefore, these results suggest that co-delivery of drugs with a suitable delivery system could potentially improve the therapeutic efficacy in colon cancers. The study can be further continued by using different types of chemotherapeutic drugs that targets different molecular targets using pH-sensitive nanocarriers. PMID:24941086

  2. The Formulation of Aptamer-Coated Paclitaxel-Polylactide Nanoconjugates and Their Targeting to Cancer Cells

    PubMed Central

    Tong, Rong; Yala, Linda; Fan, Timothy M.; Cheng, Jianjun

    2011-01-01

    Paclitaxel-polylactide (Ptxl-PLA) conjugate nanoparticles, termed as nanoconjugates (NCs), were prepared through Ptxl/(BDI)ZnN(TMS)2 (BDI = 2-((2,6-diisopropylphenyl)-amido)-4-((2,6-diisopropylphenyl)-imino)-2-pentene)-mediated controlled polymerization of lactide (LA) followed by nanoprecipitation. Nanoprecipitation of Ptxl-PLA resulted in sub-100 nm NCs with monomodal particle distributions and low polydispersities. The sizes of Ptxl-PLA NCs could be precisely controlled by using appropriate water-miscible solvents and by controlling the concentration of Ptxl-PLA during nanoprecipitation. Co-precipitation of a mixture of PLA-PEG-PLA (PLA = 14 kDa; PEG = 5kDa) and Ptxl-PLA in PBS resulted in NCs that could stay non-aggregated in PBS for an extended period of time. To develop solid formulations of NCs, we evaluated a series of lyoprotectants, aiming to identify candidates that could effectively reduce or eliminate NC aggregation during lyophilization. Albumin was found to be an excellent lyoprotectant for the preparation of NCs in solid form, allowing lyophilized NCs to be readily dispersed in PBS without noticeable aggregates. Aptamer-NCs bioconjugates were prepared and found to be able to effectively target prostate-specific membrane antigen in a cell-specific manner. PMID:20122727

  3. PEG-Derivatized Embelin as a Dual Functional Carrier for the Delivery of Paclitaxel

    PubMed Central

    Huang, Yixian; Lu, Jianqin; Gao, Xiang; Li, Jiang; Zhao, Wenchen; Sun, Ming; Stolz, Donna Beer; Venkataramanan, Raman; Rohan, Lisa Cencia; Li, Song

    2012-01-01

    Embelin, identified primarily from the Embelia ribes plant, has been shown to be a natural small molecule inhibitor of X-linked inhibitor of apoptosis protein (XIAP). It is also a potent inhibitor of NF-?B activation, which makes it a potentially effective suppressor of tumor cell survival, proliferation, invasion, angiogenesis, and inflammation. However, embelin itself is insoluble in water, which makes it unsuitable for in vivo applications. In this work, we developed a novel micelle system through conjugating embelin to a hydrophilic polymer, polyethylene glycol 3,500 (PEG3.5K) through an aspartic acid bridge. The PEG3.5k-embelin2 (PEG3.5k-EB2) conjugate readily forms micelles in aqueous solutions with a CMC of 0.0205mg/mL. Furthermore, PEG3.5k-EB2 micelles effectively solubilize paclitaxel (PTX), a model hydrophobic drug used in this study. Both drug-free and drug-loaded micelles were small in sizes (20 ~ 30 nm) with low polydispersity indexes. In vitro cytotoxicity studies with several tumor cell lines showed that PEG3.5k-EB2 is comparable to embelin in antitumor activity and synergizes with PTX at much lower doses. Our results suggest that PEG-derivatized embelin may represent a novel and dual-functional carrier to facilitate the in vivo applications of poorly water-soluble anticancer drugs such as PTX. PMID:22681537

  4. Covalent functionalization of graphene oxide with biocompatible poly(ethylene glycol) for delivery of paclitaxel.

    PubMed

    Xu, Zhiyuan; Wang, Song; Li, Yongjun; Wang, Mingwei; Shi, Ping; Huang, Xiaoyu

    2014-10-01

    Graphene oxide (GO), a novel 2D nanomaterial prepared by the oxidation of natural graphite, has been paid much attention in the area of drug delivery due to good biocompatibility and low toxicity. In the present work, 6-armed poly(ethylene glycol) was covalently introduced into the surface of GO sheets via a facile amidation process under mild conditions, making the modified GO, GO-PEG (PEG: 65 wt %, size: 50-200 nm), stable and biocompatible in physiological solution. This nanosized GO-PEG was found to be nontoxic to human lung cancer A549 and human breast cancer MCF-7 cells via cell viability assay. Furthermore, paclitaxel (PTX), a widely used cancer chemotherapy drug, was conjugated onto GO-PEG via ?-? stacking and hydrophobic interactions to afford a nanocomplex of GO-PEG/PTX with a relatively high loading capacity for PTX (11.2 wt %). This complex could quickly enter into A549 and MCF-7 cells evidenced by inverted fluorescence microscopy using Fluorescein isothiocyanate as a probe, and it also showed remarkably high cytotoxicity to A549 and MCF-7 cells in a broad range of concentration of PTX and time compared to free PTX. This kind of nanoscale drug delivery system on the basis of PEGylated GO may find potential application in biomedicine. PMID:25216036

  5. 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

  6. Blood viscosity as a sensitive indicator for paclitaxel induced oxidative stress in human whole blood.

    PubMed

    Harisa, Gamaleldin I

    2015-01-01

    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

  7. Engineering erythrocytes as a novel carrier for the targeted delivery of the anticancer drug paclitaxel.

    PubMed

    Harisa, Gamaleldin I; Ibrahim, Mohamed F; Alanazi, Fars; Shazly, Gamal A

    2014-07-01

    Paclitaxel (PTX) is formulated in a mixture of Cremophor EL and dehydrated alcohol. The intravenous administration of this formula is associated with a risk of infection and hypersensitivity reactions. The presence of Cremophor EL as a pharmaceutical vehicle contributes to these effects. Therefore, in this study, we used human erythrocytes, instead of Cremophor, as a pharmaceutical vehicle. PTX was loaded into erythrocytes using the preswelling method. Analysis of the obtained data indicates that 148.8 ?g of PTX was loaded/mL erythrocytes, with an entrapment efficiency of 46.36% and a cell recovery of 75.94%. Furthermore, we observed a significant increase in the mean cell volume values of the erythrocytes, whereas both the mean cell hemoglobin and the mean cell hemoglobin concentration decreased following the loading of PTX. The turbulence fragility index values for unloaded, sham-loaded and PTX-loaded erythrocytes were 3, 2, and 1 h, respectively. Additionally, the erythrocyte glutathione level decreased after PTX loading, whereas lipid peroxidation and protein oxidation increased. The release of PTX from loaded erythrocytes followed first-order kinetics, and about 81% of the loaded drug was released into the plasma after 48 h. The results of the present study revealed that PTX was loaded successfully into human erythrocytes with acceptable loading parameters and with some oxidative modification to the erythrocytes. PMID:25061408

  8. Reciprocal competition between lipid nanocapsules and P-gp for paclitaxel transport across Caco-2 cells.

    PubMed

    Roger, E; Lagarce, F; Garcion, E; Benoit, J-P

    2010-08-11

    Lipid nanocapsules (LNCs) have been shown to improve paclitaxel (Ptx) bioavailability and transport across an intestinal barrier model. In the present study, the interaction between P-glycoprotein (P-gp) and LNC transport across Caco-2 cells are investigated. Transport experiments have been performed on Caco-2 cells displaying different P-gp activities (early and later cell passages). The permeability of Ptx encapsulated in LNCs has been studied in the presence of P-gp inhibitors (verapamil and vinblastin) or unloaded LNCs. The uptake of dye-labelled LNCs was also observed in the presence of the same inhibitors. It was found that the permeability of Ptx varied depending on the passages with later ones showing higher absolute values (5.74+/-1.21 cms(-1) vs 133.41+/-5.74 cms(-1)). P-gp inhibition obtained with verapamil or vinblastin improved Ptx transport up to 98%. LNCs have also demonstrated their capacity to increase their own transport. Experiments performed with dye-labelled LNCs demonstrated an enhancement of the uptake of dye (Nile red), only in the presence of verapamil. These results demonstrated an effect of P-gp on the transport of Ptx when loaded in LNCs and support a direct effect of P-gp on their endocytosis in Caco-2 cells. These finding may assist in the development of new nanomedicine for oral administration. PMID:20438839

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

    2015-01-01

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

  11. nab-Paclitaxel for the treatment of aggressive metastatic breast cancer.

    PubMed

    Glück, Stefan

    2014-08-01

    Despite advances in early diagnosis, prevention, and treatment, breast cancer remains the second-leading cause of cancer-related deaths in women. The 5-year survival rate for patients with metastatic breast cancer (MBC) is just 24%. However, some forms of MBC appear to be more aggressive than others. Triple-negative breast cancer (TNBC; lacking overexpression of human epidermal growth factor receptor 2 [HER2] and expression of estrogen and progesterone receptors) and breast cancers that overexpress HER2 are the 2 biologically defined subtypes with the worst prognoses. Although a number of effective options have been developed for the treatment of HER2-overexpressing disease, TNBC remains a difficult-to-treat subtype. In addition to hormone receptor and HER2 status, multiple other factors are predictive of relatively poorer clinical outcomes, including visceral metastasis, short disease-free interval between the end of treatment for early-stage disease and diagnosis of MBC, and higher number of metastatic sites. There is an urgent need to improve therapy for patients with aggressive forms of breast cancer. Taxanes are considered among the most active classes of compounds against breast cancer. This review specifically examines the clinical trials in which nab-paclitaxel was used to treat patients with MBC and factors associated with poor prognosis. PMID:24806278

  12. [Clinical experience of nab-Paclitaxel treatment in 31 patients with breast cancer].

    PubMed

    Tauchi, Yukie; Kashiwagi, Shinichiro; Ishihara, Sae; Asano, Yuka; Sakimura, Chie; Kurata, Kento; Tokumoto, Mao; Morisaki, Tamami; Noda, Satoru; Kawajiri, Hidemi; Takashima, Tsutomu; Onoda, Naoyoshi; Hirakawa, Kosei

    2014-11-01

    Nanoparticle albumin-bound paclitaxel (nab-PTX, Abraxane®) does not require premedication, and it can be used for patients with alcohol intolerance. We administered nab-PTX to 31 patients with breast cancer between October 2010 and April 2013. Eighteen patients had progressive, recurring breast cancers and 13 patients had locally advanced operable breast cancers. The treatment schedules were 175 or 260 mg/m² every 3 weeks (q3w). No patient experienced an allergic reaction. Grade 1-3 sensory neuropathies were observed in 20 patients; however, no patient experienced grade 4 neuropathy. In patients with locally advanced, operable breast cancer, 1 patient treated with 175 mg/m² q3w had a partial response (PR), while of the patients treated with 260 mg/m² q3w, 10 patients showed a PR, and 1 patient had stable disease (SD). Of the patients with progressive, recurring breast cancer, 2 patients showed a PR and 4 patients had SD when treated with 175 mg/m² q3w, whereas 1 patient displayed a PR and 1 patient had SD when treated with 260 mg/m² q3w. Our investigation suggests that nab-PTX is well tolerated, even by patients with advanced breast cancer. PMID:25731385

  13. Management of peripheral neuropathy induced by nab-paclitaxel treatment for breast cancer.

    PubMed

    Ohno, Tsuyoshi; Mine, Takashi; Yoshioka, Hiroki; Kosaka, Mikiko; Matsuda, Sadayuki; De Kerckhove, Maiko; De Kerckhove, Charles; Irie, Junji; Inoue, Keiji; Haraguchi, Masashi; Kitajima, Masachika; Shinichiro, Ito; Tokai, Hirotaka; Tanaka, Takayuki; Izumida, Ryoko

    2014-08-01

    Nanoparticle albumin-bound paclitaxel (nab-PTX) is a key drug used in breast cancer treatment which often causes chemotherapy-induced peripheral neuropathy (CIPN). No effective approach for CIPN control has been established to date. This study assessed a new approach to CIPN integrating two concepts: compression therapy using stockings and sleeves, and medication therapy using selected prophylactic drugs, including goshajinkigan, which we named the "3S" approach. Fourteen breast cancer patients were divided into a 3S group (n=7) and a control group (n=7), and were treated with 260 mg/m(2) of nab-PTX once every three weeks. CIPN initially developed in five control-group patients and one 3S-group patient (p=0.03). Across all cycles, the CIPN grades, as determined by the Common Terminology Criteria for Adverse Events (CTCAE), were significantly lower in the 3S group than in the control group (p<0.001). The mean nab-PTX dose in the 3S group was 77.1 mg/m(2)/week versus 64.7 mg/m(2)/week in the control group (p<0.01). By controlling the development and severity of CIPN, 3S treatment appears to support the use of the recommended nab-PTX dosing for breast cancer patients. PMID:25075049

  14. Liposomal co-delivery of curcumin and albumin/paclitaxel nanoparticle for enhanced synergistic antitumor efficacy.

    PubMed

    Ruttala, Hima Bindu; Ko, Young Tag

    2015-04-01

    Paclitaxel (PTX) and curcumin (CUR) are potent chemotherapeutic agents used in the treatment of cancer. In the present study, hybrid polymer-lipid nanoparticles co-loaded with PTX and CUR were developed to investigate the therapeutic potential of a combination drug regimen. For this purpose, PTX-loaded albumin nanoparticles (APN) were prepared and encapsulated in PEGylated hybrid liposomes containing CUR (CL-APN) via a thin-film hydration technique. CL-APN was nanosized with a uniform spherical morphology. PTX and CUR release was sustained and occurred in a sequential manner, wherein CUR was expected to downregulate the nuclear factor NF-?B and Akt pathways and increase the therapeutic efficacy of PTX. The ratiometric combination of PTX and CUR was significantly more cytotoxic than the individual drugs. Importantly, dual-drug-loaded nanocarriers exhibited a superior cytotoxic effect than a cocktail combination at a lower dose. CL-APN induced significantly higher early and late apoptosis, induced a stronger G2/M arrest, and significantly increased the subG1 cell population. By combining CUR, an effective NF-?B inhibitor, with PTX, a powerful anticancer drug, in a polymer-lipid hybrid nanoparticle system, we could improve the therapeutic efficacy in cancer treatments. Our results showed that such co-loaded delivery systems could serve as a promising therapeutic approach to improve clinical outcomes against various malignancies. PMID:25797481

  15. AKT/ERK activation is associated with gastric cancer cell resistance to paclitaxel

    PubMed Central

    Wu, Gang; Qin, Xue-Qian; Guo, Jing-Jing; Li, Tian-Yi; Chen, Jin-Hong

    2014-01-01

    Paclitaxel (PTX) has shown encouraging activity in the treatment of advanced gastric cancer (GC). However, the fact that more than half of GC patients respond poorly to PTX-based chemotherapies demonstrates the urgent need for biomarkers of PTX sensitivity in GC patients. In the present work, three GC cell lines (BGC-823, HGC-27 and NCI-N87) with different sensitivities to PTX were subjected to DNA microarray analysis. The significantly differentially expressed genes and microRNAs (miRs) were identified and pathway signatures for PTX sensitivity were proposed. Ingenuity Pathway Analysis results showed that the differentially expressed genes were mainly enriched in the ErbB signaling pathway and other pathways. Additionally, the AKT/ERK signaling pathway, which is the pathway downstream of ErbB, was predicted to be active in PTX-resistant GC cell lines. ErbB3 overexpression and AKT/ERK activation in PTX-resistant cell lines were validated, respectively, by quantitative PCR and immunoblotting. Furthermore, 10 miRs were dramatically differently expressed in the three GC cell lines, and a miR-gene network was constructed from these data. Our work uncovered a reliable signature for PTX sensitivity in GC and potential therapeutic targets for GC treatments. PMID:24817940

  16. 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

  17. 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

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

    PubMed Central

    Abouzeid, Abraham H.; Patel, Niravkumar R.

    2014-01-01

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

  19. 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.

  20. Optimization of the fractional precipitation of paclitaxel from a Taxus chinensis cell culture using response surface methodology and its isolation by consecutive high-speed countercurrent chromatography.

    PubMed

    Liang, Zhikun; Xie, Zhisheng; Lam, Shingchung; Xu, Xinjun

    2014-09-01

    A consecutive preparation method for the isolation and purification of paclitaxel from the Taxus Chinensis cell culture was developed in this study. The process involved alkaline Al2O3 chromatography, fractional precipitation, and high-speed countercurrent chromatography. The original cell culture materials were first extracted with methanol using ultrasound-assisted extraction, and then the extract (the content of paclitaxel is 1.5%) was separated by alkaline Al2O3 column chromatography. Subsequently, fractional precipitation was used to obtain paclitaxel. In particular, response surface methodology was used to optimize the factors of fractional precipitation (methanol concentration, material-to-solvent ratio, and precipitating time were optimized as 48.14%, 8.85 mg/mL, and 48.71 h, respectively) and the yield of fractional precipitation product was 30.64 ± 0.60 mg (the content of paclitaxel is 89.3%, 27.37 ± 0.54 mg) from a 100 mg fraction by Al2O3 column separation (the content of paclitaxel is 32.4%). Then, the product was used for further isolation by high-speed countercurrent chromatography. About 1.00 g paclitaxel (200 ± 2 mg in each loading) with a purity up to 99.61% was isolated from 1.25 g of fractional precipitation product with a solvent system of n-hexane/ethyl acetate/methanol/water (1.2:1.8:1.5:1.5, v/v/v/v) in one run of five consecutive sample loadings without exchanging a new solvent system. PMID:24945899

  1. Tumor suppressor BLU promotes paclitaxel antitumor activity by inducing apoptosis through the down-regulation of Bcl-2 expression in tumorigenesis.

    PubMed

    Park, Sung Taek; Byun, Hyun-Jung; Kim, Boh-Ram; Dong, Seung Myung; Park, Sung Ho; Jang, Pong Rheem; Rho, Seung Bae

    2013-05-24

    In this current work, we investigated whether BLU could enhance pro-apoptotic activity of chemotherapeutic drugs in ovarian carcinoma cells. A combination with a chemotherapeutic drug showed an additive effect, and this additive effect was supplemented by the enhancement of caspase-3 and -9 activities. BLU and paclitaxel induced cell cycle arrest in the G2/M phase through the reduction of cyclin dependent kinase 1, cyclin B1, while promoting both p16 and p27 expression. In addition, both BLU and paclitaxel enhanced the expression of the pro-apoptotic protein Bax together with the suppression of anti-apoptotic protein Bcl-2, a protein which is well-known for its function as a regulator in protecting cells from apoptosis. As expected, the Bax and p21 activities were enhanced by BLU or paclitaxel, while a combination of BLU and paclitaxel were additively promoted, whereas Bcl-xL and NF-?B including Bcl-2 activity were inactivated. This study has yielded promising results, which evidence for the first time that BLU could suppress the growth of carcinoma cells. Furthermore, both BLU and paclitaxel inhibited the phosphorylation of signaling components downstream of phosphoinositide 3-kinase, such as 3-phosphoinositide-dependent protein kinase 1, and Akt. Also, BLU plus paclitaxel decreased phosphorylation of p70 ribosomal S6 kinase, as well as decreasing the phosphorylation of glycogen synthase kinase-3?, which is one of the representative targets of the mammalian target of rapamycin signaling cascade. These results provide evidence that BLU enhances G2/M cell cycle arrest and apoptotic cell death through the up-regulation of Bax, p21 and p53 expression. PMID:23628417

  2. A phase II trial of weekly chemotherapy with paclitaxel plus gemcitabine as a first-line treatment in advanced non-small-cell lung cancer

    Microsoft Academic Search

    Kiyoshi Mori; Hiroyuki Kobayashi; Yukari Kamiyama; Yasuhiko Kano; Tetsuro Kodama

    2009-01-01

    Purpose  The efficacy and toxicity of combined paclitaxel (PTX) and gemcitabine (GEM) was evaluated as a protocol for first-line chemotherapy\\u000a in 40 patients with advanced non-small-cell lung cancer (NSCLC).\\u000a \\u000a \\u000a \\u000a Methods  Paclitaxel, 100 mg\\/m2, was administered intravenously (IV) as a 1-h infusion, followed by GEM, 1,000 mg\\/m2, IV over 30 min on days 1 and 8 of a 21-day cycle. The median age of patients was

  3. Hydrogel Matrix Entrapping PLGA-Paclitaxel Microspheres: Drug Delivery with Near Zero-Order Release and Implantability Advantages for Malignant Brain Tumour Chemotherapy

    Microsoft Academic Search

    Sudhir Hulikal Ranganath; Irene Kee; William B. Krantz; Pierce Kah-Hoe Chow; Chi-Hwa Wang

    2009-01-01

    Purpose  To develop paclitaxel-delivering PLGA microspheres entrapped in a gel matrix with sustained drug release properties and implantability\\u000a advantages for local glioma chemotherapy.\\u000a \\u000a \\u000a \\u000a Methods  Paclitaxel-loaded PLGA microspheres were fabricated using electrohydrodynamic atomization and entrapped by electrospray and\\u000a gelation. The physicochemical characterizations were performed using scanning electron microscopy and differential scanning\\u000a calorimetry. The influence of various parameters on the disintegration time was investigated.

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

    PubMed

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

    2010-12-01

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

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

    PubMed Central

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

    2002-01-01

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

  6. Rapid tumor necrosis and massive hemorrhage induced by bevacizumab and paclitaxel combination therapy in a case of advanced breast cancer

    PubMed Central

    Ono, Mayu; Ito, Tokiko; Kanai, Toshiharu; Murayama, Koichi; Koyama, Hiroshi; Maeno, Kazuma; Mochizuki, Yasuhiro; Iesato, Asumi; Hanamura, Toru; Okada, Toshihiro; Watanabe, Takayuki; Ito, Ken-ichi

    2013-01-01

    Bevacizumab when combined with chemotherapy exerts significant activity against many solid tumors through tumor angiogenesis inhibition; however, it can induce severe side effects. We report the rare case of a 27-year-old premenopausal woman with locally advanced breast cancer that was marked by rapid tumor necrosis followed by massive hemorrhage shortly after bevacizumab and paclitaxel administration. On the basis of histopathological examination of a biopsy specimen and computed tomography findings, she was diagnosed with stage IV estrogen and progesterone receptor-negative and human epidermal growth factor receptor type 2-positive breast cancer with multiple organ metastases when she had entered gestational week 24. Cyclophosphamide, Adriamycin®, fluorouracil therapy was initiated, but multiple liver metastases continued to progress. A healthy fetus was delivered by induced delivery and trastuzumab-based treatment was initiated. Although the multiple liver metastases were controlled successfully by trastuzumab combined with paclitaxel, the primary tumor continued to expand even after subsequent administration of three other treatment regimens including anti-human epidermal growth factor receptor type 2 agents and cytotoxic drugs. To inhibit primary tumor growth, a combination therapy with paclitaxel and bevacizumab was subsequently initiated. Following therapy initiation, however, the large tumor occupying the patient’s entire left breast became necrotic and ulcerated rapidly. Furthermore, massive hemorrhage from the tumor occurred 5 weeks after bevacizumab-based therapy initiation. Although hemostasis was achieved by manual compression, the patient required blood transfusion for the massive blood loss. She eventually succumbed to respiratory failure. This case report demonstrates that primary breast cancer lesions with skin involvement have the potential to cause massive hemorrhage after bevacizumab-based treatment. PMID:24124381

  7. 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.

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

    PubMed

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

    2012-08-01

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

  9. Cytotoxicity of Paclitaxel in Biodegradable Self-Assembled Core-Shell Poly(Lactide-Co-Glycolide Ethylene Oxide Fumarate) Nanoparticles

    Microsoft Academic Search

    Xuezhong He; Junyu Ma; Angel E. Mercado; Weijie Xu; Esmaiel Jabbari

    2008-01-01

    Purpose  Biodegradable core-shell polymeric nanoparticles (NPs), with a hydrophobic core and hydrophilic shell, are developed for surfactant-free\\u000a encapsulation and delivery of Paclitaxel to tumor cells.\\u000a \\u000a \\u000a \\u000a Methods  Poly (lactide-co-glycolide fumarate) (PLGF) and Poly (lactide-fumarate) (PLAF) were synthesized by condensation polymerization\\u000a of ultra-low molecular weight poly(l-lactide-co-glycolide) (ULMW PLGA) with fumaryl chloride (FuCl). Similarly, poly(lactide-co-ethylene oxide fumarate) (PLEOF)\\u000a macromer was synthesized by reacting ultra-low molecular

  10. 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

  11. Lactoferrin-appended solid lipid nanoparticles of