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1

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

SciTech Connect

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

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

1994-06-15

2

Crystal and molecular structure of paclitaxel (taxol).  

PubMed Central

Paclitaxel (formerly called taxol), an important anticancer drug, inhibits cell replication by binding to and stabilizing microtubule polymers. As drug-receptor interactions are governed by the three-dimensional stereochemistries of both participants, we have determined the crystal structure of paclitaxel to identify its conformational preferences that may be related to biological activity. The monoclinic crystals contain two independent paclitaxel molecules in the asymmetric unit plus several water and dioxane solvent molecules. Taxane ring conformation is very similar in both paclitaxel molecules and is similar to the taxane ring conformation found in the crystal structure of the paclitaxel analogue docetaxel (formerly called taxotere). The two paclitaxel molecules have carbon-13 side-chain conformations that differ from each other and from that of the corresponding side chain in the docetaxel crystal structure. The carbon-13 side-chain conformation of one paclitaxel molecule is similar to what was proposed from NMR studies done in polar solvents, while that of the other paclitaxel molecule is different and hitherto unobserved. The paclitaxel molecules interact with each other and with solvent atoms through an extensive network of hydrogen bonds. Analysis of the hydrogen-bonding network together with structure-activity studies may suggest which atoms of paclitaxel are important for binding to microtubule receptors.

Mastropaolo, D; Camerman, A; Luo, Y; Brayer, G D; Camerman, N

1995-01-01

3

Microtubule-Disrupting Agents Inhibit Nitric Oxide Production in Murine Peritoneal Macrophages Stimulated with Lipopolysaccharide or Paclitaxel (Taxol)  

Microsoft Academic Search

Paclitaxel (Taxol), a yew-derived antimitotic agent which binds to microtubules, can mimic certain effects of lipopolysaccharide (LPS) on macrophages from LPS responder mouse strains. The production of nitric oxide (NO) by the peritoneal macrophages of LPS responder C3H\\/HeN mice stimulated with taxol or LPS was partially, but not completely, suppressed by microtubule-disrupting agents, such as colchicine, podophyllo- toxin,vinblastine,andnocodazole,butnotbylumicolchicine,aninactivederivativeofcolchicine.InducibleNO synthase protein

TERUO KIRIKAE; FUMIKO KIRIKAE; YOICHI OGHISO; ANDMASAYASU NAKANO

1996-01-01

4

Paclitaxel (Taxol(R)) inhibits motility of paclitaxel-resistant human ovarian carcinoma cells.  

PubMed

The effect of paclitaxel on the adhesive and motility properties of human ovarian carcinoma cell lines was investigated. Paclitaxel significantly inhibited the motility of OVCAR 5, SK-OV-3, and HOC-1OTC ovarian carcinoma cell lines (IC50 = 2.1 x 10(-8), 2 x 10(-9), and 1.9 x 10(-8) m, respectively) but did not affect the adhesion of these cells to the subendothelial matrix. The association between inhibition of motility and cytotoxic activity was investigated using an A2780 subclone (1A9) and three paclitaxel-resistant variants (designated 1A9/PTX22, 1A9/PTX10, and 1A9/PTX18). Although paclitaxel did not significantly affect the adhesion to subendothelial matrix of the sublines, it completely inhibited their migration. Inhibition of migration was similar in 1A9 cells and the resistant sublines, with an IC50 of 1 x 10(-8) for 1A9 cells and 5.4 x 10(-9), 1.1 x 10(-8), and 5.2 x 10(-9) m for 1A9/PTX22, 1A9/PTX10, and 1A9/PTX18, respectively. Paclitaxel inhibited motility induced by soluble attractant (chemotaxis) and immobilized attractant (haptotaxis). Inhibition of cell motility occurred in the absence of an antiproliferative effect, because higher concentrations of paclitaxel were required to inhibit tumor cell proliferation (IC50 = 1.9 x 10(-7) and 4.6 x 10(-6), 1 x 10(-5), and 3.1 x 10(-6) m for 1A9 and 1A9/PTX22, 1A9/PTX10, and 1A9/PTX18, respectively). These data show that paclitaxel is a potent inhibitor of ovarian carcinoma cell motility and that this activity is independent of its cytotoxic activity. PMID:9816123

Belotti, D; Rieppi, M; Nicoletti, M I; Casazza, A M; Fojo, T; Taraboletti, G; Giavazzi, R

1996-10-01

5

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

PubMed

Paclitaxel (PTXL) (Taxol), a taxane, and vinorelbine (VRB), a semisynthetic vinca alkaloid drug, have tubulin as their common intracellular target, but inhibit growth by binding to different sites. We evaluated in vitro the antiproliferative activity of these two drugs as single agents and in combination, against two human melanoma cell lines, G361 and StM111a. The SRB (sulphorhodamine B) assay was used to determine growth inhibition. Possible drug-drug interaction at the cellular level was assessed by constructing Isoboles (Isobologram analysis) and applying the concept of an 'envelope of additivity'. Both agents were active in the nanomolar range at clinically achievable concentrations. The mean IC50 for G361 was 46.6 nM (PTXL) and 19.9 nM (VRB) after a 1 h drug exposure. Mean IC50 (1 h) for StM111a was 9.7 nM (PTXL) and 26.9 nM (VRB). Isobole analysis at the isoeffect levels of 25%, 50% and 75% indicated that drug interaction was predominantly synergistic (supra-additive) when paclitaxel and VRB were added concurrently for 1 h to cultures of StM11 1a or G361. In some experiments, this synergy was observed with particularly low concentrations of paclitaxel (3 nM) and VRB (0.01 nM). A new points were located within the envelope of additivity or in the subadditive (antagonism) region of the isobole. An overall synergy was also found if the data were analysed by the median effect analysis. The effect of these agents on the cytoskeleton and ultrastructure were studied with immunofluorescence and electron microscopy, respectively. These results confirm the in vitro inhibitory activity of paclitaxel and VRB against malignant melanoma, but more importantly the two drugs appear to act synergistically at relatively low concentrations. PMID:9155533

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

1997-03-01

6

Paclitaxel (Taxol) upregulates expression of functional interleukin-6 in human ovarian cancer cells through multiple signaling pathways  

Microsoft Academic Search

Paclitaxel (Taxol) is an antineoplastic agent that specifically targets microtubules and arrests cells at the G2\\/M phase of the cell cycle. In addition to mitotic arrest, the activation of c-Jun N-terminal kinase (JNK) signaling pathway has been demonstrated to be involved in the process leading to apoptosis. In an attempt to explore what genes are transcriptionally regulated by the activated

T-H Wang; Y-H Chan; C-W Chen; W-H Kung; Y-S Lee; S-T Wang; T-C Chang; H-S Wang

2006-01-01

7

Synergistic effect of a retinoid X receptor-selective ligand bexarotene (LGD1069, Targretin) and paclitaxel (Taxol) in mammary carcinoma  

Microsoft Academic Search

We have previously shown that the retinoid X receptor (RXR) ligand bexarotene (LGD1069, Targretin) is efficacious as a chemopreventive and chemotherapeutic agent in rat N-nitroso-N-methylurea (NMU)-induced mammary carcinomas (Cancer Res 58: 479–484, 1998). To determine additional role for bexarotene in breast cancer treatment, we evaluated the effect of bexarotene on the efficacy of paclitaxel (Taxol) treatment in a rat NMU-derived

Wan-ching Yen; Rene Y. Prudente; William W. Lamph

2004-01-01

8

In vivo Toxicity and Bioavailability of Taxol ® and a Paclitaxel\\/?-Cyclodextrin Formulation in a Rat Model During HIPEC  

Microsoft Academic Search

Background  Peritoneal carcinomatosis (PC) remains a dreaded clinical syndrome and a common evolution of gastrointestinal and ovarian\\u000a cancers. In recent years, hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery has emerged as a promising\\u000a strategy in the management of PC. In this study, a novel paclitaxel (Pac) formulation was investigated for its toxicity and\\u000a bioavailability during HIPEC compared with Taxol®.\\u000a \\u000a \\u000a \\u000a \\u000a Materials and

W. Bouquet; W. Ceelen; E. Adriaens; A. Almeida; T. Quinten; F. De Vos; P. Pattyn; M. Peeters; J. P. Remon; C. Vervaet

2010-01-01

9

Metabolic engineering of taxadiene biosynthesis in yeast as a first step towards Taxol (Paclitaxel) production  

Microsoft Academic Search

Metabolic engineering in microbes could be used to produce large amounts of valuable metabolites that are difficult to extract from their natural sources and too expensive or complex to produce by chemical synthesis. As a step towards the production of Taxol in the yeast Saccharomyces cerevisiae, we introduced heterologous genes encoding biosynthetic enzymes from the early part of the taxoid

Benedikt Engels; Pia Dahm; Stefan Jennewein

2008-01-01

10

Dose-finding study of paclitaxel (Taxol) plus cisplatin in patients with non-small cell lung cancer.  

PubMed

We present preliminary results of a study undertaken in previously untreated patients with non-small cell lung cancer to determine the maximum tolerated dose of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) when administered as a 3-hour intravenous infusion in combination with cisplatin every 3 weeks; to evaluate the nature, frequency, severity, and duration of adverse events associated with this drug combination; and to evaluate the combination's antitumor efficacy. Thus far, we have treated 10 patients with cisplatin (100 mg/m2) and increasing doses of paclitaxel (135, 170, and 200 mg/m2). Among nine evaluable patients, four partial responses have been obtained, disease in three patients progressed after three courses, and no changes were seen in one patient. One patient had two cardiac arrests within 8 days of the onset of therapy, from which he recovered; he died 1 month later of massive hemoptysis. Thrombocytopenia was not seen in these patients, and neutropenia (< 1,000 granulocytes/microL) was seen in only three patients. Infections were seen in these patients and were manageable in all cases. Other toxicities consisted mainly of World Health Organization grades II and III alopecia and nausea and/or vomiting. No grade III nephrotoxicity, neurotoxicity, hypersensitivity, mucositis, or infection was seen in this series after one to three courses of chemotherapy; one patient presented with grade IV cardiotoxicity 6 days after the onset of therapy. So far, the maximum tolerated dose of the cisplatin/paclitaxel combination has not been reached; however, definitive conclusions await the full treatment of additional patients. Moreover, the possibility of cumulative and delayed toxicity must be evaluated after a sufficient duration of follow-up in adequate numbers of patients. PMID:7939762

Klastersky, J; Sculier, J P

1994-10-01

11

Effect of paclitaxel (Taxol) alone and in combination with radiation on the gastrointestinal mucosa  

Microsoft Academic Search

Purpose: Paclitaxel is a potentially useful drug for augmenting the cytotoxic action of radiotherapy because it has independent cytotoxic activity against certain cancers and blocks cells in the radiosensitive mitotic phase of the cell cycle. However, all rapidly proliferating tissues, both normal and neoplastic, may be affected by this therapeutic strategy. The aim of this study was to define the

Kathryn Ann Mason; Luka Milas; Lester J. Peters

1995-01-01

12

Metabolic engineering of taxadiene biosynthesis in yeast as a first step towards Taxol (Paclitaxel) production.  

PubMed

Metabolic engineering in microbes could be used to produce large amounts of valuable metabolites that are difficult to extract from their natural sources and too expensive or complex to produce by chemical synthesis. As a step towards the production of Taxol in the yeast Saccharomyces cerevisiae, we introduced heterologous genes encoding biosynthetic enzymes from the early part of the taxoid biosynthetic pathway, isoprenoid pathway, as well as a regulatory factor to inhibit competitive pathways, and studied their impact on taxadiene synthesis. Expression of Taxus chinensis taxadiene synthase alone did not increase taxadiene levels because of insufficient levels of the universal diterpenoid precursor geranylgeranyl diphosphate. Coexpression of T. chinensis taxadiene synthase and geranylgeranyl diphosphate synthase failed to increase levels, probably due to steroid-based negative feedback, so we also expressed a truncated version of 3-hydroxyl-3-methylglutaryl-CoA reductase (HMG-CoA reductase) isoenzyme 1 that is not subject to feedback inhibition and a mutant regulatory protein, UPC2-1, to allow steroid uptake under aerobic conditions, resulting in a 50% increase in taxadiene. Finally, we replaced the T. chinensis geranylgeranyl diphosphate synthase with its counterpart from Sulfolobus acidocaldarius, which does not compete with steroid synthesis, and codon optimized the T. chinensis taxadiene synthase gene to ensure high-level expression, resulting in a 40-fold increase in taxadiene to 8.7+/-0.85mg/l as well as significant amounts of geranylgeraniol (33.1+/-5.6mg/l), suggesting taxadiene levels could be increased even further. This is the first demonstration of such enhanced taxadiene levels in yeast and offers the prospect for Taxol production in recombinant microbes. PMID:18485776

Engels, Benedikt; Dahm, Pia; Jennewein, Stefan

2008-03-26

13

Fatal poisoning with Taxus baccata: quantification of paclitaxel (taxol A), 10-deacetyltaxol, baccatin III, 10-deacetylbaccatin III, cephalomannine (taxol B), and 3,5-dimethoxyphenol in body fluids by liquid chromatography-tandem mass spectrometry.  

PubMed

This method development was to confirm the fatal ingestion of toxic yew plant material in postmortem samples (stomach content, urine, femoral blood, cardiac blood, bile, and brain tissue) collected from a 22-year-old man who committed suicide by ingesting yew leaves. The analytical method was based on a liquid-liquid extraction under alkaline conditions followed by LC-MS-MS analysis. Chromatographic separation was achieved by HPLC on a Kinetex C18 2.6u (100 × 3 mm) coupled to a QTRAP 5500 system. The method allows the simultaneous identification and quantification of the yew alkaloids taxoids paclitaxel (taxol A), 10-deacetyltaxol, baccatin III, 10-deacetylbaccatin III, cephalomannine (taxol B), and 3,5-dimethoxyphenol; the alkaloidal diterpenoids monoacetyltaxine, taxine B, monohydroxydiacetyltaxine, triacetyltaxine, and monohydroxytriacetyltaxine were also identified. The initial hypothesis of yew tree (Taxus baccata) poisoning was confirmed. The quantitative evaluation revealed taxoid concentrations ranging from 4.5 to 132 µg/L (stomach content), 1 to 200 µg/L (urine), <0.5 to 12 µg/L (cardiac blood), <0.5 to 7.3 µg/L (femoral blood), and 4.9 to 290 µg/L (bile). In brain tissue, none of these taxoids could be detected (<0.5 µg/L). In urine, after enzymatic hydrolysis, the concentration of 3,5-dimethoxyphenol (3,5-DMP) was 23,000 µg/L. The alkaloidal diterpenoids were found in all postmortem samples. The newly developed LC-MS-MS method enables the identification of alkaloidal and non-alkaloidal diterpenoids and 3,5-dimethoxyphenol in human body fluids and tissues for the confirmation of accidental or intentional poisonings with yew plant material. PMID:22290751

Grobosch, T; Schwarze, B; Stoecklein, D; Binscheck, T

14

Drug interaction studies between paclitaxel (Taxol) and OC144-093 — A new modulator of MDR in cancer chemotherapy  

Microsoft Academic Search

Summary  The MDR modulator, OC144-093, is a potential candidate for use in cancer therapy and exhibits potent biological activityin vitro andin vivo when combined with anticancer agents such as paclitaxel [1]. Its inhibitory interaction with P-glycoprotein (Pgp), the mdr1\\u000a gene product and a mechanistic participant in multidrug resistance [2], underlies its activity as a modulator of MDR. Having\\u000a previously shown that

Emma S. Guns; Tetyana Denyssevych; Ross Dixon; Marcel B. Bally; Lawrence Mayer

2002-01-01

15

Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine  

PubMed Central

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 this organ. We have used these mdr1a(?/?) mice to study the effect of gut P-glycoprotein on the pharmacokinetics of paclitaxel. The area under the plasma concentration-time curves was 2- and 6-fold higher in mdr1a(?/?) mice than in wild-type (wt) mice after i.v. and oral drug administration, respectively. Consequently, the oral bioavailability in mice receiving 10 mg paclitaxel per kg body weight increased from only 11% in wt mice to 35% in mdr1a(?/?) mice. The cumulative fecal excretion (0–96 hr) was markedly reduced from 40% (after i.v. administration) and 87% (after oral administration) of the administered dose in wt mice to below 3% in mdr1a(?/?) mice. Biliary excretion was not significantly different in wt and mdr1a(?/?) mice. Interestingly, after i.v. drug administration of paclitaxel (10 mg/kg) to mice with a cannulated gall bladder, 11% of the dose was recovered within 90 min in the intestinal contents of wt mice vs. <3% in mdr1a(?/?) mice. We conclude that P-glycoprotein limits the oral uptake of paclitaxel and mediates direct excretion of the drug from the systemic circulation into the intestinal lumen.

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

1997-01-01

16

Interaction of taxol with human serum albumin  

Microsoft Academic Search

Taxol (paclitaxel) is an anticancer drug, which interacts with microtuble proteins, in a manner that catalyzes their formation from tubulin and stabilizes the resulting structures (Nogales et al., Nature 375 (1995) 424–427). This study was designed to examine the interaction of taxol with human serum albumin (HSA) in aqueous solution at physiological pH with drug concentrations of 0.0001–0.1 mM, and

M. Purcell; J. F. Neault; H. A. Tajmir-Riahi

2000-01-01

17

Live morphological analysis of taxol-induced cytoplasmic vacuoliazation in human lung adenocarcinoma cells  

Microsoft Academic Search

Taxol (paclitaxel), one of the most active cancer chemotherapeutic agents, can cause programmed cell death (PCD) and cytoplasmic vacuolization. The objective of this study was to analyze the morphological characteristics induced by taxol. Human lung adenocarcinoma (ASTC-a-1) cells were exposed to various concentration of taxol. CCK-8 was used to assay the cell viability. Atomic force microscopy (AFM), plasmid transfection and

Xiao-Ping Wang; Tong-Sheng Chen; Lei Sun; Ji-Ye Cai; Ming-Qian Wu; Martin Mok

2008-01-01

18

Enhanced Oral Paclitaxel Bioavailability After Administration of Paclitaxel-Loaded Lipid Nanocapsules  

Microsoft Academic Search

\\u000a Purpose  The aim of this study was to evaluate the pharmacokinetics of paclitaxel-loaded lipid nanocapsules (LNC) in rats to assess\\u000a the intrinsic effect of the dosage form on the improvement of paclitaxel oral exposure.\\u000a \\u000a \\u000a \\u000a Methods  Paclitaxel-loaded LNC were prepared and characterized in terms of size distribution, drug payload, and the kinetics of paclitaxel\\u000a crystallization. Taxol, Taxol with verapamil, or paclitaxel-loaded LNC were

Sandra Peltier; Jean-Michel Oger; Frédéric Lagarce; William Couet; Jean-Pierre Benoît

2006-01-01

19

A pilot phase II trial of all- trans retinoic acid (Vesanoid) and paclitaxel (Taxol) in patients with recurrent or metastatic breast cancer  

Microsoft Academic Search

Summary  \\u000a Purpose: We investigated a combination therapy with weekly paclitaxel and all trans-retinoic acid (ATRA) for tolerability, response to treatment, time to progression and survival in previously treated patients\\u000a with metastatic or recurrent breast cancer. Our rationale was based on preclinical studies demonstrating potentiation of the\\u000a cytotoxic effects of taxanes and induction of differentiation by ATRA. Patients and methods: Seventeen

Margarette Bryan; E. Dianne Pulte; Kathleen C. Toomey; Lillian Pliner; Anna C. Pavlick; Tracie Saunders; Robert Wieder

20

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

PubMed Central

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.

Kingston, David G. I.

2007-01-01

21

Elicitation of Taxus sp. cell cultures for production of taxol  

Microsoft Academic Search

The addition of cell extracts and cultures filtrate of Pencillium minioluteum, Botrytis cinerea, Verticillium dahliae, and Gilocladium deliqucescens on the tenth day after transferring Taxus sp. (RO1-M28) cell suspensions into an induction medium, further improved the production of TaxolTaxol is a registered trademark of Bristol Myers Squibb for paclitaxel. and total taxanes. Arachidonic acid (1mg\\/L) addition at the time of

Veeresham Ciddi; Venkatesh Srinivasan; M. L. Shuler

1995-01-01

22

Genes Determining Taxol Sensitivity.  

National Technical Information Service (NTIS)

Taxol is a chemotherapeutic compound that shows high response rate in metastatic breast carcinoma. However, some tumors are intrinsically resistant while others develop resistance to taxol in the course of treatment. We hypothesized that resistance may ar...

E. Kandel

1998-01-01

23

(-)-Epigallocatechin gallate sensitizes breast cancer cells to paclitaxel in a murine model of breast carcinoma  

Microsoft Academic Search

INTRODUCTION: Paclitaxel (Taxol®) is a microtubule-targeted agent that is widely used for cancer treatment. However, resistance to paclitaxel is frequently encountered in the clinic. There is increasing interest in identifying compounds that may increase the sensitivity to conventional chemotherapeutic agents. In this study, we investigated whether green tea polyphenol (-)-epigallocatechin gallate (EGCG) could sensitize breast carcinoma to paclitaxel in vivo.

Ting Luo; Jiao Wang; Yancun Yin; Hui Hua; Jing Jing; Xiangming Sun; Minjing Li; You Zhang; Yangfu Jiang

2010-01-01

24

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

Microsoft Academic Search

The purpose of the study was to delineate the efficacy and toxicity of paclitaxel (Taxol, Bristol Myers Squibb) in the treatment of drug resistant small-cell lung cancer (SCLC). Patients with SCLC relapsing within 3 months of cytotoxic therapy received paclitaxel 175 mg m(-2) intravenously over 3 h every 3 weeks. The dose of paclitaxel was adjusted to the toxicity encountered

EF Smit; E Fokkema; B Biesma; HJM Groen; W Snoek; PE Postmus

1998-01-01

25

Enhancement of Taxol production and excretion in Taxus chinensis cell culture by fungal elicitation and medium renewal  

Microsoft Academic Search

An endophytic fungus, Aspergillus niger, isolated from the inner bark of a Taxus chinensis tree, was used as an elicitor to stimulate the Taxol (paclitaxel) production in a Taxus chinensis cell suspension culture. Different elicitor doses and elicitation times were tested in a batch culture; and the highest volumetric Taxol yield was achieved when 40 mg of the fungal elicitor

Chuangui Wang; Jianyong Wu; Xingguo Mei

2001-01-01

26

Taxol derivatives are selective inhibitors of DNA polymerase alpha.  

PubMed

During screening for mammalian DNA polymerase inhibitors, we found and succeeded in isolating a potent inhibitor from a higher plant, Taxus cuspidate. The compound was unexpectedly determined to be taxinine, an intermediate of paclitaxel (taxol) metabolism. Taxinine was found to selectively inhibit DNA polymerase alpha (pol.alpha) and beta (pol.beta). We therefore, tested taxol and other derivatives and found that taxol itself had no such inhibitory effect, and only taxinine could inhibit both pol.alpha and beta. The other compounds used, one derivative, cephalomannine, and five intermediates synthesized chemically inhibited only the pol.alpha activity in vitro. None of the compounds, including taxinine, influenced the activities of the other DNA polymerases, which are reportedly targeted by many pol.beta inhibitors. With both pol.alpha and beta, all of the compounds tested noncompetitively inhibited with respect to both the DNA template-primer and the dNTP substrate. PMID:15110841

Oshige, Masahiko; Takenouchi, Mika; Kato, Yasutaro; Kamisuki, Sinji; Takeuchi, Toshifumi; Kuramochi, Kouji; Shiina, Isamu; Suenaga, Yoshihito; Kawakita, Yo-ichi; Kuroda, Kazufumi; Sato, Noriyuki; Kobayashi, Susumu; Sugawara, Fumio; Sakaguchi, Kengo

2004-05-15

27

Nitric oxide, cell death and increased taxol recovery  

Microsoft Academic Search

Genes for plant nitric oxide synthase (NOS) now help explain how NO is produced from nitrate, nitrite, and\\/or L-arginine in the culture medium and in cells. Evidence is presented that under aseptic conditions; plant NOS activity, NO bursts, and cell death (apoptosis) are important factors in the recovery of taxol (paclitaxel) from cell suspensions of several Taxus sp. Cell-suspension responses

Don J. DURZAN

2005-01-01

28

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

PubMed Central

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

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

2011-01-01

29

Paclitaxel Nano-Delivery Systems: A Comprehensive Review  

PubMed Central

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.

Ma, Ping; Mumper, Russell J.

2013-01-01

30

Novel Paclitaxel Copolymer for Treatment of Androgen-Independent Prostate Cancer Bone Metastases.  

National Technical Information Service (NTIS)

The human prostatic carcinoma cell lines, PC-3 and bone metastases- derived NDA-PCa-2a and MDA-PCa-2b, are susceptible to apoptotic induction in vitro by Taxol, poly-L-(glutamic acid)-paclitaxel (PGA-TXL) and hyaluronic acid- paclitaxel (HA-TXL). Paclitax...

J. Klostergaard

2004-01-01

31

Taxol biosynthetic genes.  

PubMed

The function and properties of heterologously expressed full-length cDNA clones, isolated from a Taxus cDNA library and specific to Taxol biosynthesis, are summarized. Recombinant enzymes are described that catalyze early steps of the pathway, including taxadiene synthase, taxadien-5alpha-ol-O-acetyltransferase and taxadien-5alpha-yl acetate 10beta-hydroxylase, and that catalyze late steps, including 10-deacetylbaccatin III-10beta-O-acetyltransferase and taxane 2alpha-O-benzoyltransferase. The properties of Taxus geranylgeranyl diphosphate synthase are also described; although this synthase does not mediate a committed step of Taxol biosynthesis, it does provide the universal plastidial diterpenoid precursor, geranylgeranyl diphosphate, for initiating Taxol biosynthesis. PMID:11524108

Walker, K; Croteau, R

2001-09-01

32

Determination of paclitaxel in biological fluids by micellar electrokinetic chromatography  

Microsoft Academic Search

A method has been developed for the determination of paclitaxel (Taxol) in plasma and urine using capillary electrophoresis with sodium dodecyl sulfate as additive in the run buffer. The samples are extracted and preconcentrated with tert.-butyl methyl ether. Taxotere has been used as the internal standard. The limit of detection for paclitaxel is 20 ng\\/ml. In comparison to high-performance liquid

Georg Hempel; Doris Lehmkuhl; Sebastian Krümpelmann; Gottfried Blaschke; Joachim Boos

1996-01-01

33

Peripheral Neuropathy Induced by Paclitaxel: Recent Insights and Future Perspectives  

PubMed Central

Paclitaxel is an antineoplastic agent derived from the bark of the western yew, Taxus brevifolia, with a broad spectrum of activity. Because paclitaxel promotes microtubule assembly, neurotoxicity is one of its side effects. Clinical use of paclitaxel has led to peripheral neuropathy and this has been demonstrated to be dependent upon the dose administered, the duration of the infusion, and the schedule of administration. Vehicles in the drug formulation, for example Cremophor in Taxol®, have been investigated for their potential to induce peripheral neuropathy. A variety of neuroprotective agents have been tested in animal and clinical studies to prevent paclitaxel neurotoxicity. Recently, novel paclitaxel formulations have been developed to minimize toxicities. This review focuses on recent advances in the etiology of paclitaxel-mediated peripheral neurotoxicity, and discusses current and ongoing strategies for amelioration of this side effect.

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

2006-01-01

34

Enhanced antitumor effect of novel dual-targeted paclitaxel liposomes  

NASA Astrophysics Data System (ADS)

A novel dual-targeted peptide containing an alpha V integrins specific ligand and a neuropilin-1 specific motif was developed which showed an increased specific targeting affinity to tumors. Active dual-targeted liposomes were then produced with this peptide and exhibited greater binding activity than single-targeted liposomes in vitro. Paclitaxel entrapped in this formulation greatly increased the uptake of paclitaxel in the targeting cells and significantly suppressed the growth of HUVEC and A549 cells compared with general paclitaxel injections (Taxol) and single-targeted paclitaxel liposomes. The treatment of tumor xenograft models with dual-targeted paclitaxel liposomes also resulted in better tumor growth inhibition than any other treatment groups. Therefore, the dual-targeted paclitaxel liposomes prepared in the present study might be a more promising drug for cancer treatment. Furthermore, the dual-targeting approach may produce synergistic effects that can be applied in the development of new targeted drug delivery systems.

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

2010-10-01

35

Taxol alleviates 2-methoxyestradiol-induced endothelial permeability.  

PubMed

We have previously shown that the anti-cancer agent 2-methoxyestradiol (2ME) induces hyperpermeability across endothelial monolayers. Here, we show that both microtubule disruptor, 2ME, and microtubule stabilizer, paclitaxel (taxol), increase vascular lung permeability in vitro and in vivo. Simultaneous application of 2ME and taxol alleviates 2ME-induced endothelial barrier dysfunction, which is evident by the decreased Evans Blue Dye accumulation in lung tissue and increased transendothelial resistance across monolayers. 2ME significantly increases the level of p38 and MLC phosphorylation in both endothelial monolayers and murine lungs; this increase is suppressed in the presence of taxol. Taxol treatment leads to an immediate and sustained increase in tubulin acetylation in human pulmonary artery endothelial cells (HPAEC). Surprisingly, 2ME treatment also increases tubulin acetylation; however, the onset of this process is delayed and coincides with the stage of a partial barrier restoration in HPAEC monolayer. Inhibition of histone deacetylase 6 (HDAC6) with tubacin increases tubulin acetylation level, suppresses 2ME-induced HSP27 and MLC phosphorylation, and decreases 2ME-induced barrier dysfunction, suggesting barrier-protective and/or barrier-restorative role for tubulin acetylation in vascular endothelium. PMID:22074808

Gorshkov, Boris A; Zemskova, Marina A; Verin, Alexander D; Bogatcheva, Natalia V

2011-10-30

36

Screening of a library of phage-displayed peptides identifies human Bcl2 as a taxol-binding protein1  

Microsoft Academic Search

A random library of phage displayed peptides was screened for binding to a biotinylated derivative of paclitaxel (Taxol). Affinity-selected peptides were analyzed for similarity to human proteins. There was no significant similarity between the paclitaxel-selected peptides and tubulin. However , a subset of the peptides was identified that exhibits significant similarity to a non-conserved region of the anti-apoptotic human protein

Diane J. Rodi; Robert W. Janes; Hitesh J. Sanganee; Robert A. Holton; B. A. Wallace; Lee Makowski

1999-01-01

37

The efficacy of Paclitaxel on solid tumour analysed by ATP bioluminescence assay and VEGF expression: a translational research study  

Microsoft Academic Search

Background. -Paclitaxel (Taxol), is known to induce mitotic arrest and apoptosis by inhibiting the depolymerisation of microtubules. Tumour growth and metastasis are affected by the metabolic rate and angiogenesis. We investigated the effect of Paclitaxel on tumour metabolism and markers of angiogenesis, vascular endothelial growth factor (VEGF).

W. T. Y. Loo; J. H. M. Fong; M. N. B. Cheung; L. W. C. Chow

2005-01-01

38

Paclitaxel ameliorates fibrosis in hepatic stellate cells via inhibition of TGF-?/Smad activity  

PubMed Central

AIM: To investigated if paclitaxel can attenuate hepatic fibrosis in rat hepatic stellate cells (RHSCs). METHODS: RHSCs were cultured in vitro and randomly assigned to four groups: normal control group (treated only with Dulbecco’s Modified Eagle’s Medium), Taxol group (200 nmol/L paclitaxel was added to the cell culture), transforming growth factor (TGF)-? group (5 ng/mL recombinant human TGF-?1 was added to the cell culture), and TGF-? + Taxol group. TGF-? signaling cascade and status of various extracellular matrix proteins were evaluated by real time reverse transcriptase polymerase chain reaction and Western blotting. RESULTS: The paclitaxel treatment markedly suppressed Smad2/3 phosphorylation. This was associated with attenuated expression of collagen I and III and fibronectin in RHSCs. CONCLUSION: These data indicate that 200 nmol/L paclitaxel ameliorates hepatic fibrosis via modulating TGF-? signaling, and that paclitaxel may have some therapeutic value in humans with hepatic fibrosis.

Zhou, Jun; Zhong, De-Wu; Wang, Qun-Wei; Miao, Xiong-Ying; Xu, Xun-Di

2010-01-01

39

Role of protein kinase C? and protein kinase A in a model of paclitaxel-induced painful peripheral neuropathy in the rat  

Microsoft Academic Search

The clinical use of the antineoplastic agent paclitaxel (Taxol) is significantly limited in its effectiveness by a dose-related painful peripheral neuropathy. To evaluate underlying mechanisms, we developed a model of Taxol-induced painful peripheral neuropathy in the rat and determined the involvement of two second messengers that contribute to enhanced nociception in other models of inflammatory and neuropathic pain, protein kinase

O. A Dina; X Chen; D Reichling; J. D Levine

2001-01-01

40

Heterologous expression and characterization of a "Pseudomature" form of taxadiene synthase involved in paclitaxel (Taxol) biosynthesis and evaluation of a potential intermediate and inhibitors of the multistep diterpene cyclization reaction.  

PubMed

The diterpene cyclase taxadiene synthase from yew (Taxus) species transforms geranylgeranyl diphosphate to taxa-4(5),11(12)-diene as the first committed step in the biosynthesis of the anti-cancer drug Taxol. Taxadiene synthase is translated as a preprotein bearing an N-terminal targeting sequence for localization to and processing in the plastids. Overexpression of the full-length preprotein in Escherichia coli and purification are compromised by host codon usage, inclusion body formation, and association with host chaperones, and the preprotein is catalytically impaired. Since the transit peptide-mature enzyme cleavage site could not be determined directly, a series of N-terminally truncated enzymes was created by expression of the corresponding cDNAs from a suitable vector, and each was purified and kinetically evaluated. Deletion of up to 79 residues yielded functional protein; however, deletion of 93 or more amino acids resulted in complete elimination of activity, implying a structural or catalytic role for the amino terminus. The pseudomature form of taxadiene synthase having 60 amino acids deleted from the preprotein was found to be superior with respect to level of expression, ease of purification, solubility, stability, and catalytic activity with kinetics comparable to the native enzyme. In addition to the major product, taxa-4(5),11(12)-diene (94%), this enzyme produces a small amount of the isomeric taxa-4(20), 11(12)-diene ( approximately 5%), and a product tentatively identified as verticillene ( approximately 1%). Isotopically sensitive branching experiments utilizing (4R)-[4-(2)H(1)]geranylgeranyl diphosphate confirmed that the two taxadiene isomers, and a third (taxa-3(4),11(12)-diene), are derived from the same intermediate taxenyl C4-carbocation. These results, along with the failure of the enzyme to utilize 2, 7-cyclogeranylgeranyl diphosphate as an alternate substrate, indicate that the reaction proceeds by initial ionization of the diphosphate ester and macrocyclization to the verticillyl intermediate, followed by a secondary cyclization to the taxenyl cation and deprotonation (i.e., formation of the A-ring prior to B/C-ring closure). Two potential mechanism-based inhibitors were tested with recombinant taxadiene synthase but neither provided time-dependent inactivation nor afforded more than modest competitive inhibition. PMID:10864451

Williams, D C; Wildung, M R; Jin, A Q; Dalal, D; Oliver, J S; Coates, R M; Croteau, R

2000-07-01

41

Abnormal muscle afferent function in a model of Taxol chemotherapy-induced painful neuropathy.  

PubMed

Despite muscle pain being a well-described symptom in patients with diverse forms of peripheral neuropathy, the role of neuropathic mechanisms in muscle pain have received remarkably little attention. We have recently demonstrated in a well-established model of chemotherapy-induced painful neuropathy (CIPN) that the anti-tumor drug paclitaxel (Taxol) produces mechanical hyperalgesia in skeletal muscle, of similar time course to and with shared mechanism with cutaneous symptoms. In the present study, we evaluated muscle afferent neuron function in this rat model of CIPN. The mechanical threshold of muscle afferents in rats exposed to paclitaxel was not significantly different from the mechanical threshold of muscle afferents in control animals (P = 0.07). However, paclitaxel did produce a marked increase in the number of action potentials elicited by prolonged suprathreshold fixed intensity mechanical stimulation and a marked increase in the conduction velocity. In addition, the interspike interval (ISI) analysis (to evaluate the temporal characteristics of the response of afferents to sustained mechanical stimulation) showed a significant difference in rats treated with paclitaxel; there was a significantly greater ISI percentage of paclitaxel-treated muscle afferents with 0.01- and 0.02-s ISI. In contrast, an analysis of variability of neuronal firing over time (CV2 analysis) showed no effect of paclitaxel administration. These effects of paclitaxel on muscle afferent function contrast with the previously reported effects of paclitaxel on the function of cutaneous nociceptors. PMID:21562188

Chen, Xiaojie; Green, Paul G; Levine, Jon D

2011-05-11

42

Abnormal muscle afferent function in a model of Taxol chemotherapy-induced painful neuropathy  

PubMed Central

Despite muscle pain being a well-described symptom in patients with diverse forms of peripheral neuropathy, the role of neuropathic mechanisms in muscle pain have received remarkably little attention. We have recently demonstrated in a well-established model of chemotherapy-induced painful neuropathy (CIPN) that the anti-tumor drug paclitaxel (Taxol) produces mechanical hyperalgesia in skeletal muscle, of similar time course to and with shared mechanism with cutaneous symptoms. In the present study, we evaluated muscle afferent neuron function in this rat model of CIPN. The mechanical threshold of muscle afferents in rats exposed to paclitaxel was not significantly different from the mechanical threshold of muscle afferents in control animals (P = 0.07). However, paclitaxel did produce a marked increase in the number of action potentials elicited by prolonged suprathreshold fixed intensity mechanical stimulation and a marked increase in the conduction velocity. In addition, the interspike interval (ISI) analysis (to evaluate the temporal characteristics of the response of afferents to sustained mechanical stimulation) showed a significant difference in rats treated with paclitaxel; there was a significantly greater ISI percentage of paclitaxel-treated muscle afferents with 0.01- and 0.02-s ISI. In contrast, an analysis of variability of neuronal firing over time (CV2 analysis) showed no effect of paclitaxel administration. These effects of paclitaxel on muscle afferent function contrast with the previously reported effects of paclitaxel on the function of cutaneous nociceptors.

Chen, Xiaojie; Green, Paul G.

2011-01-01

43

[Recent advances in the biosynthesis of Taxol].  

PubMed

Taxol is one of the most potent chemotherapeutic agents known, showing excellent activity against a range of cancers. In addition to anticancer, taxol has the effect of preventing graft arteriosclerosis, antiscaring formation and inhibiting angiogenesis. There are five possible routes to industrialize taxol production: isolation from the bark of the yew species, total synthesis, semisynthesis, tissue or cell culture, endophytic fungal fermentation and metabolism engineering. There are at least 14 genes related to the taxol biosynthesis had been cloned from yews and functionally expressed in different hosts. The combinational expression system of taxol makes progress as the clarification of biosynthetic pathway of taxol. PMID:17633200

Kong, Jian-qiang; Wang, Wei; Zhu, Ping; Cheng, Ke-di

2007-04-01

44

Taxomyces andreanae: a presumed paclitaxel producer demystified?  

PubMed

The 1990s brought an abundance of reports on paclitaxel-producing endophytes, initially heralded as a discovery having tremendous implications for cancer therapy. As the vision of large-scale fermentation tanks producing vast quantities of relatively inexpensive paclitaxel and novel taxanes has faded and has been replaced by controversial silence, we carried out an in-depth investigation of Taxomyces andreanae - the very first presumed endophytic synthesizer of the diterpenoid. On one hand, metabolic profiling by means of chromatographic, spectroscopic and immunoenzymatic techniques predominant in literature was taken up. On the other, the experimental procedure was brought to an alternative, previously unattempted level aiming at revealing the genetic background of paclitaxel biosynthesis in the endophyte. The profound PCR-based screening for taxadiene synthase (TXS) - a gene unique to the formation of the primary taxane-skeleton, as well as phenylpropanoyl transferase (BAPT) encoding for the catalyst of the final acylation of the core structure rendering the ultimate efficacy of the drug, confirmed the molecular blueprint for paclitaxel biosynthesis to be an inherent genetic trait of the endophyte. However, as the thorough metabolic analysis of Taxomyces andreanae commercial isolate brought no confirmation of endophytic paclitaxel production even after considerable up-scaling endeavors, we postulate that proclaiming the strain "a fungus factory for Taxol" might have been premature. PMID:19809969

Staniek, Agata; Woerdenbag, Herman J; Kayser, Oliver

2009-12-01

45

Role of specific apoptotic pathways in the restoration of paclitaxel-induced apoptosis by valspodar in doxorubicin-resistant MCF7 breast cancer cells  

Microsoft Academic Search

Paclitaxel (Taxol®) kills tumor cells by inducing both cellular necrosis and apoptosis. A major impediment to paclitaxel cytotoxicity is the establishment of multidrug resistance whereby exposure to one chemotherapeutic agent results in cross-resistance to a wide variety of other drugs. For example, selection of MCF-7 breast cancer cells for resistance to doxorubicin (MCF-7ADR cells) results in cross-resistance to paclitaxel. This

Antony Chadderton; David J. Villeneuve; Stefan Gluck; Angie F. Kirwan-Rhude; Brian R. Gannon; David E. Blais; Amadeo M. Parissenti

2000-01-01

46

Paclitaxel binding to human serum albumin--automated docking studies.  

PubMed

A computational approach was used to study the interaction of the potent anticancer drug paclitaxel (Taxol) with human serum albumin. The primary and secondary binding sites were located at the interface of subdomains IIA and IIIA, and in the cleft between domains I and III of the protein, respectively. The C13 side chain and the baccatin core of paclitaxel were found to contribute approximately equally to the binding energy at the primary site, whereas the binding mode appears to be governed by the C13 side chain. PMID:17118665

Paal, Krisztina; Shkarupin, Aliaksei; Beckford, Laura

2006-11-10

47

New, Water Soluble, Antineoplastic Derivatives of Taxol.  

National Technical Information Service (NTIS)

The invention is related to new, water soluble derivatives of taxol with antineoplastic activity. More particularly, the invention is related to 2'-0-acyl derivatives of taxol with improved water solubility while retaining antineoplasic property of the pa...

R. D. Haugwitz L. Zalkow J. Glinski M. Suffness H. M. Deutsch

1988-01-01

48

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

PubMed Central

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.

2013-01-01

49

Paclitaxel accelerates spontaneous calcium oscillations in cardiomyocytes by interacting with NCS-1 and the InsP3R  

PubMed Central

Paclitaxel (Taxol) is a microtubule-stabilizing compound that is used for cancer chemotherapy. However, Taxol administration is limited by serious side effects including cardiac arrhythmia, which cannot be explained by its microtubule-stabilizing effect. Recently, neuronal calcium sensor 1 (NCS-1), a calcium binding protein that modulates the inositol-1,4,5-trisphosphate receptor (InsP3R), was described as a binding partner of Taxol and as a substrate of calpain. We examined calcium signaling processes in cardiomyocytes after treatment with Taxol to investigate the basis of Taxol-induced cardiac arrhythmia. After treating isolated neonatal rat ventricular myocytes with a therapeutic concentration of Taxol for several hours live cell imaging experiments showed that the frequency of spontaneous calcium oscillations significantly increased. This effect was not mimicked by other tubulin-stabilizing agents. However, it was prevented by inhibiting the InsP3R. Taxol treated cells had increased expression of NCS-1, an effect also detectable after Taxol administration in vivo. Short hairpin RNA mediated knock down of NCS-1 decreased InsP3R dependent intracellular calcium release, whereas Taxol treatment, that increased NCS-1 levels, increased InsP3R dependent calcium release. The effects of Taxol were ryanodine receptor independent. At the single channel level Taxol and NCS-1 mediated an increase in InsP3R activity. Calpain activity was not affected by Taxol in cardiomyocytes suggesting a calpain independent signaling pathway. In short, our study shows that Taxol impacts calcium signaling and calcium oscillations in cardiomyocytes through NCS-1 and the InsP3R.

Zhang, Kun; Heidrich, Felix M.; DeGray, Brenda; Boehmerle, Wolfgang; Ehrlich, Barbara E.

2010-01-01

50

Mechanisms of Taxol resistance related to microtubules  

Microsoft Academic Search

Since its approval by the FDA in 1992 for the treatment of ovarian cancer, the use of Taxol has dramatically increased. Although treatment with Taxol has led to improvement in the duration and quality of life for some cancer patients, the majority eventually develop progressive disease after initially responding to Taxol treatment. Drug resistance represents a major obstacle to improving

George A Orr; Pascal Verdier-Pinard; Hayley McDaid; Susan Band Horwitz

2003-01-01

51

Taxol treatment of experimental proliferative vitreoretinopathy  

Microsoft Academic Search

Taxol is a potent stabilizer of microtubules, and inhibitor of in vitro replication, migration, and contraction of fibroblasts. It has been found to limit the development of experimental tractional retinal detachments in nonvitrectomized rabbit eyes. We used taxol in vitrectomized, phakic rabbit eyes with experimentally induced proliferative vitreoretinopathy and tractional retinal detachments. Taxol was dissolved in 30% DMSO because of

Stewart A. Daniels; Kevin G. Coonley; Marc O. Yoshizumi

1990-01-01

52

Human liver microsomal metabolism of paclitaxel and drug interactions  

Microsoft Academic Search

Summary  The aim of this study was to investigate the influence of several anticancer drugs and investigational multidrug resistance\\u000a (MDR) reversing agents on the hepatic metabolism of paclitaxel (Taxol) to its primary metabolites, 6 ?-hydroxypaclitaxel (metabolite,\\u000a MA) and 3?-p-hydroxypaclitaxel (metabolite, MB). There is significant inter-individual variability associated with the levels of these two metabolites. In many cases, 6?-hydroxypaclitaxel\\u000a has been observed

P. B. Desai; J. Z. Duan; Y. W. Zhu; S. Kouzi

1998-01-01

53

Paclitaxel-induced stomal neuropathy: a unique cause of pain in a patient with ileal conduit  

Microsoft Academic Search

We present a case of unusual chemotherapy-induced neurotoxicity in a patient who had undergone radical cystoprostatectomy and ileal conduit diversion for invasive bladder cancer. On routine computed tomography scan several years later, he was diagnosed with metastatic transitional cell carcinoma involving the retroperitoneal lymph nodes. The patient received systemic chemotherapy, including a combination of paclitaxel (Taxol) and gemcitabine (Gemzar). During

Menachem Laufer; Mark P Schoenberg; Mario A Eisenberger

2000-01-01

54

Chronic exposure to paclitaxel diminishes phosphoinositide signaling by calpain-mediated neuronal calcium sensor-1 degradation  

PubMed Central

Paclitaxel (Taxol) is a well established chemotherapeutic agent for the treatment of solid tumors, but it is limited in its usefulness by the frequent induction of peripheral neuropathy. We found that prolonged exposure of a neuroblastoma cell line and primary rat dorsal root ganglia with therapeutic concentrations of Taxol leads to a reduction in inositol trisphosphate (InsP3)-mediated Ca2+ signaling. We also observed a Taxol-specific reduction in neuronal calcium sensor 1 (NCS-1) protein levels, a known modulator of InsP3 receptor (InsP3R) activity. This reduction was also found in peripheral neuronal tissue from Taxol treated animals. We further observed that short hairpin RNA-mediated NCS-1 knockdown had a similar effect on phosphoinositide-mediated Ca2+ signaling. When NCS-1 protein levels recovered, so did InsP3-mediated Ca2+ signaling. Inhibition of the Ca2+-activated protease ?-calpain prevented alterations in phosphoinositide-mediated Ca2+ signaling and NCS-1 protein levels. We also found that NCS-1 is readily degraded by ?-calpain in vitro and that ?-calpain activity is increased in Taxol but not vehicle-treated cells. From these results, we conclude that prolonged exposure to Taxol activates ?-calpain, which leads to the degradation of NCS-1, which, in turn, attenuates InsP3mediated Ca2+ signaling. These findings provide a previously undescribed approach to understanding and treating Taxol-induced peripheral neuropathy.

Boehmerle, Wolfgang; Zhang, Kun; Sivula, Michael; Heidrich, Felix M.; Lee, Yashang; Jordt, Sven-Eric; Ehrlich, Barbara E.

2007-01-01

55

The microtubule-affecting drug paclitaxel has antiangiogenic activity.  

PubMed

Endothelial cell migration is a critical event during angiogenesis, and inhibitors of cell motility can affect the angiogenic process. Paclitaxel (Taxol(R)), a microtubule-stabilizing antineoplastic cytotoxic drug, inhibits motility and invasiveness of several cell types. The aim of this study was to investigate the effect of paclitaxel on endothelial cell functions and on angiogenesis. In vivo, paclitaxel (20-28 mg/kg i.v.) significantly inhibited the angiogenic response induced by tumor cell supernatant embedded in a pellet of reconstituted basement membrane (Matrigel) injected s.c. into C57BL/6N mice. In vitro, paclitaxel inhibited endothelial cell proliferation, motility, invasiveness, and cord formation on Matrigel in a dose-dependent manner. The antiangiogenic activity of paclitaxel was not linked to its cytotoxicity, since inhibition of endothelial cell chemotaxis and invasiveness occurred at drug concentrations which did not affect endothelial cell proliferation. Another cytotoxic drug, cisplatin, that inhibited endothelial cell proliferation in vitro, did not affect angiogenesis in vivo. These data indicate that paclitaxel has a strong antiangiogenic activity, a property that might contribute to its antineoplastic activity in vivo. PMID:9816139

Belotti, D; Vergani, V; Drudis, T; Borsotti, P; Pitelli, M R; Viale, G; Giavazzi, R; Taraboletti, G

1996-11-01

56

Paclitaxel nanosuspensions for targeted chemotherapy - nanosuspension preparation, characterization, and use.  

PubMed

Abstract Objective: The purpose of this work was to prepare a stable paclitaxel nanosuspension and test it for potential use as a targeted chemotherapeutic. Different particle coatings were employed to assess their impact on cellular uptake in vitro. In vivo work was then performed to demonstrate efficacy in tumor-bearing mouse models. Materials and method: Paclitaxel nanosuspensions were prepared using a homogenization process and coated with excipients. Surface charge was measured by zeta potential, potency by high-performance liquid chromatography, and solubility using an in-line UV probe. Cellular uptake studies were performed via flow cytometry. In vivo experiments were performed to determine residence time, maximum tolerated dose, and the efficacy of paclitaxel nanosuspensions (Paclitaxel-NS). Results: A stable paclitaxel nanosuspension was prepared and coated with various excipients. Studies in mice showed that the nanosuspension was well-tolerated and at least as effective as the IV Taxol control in prolonging mouse survival in a head and neck cancer model as well as an ovarian cancer model with a lower overall drug dose than the traditional IV administration route. Conclusions: The paclitaxel nanosuspension is suitable for cellular uptake. The nanosuspension was effective in prolonging life in two separate xenograft orthotopic murine cancer models through two separate routes of administration. PMID:23617261

Lee, Sarah E; Bairstow, Shawn F; Werling, Jane O; Chaubal, Mahesh V; Lin, Lawrence; Murphy, Mary Ann; Diorio, James P; Gass, Jerome; Rabinow, Barrett; Wang, Xiaoen; Zhang, Yong; Yang, Zhijian; Hoffman, Robert M

2013-04-25

57

Novel vitamin D3 analog (CB1093) when combined with paclitaxel and cisplatin inhibit growth of MCF-7 human breast cancer cells in vivo.  

PubMed

Vitamin D3 compounds paclitaxel (Taxol) and cisplatin (CDDP, cis-diamminodichloroplatinum) inhibit growth of a variety of malignant cells. We examined the ability of a novel 20-epi-vitamin D3 analog (code name, CB1093), Taxol and CDDP either alone or in combination to inhibit the growth of a human mammary cancer (MCF-7) growing in BNX triple immunodeficient mice. Tumors in control animals demonstrated infiltrating poorly differentiated adenocarcinomas. At the doses chosen, the antitumor effect of Taxol alone was greater than that of either CB1093 or CDDP alone; and additive effects were observed when either CB 1093 + Taxol or CB 1093 + CDDP + Taxol were administered together. The combination of CB 1093 + Taxol + CDDP was most potent, inhibiting tumor weights by nearly 83% compared to control tumors and producing extensive necrosis of the remaining tumor mass. No additive effect occurred by combining either CB1093 + CDDP or Taxol + CDDP compared to Taxol alone. For all cohorts, their complete hematopoietic blood counts, serum electrolyte analyses including serum calciums as well as their liver and renal functions were within the normal range. Extensive histological analyses of the liver, spleen, kidneys, bone marrow, skin and subcutaneous fat pads from these mice showed no abnormalities. In summary, combined therapy with CB1093 (a potent vitamin D3 analog), Taxol and CDDP, which have non-cross reactive toxicities, holds promise in the treatment of patients with breast cancer. PMID:9683773

Koshizuka, K; Koike, M; Kubota, T; Said, J; Binderup, L; Koeffler, H P

1998-09-01

58

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

PubMed

Breast cancer is the second most prevalent cancer worldwide and their incidence increases gradually. Taxol (paclitaxel), a potent anticancer drug, is naturally isolated from the bark of the Pacific yew. Taxol is widely used in the treatment of ovarian, lung and breast cancer. The increased demand for taxol, coupled with its limited availability from the protected Pacific yew, has had researchers scrambling for alternate sources. The purpose of the present study is to investigate chemopreventive effect of fungal taxol derived from a novel endophytic fungus Botryodiplodia theobromae Pat., isolated from a medicinal plant Morinda citrifolia Linn. The fungal taxol is found to be active against the 7, 12 dimethyl benz(a)anthracene (DMBA)-induced mammary gland carcinogenesis in Sprague dawley rats. The enzymic and non-enzymic antioxidants i.e. superoxide dismutase (SOD), catalase (CAT), glutatione peroxidase (GPx), glutatione-S-transferase (GST), reduced glutathione (GSH), vitamin C and vitamin E were evaluated in control and experimental groups. Lipid peroxides levels (LPO) were also tested. Histological analysis of breast tissue was analyzed by haematoxylin and eosin staining to assess the cytoprotective role of fungal taxol active against breast cancer. Immunohistochemical analyses were also performed to evaluate the effect of fungal taxol on the inflammatory marker such as Cyclooxygenase-2 (COX-2) in control and experimental groups. The results showed that the fungal taxol significantly suppresses the DMBA-induced breast cancer in Sprague dawley rats. PMID:19762199

Pandi, M; Manikandan, R; Muthumary, J

2009-09-03

59

Paclitaxel Nanocrystals for Overcoming Multidrug Resistance in Cancer  

PubMed Central

Here we described a paclitaxel (PTX) nanocrystals formulation using D-?-tocopheryl polyethylene glycol 1000 succinate (TPGS) as the sole excipient for overcoming multidrug resistance (MDR), a key challenge in current cancer therapy. To the best of our knowledge, it is the first report on PTX nanocrystals which can reverse MDR. TPGS serves as a surfactant to stabilize the nanocrystals and a P-gp inhibitor to reverse MDR. The size and morphology of the nanocrystals were studied by transmission electron microscopy and the crystalline structure was determined by powder X-ray diffraction. In vitro drug release profile showed that the nanocrystals exhibited sustained release kinetics compared to Taxol which is the clinical paclitaxel formulation. The cytotoxicity and antitumor efficacy in xenograft models were also investigated. It is demonstrated that PTX/TPGS nanocrystals have significant advantages over Taxol in achieving better therapeutic effect in Taxol-resistant cancer cells both in vitro and in vivo, which was also confirmed by apoptosis assays. We envision that further development of this type of nanocrystals will provide a novel strategy for drug delivery and multidrug resistance treatment.

Liu, Yang; Huang, Leaf; Liu, Feng

2013-01-01

60

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

PubMed

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

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

2011-05-10

61

HPLC Separation of Taxol and Cephalomannine  

Microsoft Academic Search

Taxol [1], a highly functionalized antimitotic diterpene which occurs as a minor component of extracts of the bark from trees of the genus Taxus, is required in increasingly larger quantities for clinical trials. Final purification of taxol requires separation from cephalomannine [2]. an efficient separation of those closely related analogs has been achieved by normal phase HPLC on a cyanopropyl

John H. Cardellina II

1991-01-01

62

Biodistribution and pharmacokinetics of a telodendrimer micellar paclitaxel nanoformulation in a mouse xenograft model of ovarian cancer  

PubMed Central

Background A multifunctional telodendrimer-based micelle system was characterized for delivery of imaging and chemotherapy agents to mouse tumor xenografts. Previous optical imaging studies demonstrated qualitatively that these classes of nanoparticles, called nanomicelles, preferentially accumulate at tumor sites in mice. The research reported herein describes the detailed quantitative imaging and biodistribution profiling of nanomicelles loaded with a cargo of paclitaxel. Methods The telodendrimer was covalently labeled with 125I and the nanomicelles were loaded with 14C-paclitaxel, which allowed measurement of pharmacokinetics and biodistribution in the mice using microSPECT/CT imaging and liquid scintillation counting, respectively. Results The radio imaging data showed preferential accumulation of nanomicelles at the tumor site along with a slower clearance rate than paclitaxel formulated in Cremophor EL (Taxol®). Liquid scintillation counting confirmed that 14C-labeled paclitaxel sequestered in nanomicelles had increased uptake by tumor tissue and slower pharmacokinetics than Taxol. Conclusion Overall, the results indicate that nanomicelle-formulated paclitaxel is a potentially superior formulation compared with Taxol in terms of water solubility, pharmacokinetics, and tumor accumulation, and may be clinically useful for both tumor imaging and improved chemotherapy applications.

Xiao, Wenwu; Luo, Juntao; Jain, Teesta; Riggs, John W; Tseng, Harry P; Henderson, Paul T; Cherry, Simon R; Rowland, Douglas; Lam, Kit S

2012-01-01

63

Paclitaxel-induced apoptosis is BAK-dependent, but BAX and BIM-independent in breast tumor.  

PubMed

Paclitaxel (Taxol)-induced cell death requires the intrinsic cell death pathway, but the specific participants and the precise mechanisms are poorly understood. Previous studies indicate that a BH3-only protein BIM (BCL-2 Interacting Mediator of cell death) plays a role in paclitaxel-induced apoptosis. We show here that BIM is dispensable in apoptosis with paclitaxel treatment using bim(-/-) MEFs (mouse embryonic fibroblasts), the bim(-/-) mouse breast tumor model, and shRNA-mediated down-regulation of BIM in human breast cancer cells. In contrast, both bak (-/-) MEFs and human breast cancer cells in which BAK was down-regulated by shRNA were more resistant to paclitaxel. However, paclitaxel sensitivity was not affected in bax(-/-) MEFs or in human breast cancer cells in which BAX was down-regulated, suggesting that paclitaxel-induced apoptosis is BAK-dependent, but BAX-independent. In human breast cancer cells, paclitaxel treatment resulted in MCL-1 degradation which was prevented by a proteasome inhibitor, MG132. A Cdk inhibitor, roscovitine, blocked paclitaxel-induced MCL-1 degradation and apoptosis, suggesting that Cdk activation at mitotic arrest could induce subsequent MCL-1 degradation in a proteasome-dependent manner. BAK was associated with MCL-1 in untreated cells and became activated in concert with loss of MCL-1 expression and its release from the complex. Our data suggest that BAK is the mediator of paclitaxel-induced apoptosis and could be an alternative target for overcoming paclitaxel resistance. PMID:23577147

Miller, Anna V; Hicks, Mark A; Nakajima, Wataru; Richardson, Amanda C; Windle, Jolene J; Harada, Hisashi

2013-04-05

64

Effect of taxol feeding on taxol and related taxane production in Taxus baccata suspension cultures.  

PubMed

To achieve a better understanding of taxol metabolism and accumulation in Taxus cell cultures, a T. baccata cell line growing for 20 days in a selected growth medium was treated at the beginning of the experiment with several concentrations of taxol (25, 50, 100 and 200mgL(-1)). Compared with an untreated control, all these taxol concentrations stimulated cell-associated taxol content (up to 32.7 times in the presence of 200mgL(-1) exogenous taxol), although higher concentrations significantly depressed cell viability. DNA laddering analysis revealed that the viability reduction was not related to apoptosis, suggesting that taxol itself was the primary responsible factor. On the basis of RT-PCR expression analysis of genes encoding taxadiene synthase (ts) and 1-deoxy-d-xylulose-5-phosphate synthase (dxs) from treated and nontreated T. baccata cell line cultures, it was observed that exogenous taxol clearly induced the mRNA levels of both taxane-related enzymes. Additionally, we found that exogenous taxol caused a considerable increase in taxadiene synthase activity, although in no case did this coincide with the highest levels of taxol observed at the end of the culture. The effect of exogenous taxol on the content of other related taxanes was also considered. PMID:19101660

Expósito, Oscar; Bonfill, Mercedes; Onrubia, Miriam; Jané, Albert; Moyano, Elisabet; Cusidó, Rosa M; Palazón, Javier; Piñol, M Teresa

2008-12-03

65

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

PubMed

Drug-induced lupus erythematosus (dile) syndromes are documented complications of chemotherapeutic agents, including paclitaxel. Subacute cutaneous lupus erythematosus (scle) is a distinct dile syndrome presenting with characteristic annular or papulosquamous skin lesions in a photosensitive distribution with associated high anti-ssa titres. Previously, dile syndromes complicating paclitaxel therapy have been attributed to polyethoxylated castor oil (Kolliphor EL: BASF, Ludwigshafen, Germany), the biologic solvent included in the drug's original formulation (Taxol: Bristol-Myers Squibb, Montreal, QC), rather than the parent chemotherapy molecule. Here, we report a characteristic case of drug-induced scle complicating treatment with nanoparticle albumin bound (nab)-paclitaxel (Abraxane: Celgene, Summit, NJ, U.S.A.), a solvent-free taxane formulation. The pertinent English-language literature is also discussed. This case report is the first to link solvent-free paclitaxel with scle, and it suggests that the parent molecule is responsible for the reaction. PMID:24155645

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

2013-10-01

66

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

PubMed Central

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

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

2013-01-01

67

[Preparation of superparamagnetic paclitaxel nanoparticles from modified chitosan and their cytotoxicity against malignant brain glioma].  

PubMed

We synthesized the superparamagnetic paclitaxel nanoparticles from modified chitosan tangling around Fe3O4 ferrofluid and taxol, and observed the nanoparticles with transmission electronic microscopy (TEM). Then we evaluated the paramagnetism of the particles by vibration specimen magnetometer (VSM) and tested their cytotoxicity with flow cytometry (FCM). The prepared nanoparticle solution was black without any floccule or sediment and appeared transparent after diluted. The nanoparticles were spherical and dispersed in water with mean diameter of 15 nm under TEM and showed superparamagnetic character. FCM test showed the nanoparticles had significant toxic effects against malignant astrocytoma U251 cell lines, equal to taxol alone. These results showed that the superparamagnetic nanoparticle not only enhanced the solubility of paclitaxel in water, but also was superparamagnetic and cytotoxic, which make suitable tools for magnetic targeting chemotherapy of brain gliomas. PMID:21774213

Zhao, Ming; Li, Anmin; Chang, Jin; Wang, Hanjie; Liang, Shuli; Zhang, Jiajing; Yan, Runmin

2011-06-01

68

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

PubMed Central

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

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

2010-01-01

69

Linearized Colorimetric Assay for Cremophor EL: Application to Pharmacokinetics after 1Hour Paclitaxel Infusions  

Microsoft Academic Search

Cremophor EL (CrEL) is a polyoxyethylated castor oil surfactant used in the intravenous formulation of the anticancer drug paclitaxel (Taxol). Quantitative determination of CrEL in patient samples can be achieved by complexation of the compound with the Coomassie brilliant blue G-250 dye in protein-free extracts [Sparreboom, A., Loos, W. J., Verweij, J., De Vos, A. I., Van der Burg, M.

Eric Brouwer; Jaap Verweij; Bernhard Hauns; Walter J. Loos; Kees Nooter; Klaus Mross; Gerrit Stoter; Alex Sparreboom

1998-01-01

70

Taxol: efficacy against oral squamous cell carcinoma.  

PubMed

In medicinal chemistry, one of the most studied molecules in recent history is taxol. Taxol is a versatile natural product that is used in various cancer treatment regimens. It is administered to patients with breast, lung, and ovarian cancers, and is currently being studied for the treatment of squamous cell carcinoma of the oral cavity and tongue. Taxol has been tested in a number of research and clinical phase trials to determine feasibility, toxicity, and cytotoxicity against oral squamous cell carcinoma as a single drug regimen and as a contributing drug component in treatment plans. This paper reviews over forty articles that examine cell lines, murine models, and human results for the response of taxol against squamous cell carcinoma (SCC) of the oral cavity and the tongue. PMID:23373651

Ledwitch, Kaitlyn; Ogburn, Ryenne; Cox, Jodi; Graham, Rebekah; Fritzsche, Allison; Gosnell, Donna; Manning, Thomas

2013-04-01

71

Paclitaxel effects on the proteome of HL-60 promyelocytic leukemic cells: comparison to peloruside A.  

PubMed

Paclitaxel (Taxol®), a drug used to treat solid tumors of the breast, ovary and lung, stabilizes microtubules and arrests cells in G(2)/M of the cell cycle. Using two-dimensional differential in-gel electrophoresis (DIGE), we examined the proteomic response of a human HL-60 promyeloid leukemic cell line to paclitaxel. Our intention was to compare the effects of paclitaxel to those of a new-generation microtubule-stabilizing agent, peloruside A, investigated in an earlier study. In response to 100 nM paclitaxel treatment for 24 h, 21 identified proteins changed in abundance, with 13 increases and 8 decreases. In addition, 21 other unidentified proteins were also changed by treatment with paclitaxel. Using Western blotting, the transcription factor c-Myc was shown to be reduced in abundance by both drugs. Our results showed both differences and similarities at the single protein level between paclitaxel and peloruside A, although the same general classes of proteins: cytoskeletal, nucleic acid binding, stress, and apoptotic proteins, changed following exposure. The proteomic response to paclitaxel was more extensive than the response to an equipotent dose of peloruside A. PMID:20862516

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

2010-09-23

72

Global inhibition of reactive oxygen species (ROS) inhibits paclitaxel-induced painful peripheral neuropathy.  

PubMed

Paclitaxel (Taxol®) is a widely used chemotherapeutic agent that has a major dose limiting side-effect of painful peripheral neuropathy. Currently there is no effective therapy for the prevention or treatment of chemotherapy-induced painful peripheral neuropathies. Evidence for mitochondrial dysfunction during paclitaxel-induced pain was previously indicated with the presence of swollen and vacuolated neuronal mitochondria. As mitochondria are a major source of reactive oxygen species (ROS), the aim of this study was to examine whether pharmacological inhibition of ROS could reverse established paclitaxel-induced pain or prevent the development of paclitaxel-induced pain. Using a rat model of paclitaxel-induced pain (intraperitoneal 2 mg/kg paclitaxel on days 0, 2, 4 & 6), the effects of a non-specific ROS scavenger, N-tert-Butyl-?-phenylnitrone (PBN) and a superoxide selective scavenger, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL) were compared. Systemic 100 mg/kg PBN administration markedly inhibited established paclitaxel-induced mechanical hypersensitivity to von Frey 8 g and 15 g stimulation and cold hypersensitivity to plantar acetone application. Daily systemic administration of 50 mg/kg PBN (days -1 to 13) completely prevented mechanical hypersensitivity to von Frey 4 g and 8 g stimulation and significantly attenuated mechanical hypersensitivity to von Frey 15 g. Systemic 100 mg/kg TEMPOL had no effect on established paclitaxel-induced mechanical or cold hypersensitivity. High dose (250 mg/kg) systemic TEMPOL significantly inhibited mechanical hypersensitivity to von Frey 8 g & 15 g, but to a lesser extent than PBN. Daily systemic administration of 100 mg/kg TEMPOL (day -1 to 12) did not affect the development of paclitaxel-induced mechanical hypersensitivity. These data suggest that ROS play a causal role in the development and maintenance of paclitaxel-induced pain, but such effects cannot be attributed to superoxide radicals alone. PMID:21966458

Fidanboylu, Mehmet; Griffiths, Lisa A; Flatters, Sarah J L

2011-09-26

73

Synergy of Taxol and Radioimmunotherapy with Yttrium90-Labeled Chimeric L6 Antibody: Efficacy and Toxicity in Breast Cancer Xenografts  

Microsoft Academic Search

Synergistic multimodality therapy is needed for breast cancer. Breast cancer frequently has p53 mutations that result in cells less likely to undergo apoptosis when exposed to DNA damaging therapies. Taxol (paclitaxel) is more effective in the presence of mutant p53. 90Y-labeled DOTA-peptide-ChL6 (90Y-ChL6, where ChL6 is chimeric L6 antibody and DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N' ',N' ' '-tetraacetic acid) is a novel

Sally J. Denardo; David L. Kukis; Linda A. Kroger; Robert T. O'Donnell; Kathleen R. Lamborn; Laird A. Miers; David G. Denardo; Claude F. Meares; Gerald L. Denardo

1997-01-01

74

Endophytic taxol-producing fungi from bald cypress, Taxodium distichum  

Microsoft Academic Search

as determined by the reactivity of partially purified culture extracts with specific monoclonal antibodies against taxol. In the case of one strain of P. microspora (CP-4), taxol was isolated from culture medium and was shown to be identical to authentic taxol by chromatographic and spectroscopic means.

Jia-yao Li; Gary Strobel; Rajinder Sidhu; W. M. Hess; E. J. Ford

1996-01-01

75

Effect of the plant peptide regulator, phytosulfokine-alpha, on the growth and Taxol production from Taxus sp. suspension cultures.  

PubMed

Phytosulfokine-alpha (PSK-alpha) is a small plant peptide (5 amino acids) that displays characteristics typically associated with animal peptide hormones. PSK-alpha was originally isolated based on its mitogenic activity with plant cultures; it has been reported to increase production of tropane alkaloids from Atropa belladonna, although its general influence on secondary metabolite production is unknown. The studies reported in this article were initiated to evaluate the effects of PSK-alpha supplementation on production of Taxol (paclitaxel) from plant cell cultures of Taxus sp. particularly when methyl jasmonate (MeJA) is added as an elicitor of secondary metabolism. The response to PSK-alpha supplementation was cell line dependent. Taxus cuspidata P93AF showed no statistically significant response to PSK-alpha supplementation while Taxus canadensis C93AD and T. cuspidata PO93X displayed a concentration-dependent response (up to 100 nM PSK-alpha added in first 24 h of culture) with a decrease in initial growth rate, an increase in cell density (dry weight/fresh weight), and increased Taxol production. More remarkably with T. canadensis (C93AD), a very strong synergistic response of PSK-alpha (100 nM) and methyl jasmonate (MeJA, 100 microM) elicitation was observed, resulting in Taxol level of 35.3 +/- 2.1 mg/L or 1.83 +/- 0.02 mg Taxol/g dry cell weight achieved at day 21, a level of approximately 10-fold higher than for either treatment by itself. Although the level of Taxol production achieved is not remarkable, this synergistic treatment was able to partially revive taxane production in cultures that have lost productivity due to extended time (over 10 years) in continuous subculture. PMID:16586507

Kim, Beum Jun; Gibson, Donna M; Shuler, Michael L

2006-09-01

76

Multi trigger responsive, surface active lipid nanovesicle aerosols for improved efficacy of paclitaxel in lung cancer.  

PubMed

The present study focuses on the development of multi-trigger responsive surface active lipid nanovesicles encapsulating paclitaxel with the hypothesis that pulmonary surfactant mimetic lipid vesicles sensitive to temperature and enzyme simultaneously will offer synergistic advantage towards improved therapeutic efficacy of paclitaxel via aerosol administration. The nanovesicles showed a unimodal size distribution of the particles (100-150 nm) and high encapsulation efficiency of paclitaxel (82%). Triggered release of paclitaxel was observed at ?42 °C in the presence of secretory phospholipase A(2) enzyme with maximum release observed with both the triggers used simultaneously. Since these nanovesicles are intended for aerosol administration in the treatment of lung cancer, they were engineered to have high surface activity and airway patency, in order to mimic pulmonary surfactant functions. High deposition of nanovesicles in the lower impingement chamber of a twin impinger upon nebulization suggested them to be capable of reaching the terminal regions of the lungs. Nanovesicles showed facilitated and ATP dependent active uptake by A549 cells. The cytotoxic potential of the nanovesicles was significantly increased upon simultaneous use of both the triggers with an IC(50) of 49.3 nM. Overall, these studies suggest the therapeutic potential and advantages of multi trigger responsive lipid nanovesicles with encapsulated paclitaxel over that of the commercially available form of paclitaxel namely Taxol, and suggests the feasibility of aerosol administration in the treatment of lung cancer and pulmonary metastasis. PMID:22911380

Joshi, Nitin; Kaviratna, Anubhav; Banerjee, Rinti

2013-01-01

77

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

PubMed

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

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

2013-02-16

78

Proapoptotic lipid nanovesicles: synergism with paclitaxel in human lung adenocarcinoma A549 cells.  

PubMed

The present study focuses on the development and evaluation of phosphatidylserine based proapoptotic lipid nanovesicles (PSN-PTX) as aerosols for synergistic activity with paclitaxel against lung cancer. PSN-PTX showed a unimodal size distribution of the particles (100-200 nm), negative surface charge of -29 mV and high encapsulation efficiency of paclitaxel (82%) with 19% of it releasing in 48 h. PSN-PTX was found to be highly surface active as compared to Taxol®, marketed formulation of paclitaxel, whose surface activity was found to be detrimental for pulmonary mechanics. PSN-PTX also showed high airway patency in capillary surfactometer unlike Taxol®, suggesting its ability to mimic pulmonary surfactant functions. High deposition of PSN-PTX in lower impingement chamber of twin impinger upon nebulization suggested it to be capable of reaching the terminal regions of the lungs. Nanovesicles showed facilitated and ATP dependent active uptake by A549 cells. The combination of phosphatidylserine nanovesicles and paclitaxel as PSN-PTX enhanced cytotoxicity in A549 cell line showing an IC(50) of 18 nM which is10-50 folds less than the IC(50) values observed for blank phosphtidylserine nanovesicles and paclitaxel alone. Further, the combination index was found to be less than one which indicates a synergism of the two components. DNA fragmentation study showed that blank phosphatidylserine nanovesicles induce apoptosis in A549 cells and hence behave as proapoptotic nanovesicles in the combination therapy. Overall, these studies suggest the therapeutic potential and advantages of combination chemotherapy of proapoptotic lipid nanovesicles with encapsulated paclitaxel and their feasibility for aerosol administration in the treatment of lung cancer. PMID:21807043

Joshi, Nitin; Shanmugam, Thanigaivel; Kaviratna, Anubhav; Banerjee, Rinti

2011-07-23

79

Taxol: a history of pharmaceutical development and current pharmaceutical concerns.  

PubMed

Taxol, a unique diterpene anticancer compound derived from the bark of the Taxus brevifolia (Pacific yew) tree, induces cytotoxicity by a novel mechanism of action. An antimicrotubule agent, Taxol promotes the formation and stabilization of the tubulin polymer unlike other anticancer agents that induce microtubule disassembly. Because of its poor aqueous solubility, Taxol is formulated as a solution in 50% Cremophor EL and 50% dehydrated alcohol, USP. The Cremophor EL and dehydrated alcohol vehicle used in the formulation of Taxol creates some interesting challenges for its preparation and administration. The pharmaceutical concerns associated with the preparation and administration of Taxol are discussed. PMID:7912520

Adams, J D; Flora, K P; Goldspiel, B R; Wilson, J W; Arbuck, S G; Finley, R

1993-01-01

80

Quantitation of paclitaxel and its two major metabolites using a liquid chromatography–electrospray ionization tandem mass spectrometry  

Microsoft Academic Search

A sensitive and selective liquid chromatographic–tandem mass spectrometric (LC–MS\\/MS) method for the determination of paclitaxel (Taxol) and its two major metabolites in human plasma has been developed. Samples were prepared after liquid–liquid extraction and analyzed on a C18 column interfaced with a Q-Trap tandem mass spectrometer. Positive electrospray ionization was employed as the ionization source. The mobile phase consisted of

Wei Zhang; Ginger E. Dutschman; Xin Li; Yung-Chi Cheng

2011-01-01

81

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

Microsoft Academic Search

Taxol® is a marketed product for the treatment of ovarian, breast, non-small cell lung cancer and AIDS-related Kaposi's Sarcoma. It is thus far one of the most effective anticancer drugs available on the market. However, paclitaxel is only sparingly soluble in water and therefore, intravenous administration depends on the use of the non-ionic surfactant Cremophor® EL (polyethoxylated castor oil) to

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

2005-01-01

82

Phase II study on paclitaxel in patients with recurrent, metastatic or locally advanced vulvar cancer not amenable to surgery or radiotherapy: a study of the EORTC-GCG (European Organisation for Research and Treatment of Cancer-Gynaecological Cancer Group)  

Microsoft Academic Search

Patients and methods: In this phase II study, patients with advanced vulvar cancer received paclitaxel (Taxol) every 3 weeks for up to 10 cycles. Primary objective was response rate. Secondary objectives were response duration and toxicity. Response evaluation was assessed by World Health Organisation criteria, toxicity according to Common Toxicity Criteria. Results: Thirty-one women from 10 institutions were included, with

P. O. Witteveen; J. van der Velden; I. Vergote; C. Guerra; C. Scarabeli; C. Coens; G. Demonty; N. Reed

2009-01-01

83

The gemcitabine/epirubicin/paclitaxel trials in advanced breast cancer.  

PubMed

Numerous trials have shown that the pharmacokinetic interferences of epirubicin (Ellence)/paclitaxel (Taxol) combinations produce less pharmacodynamic effect than doxorubicin/paclitaxel regimens. Paclitaxel is more easily combined when infused over 3 (as compared to 24) hours; the administration of optimal doses of both agents is important. Based on these findings, a phase II study was performed to evaluate the feasibility and activity of the combination of gemcitabine (Gemzar), epirubicin, and paclitaxel as first-line therapy in advanced breast cancer. Patients received gemcitabine at 1,000 mg/m2 on days 1 and 4, plus epirubicin at 90 mg/m2 on day 1, plus paclitaxel at 175 mg/m2/d on day 1 every 21 days. After six courses, patients less than 60 years old and in complete or partial remission or stable disease were treated with high-dose chemotherapy as consolidation treatment. The overall response rate was 92%, with 31% complete responses; 25 patients received high-dose chemotherapy, achieving a final overall response rate of 97%, with 47% complete responses. At a median follow-up of 25 months, median progression-free survival is 21 months. Grade 4 neutropenia was observed in 64% of patients. Other hematologic toxicities were mild. Mild to moderate peripheral neuropathy was experienced by 39% of patients; grade 2 or 3 mucositis occurred in 25% and 17% of patients, respectively. Based on these results, a multicenter trial has been started in seven Italian centers to confirm the feasibility of this regimen. PMID:11252889

Conte, P; Salvadori, B; Donati, S; Gennari, A; Cetto, G L; Molino, A; Crino, L; Mazzoni, F; Galligioni, E; Mansutti, M

2001-02-01

84

Paclitaxel in the treatment of carcinoma of the esophagus.  

PubMed

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

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

1995-06-01

85

Hyaluronic acid-based hydrogel for regional delivery of paclitaxel to intraperitoneal tumors  

PubMed Central

Intraperitoneal (IP) chemotherapy is an effective way of treating local and regional malignancies confined in the peritoneal cavity such as ovarian cancer. However, a persistent major challenge in IP chemotherapy is the need to provide effective drug concentrations in the peritoneal cavity for an extended period of time. We hypothesized that hyaluronic acid (HA)-based in-situ crosslinkable hydrogel would serve as a carrier of paclitaxel (PTX) particles to improve their IP retention and therapeutic effects. In-vitro gel degradation and release kinetics studies demonstrated that HA gels could entrap microparticulate PTX (>100 ?m) and release the drug over 10 days, gradually degraded by hyaluronidase, but had limited effect on retention of Taxol, a 14-nm micelle form of PTX. When administered IP to tumor-bearing nude mice, PTX was best retained in the peritoneal cavity as PTX-gel (microparticulate PTX entrapped in the HA gel), whereas Taxol-gel and other Taxol-based formulations left negligible amount of PTX in the cavity after 14 days. Despite the increase in IP retention of PTX, PTX-gel did not further decrease the tumor burdens than Taxol-based formulations, presumably due to the limited dissolution of PTX. This result indicates that spatial availability of a drug does not necessarily translate to the enhanced anti-tumor effect unless it is accompanied by the temporal availability.

Bajaj, Gaurav; Kim, Mi Ran; Mohammed, Sulma I.; Yeo, Yoon

2012-01-01

86

Clinical and economic implications of the use of nanoparticle paclitaxel (Nanoxel) in India.  

PubMed

Paclitaxel (Taxol), one of the most commonly used chemotherapeutic agents, is poorly soluble in water and requires cremophor, which often causes infusion reactions, as a solvent. Nanoxel, a nanoparticle formulation of the taxane, has been approved by the Indian regulatory authority. In the present article, we aim to describe the experience with the use of Nanoxel in India and its clinical and economic implications. We present three retrospective series in a common practice environment and an economic model. The first series shows no reactions in 596 Nanoxel infusions; the second series shows comparable adverse events other than infusion reactions between 83 patients who received Nanoxel and 32 treated with conventional paclitaxel. The third reveals comparable clinical outcomes for 51 patients treated with Nanoxel or conventional paclitaxel for gastroesophageal tumors. Finally, we describe an economic model which estimates savings of 21 580 Indian rupees per cycle with Nanoxel vis-à-vis conventional paclitaxel in the treatment of solid tumors in India. In conclusion, in an era in which the greatest challenge we face as medical oncologists is how to conciliate hard-won and incremental-but small-improvements in survival with exponentially rising drugs costs, it is refreshing to see a potential new formulation of a commonly used drug that may actually generate cost-savings while improving clinical outcomes and patient well-being. Further studies are clearly warranted to determine the optimal dose and schedule for Nanoxel as well as its comparative effectiveness to cremophor-based paclitaxel. PMID:23975704

Ranade, A A; Joshi, D A; Phadke, G K; Patil, P P; Kasbekar, R B; Apte, T G; Dasare, R R; Mengde, S D; Parikh, P M; Bhattacharyya, G S; Lopes, G L

2013-09-01

87

Taxol transport in Taxus baccata cell suspension cultures  

Microsoft Academic Search

Taxol transport in Taxus baccata L. cell suspension cultures was studied using ?14C?-taxol as a tracer. The time course of uptake showed a saturable absorption that reached a maximum within 20 min. The uptake depended on its exogenous concentration and its accumulation was highly stimulated in the presence of 10–15 ?M exogenous taxol. The absorbed molecule was found to localise both in

Silvia Fornalè; Davide Degli Esposti; Alberto Navia-Osorio; Rosa M Cusidò; Javier Palazòn; M Teresa Piñol; Nello Bagni

2002-01-01

88

Microbial paclitaxel: advances and perspectives  

Microsoft Academic Search

Paclitaxel is a potent and widely used antitumor agent. Considerable worldwide research efforts have been carried out on different production alternatives. Since the description of the first paclitaxel-producing fungi, more than 15 years ago, microorganisms have been investigated as potential alternatives for an environmentally acceptable, relatively simple and inexpensive method to produce paclitaxel. However, in spite of significant research on

Zoila R Flores-Bustamante; Flor N Rivera-Orduña; Anahí Martínez-Cárdenas; Luis B Flores-Cotera

2010-01-01

89

Mixed micelles of PEG(2000)-DSPE and vitamin-E TPGS for concurrent delivery of paclitaxel and parthenolide: enhanced chemosenstization and antitumor efficacy against non-small cell lung cancer (NSCLC) cell lines.  

PubMed

Concurrent combination of chemotherapeutic drugs is a promising alternative to single-agent therapies in cancer. In the present study, paclitaxel and parthenolide were loaded into mixed micelles and tested against taxol sensitive (A549) and resistant (A549-T24) NSCLC cell lines. Combination chemotherapy was further evaluated by isobologram analyses and combination index calculations. Drugs were loaded into micelles by the film casting method using PEG(2000)-DSPE and vitamin E-TPGS. Micelle characterization studies included the determination of particle size, encapsulation efficiency, in vitro release kinetics, as well as 1H NMR analysis. The in vitro release of both drugs was slower from the mixed micelles, which maintained an encapsulation efficiency >95% and chemical stability over a storage period of 45 days. The IC50 of paclitaxel and parthenolide determined by MTT assay were 108.6nM and 21?M, respectively, while the combination had an IC50 of 64.15nM in A549 cells. In the taxol resistant cell lines, the IC50 values of paclitaxel and parthenolide were 233nM and 32?M, respectively, while the combination had an IC(50) of 128nM. The efficacy of paclitaxel and parthenolide against both cell lines significantly increased when the drugs were coencapsulted in mixed micelles. Mixed micelles caused 79% cell death, which was significantly higher than the 46% cell death caused by the drugs in solution against taxol sensitive cell lines. In taxol resistant cell lines, the cell death caused by mixed micelles was 70% as compared to 45% cell death caused by un-encapsulated drugs. Co-encapsulation of parthenolide with paclitaxel in mixed micelles increased the anticancer activity of paclitaxel against resistant and sensitive lung cancer cell lines. PMID:22369858

Gill, Kanwaldeep K; Kaddoumi, Amal; Nazzal, Sami

2012-02-21

90

Establishment and characterization of a paclitaxel?resistant human esophageal carcinoma cell line.  

PubMed

The aim of this study was to establish a new paclitaxel (PTX)-resistant human esophageal squamous carcinoma (ESCC) cell line and investigate its biological characteristics. The resistant cell line (EC109/Taxol) was developed in vitro by intermittent exposure of the human ESCC cell line EC109 to a high concentration of PTX with time-stepwise increment over a period of 6 months. The MTT assay was performed to test the drug resistance of EC109 and EC109/Taxol cells. The morphological features were observed using inverted microscopy and apoptosis was measured by flow cytometry (FCM) and Hoechst 33258 fluorescence staining. Cell growth curves and colony formation of EC109 and EC109/Taxol cells were compared. FCM was also used to determine the distribution of the cell cycle. The protein levels of Bcl-2, Bax, Procaspase-3 and P-gp were detected by western blotting. P-gp activity was evaluated by Rh123 accumulation and efflux assay. In vivo resistance characterization was investigated. EC109/Taxol cells were 67.2-fold resistant to PTX in comparison with EC109 cells, and also exhibited cross-resistance to 5-fluorouracil (5-FU), cisplatin (CDDP) and epirubicin (EPI). FCM and Hoechst 33258 fluorescence staining confirmed that EC109 cells treated with PTX showed significantly higher percentage of apoptotic cells compared to EC109/Taxol cells. Simultaneously, EC109/Taxol cells exhibited changes in morphology, proliferation rate, doubling time, cell cycle distribution and colony formation rate were detected as compared with EC109 cells. The resistant cell line overexpressed Bcl-2, Procaspase-3 and P-gp protein, and showed decreased Bax expression. Further, EC109/Taxol cells did not change PTX resistance in vivo. This is the first report on the establishment of an EC109/Taxol cell line with higher resistance. Bcl-2, Bax, Procaspase-3 and P-gp are involved in the resistance of cell lines to PTX, which are invaluable tools to study the resistance of anticancer drugs and to identify the methods to overcome resistance. PMID:24002547

Wang, Cong; Guo, Liu-Bin; Ma, Jun-Yuan; Li, Yong-Mei; Liu, Hong-Min

2013-08-29

91

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

NASA Astrophysics Data System (ADS)

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.

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

92

1-?-d-arabinofuranosylcytosine-, mitoxantrone-, and paclitaxel-induced apoptosis in HL60 cells: improved method for detection of internucleosomal DNA fragmentation  

Microsoft Academic Search

We investigated the ability of different doses and durations of exposure to the chemotherapeutic drugs 1-ß-d-arabinofuranosylcytosine (Ara-C), mitoxantrone (MTN), and paclitaxel (taxol, TXL) to induce internucleosomal DNA fragmentation and apoptosis in human acute myeloid leukemia (AML) HL-60 cells in suspension culture. At clinically achievable concentrations, all three drugs have been shown to induced apoptosis in HL-60 cells. An improved method

Swapan Ray; Vidya Ponnathpur; Yue Huang; Caroline Tang; Mary Ella Mahoney; Ana Maria Ibrado; Gloria Bullock; Kapil Bhalla

1994-01-01

93

1-ß-D-Arabinofuranosylcytosine-, mitoxantrone-, and paclitaxel-induced apoptosis in HL60 cells: improved method for detection of internucleosomal DNA fragmentation  

Microsoft Academic Search

We investigated the ability of different doses and durations of exposure to the chemotherapeutic drugs 1-ß-D-arabinofuranosylcytosine (Ara-C), mitoxantrone (MTN), and paclitaxel (taxol, TXL) to induce internucleosomal DNA fragmentation and apoptosis in human acute myeloid leukemia (AML) HL-60 cells in suspension culture. At clinically achievable concentrations, all three drugs have been shown to induce apoptosis in HL-60 cells. An improved method

Swapan Ray; Vidya Ponnathpur; Yue Huang; Caroline Tang; Mary Ella Mahoney; Ana Maria Ibrado; Gloria Bullock; Kapil Bhalla

1994-01-01

94

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

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

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

2003-01-01

95

Taxol from Pestalotiopsis microspora, an endophytic fungus of Taxus wallachiana  

Microsoft Academic Search

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.

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

1996-01-01

96

Pharmacokinetics and biodistribution of paclitaxel loaded in pegylated solid lipid nanoparticles after intravenous administration.  

PubMed

In an effort to develop an alternative formulation of paclitaxel (PTX) suitable for intravenous administration, PTX-loaded sterically stabilized solid lipid nanoparticles (SLNs) were prepared and their pharmacokinetics and biodistribution were investigated. The pegylated SLNs were comprised of trimyristin (TM) as a solid lipid core and egg phosphatidylcholine and pegylated phospholipid as stabilizers. The prepared pegylated TM-SLNs containing PTX exhibited monodispersed size distribution with 217.4 ± 32.8 nm of mean diameter and 99% of distribution was smaller than 556.2 ± 89.9 nm. After PTX in the pegylated TM-SLNs or commercial product, Taxol®, was intravenously administered into femoral vein of rats, concentrations of PTX in plasma and organs such as liver, spleen, kidney, heart and lung were analyzed by HPLC following liquid extraction. Plasma profile of PTX for pegylated TM-SLNs was similar to that for Taxol®, with no statistically significant difference at each time point, although mean plasma levels of PTX at each point tended to be slightly lower in pegylated TM-SLNs than in Taxol®. PTX in the pegylated TM-SLNs was taken up mainly into reticuloendothelial system showing 8-fold and 3-fold higher levels in liver and spleen, respectively, 8 h after administration compared to PTX in Taxol®. Meanwhile, PTX levels in kidney, heart and lung were not different between two formulations. There were no statistically significant differences in pharmacokinetic parameters. Taken together the results, the pegylated TM-SLNs provided similar circulation compared with commercial formulation, Taxol®. PMID:21380818

Li, Rihua; Eun, Jae Soon; Lee, Mi-Kyung

2011-03-06

97

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

Microsoft Academic Search

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

Ming Zhou; Yuhua Zhao; Yan Ding; Hao Liu; Zixing Liu; Oystein Fodstad; Adam I Riker; Sushama Kamarajugadda; Jianrong Lu; Laurie B Owen; Susan P Ledoux; Ming Tan

2010-01-01

98

Inhibition of neurite initiation and growth by taxol  

PubMed Central

We cultured sensory neurons from chick embryos in media containing the alkaloid taxol at concentrations from 7 X 10(-9) to 3.5 X 10(-6) M. When plated at taxol concentrations above 7 X 10(-8) M for 24 h, neurons have short broad extensions that do not elongate on the culture substratum. When actively growing neurites are exposed to these levels of taxol, neurite growth stops immediately and does not recommence. The broad processes of neurons cultured 24 h with taxol contain densely packed arrays of microtubules that loop back at the ends of the process. Neurofilaments are segregated from microtubules into bundles and tangled masses in these taxol-treated neurons. At the ends of neurites treated for 5 min with taxol, microtubules also turn and loop back abnormally toward the perikaryon. In the presence of 7 X 10(-9) M taxol neurites do grow, although they are broader and less branched than normally. The neurites of these cells appear to have normal structure except for a large number of microtubules. Taxol probably stimulates microtubule polymerization in these cultured neurons. At high levels of the drug, this action inhibits neurite initiation and outgrowth by removing free tubulin from the cytoplasm and destroying the normal control of microtubule assembly in growing neurites. The rapid inhibition suggests that microtubule assembly may occur at neurite tips. At lower concentrations, taxol may slightly enhance the mechanisms of microtubule assembly in neurons, and this alteration of normal processes changes the morphogenetic properties of the growing neurites.

1984-01-01

99

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

PubMed

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

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

2008-07-01

100

Modulation of septin and molecular motor recruitment in the microtubule environment of the Taxol-resistant human breast cancer cell line MDA-MB-231.  

PubMed

Cell resistance to low doses of paclitaxel (Taxol) involves a modulation of microtubule (MT) dynamics. We applied a proteomic approach based on 2-DE coupled with MS to identify changes in the MT environment of Taxol-resistant breast cancer cells. Having established a proteomic pattern of the microtubular proteins extracted from MDA-MB-231 cells, we verified by Western blotting that in resistant cells, ?- and ?-tubulins (more specifically the ?III and ?IV isotypes) increased. Interestingly, four septins (SEPT2, 8, 9 and 11), which are GTPases involved in cytokinesis and in MT/actin cytoskeleton organization, were overexpressed and enriched in the MT environment of Taxol-resistant cells compared to their sensitive counterpart. Changes in the MT proteome of resistant cells also comprised increased kinesin-1 heavy chain expression and recruitment on MTs while dynein light chain-1 was downregulated. Modulation of motor protein recruitment around MTs might reflect their important role in controlling MT dynamics via the organization of signaling pathways. The identification of proteins previously unknown to be linked to taxane-resistance could also be valuable to identify new biological markers of resistance. PMID:21761557

Froidevaux-Klipfel, Laurence; Poirier, Florence; Boursier, Céline; Crépin, Ronan; Poüs, Christian; Baudin, Bruno; Baillet, Anita

2011-08-18

101

Metabolic engineering of isoprenoid biosynthesis in Arabidopsis for the production of taxadiene, the first committed precursor of Taxol.  

PubMed

Paclitaxel (Taxol) is a widely used anticancer isoprenoid produced by the secondary metabolism of yew (Taxus sp.) trees. However, only limited amounts of Taxol or related metabolites (taxoids) can be obtained from the currently available sources. In this work we have taken the first step toward genetically engineering the biosynthesis of taxoids in angiosperms. The first committed step in Taxol biosynthesis is the production of taxadiene from geranylgeranyl diphosphate (GGPP), catalyzed by the plastid-localized enzyme taxadiene synthase (TXS). A recombinant T. baccata TXS lacking the putative plastid targeting peptide and fused to a C-terminal histidine (His) tag was shown to be enzymatically active in Escherichia coli. Constitutive production of the full-length His-tagged enzyme in Arabidopsis thaliana plants led to the accumulation of taxadiene and concomitant growth retardation and decreased levels of photosynthetic pigment in transgenic plants. Although these phenotypes may derive from a toxic effect of taxadiene, the lower accumulation of endogenous plastid isoprenoid products such as carotenoids and chlorophylls in transgenic plants also suggests that the constitutive production of an active TXS enzyme might alter the balance of the GGPP pool. Induction of transgene expression using a glucocorticoid-mediated system consistently resulted in a more efficient recruitment of GGPP for the production of taxadiene, which reached levels 30-fold higher than those in plants constitutively expressing the transgene. This accomplishment illustrates the possibility of engineering the production of taxoids and other GGPP-derived isoprenoids in crop plants despite the constraints associated with limited knowledge with regard to regulation of GGPP availability. PMID:15449291

Besumbes, Oscar; Sauret-Güeto, Susanna; Phillips, Michael A; Imperial, Santiago; Rodríguez-Concepción, Manuel; Boronat, Albert

2004-10-20

102

Phase I Clinical and Pharmacokinetic Study of Taxol1  

Microsoft Academic Search

Taxol, selected for clinical trial because of its animal antitumor activity and unique structure and mechanism of action, was administered in Cremophor by i.v. infusion over 6 h in a phase I study. Eastern Cooper ative Oncology Group toxicity grading was used. Eighty-three taxol courses were administered to 34 patients. Grade 3-4 hypersensitivity reactions occurred in 4 of 13 courses

Peter H. Wiernik; Janice J. Strauman; Janice P. Dutcher; Richard B. Lipton; Elisabeth Paietta

1987-01-01

103

Promotion of microtubule assembly in vitro by taxol  

Microsoft Academic Search

TAXOL (Fig. 1) was isolated from the plant Taxus brevifolia (western yew) by Wani et al., who reported that the molecule has antitumour activity in several experimental systems1. In our laboratory we have found that taxol, a low molecular weight neutral compound, completely inhibits division of exponentially growing HeLa cells at low concentrations of drug (0.25 µM) that have no

Peter B. Schiff; Jane Fant; Susan B. Horwitz

1979-01-01

104

Taxol production in suspension cultures of Taxus baccata  

Microsoft Academic Search

The response of Taxus baccata (PC2) to basic manipulations of culture conditions is described. Suspension cultures of Taxus baccata (PC2) were maintained at 25°C on a modified B5 medium with two-week transfers. Under these conditions, no taxol® is formed. However, if the cells are left in the same medium for 7 or more additional days, taxol is produced and released

Thomas J. Hirasuna; Luis J. Pestchanker; Venkatesh Srinivasan; Michael L. Shuler

1996-01-01

105

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

PubMed Central

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.

2012-01-01

106

Antitumour Efficacy of Two Paclitaxel Formulations for Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in an In Vivo Rat Model  

Microsoft Academic Search

Purpose  To evaluate the tumour growth delay of a peritoneal carcinomatosis (PC) of colorectal origin after intraperitoneal chemotherapy\\u000a with paclitaxel\\/randomly-methylated-?-cyclodextrin (Pac\\/RAME-?-CD) versus Taxol® at normo- and hyperthermic conditions in rats.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  Hyperthermic intraperitoneal chemotherapy (HIPEC) was performed 7 days post implantation of the tumour with both formulations\\u000a at a Pac concentration of 0.24 mg\\/ml. Tumour evaluation was performed via positron emission tomography (PET) and

Wim Bouquet; Steven Deleye; Steven Staelens; Lieselotte De Smet; Nancy Van Damme; Isabelle Debergh; Wim P. Ceelen; Filip De Vos; Jean Paul Remon; Chris Vervaet

2011-01-01

107

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

Microsoft Academic Search

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

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

2009-01-01

108

Coordinate Depression of Bradykinin Receptor Recycling and Microtubule-Dependent Transport by Taxol  

Microsoft Academic Search

Significant cardiovascular side effects have limited the use of taxol as an anticancer drug. A link between decreased plasma membrane dynamics and taxol has been implied because taxol can inhibit intracellular vesicle movements. Reduced membrane recycling caused by taxol could inhibit agonist-evoked Ca2+ signaling within endothelial cells, resulting in endothelium-dependent vasodilation. Bradykinin and ATP are two agonists that evoke Ca2+

Sarah F. Hamm-Alvarez; Bruce E. Alayof; Herbert M. Himmel; Preston Y. Kim; Anne L. Crews; Harold C. Strauss; Michael P. Sheetz

1994-01-01

109

A review: recent advances and future prospects of taxol-producing endophytic fungi  

Microsoft Academic Search

In the urgent search for more effective ways to treat cancer, new extraction methods of taxol from endophytic fungus have\\u000a demonstrated high potential in increasing the efficiency of taxol extraction for more efficient and sustainable production\\u000a of taxol and cancer treatment products. This paper summarizes recent advances in taxol-producing endophytic fungi, both in\\u000a China and abroad, in the following areas:

Xuanwei Zhou; Huifang Zhu; Lu Liu; Juan Lin; Kexuan Tang

2010-01-01

110

Phase I studies of combined paclitaxel/epirubicin and paclitaxel/epirubicin/cyclophosphamide in patients with metastatic offast cancer: the French experience.  

PubMed

In an attempt to develop new, active, and convenient outpatient combination-chemotherapy regimens for patients with metastatic breast cancer, we performed two phase I studies combining paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) plus anthracycline for the first-line treatment of metastatic disease, without the use of hematopoietic growth factors. Study I was designed to test the tolerability and antitumor activity of a 3-hour infusion of paclitaxel in combination with an epirubicin intravenous bolus. Study 2 explored a three-drug chemotherapy regimen: a 3-hour paclitaxel infusion with epirubicin and cyclophosphamide. Courses were repeated every 3 weeks. If any dose-limiting events occurred in two or more of six patients in the first course of a given dose level, that dose level was defined as the maximum tolerated dose. Dose-limiting criteria included the following: neutrophils less than 0.25 x 10(9)/L lasting for > or = 5 days, any febrile neutropenia, World Health Organization grade 4 thrombocytopenia, World Health Organization grade > or = 3 nonhematologic toxicity or grade > or = 3 mucositis for more than 5 days, and absence of hematologic recovery at day 35. In both studies, paclitaxel doses were escalated in subsequent groups of three to six patients. For study I, the initial dose level consisted of paclitaxel (110 mg/m2)/epirubicin (50 mg/m2). To date 40 patients have entered the study at eight dose levels. Of the 181 cycles evaluated, grade 3 or 4 neutropenic episodes were observed in 63% of courses, with only five episodes of febrile neutropenia. Grade 2 or 3 neurotoxicity was observed in 43% of patients. Two patients experienced clinical heart failure. The dose-limiting toxicity has not been reached so far. At dose level 7 (paclitaxel [250 mg/m2]/epirubicin [50 mg/m2]), only one patient of six experienced febrile neutropenia. We are currently testing paclitaxel (200 mg/m2)/epirubicin (75 mg/m2). Preliminary evaluation of response documents two complete and 16 partial responses in 37 evaluable patients (48% overall response rate). In study 2, the initial dose level consisted of paclitaxel (150 mg/m2)/epirubicin (50 mg/m2)/cyclophosphamide (500 mg/m2). To date, three dose levels have been investigated in 16 evaluable patients (82 cycles). Grade 3 or 4 neutropenic episodes were observed in 80% of courses, and five episodes were associated with neutropenic fever. Grade 2 neurotoxicity was observed in 28% of patients. The dose-limiting toxicity has not been reached, and we are currently investigating dose level 4 (paclitaxel 225 mg/m2). These trials confirm the tolerability of combined paclitaxel/epirubicin and paclitaxel/epirubicin/cyclophosphamide. The antitumor activity is encouraging. PMID:9071333

Catimel, G; Spielmann, M; Dieras, V; Tubiana-Hulin, M; Bonneterre, J; Pouillart, P; Kayitalire, L; Guastalla, J P; Graffand, N; Garet, F; Dumortier, A; Pellae-Cosset, B

1997-02-01

111

Phase I Study of Paclitaxel with Standard Dose Ifosfamide in Children with Refractory Solid Tumors: A Pediatric Oncology Group Study (POG 9376)  

PubMed Central

PURPOSE A dose-escalation Phase I study of taxol (paclitaxel) administered in combination with standard dose ifosfamide was conducted in children with relapsed or refractory solid tumors. Primary objectives were to estimate the maximum-tolerated dose (MTD) and to describe the dose-limiting toxicities (DLTs). PATIENTS AND METHODS Paclitaxel was administered as a 6-hour continuous infusion (hr 0–6), followed by intravenous ifosfamide (2 gm/m2 /day × 3days) over 1 hr at hours 6–7, 24–25, and 48–49. Patients at dose level 1 received 250 mg/m2 paclitaxel. Subsequent dose escalation proceeded using a standard 3×3 Phase I design. RESULTS Fifteen patients received a combined 46 courses of therapy. The median age was 14.5 years (range, 2 to 19 years), and diagnoses included sarcoma (7), neuroblastoma (3), and other (5). Three patients received paclitaxel at 250 mg/m2 (10 courses), six at 325 mg/m2 (19 courses), three at 425 mg/m2 (8 courses), and three at 550 mg/m2 (9 courses). DLTs occurred in 2/3 patients at 550 mg/m2 paclitaxel during cycle 1, including grade 3 hypotension and grade 4 anaphylaxis in 1 patient each. Common non-dose limiting toxicities included bone marrow suppression and peripheral neuropathy. Response was evaluable in 14 patients and included mixed response (3), stable disease (5) and progressive disease (6). CONCLUSION Paclitaxel hypersensitivity reactions were dose limiting when the drug was administered as a 6-hour infusion. The MTD and recommended Phase II dose of paclitaxel administered as a six-hour continuous intravenous infusion followed by standard dose intravenous ifosfamide is 425 mg/m2 paclitaxel.

Geller, James I.; Wall, Donna; Perentesis, John; Blaney, Susan M.; Bernstein, Mark

2009-01-01

112

Production of taxol and related taxanes in Taxus brevifolia cell cultures: Effect of sugar  

Microsoft Academic Search

Suspension cells of Taxus brevifolia were cultured as an alternative source of taxol and related taxanes. The effects of basal medium, sugar type, and sugar concentration on growth and taxane production were investigated. To induce taxol production, modification of medium composition was necessary. Fructose supported the best taxol yield and the use of high concentration of sugar was desirable. The

Jin-Hoon Kim; Jeong-Hwan Yun; Yong-Soon Hwang; Sang Yo Byuna; Dong-Il Kim

1995-01-01

113

Lysophosphatidate Induces ChemoResistance by Releasing Breast Cancer Cells from Taxol-Induced Mitotic Arrest  

Microsoft Academic Search

BackgroundTaxol is a microtubule stabilizing agent that arrests cells in mitosis leading to cell death. Taxol is widely used to treat breast cancer, but resistance occurs in 25–69% of patients and it is vital to understand how Taxol resistance develops to improve chemotherapy. The effects of chemotherapeutic agents are overcome by survival signals that cancer cells receive. We focused our

Nasser Samadi; Raie T. Bekele; Ing Swie Goping; Luis M. Schang; David N. Brindley; Hava Karsenty Avraham

2011-01-01

114

High-Speed Countercurrent Chromatography Separation of Taxol and Related Diterpenoids from Taxus Baccata  

Microsoft Academic Search

Taxol and related taxane diterpenoids were isolated from pre-purified extracts of stem-barks of Taxus bacccata by HSCCC. The described method allowed to obtain a mixture of taxol and cephalomannine without any other interfering constituent and furthermore a partial separation of taxol (40 % of the total recovery) from cephalomannine. In addition, the HPLC and TLC separation conditions of these compounds

R. Vanhaelen-Fastre; B. Diallo; M. Jaziri; M. L. Faes; J. Homes; M. Vanhaelen

1992-01-01

115

Quantitation of paclitaxel and its two major metabolites using a liquid chromatography-electrospray ionization tandem mass spectrometry.  

PubMed

A sensitive and selective liquid chromatographic-tandem mass spectrometric (LC-MS/MS) method for the determination of paclitaxel (Taxol) and its two major metabolites in human plasma has been developed. Samples were prepared after liquid-liquid extraction and analyzed on a C(18) column interfaced with a Q-Trap tandem mass spectrometer. Positive electrospray ionization was employed as the ionization source. The mobile phase consisted of acetonitrile-water (0.05% formic acid) (65:35) at the flow rate of 0.25 mL/min. The analytes and internal standard docetaxel were both detected by use of multiple reaction monitoring mode. The method was linear in the concentration range of 0.5-500.0 ng/mL for paclitaxel, 6?-hydroxypaclitaxel and p-3'-hydroxypaclitaxel, respectively. The lower limit of quantification (LLOQ) was 0.5 ng/mL for paclitaxel, 6?-hydroxypaclitaxel and p-3'-hydroxypaclitaxel, respectively. The intra- and inter-day relative standard deviation across three validation runs over the entire concentration range was less than 8.18%. The accuracy determined at three concentrations was within ±10.8% in terms of relative error. The total run time was 7.0 min. This assay offers advantages in terms of expediency, and suitability for the analysis of paclitaxel and its metabolites in various biological fluids. PMID:21705287

Zhang, Wei; Dutschman, Ginger E; Li, Xin; Cheng, Yung-Chi

2011-05-25

116

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

NASA Astrophysics Data System (ADS)

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.

Wang, Chao-Yang; Chen, Tong-Sheng

2011-02-01

117

Paclitaxel plus Bevacizumab versus Paclitaxel Alone for Metastatic Breast Cancer  

Microsoft Academic Search

vs. 0.0%, P<0.001), proteinuria (3.6% vs. 0.0%, P<0.001), headache (2.2% vs. 0.0%, P = 0.008), and cerebrovascular ischemia (1.9% vs. 0.0%, P = 0.02) were more frequent in patients receiving paclitaxel plus bevacizumab. Infection was more common in patients receiving paclitaxel plus bevacizumab (9.3% vs. 2.9%, P<0.001), but febrile neutropenia was uncommon (<1% overall). Conclusions Initial therapy of metastatic breast

Kathy Miller; Molin Wang; Julie Gralow; Maura Dickler; Melody Cobleigh; Edith A. Perez; Tamara Shenkier; David Cella; Nancy E. Davidson

2007-01-01

118

Suppression of endotoxin-induced inflammation by taxol  

Microsoft Academic Search

The pathogenesis of acute lung injury includes transendothelial diapedesis of leukocytes into lung tissues and disruption of endothelial\\/epithelial barriers leading to protein- rich oedema. In vitro studies show that the microtubule network plays a role in the regulation of endothelial permeability as well as in neutrophil locomotion. It was hypothesised that the microtubule-stabilising agent, taxol, might attenuate inflammation and vascular

T. Mirzapoiazova; I. A. Kolosova; L. Moreno; S. Sammani; J. G. N. Garcia; A. D. Verin

2007-01-01

119

Taxol Production by an Endophytic Fungus, Fusarium redolens, Isolated from Himalayan Yew.  

PubMed

Different endophytic fungi isolated from Himalayan Yew plants were tested for their ability to produce taxol. The BAPT gene (C-13 phenylpropanoid side chain-CoA acetyl transferase) involved in the taxol biosynthetic pathway was used as a molecular marker to screen taxolproducing endophytic fungi. Taxol extracted from fungal strain TBPJ-B was identified by HPLC and MS analysis. Strain TBPJ-B was identified as Fusarium redolens based on the morphology and internal transcribed spacer region of nrDNA analysis. HPLC quantification of fungal taxol showed that F. redolens was capable of producing 66 ?g/l of taxol in fermentation broth. The antitumour activity of the fungal taxol was tested by potato disc tumor induction assay using Agrobacterium tumefaciens as the tumor induction agent. The present study results showed that PCR amplification of genes involved in taxol biosynthesis is an efficient and reliable method for prescreening taxol-producing fungi. We are reporting for the first time the production of taxol by F. redolens from Taxus baccata L. subsp. wallichiana (Zucc.) Pilger. This study offers important information and a new source for the production of the important anticancer drug taxol by endophytic fungus fermentation. PMID:23801250

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

2013-10-28

120

Enhancement of taxol-induced apoptosis by inhibition of NF-?B with ursorlic acid  

NASA Astrophysics Data System (ADS)

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

Li, Yunlong; Xing, Da

2007-05-01

121

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

Microsoft Academic Search

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

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

1993-01-01

122

Screening and breeding of high taxol producing fungi by genome shuffling  

Microsoft Academic Search

To apply the fundamental principles of genome shuffling in breeding of taxol-producing fungi, Nodulisporium sylviform was used as starting strain in this work. The procedures of protoplast fusion and genome shuffling were studied. Three hereditarily\\u000a stable strains with high taxol production were obtained by four cycles of genome shuffling. The qualitative and quantitative\\u000a analysis of taxol produced was confirmed using

Kai Zhao; WenXiang Ping; LiNa Zhang; Jun Liu; Yan Lin; Tao Jin; DongPo Zhou

2008-01-01

123

Molecular and Morphological Characterization of a Taxol-Producing Endophytic Fungus, Gliocladium sp., from Taxus baccata.  

PubMed

The endophytic fungal populations of different tissues of Taxus baccata grown at high altitudes in West Bengal, India were explored. These isolated fungal populations represented different genera, which were screened for taxol production using immunoassay technique. The culture AAT-TS-4(1) that produced taxol was identified as Gliocladium sp. based on its cultural, morphological characteristics, internal transcribed spacer, and 18S rRNA sequence analysis. Kinetics of taxol production as a function of culture growth were investigated. PMID:22783096

Sreekanth, D; Sushim, G K; Syed, A; Khan, B M; Ahmad, A

2011-09-27

124

Molecular and Morphological Characterization of a Taxol-Producing Endophytic Fungus, Gliocladium sp., from Taxus baccata  

PubMed Central

The endophytic fungal populations of different tissues of Taxus baccata grown at high altitudes in West Bengal, India were explored. These isolated fungal populations represented different genera, which were screened for taxol production using immunoassay technique. The culture AAT-TS-41 that produced taxol was identified as Gliocladium sp. based on its cultural, morphological characteristics, internal transcribed spacer, and 18S rRNA sequence analysis. Kinetics of taxol production as a function of culture growth were investigated.

Sushim, G. K.; Syed, A.; Khan, B. M.; Ahmad, A.

2011-01-01

125

Stimulation of taxol production and excretion in Taxus spp cell cultures by rare earth chemical lanthanum  

Microsoft Academic Search

The trivalent ion of a rare earth element, lanthanum, was tested for elicitor-like effects on taxol production in suspension cultures of four different Taxus spp cells. In T. yunnanensis cell cultures, the lanthanum ion at concentrations from 1.15 to 23.0 ?M stimulated taxol production. The lanthanum ion also promoted taxol excretion by the T. yunnanensis cells considerably. The maximum stimulation

Jianyong Wu; Chuangui Wang; Xingguo Mei

2001-01-01

126

Taxol Induces bcl-2 Phosphorylation and Death of Prostate Cancer Cells1  

Microsoft Academic Search

Treatment of prostate cancer cell lines expressing bcl-2 with taxol induces bcl-2 phosphorylation and programmed cell death, whereas treat ment of ¿>c\\/-2-negativeprostate cancer cells with taxol does not induce apoptosis. bcl-2 phosphorylation seems to inhibit its binding to box since less box was observed in immunocomplex with bcl-2 in taxol-treated cancer cells. These findings support the use of the anticancer

Subrata Haldar; Janaki Chintapalli; Carlo M. Croce

1996-01-01

127

Bioprocessing of plant in vitro systems for the mass production of pharmaceutically important metabolites: paclitaxel and its derivatives.  

PubMed

Taxol (paclitaxel) and its derivatives are microtubule-stabilizing drugs widely used in the treatment of several types of cancer, including mammary, prostate, ovarian and non-small-cell lung carcinoma, as well as AIDS-associated Kaposi's sarcoma and other types of tumor. Taxanes stabilize microtubules by enhancing their polymerization and inhibiting depolymerization. Microtubule dynamics are crucial to mitotic spindle formation and function; therefore, cells exposed to taxanes are unable to undergo chromosomal separation during mitosis, become arrested in the G2/M phases of the cell cycle, and are subsequently targeted for apoptosis. Plant cell cultures are used for industrial-scale biotechnological production of important bioactive plant secondary metabolites, including the anticancer agent paclitaxel. In the last two decades, there have been numerous empirical approaches to improve the biotechnological production of taxanes, leading to the conclusion that treatment of Taxus sp. cells with methyl jasmonate or other elicitors is the most effective strategy. However, little insight has been gained into how the elicitors increase taxane biosynthesis or how this process is regulated. In recent years, with the help of "omics" tools, a rational approach has provided new information about taxane metabolism and its control. Once pathway bottlenecks have been identified, it will be possible to engineer Taxus sp. cell lines with overexpression of genes that control the flux-limiting steps, thus boosting taxane productivity. This review describes the chemical and biological characterization of paclitaxel and its derivatives and discusses future prospects for their biotechnological production. PMID:23210777

Onrubia, M; Cusidó, R M; Ramirez, K; Hernández-Vázquez, L; Moyano, E; Bonfill, M; Palazon, J

2013-01-01

128

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

PubMed

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

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

2013-02-10

129

Metformin-mediated downregulation of p38 mitogen-activated protein kinase-dependent excision repair cross-complementing 1 decreases DNA repair capacity and sensitizes human lung cancer cells to paclitaxel.  

PubMed

Metformin, an extensively used and well-tolerated drug for treating individuals with type 2 diabetes, has recently gained significant attention as an anticancer drug. On the other hand, paclitaxel (Taxol) is a new antineoplastic drug that has shown promise in the treatment of non-small cell lung cancer (NSCLC). High expression levels of excision repair cross-complementary 1 (ERCC1) in cancers have been positively associated with the DNA repair capacity and a poor prognosis in NSCLC patients treated with platinum-containing chemotherapy. In this current study, paclitaxel was found to increase phosphorylation of mitogen-activated protein kinase (MAPK) kinase 3/6 (MKK3/6)-p38 MAPK as well as protein and mRNA levels of ERCC1 in H1650 and H1703 cells. Moreover, paclitaxel-induced ERCC1 protein and mRNA levels significantly decreased via the downregulation of p38 activity by either a p38 MAPK inhibitor SB202190 or p38 knockdown with specific small interfering RNA (siRNA). Specific inhibition of ERCC1 with siRNA was found to enhance the paclitaxel-induced cytotoxic effect and growth inhibition. Furthermore, metformin was able to not only decrease the paclitaxel-induced p38 MAPK-mediated ERCC1 expression, but also augment the cytotoxic effect induced by paclitaxel. Finally, expression of constitutive activate MKK6 or HA-p38 MAPK vectors in lung cancer cells was able to abrogate ERCC1 downregulation by metformin and paclitaxel as well as cell viability and DNA repair capacity. Overall, our results suggest that inhibition of the p38 MAPK signaling by metformin coupled with paclitaxel therapy in human NSCLC cells may be a clinically useful combination, which however will require further validation. PMID:23228696

Tseng, Sheng-Chieh; Huang, Yu-Ching; Chen, Huang-Jen; Chiu, Hsien-Chun; Huang, Yi-Jhen; Wo, Ting-Yu; Weng, Shao-Hsing; Lin, Yun-Wei

2012-12-07

130

Taxol-induced rose microtubule polymerization in vitro and its inhibition by colchicine  

PubMed Central

Tubulin was isolated from cultured cells of rose (Rosa, sp.cv. Paul's scarlet) by DEAE-Sephadex A50 chromatography, and the taxol-induced polymerization of microtubules in vitro was characterized at 24 degrees C by turbidity development, sedimentation analysis, and electron microscopy. Numerous, short microtubules were formed in the presence of taxol, and maximum levels of turbidity and polymer yield were obtained at approximately 2:1 molar ratios of taxol to tubulin. The critical concentration of rose tubulin for polymerization in saturating taxol was estimated to be 0.21 mg/ml. Colchicine inhibited the taxol-induced polymerization of tubulin as shown by sedimentation assays; however, much higher concentrations of colchicine were required for the inhibition of taxol-induced rose tubulin assembly than for inhibition of taxol-induced mammalian brain tubulin assembly. On the basis of the relative sensitivity of rose tubulin assembly to taxol and its insensitivity to colchicine, we propose that the taxol-binding site(s) on plant and animal tubulins have been more conserved over evolution than the colchicine-binding site(s).

1984-01-01

131

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

PubMed

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

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

2009-05-30

132

Optimization of the extraction of paclitaxel from Taxus baccata L. by the use of microwave energy.  

PubMed

A simple and rapid microwave-assisted extraction (MAE) procedure was developed and optimized for the extraction of paclitaxel (Taxol) from the needles of yew trees Taxus baccata L. grown in Iranian habitats. The samples, immersed in a methanol-water mixture, were irradiated with microwaves in a closed-vessel system. The method was evaluated using a factorial design approach based on parameters such as extraction time, temperature, methanol concentration in water (v/v), and the ratio of grams of sample to 10 mL of solvent. Statistical treatment of the results revealed that the selected parameters were all significant except the extraction time. Optimum conditions would be 1.5 g samples in 10 mL solvent (90% methanol), an extraction temperature of 95 degrees C, and an extraction time of 7 min. The extracts has been analyzed by reverse-phase high-performance liquid chromatography with UV detection (LC/UV) at 227 nm for quantification. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used for confirmation. The main advantage of the proposed MAE method versus conventional solvent extraction (CSE) are the considerable reductions in time (7 min versus 16 h) and in solvent consumption (20 mL versus 150 mL). The MAE procedure yielded extracts that could be analyzed directly without any preliminary clean-up or solvent exchange steps. Both extraction methods show RSDs lower than 10% and lead to comparable recoveries of paclitaxel (87-92%). PMID:15495416

Talebi, Mohammad; Ghassempour, Alireza; Talebpour, Zahra; Rassouli, Ali; Dolatyari, Lila

2004-09-01

133

Isolation of Colletotrichum gloeosporioides, a novel endophytic taxol-producing fungus from the leaves of a medicinal plant, Justicia gendarussa  

Microsoft Academic Search

Taxol is a potent anticancer drug used widely in the treatment of a variety of cancers. An endophytic fungus Colletotrichum gloeosporioides (strain JGC-9) was isolated from Justicia gendarussa, a medicinal plant and screened for taxol production. Th e fungus was identifi ed based on the morphology of the fungal culture and the characteristics of the spores and screened for taxol

V. Gangadevi; J. Muthumary

2008-01-01

134

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

Microsoft Academic Search

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

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

2005-01-01

135

Separation and purification of taxol and cephalomannine from Taxus Cuspidada by normal phase chromatography and twice-reversed-phase chromatography  

Microsoft Academic Search

Taxol is a kind of terpene compounds, which was separated from Taxus brevifolia by Wani et al. [1] originally. Because of the special anticancer mechanics and special curative effect for some kinds of tumor, taxol has attracted much attention recently. At present, an effective method used to ob tain taxol is extraction and separation frorm taxus. It is very difficult

Huiru Dong; Lina Luo; Shan Zhou; Pengyu Bi; Kailu Liu; Jingcheng Zhao

2007-01-01

136

Improved development by Taxol pretreatment after vitrification of in vitro matured porcine oocytes  

Microsoft Academic Search

This study was designed to examine the effect of Taxol pretreatment on vitrification of porcine oocytes matured in vitro by an open pulled straw (OPS) method. In the first experiment, the effect of Taxol pretreatment and fluorescein diacetate (FDA) staining on parthenogenetic development of oocytes was evaluated. In the second experiment, viability, microtubule organiz- ation and embryo development of oocytes

Wen-Qing Shi; Shi-En Zhu; Dong Zhang; Wei-Hua Wang; Guo-Liang Tang; Yun-Peng Hou; Shu-Jun Tian

2006-01-01

137

Occurrence of taxol and related taxanes in the wood of Pacific yew  

Treesearch

Description: Maximizing the yield of taxol per tree is important for the best management ... Initial reports form our laboratory, in cooperation with the National Cancer ... compared to bark indicated a potentially significant additional source of taxol. ... International Yew Resources Conference : yew (Taxus) conservation biology ...

138

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

Microsoft Academic Search

The diterpenoid taxol is an important anticancer agent used widely in the clinic. The purpose of this work was to identify a taxol-producing endophytic fungus (strain TF5) isolated from Taxus mairei and study its anticancer activities. Strain TF5 was identified as a Tubercularia sp. according to the morphology of the fungal culture, the mechanism of spore production and the characteristics

Jianfeng Wang; Guiling Li; Huaying Lu; Zhonghui Zheng; Yaojian Huang; Wenjin Su

2000-01-01

139

Taxol-producing [corrected] fungal endophyte, Pestalotiopsis species isolated from Taxus cuspidata.  

PubMed

The endophytic fungi, Pestalotiopsis versicolor and Pestalotiopsis neglecta, were isolated from the healthy leaves and bark of the Japanese Yew tree, Taxus cuspidata. The fungal species were identified by their characteristic culture morphology and molecular analysis. For the first time, the test fungi were screened for the production of taxol in modified liquid medium. The presence of taxol was confirmed by HPLC, (1)H NMR, and LC-MS methods of analysis. The maximum amount of taxol production in P. versicolor was recorded as 478 ?g/l. The production rate was increased to 9560-fold than that found in the culture broth of earlier reported fungus, Taxomyces andreanae. The extracted fungal taxol showed a strong cytotoxic activity in the in vitro culture of tested human cancer cells by apoptotic assay indicating that the increase in taxol concentration induces increased cell death. A PCR-based screening for ts, a unique gene in the formation of the taxane skeleton, confirmed the molecular blueprint for taxol biosynthesis. The results designate that the fungal endophyte, P. versicolor, is an excellent candidate for an alternate source of taxol supply and can also serve as a potential species for genetic engineering to enhance the production of taxol to a higher level. PMID:20634132

Kumaran, Rangarajulu Senthil; Kim, Hyung Joo; Hur, Byung-Ki

2010-07-15

140

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

Microsoft Academic Search

Pestalotiopsis microspora, isolate NE-32, is an endophyte of the Himalayan yew (Taxus wallichiana) that produces taxol, an important chemotherapeutic drug used in the treatment of breast and ovarian cancers. Conditions were determined to induce the perfect stage (teleomorph) of this organism in the laboratory as a critical first step to study inheritance of taxol biosynthetic genes. The perfect stage of

Anneke M. Metz; Asmahan Haddad; Jeerapun Worapong; David M. Long; Eugene J. Ford; W. M. Hess; Gary A. Strobel

141

Disulfide bond reduction-triggered molecular hydrogels of folic acid-Taxol conjugates.  

PubMed

Molecular hydrogels of therapeutic agents are a novel kind of self-delivery system that can sustain release of drugs or pro-drugs. We have previously developed a molecular hydrogelator of folic acid (FA)-Taxol conjugate triggered by phosphatase. In this paper, we report a novel molecular hydrogelator system of FA-Taxol conjugates with improved synthetic strategy. The hydrogels are formed by the reduction of disulfide bond by glutathione (GSH). These hydrogels could sustain release of Taxol through ester bond hydrolysis. Compared with intravenous (i.v.) injection of clinically used Taxol® with four times the dosage, our hydrogel could inhibit tumor growth more efficiently by a single dose of intra-tumor (i.t.) administration. These observations suggested the big potential of this novel gelation system of Taxol for cancer therapy. PMID:23989242

Yang, Chengbiao; Li, Dongxia; Fengzhao, Qianqi; Wang, Lianyong; Wang, Ling; Yang, Zhimou

2013-09-25

142

Reactive oxygen species (ROS) is not a promotor of taxol-induced cytoplasmic vacuolization  

NASA Astrophysics Data System (ADS)

we have previously reported that taxol, a potent anticancer agent, induces caspase-independent cell death and cytoplasmic vacuolization in human lung adenocarcinoma (ASTC-a-1) cells. However, the mechanisms of taxol-induced cytoplasmic vacuolization are poorly understood. Reactive oxygen species (ROS) has been reported to be involved in the taxol-induced cell death. Here, we employed confocal fluorescence microscopy imaging to explore the role of ROS in taxol-induced cytoplasmic vacuolization. We found that ROS inhibition by addition of N-acetycysteine (NAC), a total ROS scavenger, did not suppress these vacuolization but instead increased vacuolization. Take together, our results showed that ROS is not a promotor of the taxol-induced cytoplasmic vacuolization.

Sun, Qingrui; Chen, Tongsheng

2009-02-01

143

Effects of genetic, epigenetic, and environmental factors on taxol content in Taxus brevifolia and related species.  

PubMed

The demand for taxol, a promising cancer chemotherapeutic agent, far exceeds supply. Presently, taxol is derived from the bark of the Pacific yew, Taxus brevifolia, a small, slow-growing evergreen tree native to the northwestern United States. Knowledge of the distribution and magnitude of genetic and non-genetic sources of variation in taxol content in the genus Taxus is necessary if supply issues are to be met through plant harvesting. Analytical determinations of taxol, cephalomannine, and baccatin III in more than 200 trees representing several populations of T. brevifolia and other yew taxa indicate that (1) significant variation in taxane content exists among and within populations and species, (2) taxol levels exceeding those reported for T. brevifolia bark were found in shoots of individual trees from most taxa studied, and (3) the season in which samples are collected and handling procedures can influence taxane content. PMID:1355111

Wheeler, N C; Jech, K; Masters, S; Brobst, S W; Alvarado, A B; Hoover, A J; Snader, K M

1992-04-01

144

A Phase I/II study of paclitaxel and doxorubicin in the treatment of advanced breast cancer.  

PubMed

We designed a clinical study in which fixed doses of doxorubicin were infused by intravenous bolus 16 hours before escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, princeton, NJ) for the treatment of patients with advanced breast cancer, an interval selected to allow systemic clearance of doxorubicin before administration of paclitaxel in an outpatient setting. Courses of fixed-dose doxorubicin 50 mg/m2 by intravenous bolus and paclitaxel (doses escalated from 130 mg/m2 to 250 mg/m2 via dose escalation of 30 mg/m2) were repeated every 21 days, to a maximum of eight cycles. Maximum tolerated dose was reached if two or more of six patients at a given dose level were affected by the following events: absolute neutrophil count less than 500/microliter for > or = 7 days, absolute neutrophil count less than 100/microliter for > or = 3 days, insufficient hematopoietic recovery with absolute neutrophil count less than 1,500/microliter on day 21, febrile neutropenia, grade 4 thrombocytopenia, any World Health Organization grade 3 nonhematologic toxicity for more than 7 days. There were 19 patients enrolled; the patients received a total of 128 treatment courses. Grade 4 neutropenia was the main side effect, occurring in 20% of courses but generally not associated with clinical events. No relevant clinical cardiac toxicity or alteration of left ventricular ejection fraction was observed. Other toxicities included complete alopecia, mild peripheral neuropathy, and mild myalgia. There was a reduction of one dose level for moderate myalgia in one patient (190 mg/m2 level). Complete alopecia was always present. Maximum tolerated dose was not reached at paclitaxel 250 mg/m2. Ultimately, the introduction of this combination in the adjuvant setting is warranted. PMID:8629031

Amadori, D; Frassineti, G L; Zoli, W; Tienghi, A; Ravaioli, A; Casadei Giunchi, D; Gentile, A; Salzano, E

1996-02-01

145

Paclitaxel, carboplatin, and oral etoposide: a phase II trial in limited-stage small cell lung cancer.  

PubMed

Carboplatin/etoposide is an active regimen in the treatment of small cell lung cancer. This phase II trial evaluated whether adding paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to this two-drug combination might increase its efficacy. Since April 1996, 55 patients were entered into the ongoing protocol. To date, 35 patients are evaluable for efficacy and toxicity. Most of the evaluable patients are male (28). The patients' median age is 60 years (range, 36 to 74 years); 32 patients have Eastern Cooperative Oncology Group performance status ratings of 1, and the balance are Eastern Cooperative Oncology Group performance status 0. All patients had limited-stage disease. Patients received paclitaxel 175 mg/m2 via 1-hour intravenous infusion on day 1, carboplatin dosed to an area under the concentration-time curve of 5, also on day 1, and oral etoposide 100 mg on days 2 through 8. Overall, 31 patients responded to paclitaxel/carboplatin/etoposide therapy, including complete response in 13 patients (37.1%) and partial response in 18 patients (51.4%). Disease was stable in three patients (8.6%) and disease progressed in one (2.0%). Hematologic toxicity included neutropenia (World Health Organization grade 3 in 24.1% of patients, grade 4 in 31.3%), anemia (4% grade 3, no grade 4), and thrombocytopenia (3.2% grade 3, 2.1% grade 4). Nonhematologic adverse events included minor nausea/vomiting (1.5% grade 3, 9.2% grade 2), polyneuropathy (2.3% grade 2, 17.5% grade 1), and myalgia/arthralgia (8.2% grade 2, 16.4% grade 1). Paclitaxel/carboplatin/etoposide is active in small cell lung cancer with moderate toxicity and good subjective tolerance. There were no life-threatening hematologic or nonhematologic complications in this phase II trial. PMID:9331141

Gatzemeier, U; Jagos, U; Kaukel, E; Koschel, G; von Pawel, J

1997-08-01

146

Phase I study of dose-escalated paclitaxel, ifosfamide, and cisplatin (PIC) combination chemotherapy in advanced solid tumours  

PubMed Central

Based on the already known in vitro synergy between paclitaxel (taxol), cisplatin and oxazophosphorine cytostatics and the broad spectrum of activity of the above drugs we sought to evaluate the paclitaxel (taxol)-ifosfamide-cisplatin (PIC) combination in the outpatient setting in individuals with a variety of advanced solid tumours. Cohorts of patients were entered into six successive dose levels (DLs) with drug doses ranging as follows: paclitaxel 135–215 mg m?2day 1 – (1 h infusion), ifosfamide 4.5–6.0 g m?2(total dose) – divided over days 1 and 2, and cisplatin 80–100 mg m?2(total) – divided over days 1 and 2. Granulocyte colony-stimulating factor was given from day 5 to 14. Forty-two patients were entered. Eighteen patients had 2–8 cycles of prior chemotherapy with no taxanes or ifosfamide (cisplatin was allowed). The regimen was tolerated with outpatient administration in 36/42 patients. Toxicities included: grade 4 neutropenia for ? 5 days in 27% of cycles; 5 episodes of febrile neutropenia in three patients at DL-III, -V and -VI. Grade 3/4 thrombocytopenia and cumulative grade 3 anaemia were seen in 7% and 13% of cycles respectively. Three cases of severe grade 3 neuromotor/sensory neuropathy were recorded at DL-II, -III, and -V, all after cycle 3. The maximum tolerated dose was not formally reached at DL-V, but because of progressive anaemia and asthenia/fatigue, it was decided to test a new DL-VI with doses of paclitaxel 200 mg m?2, ifosfamide 5.0 g m?2and cisplatin 100 mg m?2; this appeared to be tolerable and is recommended for further phase II testing. The response rate was 47.5% (complete response + partial response: 20/42). The PIC regimen appears to be feasible and safe in the outpatient setting. Care should be paid to neurotoxicity. Phase II studies are starting in non-small-cell lung cancer, ovarian cancer and head and neck cancer at DL-VI. © 2000 Cancer Research Campaign

Kosmas, C; Tsavaris, N B; Polyzos, A; Malamos, N A; Katsikas, M; Antonopoulos, M J

2000-01-01

147

Taxol-induced apoptosis in human SKOV3 ovarian and MCF7 breast carcinoma cells is caspase-3 and caspase-9 independent  

Microsoft Academic Search

Taxol is used in chemotherapy regimens against breast and ovarian cancer. Treatment of tumor model cell lines with taxol induces apoptosis, but exact mechanism is not sufficiently understood. Our results demonstrate that in response to taxol, various cell types differentially utilize distinct apoptotic pathways. Using MCF7 breast carcinoma cells transfected with caspase-3 gene, we showed that taxol-induced apoptosis occurred in

R Ofir; R Seidman; T Rabinski; M Krup; V Yavelsky; Y Weinstein; M Wolfson

2002-01-01

148

Targeted delivery of insoluble cargo (paclitaxel) by PEGylated chitosan nanoparticles grafted with Arg-Gly-Asp (RGD).  

PubMed

Poor delivery of insoluble anticancer drugs has so far precluded their clinical application. In this study, we developed a tumor-targeting delivery system for insoluble drug (paclitaxel, PTX) by PEGylated O-carboxymethyl-chitosan (CMC) nanoparticles grafted with cyclic Arg-Gly-Asp (RGD) peptide. To improve the loading efficiency (LE), we combined O/W/O double emulsion method with temperature-programmed solidification technique and controlled PTX within the matrix network as in situ nanocrystallite form. Furthermore, these CMC nanoparticles were PEGylated, which could reduce recognition by the reticuloendothelial system (RES) and prolong the circulation time in blood. In addition, further graft of cyclic RGD peptide at the terminal of PEG chain endowed these nanoparticles with higher affinity to in vitro Lewis lung carcinoma (LLC) cells and in vivo tumor tissue. These outstanding properties enabled as-designed nanodevice to exhibit a greater tumor growth inhibition effect and much lower side effects over the commercial formulation Taxol. PMID:22559746

Lv, Pi-Ping; Ma, Yu-Feng; Yu, Rong; Yue, Hua; Ni, De-Zhi; Wei, Wei; Ma, Guang-Hui

2012-05-15

149

Oral paclitaxel and concurrent cyclosporin A: targeting clinically relevant systemic exposure to paclitaxel.  

PubMed

Oral paclitaxel is not inherently bioavailable because of the overexpression of P-glycoprotein by intestinal cells and the significant first-pass extraction by cytochrome P450-dependent processes. This study sought to simulate the toxicological and pharmacological profile of a clinically relevant schedule of paclitaxel administered on clinically relevant i.v. dosing schedules in patients with advanced solid malignancies using oral paclitaxel administered with cyclosporin A, an inhibitor of both P-glycoprotein and P450 CYP3A. Nine patients were treated with a single course of oral paclitaxel in its parenteral formulation at a paclitaxel dose level of 180, 360, or 540 mg. Cyclosporin A was administered at a dose of 5 mg/kg p.o. 1 h before and concurrently with oral paclitaxel. Blood sampling was performed to evaluate the pharmacokinetics of paclitaxel, 6-alpha-hydroxypaclitaxel, 3-p-hydroxypaclitaxel, and cyclosporin A. The pharmacokinetic behavior of paclitaxel was characterized using both compartmental and noncompartmental methods. Model-estimated parameters were used to simulate paclitaxel concentrations after once daily and twice daily oral administration of paclitaxel and cyclosporin A. Aside from an unpleasant taste, the oral regimen was well tolerated, and there were no grade 3 or 4 drug-related toxicities. The systemic exposure to paclitaxel, as assessed by maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve (AUC) values, did not increase as the dose of paclitaxel was increased from 180 to 540 mg, and there was substantial interindividual variability (4-6-fold) at each dose level. Mean paclitaxel Cmax values approached plasma concentrations achieved with clinically relevant parenteral dose schedules, averaging 268+/-164 ng/ml. AUC values averaged 3306+/-1977 ng x h/ ml, which was significantly lower than AUC values achieved with clinically relevant i.v. paclitaxel dose schedules. However, computer simulations using pharmacokinetic parameters derived from the present study demonstrated that pharmacodynamically relevant steady-state plasma paclitaxel concentrations of at least 0.06 microM would be achieved after protracted once daily and twice daily dosing with oral paclitaxel and cyclosporin A. Paclitaxel metabolites were detectable in three patients, and the 6-alpha-hydroxypaclitaxel: paclitaxel and 3-p-hydroxypaclitaxel:paclitaxel AUC ratios averaged 0.63 and 0.86, respectively; these values were substantially higher than values reported in patients treated with i.v. paclitaxel. Oral paclitaxel was bioavailable in humans when administered in combination with oral cyclosporin A 5 mg/kg 1 h before and concurrently with paclitaxel treatment, and plasma paclitaxel concentrations achieved with this schedule were biologically relevant and approached concentrations attained with clinically relevant parenteral dose schedules. However, treatment of patients with oral paclitaxel using a single oral dose administration schedule failed to achieve sufficiently high systemic drug exposure and pharmacodynamic effects. In contrast, computer simulations demonstrated that clinically relevant pharmacodynamic effects are likely to be achieved with multiple once daily and twice daily oral paclitaxel-cyclosporin A dosing schedules. PMID:10999729

Britten, C D; Baker, S D; Denis, L J; Johnson, T; Drengler, R; Siu, L L; Duchin, K; Kuhn, J; Rowinsky, E K

2000-09-01

150

Genetic engineering of taxol biosynthetic genes in Saccharomyces cerevisiae.  

PubMed

Baccatin III, an intermediate of Taxol biosynthesis and a useful precursor for semisynthesis of the anti-cancer drug, is produced in yew (Taxus) species by a sequence of 15 enzymatic steps from primary metabolism. Ten genes encoding enzymes of this extended pathway have been described, thereby permitting a preliminary attempt to reconstruct early steps of taxane diterpenoid (taxoid) metabolism in Saccharomyces cerevisiae as a microbial production host. Eight of these taxoid biosynthetic genes were functionally expressed in yeast from episomal vectors containing one or more gene cassettes incorporating various epitope tags to permit protein surveillance and differentiation of those pathway enzymes of similar size. All eight recombinant proteins were readily detected by immunoblotting using specific monoclonal antibodies and each expressed protein was determined to be functional by in vitro enzyme assay, although activity levels differed considerably between enzyme types. Using three plasmids carrying different promoters and selection markers, genes encoding five sequential pathway steps leading from primary isoprenoid metabolism to the intermediate taxadien-5alpha- acetoxy-10beta-ol were installed in a single yeast host. Metabolite analysis showed that yeast isoprenoid precursors could be utilized in the reconstituted pathway because products accumulated from the first two engineered pathway steps (leading to the committed intermediate taxadiene); however, a pathway restriction was encountered at the first cytochrome P450 hydroxylation step. The means of overcoming this limitation are described in the context of further development of this novel approach for production of Taxol precursors and related taxoids in yeast. PMID:16161138

Dejong, JingHong M; Liu, Yule; Bollon, Arthur P; Long, Robert M; Jennewein, Stefan; Williams, David; Croteau, Rodney B

2006-02-01

151

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

NASA Astrophysics Data System (ADS)

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

Castro Carmona, Javier Servando

152

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

Microsoft Academic Search

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

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

153

Improving anti-tumor activity with polymeric micelles entrapping paclitaxel in pulmonary carcinoma.  

PubMed

Nanoscale polymeric micelles have promising applications as drug delivery systems (DDS). In this work, to improve the anti-tumor activity and eliminate toxicity of the commercial formulation (cremophor EL and ethanol) of paclitaxel (PTX), we developed biodegradable poly(ethylene glycol)-poly(?-caprolactone) (MPEG-PCL) micelles entrapping PTX by a simple one-step solid dispersion method, which is without any surfactants or additives and is easy to scale up. In addition, the PTX micelles could be lyophilized into powder without any adjuvant and the re-dissolved PTX micelles are stable and homogeneous. The prepared PTX micelles have a mean particle size of 38.06 ± 2.30 nm, a polydispersity index of 0.168 ± 0.014, a drug loading of 14.89 ± 0.06% and an encapsulation efficiency of 99.25 ± 0.38%. A molecular modeling study implied that PTX interacted with PCL as a core, which was embraced by PEG as a shell. The encapsulation of PTX in polymeric micelles enhanced its cytotoxicity by increasing the uptake by LL/2 cells. A sustained in vitro release behavior and slow extravasation behavior from blood vessels in a transgenic zebrafish model were observed in the PTX micelles. Furthermore, compared with Taxol®, the PTX micelles were more effective in suppressing tumor growth in the subcutaneous LL/2 tumor model. The PTX micelles also inhibited metastases in the pulmonary metastatic LL/2 tumor model and prolonged survival in both mouse models. Pharmacokinetic and tissue distribution studies showed that after PTX was encapsulated in polymeric micelles, the biodistribution pattern of PTX was altered and the PTX concentration in tumors was increased compared with Taxol® after intravenous injection. In conclusion, we have developed a polymeric micelles entrapping PTX that enhanced cytotoxicity in vitro and improved anti-tumor activity in vivo with low systemic toxicity on pulmonary carcinoma. The biodegradable MPEG-PCL micelles entrapping PTX may have promising applications in pulmonary carcinoma therapy. PMID:22910790

Gong, Changyang; Xie, Yongmei; Wu, Qinjie; Wang, Yujun; Deng, Senyi; Xiong, Dake; Liu, Lei; Xiang, Mingli; Qian, Zhiyong; Wei, Yuquan

2012-08-22

154

Paclitaxel: cost-effectiveness in ovarian cancer.  

PubMed

Ovarian cancer accounts for a significant burden of healthcare costs worldwide. Therapy of this disease consists of a combined surgical and chemotherapeutic approach. Remarkable advances in chemotherapy have been made with the introduction of new agents such as paclitaxel. Based on positive clinical data from randomized trials, numerous cost studies have been undertaken to analyze the cost-effectiveness of paclitaxel. Reviewing all the available cost studies, the authors conclude that paclitaxel plus cisplatin treatment is cost effective. Paclitaxel demonstrated survival and utility gains in combination with cisplatin as first-line treatment in patients with Stage II-IV ovarian cancer compared with cyclophosphamide and cisplatin. Incremental costs of USD 6600-22,000 per life year gained are within an accepted range for new treatments. PMID:19807593

Dedes, Konstantin J; Bramkamp, Matthias; Szucs, Thomas D

2005-06-01

155

Management of paclitaxel-induced neurotoxicity  

Microsoft Academic Search

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

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

2010-01-01

156

Src family kinases and paclitaxel sensitivity  

PubMed Central

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.

2011-01-01

157

Src family kinases and paclitaxel sensitivity.  

PubMed

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

Le, Xiao-Feng; Bast, Robert C

2011-08-15

158

Spinal glial glutamate transporters downregulate in rats with taxol-induced hyperalgesia.  

PubMed

Changes in the expression of glial glutamate transporters (GLAST and GLT-1) were examined in the spinal cord of rats with chemotherapy (taxol)-induced mechanical hyperalgesia. Immunohistochemical studies show that the expression of both GLAST and GLT-1 in the L4-L5 spinal dorsal horn is decreased by 24% (P<0.001) and 23% (P<0.001), respectively, in rats with taxol-induced hyperalgesia as compared with those in control rats. These changes were further confirmed using an enzyme-linked immunosorbent assay that confirmed downregulation of GLAST by 36% (P<0.05) and GLT-1 by 18% (P<0.05) in the L4-L5 spinal cord of taxol-treated rats. These data indicate that downregulation of glutamate transporters may contribute to the development of hyperalgesia induced by taxol and suggest that glutamate transporters may be a new target for treatment of pain. PMID:15975716

Weng, Han-Rong; Aravindan, Natarajan; Cata, Juan P; Chen, Jing-Hong; Shaw, Andrew D S; Dougherty, Patrick M

2005-09-23

159

An endophytic taxol-producing fungus from Taxus x media, Aspergillus candidus MD3.  

PubMed

An endophytic taxol-producing fungus (strain MD3) isolated from the inner bark of Taxus x media was identified as Aspergillus candidus according to its morphological characteristics, physiological and biochemical characteristics, and 18S rRNA gene sequence analysis. Taxol produced by A. candidus MD3 was shown to be identical to authentic taxol analyzed by UV, HPLC, MS and nuclear magnetic resonance spectroscopy. The gene encoding the 10-deacetylbaccatin III-10-O-acetyl transferase, which catalyzes formation of the last diterpene intermediate in the taxol biosynthetic pathway, has been cloned from A. candidus MD3 for the first time and possesses high homology to the same gene found in Taxus spp. PMID:19239498

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

2009-02-23

160

Screening of taxol-producing endophytic fungi from Taxus chinensis var. mairei.  

PubMed

A total of 38 endophytic fungus strains were isolated from Taxus chinensis var. mairei by aseptic technique. Genomic DNA was extracted from isolated endophytic fungi and subjected to polymerase chain reaction (PCR) analysis for the presence of Taxus taxadiene synthase (TS) gene, a rate-limiting enzyme gene in the taxol biosynthetic pathway. Twelve out of 38 isolated endophytic fungus strains showed PCR positive for the ts gene. Subsequently, taxol and its related compounds were extracted from culture filtrates and mycelia of the PCR positive strains, separated by column chromatography and analyzed by High Performance Liquid Chromatography and Mass Spectrum. The analysis result showed that 3 strains could produce taxol and its related compounds at the detectible level. This study indicates that molecular detection of the ts gene is an efficient method for primary screening of taxol or its related compounds-producing endophytic fungi which can improve prominently screening efficiency. PMID:17929579

Zhou, X; Wang, Z; Jiang, K; Wei, Y; Lin, J; Sun, X; Tang, K

161

Production of taxol from Phyllosticta dioscoreae , a leaf spot fungus isolated from Hibiscus rosa-sinensis  

Microsoft Academic Search

Taxol is a highly functionalized anticancer drug widely used in hospitals and clinics. The leaf spot fungus, Phyllosticta dioscoreae was isolated from diseased leaves of Hibiscus rosa-sinensis and screened for extracellular production of taxol in M1D (Modified liquid medium) and PDB (Potato dextrose broth) medium\\u000a for the first time. The fungus was identified by its morphological and conidial features in

Rangarajulu Senthil Kumaran; Johnpaul Muthumary; Eun-Ki Kim; Byung-Ki Hur

2009-01-01

162

Analysis of taxol, 10-deacetylbaccatin III and related compounds in Taxus baccata  

Microsoft Academic Search

A method is described for the analysis of taxol and related taxanes in the foliage of Taxus spp. such as T. baccata. The method has been optimised for recovery and analysis of a range of taxanes of differing polarity, namely: taxol, cephalomannine, baccatin III and 10-deacetylbaccatin III (10-DAB-III). Measured recoveries for all these compounds generally exceeded 84%. The reversed-phase high-performance

Denis R. Lauren; Dwayne J. Jensen; James A. Douglas

1995-01-01

163

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

Microsoft Academic Search

.   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

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

1997-01-01

164

Enhanced production of taxol in suspension cultures of Taxus chinensis by controlling inoculum size  

Microsoft Academic Search

Inoculum size (1.5-6.0g dry weight\\/l) significantly affected cell growth and accumulation of intracellular and extracellular taxol in Taxus chinensis. A shorter cultivation time and a higher biomass productivity were achieved using inoculum size of 6.0g DW\\/l. Both the intracellular content and total production of taxol were increased almost 30% with an increase of inoculum size from 1.5 to 3.0g DW\\/l,

Hong-Qiang Wang; Jian-Jiang Zhong; Jun-Tang Yu

1997-01-01

165

The paradox of paclitaxel neurotoxicity: Mechanisms and unanswered questions.  

PubMed

Paclitaxel is a microtubule-binding compound that is widely used as a chemotherapeutic in the treatment of common cancers, including breast and ovarian cancer. Paclitaxel binding along the length of microtubules stabilizes them and suppresses their dynamics, leading to mitotic arrest and apoptosis in dividing cells. Though they are not dividing cells, neurons are also susceptible to paclitaxel, and paclitaxel exposure results in axonal degeneration. Thus a frequent side effect of paclitaxel treatment in patients is peripheral neuropathy, which can necessitate dose reductions and have lasting symptoms. An understanding of the mechanisms underlying paclitaxel's neurotoxicity is important for development of therapeutics to prevent and alleviate the neuropathy. Here we will review approaches taken to investigate mechanisms of paclitaxel-induced neuropathy and evidence for potential mechanisms of the axonal degeneration downstream of or distinct from microtubule stabilization by paclitaxel. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'. PMID:23978385

Gornstein, Erica; Schwarz, Thomas L

2013-08-24

166

Linearized colorimetric assay for cremophor EL: application to pharmacokinetics after 1-hour paclitaxel infusions.  

PubMed

Cremophor EL (CrEL) is a polyoxyethylated castor oil surfactant used in the intravenous formulation of the anticancer drug paclitaxel (Taxol). Quantitative determination of CrEL in patient samples can be achieved by complexation of the compound with the Coomassie brilliant blue G-250 dye in protein-free extracts [Sparreboom, A., Loos, W. J., Verweij, J., De Vos, A. I., Van der Burg, M. E. L., Stoter, G., and Nooter, K., Anal. Biochem. 255, 171-175 (1998)]. A disadvantage of this method of CrEL determination is that the assay plot of absorbance at 595 nm, the peak wavelength of the CrEL-dye complex, versus the concentration of the surfactant is not linear. The present study shows that the nonlinearity is associated with a decrease in the free dye concentration and a reduction in complex formation by increasing the CrEL concentration. By measurement of the ratio of absorbances at the maxima of the red (450 nm) and blue charge forms (595 nm) of Coomassie brilliant blue G-250, a full-scale linear relationship can be obtained over the entire range studied (0.500 to 10.0 microliter/mL). Validation data revealed that transformation of the detection procedure exhibits significantly improved specificity, accuracy(paclitaxel. PMID:9716422

Brouwer, E; Verweij, J; Hauns, B; Loos, W J; Nooter, K; Mross, K; Stoter, G; Sparreboom, A

1998-08-01

167

Targeting the Overproduction of Peroxynitrite for the Prevention and Reversal of Paclitaxel-Induced Neuropathic Pain  

PubMed Central

Chemotherapy-induced peripheral neuropathy (CIPN) accompanied by chronic neuropathic pain is a major dose-limiting side effect of a large number of antitumoral agents including paclitaxel (Taxol). Thus, CIPN is one of most common causes of dose reduction and discontinuation of what is otherwise a life-saving therapy. Neuropathological changes in spinal cord are linked to CIPN, but the causative mediators and mechanisms remain poorly understood. We report that formation of peroxynitrite (PN) in response to activation of nitric oxide synthases and NADPH oxidase in spinal cord contributes to neuropathological changes through two mechanisms. The first involves modulation of neuroexcitatory and proinflammatory (TNF-? and IL-1?) and anti-inflammatory (IL-10 and IL-4) cytokines in favor of the former. The second involves post-translational nitration and modification of glia-derived proteins known to be involved in glutamatergic neurotransmission (astrocyte-restricted glutamate transporters and glutamine synthetase). Targeting PN with PN decomposition catalysts (PNDCs) not only blocked the development of paclitaxel-induced neuropathic pain without interfering with antitumor effects, but also reversed it once established. Herein, we describe our mechanistic study on the role(s) of PN and the prevention of neuropathic pain in rats using known PNDCs (FeTMPyP5+ and MnTE-2-PyP5+). We also demonstrate the prevention of CIPN with our two new orally active PNDCs, SRI6 and SRI110. The improved chemical design of SRI6 and SRI110 also affords selectivity for PN over other reactive oxygen species (such as superoxide). Our findings identify PN as a critical determinant of CIPN, while providing the rationale toward development of superoxide-sparing and “PN-targeted” therapeutics.

Doyle, Timothy; Chen, Zhoumou; Muscoli, Carolina; Bryant, Leesa; Esposito, Emanuela; Cuzzocrea, Salvatore; Dagostino, Concetta; Ryerse, Jan; Rausaria, Smita; Kamadulski, Andrew; Neumann, William L.

2012-01-01

168

Targeting the overproduction of peroxynitrite for the prevention and reversal of paclitaxel-induced neuropathic pain.  

PubMed

Chemotherapy-induced peripheral neuropathy (CIPN) accompanied by chronic neuropathic pain is a major dose-limiting side effect of a large number of antitumoral agents including paclitaxel (Taxol). Thus, CIPN is one of most common causes of dose reduction and discontinuation of what is otherwise a life-saving therapy. Neuropathological changes in spinal cord are linked to CIPN, but the causative mediators and mechanisms remain poorly understood. We report that formation of peroxynitrite (PN) in response to activation of nitric oxide synthases and NADPH oxidase in spinal cord contributes to neuropathological changes through two mechanisms. The first involves modulation of neuroexcitatory and proinflammatory (TNF-? and IL-1?) and anti-inflammatory (IL-10 and IL-4) cytokines in favor of the former. The second involves post-translational nitration and modification of glia-derived proteins known to be involved in glutamatergic neurotransmission (astrocyte-restricted glutamate transporters and glutamine synthetase). Targeting PN with PN decomposition catalysts (PNDCs) not only blocked the development of paclitaxel-induced neuropathic pain without interfering with antitumor effects, but also reversed it once established. Herein, we describe our mechanistic study on the role(s) of PN and the prevention of neuropathic pain in rats using known PNDCs (FeTMPyP(5+) and MnTE-2-PyP(5+)). We also demonstrate the prevention of CIPN with our two new orally active PNDCs, SRI6 and SRI110. The improved chemical design of SRI6 and SRI110 also affords selectivity for PN over other reactive oxygen species (such as superoxide). Our findings identify PN as a critical determinant of CIPN, while providing the rationale toward development of superoxide-sparing and "PN-targeted" therapeutics. PMID:22553021

Doyle, Timothy; Chen, Zhoumou; Muscoli, Carolina; Bryant, Leesa; Esposito, Emanuela; Cuzzocrea, Salvatore; Dagostino, Concetta; Ryerse, Jan; Rausaria, Smita; Kamadulski, Andrew; Neumann, William L; Salvemini, Daniela

2012-05-01

169

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

PubMed

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(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(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(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(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. PMID:19111674

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

2008-12-26

170

Enhancement of esculetin on Taxol-induced apoptosis in human hepatoma HepG2 cells  

SciTech Connect

The potential use of low dose chemotherapy has been appealing since lower dosages are more attainable during cancer therapy and cause less toxicity in patients. Combination therapy of Taxol, a promising frontline chemotherapy agent, with natural anti-tumor agents that are considerably less toxic with a capability of activating additional apoptotic signals or inhibiting survival signals may provide a rational molecular basis for novel chemotherapeutic strategies. Esculetin, a well-known lipoxygenase inhibitor, showed an inhibitory effect on the cell cycle progression of HL-60 cells in our previous study. In this report, the effects of a concomitant administration of esculetin and Taxol were investigated in human hepatoma HepG2 cells. Firstly, esculetin alone could exert an antiproliferation effect together with an inhibitory effect on the activation of ERKs and p38 MAPK. As compared to the treatment with Taxol only, a co-administration with esculetin and Taxol could result in a further enhancement of apoptosis as revealed by DNA fragmentation assay and Annexin-V-based assay. Meanwhile, immunoblotting analysis also showed that the co-administration of esculetin and Taxol could increase the expression of Bax and the cytosolic release of cytochrome C and enhance the expression of Fas and Fas ligand while the activation of caspase-8 and caspase-3 was also increased. Finally, the ERK cascade was proven to be involved in the enhancement of esculetin on the Taxol-induced apoptosis.

Kuo, H.-C. [Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Chien Kuo N. Road, Taichung 402, Taiwan (China); Lee, H.-J. [Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Chien Kuo N. Road, Taichung 402, Taiwan (China); Hu, C.-C. [School of Applied Chemistry, Chung Shan Medical University, No. 110, Section 1, Chien Kuo N. Road, Taichung 402, Taiwan (China); Shun, H.-I [Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Chien Kuo N. Road, Taichung 402, Taiwan (China); Tseng, T.-H. [School of Applied Chemistry, Chung Shan Medical University, No. 110, Section 1, Chien Kuo N. Road, Taichung 402, Taiwan (China)]. E-mail: tht@csmu.edu.tw

2006-01-15

171

Taxus spp. needles contain amounts of taxol comparable to the bark of Taxus brevifolia: analysis and isolation.  

PubMed

New sources for the antitumor natural product taxol [1] are needed as demands for this promising cancer chemotherapeutic agent increase. Presently, supplies of taxol for clinical studies are obtained from the bark of Taxus brevifolia, a potentially limited source. Using analytical methods, the needles and stems of six Taxus species have been examined for taxol [1] and 10-deacetylbaccatin III [5], a related compound that can be converted to taxol through a semi-synthetic route. Amounts of taxol comparable to quantities reported from the bark of T. brevifolia were found in the needles of four of the Taxus species investigated. In addition, taxol was isolated from the needles of one Taxus species. Thus, Taxus needles may provide a renewable source of this valuable compound. PMID:1981374

Witherup, K M; Look, S A; Stasko, M W; Ghiorzi, T J; Muschik, G M; Cragg, G M

172

Targeted Paclitaxel by conjugation to iron oxide and gold nanoparticles.  

PubMed

The Fe(3)O(4) nanoparticles, tailored with maleimidyl 3-succinimidopropionate ligands, were conjugated with paclitaxel molecules that were attached with a poly(ethylene glycol) (PEG) spacer through a phosphodiester moiety at the (C-2')-OH position. The average number of paclitaxel molecules/nanoparticles was determined as 83. These nanoparticles liberated paclitaxel molecules upon exposure to phosphodiesterase. PMID:19072111

Hwu, Jih Ru; Lin, Yu Sern; Josephrajan, Thainashmuthu; Hsu, Ming-Hua; Cheng, Fong-Yu; Yeh, Chen-Sheng; Su, Wu-Chou; Shieh, Dar-Bin

2009-01-14

173

Preliminary results of a phase II study of epirubicin and paclitaxel as first-line treatment in patients with metastatic breast cancer.  

PubMed

Preliminary results of this ongoing phase II study of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) plus epirubicin administered as first-line treatment to women with metastatic breast cancer indicate encouraging response rates and no severe toxicity. Among the 57 patients admitted to this study, 52% had received prior adjuvant chemotherapy (85% with cyclophosphamide/methotrexate/5-fluorouracil), 46% had received radiotherapy, and 30% had received both forms of therapy; 63% of patients were postmenopausal, mainly with poorly differentiated tumors, and 80% presented with > or = 2 metastatic sites. Epirubicin 60 mg/m2 was administered intravenously as a 1-hour infusion followed by paclitaxel 175 mg/m2 infused over 3 hours. Standard premedication was given. Granulocyte colony-stimulating factor support was not used. Neutropenia was evident in 72% of cycles but was not severe. Instances of anemia and thrombocytopenia were rare. Alopecia was universal. All nonhematologic toxicity observed was mild or moderate (peripheral neuropathy, myalgia, nausea, vomiting World Health Organization toxicity grade < 2). At this time, 41 patients are currently evaluable for response, complete and partial remission are evident in seven and 21 patients, respectively. The overall response rate so far is 68%. An additional 12 patients show evidence of stable disease, and one has shown disease progression. Paclitaxel is considered a promising new drug in the adjuvant treatment of patients with metastatic breast cancer. Combining it with epirubicin allows safe administration with no evidence of severe cardiotoxicity. The incidence of adverse cardiac events was much lower than that observed with combinations of paclitaxel and doxorubicin. PMID:9071334

Lück, H J; Thomssen, C; du Bois, A; Lisboa, B W; Untch, M; Kühnle, H; Jänicke, F; Meerpohl, H G; Lindner, C; Konecny, G; Hecker, D; Diergarten, K

1997-02-01

174

Automated synthesis of 18F analogue of paclitaxel (PAC): [18F]Paclitaxel (FPAC).  

PubMed

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 G Bq/micromol. [18F]Paclitaxel activities of 1.33+/-0.729 G Bq (n=7) were obtained in sterile, pyrogen-free solution for IV administration. PMID:17161952

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

2006-12-11

175

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

PubMed Central

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.

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

2007-01-01

176

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

PubMed

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

Walsh, V; Goodman, J

1999-11-01

177

Taxol and LPS Modulation of c-kit and nm23 Expression in Macrophages and Normal vs. Malignanat Breast Cancer Cell Lines.  

National Technical Information Service (NTIS)

Taxol is a microtubule poison that has been used successfully in refractory breast cancer. Apart from its well characterized anti-mitotic effects, Taxol shares with bacterial lipopoly- saccharide (LPS) the capacity to elicit microtubule-independent, intra...

S. N. Vogel

1997-01-01

178

Taxol and LPS Modulation of c-kit and nm23 Expression in Macrophages and Normal vs. Malignant Breast Cancer Cell Lines.  

National Technical Information Service (NTIS)

Taxol is a microtubule poison that has been used successfully in refractory breast cancer. Apart from its well characterized anti-mitotic effects, Taxol shares with bacterial lipopolysaccharide (LPS) the capacity to elicit microtubule-independent, intrace...

S. N. Vogel

1998-01-01

179

Paclitaxel Induces Thrombomodulin Downregulation in Human Aortic Endothelial Cells  

PubMed Central

Patients with paclitaxel-eluting stents are at risk of developing stent thrombosis upon premature discontinuation of dual antiplatelet therapy. In this study, we set out to clarify whether paclitaxel can modulate thrombomodulin expression in human aortic endothelial cells. Human aortic endothelial cells were stimulated with paclitaxel. Methoxyphenyl tetrazolium inner salt cell viability assay, Western blot analysis, real-time polymerase chain reaction, and immunohistochemical assay were performed. In human aortic endothelial cells, paclitaxel (10?5 to 10?9 mol/L) treatment for 13 hours caused significant cytotoxicity at drug concentrations greater than 10?7 mol/L. Paclitaxel (10?5 to 10?9 mol/L) treatment for 5 hours downregulated thrombomodulin expression dose-dependently, persisting even at 13 hours. Cotreatment with thrombin and paclitaxel did not alter the effect of paclitaxel on thrombomodulin downregulation. Paclitaxel caused a 0.63-fold decrease in thrombomodulin messenger RNA expression, and thrombin cotreatment did not alter this decrease. In vivo studies confirmed that paclitaxel (10 mg/kg) caused endothelial thrombomodulin downregulation in mice. In summary, paclitaxel downregulates thrombomodulin expression regardless of thrombin stimulation, which is an important factor for patients receiving paclitaxel-eluting stents. Therefore, further designs of drug-eluting stents should consider the influence of the eluted drugs on endothelial thrombogenicity.

Wang, Huang-Joe; Lu, Te-Ling; Huang, Haimei; Huang, Huey-Chun

2011-01-01

180

Paclitaxel plus carboplatin–induced peripheral neuropathy  

Microsoft Academic Search

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

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

2005-01-01

181

Elevated Levels of Microtubule Destabilizing Factors in a Taxol-resistant\\/dependent A549 Cell Line with an Tubulin Mutation1  

Microsoft Academic Search

The A549 Taxol-resistant cell lines, A549-T12 and A549-T24, were isolated in our laboratory, and are dependent on Taxol for normal growth. The microtubules in these cells displayed increased dynamicity in the absence of Taxol. In the present study, a heterozygous point mutation in K1-tubulin was discovered at 379 (Ser to Ser\\/Arg). Although Taxol binds to -tubulin in the microtubule, sequencing

Laura A. Martello; Pascal Verdier-Pinard; Heng-Jia Shen; Lifeng He; Keila Torres; George A. Orr; Susan Band Horwitz

2003-01-01

182

The effect of taxol microinjection on the microtubular structure in polar body formation of starfish oocytes.  

PubMed

In starfish oocytes, microtubules (MTs) form a spindle, which plays an important role in contributing to the selective loss of chromosomes and centrosomes to the polar bodies (PBs) during meiosis. When Taxol was locally injected near the germinal vesicle (GV) or the mitotic apparatus during meiosis I, PB formation was inhibited as mentioned below. In the oocytes, which were injected with Taxol after spindle formation, the spindle became large, and then the volume of the first PB also increased more than that of the control. In contrast, in the oocytes injected with Taxol before the spindle formation, chromosome capture and alignment were inhibited. These oocytes did not form PB, but only a bulge at the cell cortex was occasionally observed. Moreover, in the oocytes injected with Taxol before GV breakdown, the chromosomes did not gather in one place, and then two asters were observed at distant positions from the cell cortex. These results suggested that MTs lost not only the ability to obtain the bipolar attachment of chromosomes by Taxol injection but also the aster closer to the cell cortex lost its interaction with the cell cortex of the animal pole. PMID:22213712

Kikuchi, Yohei; Hamaguchi, Yukihisa

2012-01-18

183

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

PubMed

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

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

2012-03-14

184

Fabrication of monodispersed Taxol-loaded particles using electrohydrodynamic atomization.  

PubMed

In the fabrication of controlled drug release matrix, monodispersed particle sizes are usually preferred as they give a more uniform and precisely controlled release profile. Electrohydrodynamic atomization (EHDA) [J.C. Ijsebaert, K.B. Geerse, J.C.M. Marijnissen, J.W.J Lammers, P. Zannen, Electro-Hydrodynamic atomization of drug solutions for inhalation purposes, J. Appl. Physiol. 91(2001), 2735-2741.] is a method that can potentially produce particles with very low polydispersity. In the present work, Taxol-loaded poly-caprolactone (PCL) particles were fabricated using EHDA. Effort was undertaken to investigate the cause of the low yield of EHDA and to improve it to around 80%. This was achieved by increasing the ventilation and properly discharging the residual charges on the particulate cake at the filter paper. A phase Doppler particle analyzer (PDPA) was used to detect the spray modes of EHDA and the optimum operating conditions were determined. With differential scanning calorimetry (DSC), the uniformity of drug and polymer matrix is investigated. Moderate zeta potential values together with laser confocal micrographs give a possible explanation for the in vitro cell uptake data. These results are substantiated by a reasonably high encapsulation efficiency (EE) and sustained release profiles over 1-month period. The EHDA method is shown to be a potentially suitable technique to prepare close to monodispersed drug release particles. PMID:15653160

Ding, Luna; Lee, Timothy; Wang, Chi-Hwa

2005-02-01

185

Effects of paclitaxel-producing fungal endophytes on growth and paclitaxel formation of Taxus cuspidata cells  

Microsoft Academic Search

Effects of a fungal endophyte, Fusarium mairei, on growth and paclitaxel formation of Taxus cuspidata cells were investigated by adding fungal endophyte culture supernatant (FECS) to suspension cultures of T. cuspidata cells. The main effective chemical responsible for paclitaxel formation in FECS was an exopolysaccharide (EPS) of molecular\\u000a weight ~2 kDa. FECS fractions except EPS stimulated growth of Taxus cells but had

Yong-Cheng Li; Wen-Yi Tao

2009-01-01

186

Clusterin Interacts with Paclitaxel and Confer Paclitaxel Resistance in Ovarian Cancer12  

PubMed Central

Optimal debulking followed by chemotherapy is the standard treatment of managing late-stage ovarian cancer, but chemoresistance is still a major problem. In this study, we compared expression profiles of primary tumor tissue from five long-term (>8 years) and five short-term (<2 years) ovarian cancer survivors and identified clusterin as one of the genes that were significantly up-regulated in short-term survivors. We then evaluated the prognostic significance of clusterin and its possible correlation with chemoresistance in ovarian cancer by immunohistostaining of clusterin in 62 tumor samples from patients with stage III, high-grade serous ovarian cancer. After adjusting for debulking status and age, Cox regression analyses showed that high levels of clusterin expression correlate with poor survival (hazard ratio, 1.07; 95% confidence interval, 1.002–1.443; P = .04). We also investigated clusterin in paclitaxel resistance by modulating the endogenous clusterin expression in ovarian cancer cells and treating the cells with purified clusterin. Results indicate that high-clusterin-expressing ovarian cancer cells are more resistant to paclitaxel. Moreover, exposing ovarian cancer cells to exogenous clusterin increases cells' resistance to paclitaxel. Finally, using size exclusion chromatography and fluorescently labeled paclitaxel, we demonstrated that clusterin binds to paclitaxel. In summary, our findings suggest that high levels of clusterin expression increase paclitaxel resistance in ovarian cancer cells by physically binding to paclitaxel, which may prevent paclitaxel from interacting with microtubules to induce apoptosis. Thus, clusterin is a potential therapeutic target for enhancing chemoresponsiveness in patients with a high-level clusterin expression.

Park, Dong Choon; Yeo, Seung Geun; Wilson, Mark R; Yerbury, Justin J; Kwong, Joseph; Welch, William R; Choi, Yang Kyu; Birrer, Michael J; Mok, Samuel C; Wong, Kwong-Kwok

2008-01-01

187

Interim Analysis of a Phase II study of epirubicin and paclitaxel as first-line therapy in patients with metastatic breast cancer.  

PubMed

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), the first taxane to be used routinely in clinical practice, has aroused considerable interest for its high single-agent activity in breast cancer and its novel mechanism of action. The 4' epimer of doxorubicin, epirubicin is an agent with high activity against breast cancer but a lower rate of toxic side effects, especially cardiotoxic events, than its parent compound. Although the paclitaxel/doxorubicin combination has yielded response rates between 63% and 94% in phase I/II studies, some severe cardiotoxic events were reported. The rationale for our study was to evaluate the paclitaxel/epirubicin combination, focusing mainly on cardiotoxicity. In all, 57 patients with metastatic breast cancer entered the study, 28% of whom had primary metastatic breast cancer with large tumors at the primary site. Half of the patients had received adjuvant chemotherapy. Study medication consisted of 60 mg/m2 epirubicin given intravenously over 1 hour, followed by paclitaxel 175 mg/m2 administered as a 3-hour intravenous infusion after premedication with steroids, antihistamines, and H2 antagonists. The main toxicity was neutropenia (World Health Organization toxicity index grade 3/4, 72%). Other hematologic side effects were rare and no febrile neutropenia was reported. Peripheral neuropathy, arthralgia, and myalgia were mild (only World Health Organization grade 1 and 2). All patients had alopecia. The paclitaxel dose was escalated to 200 mg/m2 in eight patients, four of whom received a further escalation to 225 mg/m2. Severe neutropenia necessitated dose reductions in eight patients. No cardiac adverse events were reported. Of 41 patients evaluable for response, seven had complete remissions and 21 had partial remissions (68%). An additional 12 patients (29%) had stable disease. The combination of paclitaxel 175 mg/m2 and epirubicin 60 mg/m2 can be administered safely to patients with metastatic breast cancer. Although response was not the primary end point of this trial, the response data are nonetheless encouraging and suggest that further evaluation of the role of this combination in the first-line treatment of metastatic breast cancer is warranted. PMID:8629034

Luck, H J; Thomssen, C; duBois, A; Lisboa, B W; Untch, M; Kuhnle, H; Konecny, G; Janicke, F; Meerpohl, H G; Lindner, C; Hecker, D; Diergarten, K

1996-02-01

188

EGFR-Specific Single-Chain Antibody-Taxol Conjugate for Radiosensitizing Breast Carcinomas.  

National Technical Information Service (NTIS)

We propose to conjugate paclitaxel to a single-chain antibody that specifically binds to the extracellular domain of the EGFR. The scFv-paclitaxel conjugate will be able to localize to the tumor rapidly, penetrate deeper, be eliminated quickly, and induce...

K. P. Raisch

2001-01-01

189

Economic considerations in cooperative research and development agreements (CRADA): The case of Taxol, NIH, and technology transfer  

Microsoft Academic Search

The General Accounting Office (GAO) of the U.S. Congress released a 2003 report examining the legal and financial issues by the National Institutes of Health (NIH) in the technology transfer of Taxol, a cancer treatment drug, which was commercialized quickly by Bristol-Myers Squibb (BMS). The GAO concludes that the 1991 cooperative research and development agreement (CRADA) transferring Taxol to the

Thomas A. Hemphill

2006-01-01

190

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

PubMed Central

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.

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

2013-01-01

191

Random sequencing of an induced Taxus cell cDNA library for identification of clones involved in Taxol biosynthesis  

Microsoft Academic Search

Biosynthesis of the anticancer drug Taxol involves 19 enzymatic steps from the universal diterpenoid progenitor geranylgeranyl diphosphate derived by the plastidial methylerythritol phosphate pathway for isoprenoid precursor supply. 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, random

Stefan Jennewein; Mark R. Wildung; Mydoanh Chau; Kevin Walker; Rodney Croteau

2004-01-01

192

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

PubMed

Taxol is produced by a few microorganisms and plants such as yew (Taxus sp.). Recent researches have shown that hazel (Corylus avellana L.) is also able to produce Taxol. In the present study, effects of different concentrations of phenylalanine (Phe) on the production of Taxol, antioxidant activity, and cytotoxic effects of extracts of suspension-cultured hazel cells were investigated. The cells were treated with different concentrations of Phe on day 7 of subculture and were harvested on day 14. The results showed that the amounts of Taxol and antioxidant activity were increased by increasing the phenylalanine supply. Interestingly, the cytotoxic effects of hazel cell extract were even stronger than that of pure Taxol (standard), suggesting hazel cell extract as a novel and suitable probe for treating human cancer. Application of phenylalanine to hazel cells exaggerates their effects. PMID:22847380

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

2012-07-31

193

Isolation of differential genes in suspension cultures of Taxus cuspidata induced by additional taxol.  

PubMed

Addition of taxol into suspension cultures of Taxus cuspidata induced cell apoptosis, which was confirmed by gel electrophoresis of the DNA ladders indicating the progressive delineation of fragmented nuclear DNA (nDNA) into distinct bodies. The additional taxol not only changed the microtubule assembly of cells, but also affected the gene expression. Fourteen cDNA fragments, named as TIGT9-22, were isolated after addition of taxol and their GenBank accession numbers were given as BF704560-BF704573, respectively. Among them, TIGT13 and TIGT21 were apparently homogeneous with apbE and carbamoylphosphate synthetase, respectively. Other cDNA fragments showed no significant analogy with the known sequences in GenBank. PMID:11876470

Yuan, Ying-Jin; Ma, Zhen-Yi; Wu, Jin-Chuan

2002-02-01

194

Improved growth and taxol yield in developing calli of Taxus cuspidata by medium composition modification.  

PubMed

Cell culture of Taxus spp. represents a potential alternative source of taxol and related taxanes used in cancer chemotherapy. We have analyzed the effect of different culture media components on growth and production of taxol in developing callus cultures of T. cuspidata. Several sequential modifications were made to the basal B5 medium, which included addition and/or variation in the concentration of sucrose, B5 organic supplements, gibberellic acid, 36 combinations of 2,4-D/kinetin ratios, media salts and organic supplements, phenylalanine, casein hydrolysate and medium pH. The experiments were conducted during a 55 day-growth period followed by taxane extraction and analysis. Significant increases in taxol yield and growth over basal medium grown calli were observed with some of the modified media. PMID:7765304

Fett-Neto, A G; Melanson, S J; Sakata, K; DiCosmo, F

1993-06-01

195

Studies directed toward the synthesis of the A-ring of taxol  

SciTech Connect

Taxol 1, a novel anticancer agent, isolated from Taxus brevifolia, is a member of the class of taxane diterpenes. Since its isolation and characterization many groups around the world using varied approaches have made significant contributions toward the assembly of the taxane framework and ultimately to taxol itself. The focus of this investigation was directed towards making a fully functionalized A-ring synthon of taxol. Toward this end three approaches were explored. These approaches to the A-ring involve a Robinson annulation, an alkoxide accelerated vinylcyclobutane to cyclohexenol rearrangement and acid catalyzed electrophilic cyclization of geranyl acetate and its derivatives. Early difficulties with the alkoxide accelerated ring expansion approach resulted in it being aborted. The other two approaches led to interesting intermediates with the requisite number of carbon atoms and latent functionalities. However, later efforts to transform these intermediates to the targeted A-ring synthon (93), were futile.

Hamilton, P.M.

1992-01-01

196

Distinct Pose of Discodermolide in Taxol Binding Pocket Drives a Complementary Mode of Microtubule Stabilization  

PubMed Central

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

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

2010-01-01

197

Synthesis, physico-chemical and biological characterization of a paclitaxel macromolecular prodrug  

Microsoft Academic Search

Paclitaxel was attached to poly(hydroxyethylaspartamide) via a succinic spacer arm by a two-step protocol: (1) synthesis of 2?-O-succinyl-paclitaxel; (2) synthesis of PHEA-2?-O-succinyl-paclitaxel. The 2?-O-succinyl-paclitaxel derivative and the macromolecular conjugate were characterized by UV, IR, NMR and mass spectrometry analysis. The reaction yields were over 95% and the purity of products over 98%. Paclitaxel release and degradation from 2?-O-succinyl-paclitaxel occurred at

G. Cavallaro; M. Licciardi; P. Caliceti; S. Salmaso; G. Giammona

2004-01-01

198

Improved Taxol production by combination of inducing factors in suspension cell culture of Taxus baccata.  

PubMed

To date enormous attempts have been devoted to improve Taxol production exploiting various methodologies from bioprocess engineering to biotechnological and synthetic approaches. We have developed a 2-stage suspension cell culture of Taxus baccata L. using modified B5 medium in order to improve cell growth as well as productivity. After callus induction and cell line selection, B5 medium was supplemented with vanadyl sulfate (0.1 mg/l), silver nitrate (0.3 mg/l) and cobalt chloride (0.25 mg/l) at the first day of stage I culture to maximize cell growth. This medium was further supplemented with sucrose (1%) and ammonium citrate (50 mg/l) on day 10 and sucrose (1%) and phenylalanine (0.1 mM) on day 20 (i.e., biomass growth medium). At stage II (day 25), two different concentrations of several elicitors such as methyl jasmonate (10 or 20 mg/l), salicylic acid (50 or 100 mg/l) and fungal elicitor (25 or 50 mg/l) were added to the biomass growth medium with the aim of improving cellular productivity. For morphological analysis, microscopic inspection was carried out during cultivation. Cell-associated and extracellular amount of Taxol were detected and measured using HPLC methodology. At stage I, overall Taxol amount of biomass growth medium was 13.75 mg/l (i.e., 5.6-fold higher than that of untreated B5 control). At stage II, treated cells with methyl jasmonate (10 mg/l), salicylic acid (100 mg/l) and fungal elicitor (25 mg/l) produced the highest amount of Taxol (39.5 mg/l), which is 16-fold higher than that of untreated B5 control (2.45 mg/l). Microscopic analyses of Taxus cells in suspension cultures showed various positional auto-fluorescence showing direct correlation with Taxol production. Our studies revealed that intervallic supplementation of B5 medium with combination of biomass growth factors at stage I and mixture of elicitors at stage II could significantly increase Taxol production. Thus, we suggest that the exploitation of this methodology may improve the production of Taxol since demands for Taxol pharmaceuticals are increasingly growing and resource paucities have limited its direct harvesting from Taxus trees. PMID:16378737

Khosroushahi, A Yari; Valizadeh, M; Ghasempour, A; Khosrowshahli, M; Naghdibadi, H; Dadpour, M R; Omidi, Y

2005-12-27

199

Synthesis, isolation, stereostructure and cytotoxicity of paclitaxel analogs from cephalomannine.  

PubMed

Four paclitaxel derivatives were afforded by preparative HPLC separation of two pairs of diastereoisomers, which were obtained by catalytic hydrogenation and epoxidation of the C-13 side-chain double bond of cephalomannine, a naturally occurring paclitaxel analog. The four paclitaxel derivatives were analyzed using NMR, CD spectroscopy, and side-chain hydrolysis in order to measure their optical rotations and GC characteristics. In this way, the stereoconfigurations of the products were determined. Evaluation of the compounds' activity indicated that they had differing cytotoxic activities: compound 5 had superior activity in BCG-823 tumor cells compared to paclitaxel, while compound 7 had superior activity in HCT-8 and A549 tumor cells compared to paclitaxel. These results indicate that the stereoconfiguration of the paclitaxel N-acyl side chain has a significant impact on its activity. PMID:23876369

Gao, Feng; Wang, Dan; Huang, Xing

2013-07-20

200

Supramolecular micellar nanoaggregates based on a novel chitosan/vitamin E succinate copolymer for paclitaxel selective delivery  

PubMed Central

Background Nowadays, many cytotoxic anticancer drugs exhibit low solubility and poor tumor selectivity, which means that the drug formulation is very important. For example, in the case of paclitaxel (PTX), Cremophor EL® (BASF, Ludwigshafen, Germany) needs to be used as a solubilizer in its clinical formulation (Taxol®, Bristol-Myers Squibb, New York, NY), although it can cause serious side effects. Nanomicellar systems are promising carriers to resolve the above problems, and the polymer chosen is the key element. Methods In this study, a novel amphiphilic chitosan/vitamin E succinate (CS-VES) copolymer was successfully synthesized for self-assembling polymeric micelles. Proton nuclear magnetic resonance spectroscopy and infrared were used to characterize the molecular structure of the copolymer. The PTX-loaded CS-VES polymeric micelles (PTX-micelles) were characterized by dynamic light scattering, transmission electron microscopy, X-ray diffraction, and differential scanning calorimetry. Results The critical micelle concentration of CS-VES was about 12.6 ?g/mL, with the degree of amino group substitution being 20.4%. PTX-micelles were prepared by a nanoprecipitation/dispersion technique without any surfactant being involved. PTX-micelles exhibited a drug loading as high as 21.37% and an encapsulation efficiency of 81.12%, with a particle size ranging from 326.3 to 380.8 nm and a zeta potential of +20 mV. In vitro release study showed a near zero-order sustained release, with 51.06%, 50.88%, and 44.35% of the PTX in the micelles being released up to 168 hours at three drug loadings of 7.52%, 14.09%, and 21.37%, respectively. The cellular uptake experiments, conducted by confocal laser scanning microscopy, showed an enhanced cellular uptake efficiency of the CS-VES micelles in MCF-7 cells compared with Taxol. The PTX-micelles exhibited a comparable but delayed cytotoxic effect compared with Taxol against MCF-7 cells, due to the sustained-release characteristics of the nanomicelles. More interestingly, blank nanomicelles based on CS-VES copolymer demonstrated significant cytotoxicity against MCF-7 cells. Conclusion The supramolecular micellar aggregates based on CS-VES copolymer is a promising nanocarrier and efficacy enhancer when used as an anticancer drug-delivery system.

Lian, He; Sun, Jin; Yu, Yan Ping; Liu, Yan Hua; Cao, Wen; Wang, Yong Jun; Sun, Ying Hua; Wang, Si Ling; He, Zhong Gui

2011-01-01

201

Kinetics of paclitaxel 2?-N-methylpyridinium mesylate decomposition  

Microsoft Academic Search

This study was designed to examine the kinetics of decomposition of paclitaxel 2?-N-methylpyridinium mesylate (PNMM), a derivative\\u000a of paclitaxel. Further, the potential for PNMM to act as a prodrug of paclitaxel was assessed in vitro. Stability studies\\u000a of PNMM were conducted over a pH range of 4.0 to 8.0 at 25°C. The critical micelle concentration (CMC) of PNMM was determined

Jaber G. Qasem; Paul M. Bummer; George A. Digenis

2003-01-01

202

Paclitaxel-Coated Balloon Catheter Versus Paclitaxel-Coated Stent for the Treatment of Coronary In-Stent Restenosis  

Microsoft Academic Search

Background—Treatment of in-stent restenosis with paclitaxel-coated balloon catheter as compared with plain balloon angioplasty has shown surprisingly low late lumen loss at 6 months and fewer major adverse cardiac events up to 2 years. We compared the efficacy and safety of a paclitaxel-coated balloon with a paclitaxel-eluting stent as the current standard of care. Methods and Results—One hundred thirty-one patients

Martin Unverdorben; Christian Vallbracht; Bodo Cremers; Hubertus Heuer; Christian Hengstenberg; Christian Maikowski; Gerald S. Werner; Diethmar Antoni; Franz X. Kleber; Wolfgang Bocksch; Matthias Leschke; Hanns Ackermann; Michael Boxberger; Ulrich Speck; Ralf Degenhardt; Bruno Scheller

2010-01-01

203

Description of a short-term Taxol ®-induced nociceptive neuropathy in rats  

Microsoft Academic Search

This work describes a new animal model of neuropathic pain produced by the single intraperitoneal administration of Taxol® (32 mg\\/kg) to male Sprague–Dawley rats. During the course of the experiment, the clinical status of the rats remained satisfactory and motor function was not altered. A number of classical behavioural tests of nociception as well as histological and electrophysiological investigations were

Nicolas Authier; Jean-Pierre Gillet; Joseph Fialip; Alain Eschalier; François Coudore

2000-01-01

204

Chemosensitization of human leukemia K562 cells to taxol by a Vanadium-salen complex.  

PubMed

Vanadium complexes are a heterogeneous class of compounds exhibiting interesting biological properties. Herein, we report the effect of a vanadium-salen complex (VO-salen) on proliferative behavior of K562 cell line. The results revealed that VO-salen at 6-32 ?M inhibited K562 proliferation with no distinct alteration in cell morphology, extent of apoptosis and/or differentiation. Our results indicated that VO-salen complex has just a cytostatic effect and capable of arresting the affected cells in G2/M phase of cell cycle. In addition, we evaluated the combined effects of VO-salen complex and taxol. The cell cycle analyses showed that VO-salen complex enhanced taxol-induced G2/M arrest and also increased taxol-induced apoptosis through a decrease in the ratio of Bcl-2/Bax which might account for the decrease in the apoptosis threshold among the affected cells. These findings support that combination of VO-salen, as a chemosensitizer, and taxol might constitute an affective new strategy for leukemia therapy. PMID:20816953

Meshkini, Azadeh; Yazdanparast, Razieh

2010-09-09

205

The effects of thalidomide and minocycline on taxol-induced hyperalgesia in rats  

PubMed Central

Chemotherapy-induced pain is the most common treatment-limiting complication encountered by cancer patients receiving taxane-, vinca alkaloid- or platin-based chemotherapy. Several lines of evidence indicate that activation of pro-inflammatory cascades involving the release of cytokines including tumor necrosis factor-alpha (TNF-?), interleukin-1 beta (IL-1?) and interleukin-6 (IL-6) as well as various growth factors are key events in the pathogenesis of many types of nerve-injury related pain. Similar mechanisms might also be involved in the etiology of chemotherapy-induced pain. Thalidomide and minocycline have profound immunomodulatory actions in addition to their originally intended pharmacological actions. These compounds were evaluated here for effects in preventing the development of taxol-induced mechanical and thermal hyperalgesia in rats. Thalidomide (50.0 mg/kg) reduced taxol-induced mechanical allodynia and hyperalgesia whereas minocycline (20.0 mg/kg) reduced taxol-induced mechanical hyperalgesia and allodynia as well as taxol-induced thermal hyperalgesia. These results suggest that immunomodulatory agents may provide a treatment option for the protection or reversal of chemotherapy-related pain.

Cata, Juan P.; Weng, Han-Rong

2008-01-01

206

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

Microsoft Academic Search

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

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

2010-01-01

207

Novel molecules that interact with microtubules and have functional activity similar to Taxol  

Microsoft Academic Search

Taxol™ is an antitumor drug approved by the FDA for the treatment of ovarian, breast and non-small-cell lung carcinomas. Originally isolated from the bark of the Pacific yew, Taxus brevifolia, it was the first natural product described that stabilized microtubules. In the past five years, a group of novel natural products, including the epothilones, discodermolide, eleutherobin, sarcodictyins and the laulimalides,

Lifeng He; George A Orr; Susan Band Horwitz

2001-01-01

208

Upregulation of caveolin-1 and caveolae organelles in Taxol-resistant A549 cells  

Microsoft Academic Search

Caveolin is a principal component of caveolae membranes. It has been demonstrated that the interaction of the caveolin scaffolding domain with signaling molecules can functionally inhibit the activity of these molecules. Taxol is an antitumor agent that suppresses microtubule dynamics and binds to microtubules thereby stabilizing them against depolymerization. The drug also has been implicated in the induction of apoptosis

Chia-Ping Huang Yang; Ferruccio Galbiati; Daniela Volonté; Susan Band Horwitz; Michael P Lisanti

1998-01-01

209

Xylogenesis in tissue culture: Taxol effects on microtubule reorientation and lateral association in differentiating cells  

Microsoft Academic Search

Summary InZinnia elegans tissue cultures, cortical microtubules reorient from longitudinal to transverse arrays as the culture age increases and before differentiation of tracheary elements is visible. The orientation of microtubules, in the period just before visible differentiation, determines the direction of the secondary wall bands in forming tracheary elements. Taxol, applied early in culture, stabilizes the microtubules of most cells

Marcia M. Falconer; R. W. Seagull

1985-01-01

210

Taxol impairs anterograde axonal transport of microinjected horseradish peroxidase in dorsal root ganglia neurons in vitro  

Microsoft Academic Search

We have investigated the effects of taxol on the axonal transport of horseradish peroxidase (HRP) in dorsal root ganglia (DRG) cells and their neuronal cytoskeleton. The former were analysed by microinjection of HRP into single DRG cells and the latter was studied by means of immunohistochemistry and cryo-electron microscopy. In cultured and untreated DRG cells, microinjected HRP was typically transported

Carsten Theiss; Karl Meller

2000-01-01

211

Improved Taxol production by combination of inducing factors in suspension cell culture of Taxus baccata  

Microsoft Academic Search

To date enormous attempts have been devoted to improve Taxol production exploiting various methodologies from bioprocess engineering to biotechnological and synthetic approaches. We have developed a 2-stage suspension cell culture of Taxus baccata L. using modified B5 medium in order to improve cell growth as well as productivity. After callus induction and cell line selection, B5 medium was supplemented with

A. Yari Khosroushahi; M. Valizadeh; A. Ghasempour; M. Khosrowshahli; H. Naghdibadi; M. R. Dadpour; Y. Omidi

2006-01-01

212

Source of isopentenyl diphosphate for taxol and baccatin III biosynthesis in cell cultures of Taxus baccata  

Microsoft Academic Search

To achieve a better understanding of the metabolism and accumulation of taxol and baccatin III in cell cultures of Taxus, three cell lines (I, II and III) of T. baccata were treated (on day 7) with several concentrations of fosmidomycin (100, 200 and 300?M), an inhibitor of the non-mevalonate branch of the terpenoid pathway, or mevinolin (1, 3 and 5?M),

Rosa M. Cusidó; Javier Palazón; Mercedes Bonfill; Oscar Expósito; Elisabet Moyano; M. Teresa Piñol

2007-01-01

213

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

PubMed

Polycystic kidney disease (PKD) a is common disease in the human population that can lead to renal failure and death. Taxol 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 treatment on the development of renal cysts and biliary hyperplasia/dysplasia/fibrosis in the orpk mouse mutant, a unique murine model for human autosomal recessive PKD. We report no significant differences between the treatment and control groups with respect to weight gain, survival, urine to serum osmolality ratio, and serum concentration of liver enzymes. Moreover, renal cystic development was not affected by taxol treatment in the orpk mutant animals. This was confirmed by lectin staining and morphometric analysis of the renal cysts, which indicated no significant differences between treatment groups. Therefore, while taxol has a positive effect on the cystic kidney disease in cpk mutant mice, this effect is not applicable to all forms of PKD. PMID:9438653

Sommardahl, C S; Woychik, R P; Sweeney, W E; Avner, E D; Wilkinson, J E

1997-12-01

214

One-hour paclitaxel, carboplatin, and extended-schedule etoposide in the treatment of carcinoma of unknown primary site.  

PubMed

This phase II study was conducted to evaluate the efficacy and toxicity of a novel chemotherapy combination that included paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), carboplatin, and extended-schedule etoposide for the treatment of patients with carcinoma of unknown primary site. Fifty-five patients were treated with the following regimen, administered every 21 days: paclitaxel 200 mg/m2 by 1-hour intravenous infusion, day 1; carboplatin at an estimated area under the concentration-time curve of 6.0, day 1; and etoposide 50 mg alternating with 100 mg orally, days 1 through 10. The following histologies were included: well-differentiated adenocarcinoma, 30 patients; poorly differentiated carcinoma or poorly differentiated adenocarcinoma, 21 patients; poorly differentiated neuroendocrine carcinoma, three patients; and squamous carcinoma, one patient. All patients had advanced tumor, and two thirds had two or more organ systems involved with cancer. Twenty-five of 53 evaluable patients (47%) had major objective responses to treatment. Seven patients (13%) had complete responses. Response rates were similar in patients with well-differentiated adenocarcinoma versus poorly differentiated carcinoma (45% and 48%, respectively). Median survival for the entire group was 13.4 months. The regimen was well tolerated, with only seven hospitalizations for treatment of fever associated with neutropenia and no treatment-related deaths. This combination regimen is very active and well tolerated in patients with carcinoma of unknown primary site. Response rates and survival in this multicenter community-based trial appear superior to all previously studied empiric regimens. This regimen is substantially less toxic and easier to administer than the cisplatin-based regimens. Should this efficacy be confirmed in other trials, this treatment should be considered standard initial therapy for patients with carcinoma of unknown primary site. PMID:9427278

Greco, F A; Hainsworth, J D

1997-12-01

215

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

PubMed

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

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

216

AN EVOLVING CELLULAR PATHOLOGY OCCURS IN DORSAL ROOT GANGLIA, PERIPHERAL NERVE AND SPINAL CORD FOLLOWING INTRAVENOUS ADMINISTRATION OF PACLITAXEL IN THE RAT  

PubMed Central

Paclitaxel (Taxol®) is a frontline antineoplastic agent used to treat a variety of solid tumors including breast, ovarian, or lung cancer. The major dose limiting side effect of paclitaxel is a peripheral sensory neuropathy that can last days to a lifetime. To begin to understand the cellular events that contribute to this neuropathy, we examined a marker of cell injury/regeneration (activating transcription factor 3; ATF3), macrophage hyperplasia/hypertrophy; satellite cell hypertrophy in the dorsal root ganglion (DRG) and sciatic nerve as well as astrocyte and microglial activation within the spinal cord at 1, 4, 6 and 10 days following intravenous infusion of therapeutically relevant doses of paclitaxel. At day 1 post-infusion there was an up-regulation of ATF3 in a subpopulation of large and small DRG neurons and this up-regulation was present through day 10. In contrast, hypertrophy of DRG satellite cells, hypertrophy and hyperplasia of CD68+ macrophages in the DRG and sciatic nerve, ATF3 expression in S100?+ Schwann cells and increased expression of the microglial marker (CD11b) and the astrocyte marker glial fibrillary acidic protein in the spinal cord were not observed until day 6 post infusion. The present results demonstrate that using the time points and markers examined, DRG neurons show the first sign of injury which is followed days later by other neuropathological changes in the DRG, peripheral nerve and dorsal horn of the spinal cord. Understanding the cellular changes that generate and maintain this neuropathy may allow the development of mechanism-based therapies to attenuate or block this frequently painful and debilitating condition.

Peters, Christopher M.; Jimenez-Andrade, Juan Miguel; Kuskowski, Michael A.; Ghilardi, Joseph R.; Mantyh, Patrick W.

2007-01-01

217

Design, Synthesis and Applications of Hyaluronic Acid-Paclitaxel Bioconjugates†  

Microsoft Academic Search

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

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

2008-01-01

218

Prevention of paclitaxel-induced peripheral neuropathy by lithium pretreatment.  

PubMed

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

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

2012-08-13

219

A novel prepurification for paclitaxel from plant cell cultures  

Microsoft Academic Search

A novel prepurification method was developed for producing paclitaxel, to guarantee high purity and yield from plant cell cultures. This method was a simple and efficient procedure, for the isolation and prepurification of paclitaxel from the biomass of Taxus chinensis, consisting of active clay treatment, followed by two steps of precipitation. The use of active clay treatment and precipitation in

J. H. Kim; I. S. Kang; H. K. Choi; S. S. Hong; H. S. Lee

2002-01-01

220

Paclitaxel production in suspension cell cultures of Taxus  

Microsoft Academic Search

Five separate cell lines, three of Taxus canadensis Marsh. and two of Taxus cuspidata Sieb. et Zucc., were used to test the effect of carbohydrates and plant growth regulators on the growth of cells and production of paclitaxel in culture. There was no significant correlation between growth of cells and paclitaxel production. While no single medium was developed that was

R. E. B. Ketchum; D. M. Gibson

1996-01-01

221

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

PubMed

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

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

2012-01-08

222

Taxol cytotoxicity on human leukemia cell lines is a function of their susceptibility to programmed cell death  

Microsoft Academic Search

Taxol is the prototype of a class of antineoplastic drugs that target microtubules. It enhances tubulin-monomer polymerization and stabilizes tubulin polymers, increasing the fraction of cells in the G2 or M phase of the cell cycle. We report that treatment of HL-60 and U937 myeloid cell lines with 1–10 µM taxol induces DNA fragmentation and the appearance of morphological features

Rosaria M. R. Gangemi; Micaela Tiso; Carla Marchetti; Antonio Bargellesi Severi; Marina Fabbi

1995-01-01

223

Enhancement of taxol production and release in Taxus chinensis cell cultures by ultrasound, methyl jasmonate and in situ solvent extraction  

Microsoft Academic Search

This study evaluates the use of a novel mechanical stimulus, ultrasound (US), and a putative chemical elicitor, methyl jasmonate (MJ), combined with in situ solvent extraction (two-phase culture), to enhance taxol production by Taxus chinensis cells in suspension culture. The volumetric taxol yield was increased 1.5- to 1.8-fold with 2 min US treatment once or twice during a 4-week culture period,

J. Wu; L. Lin

2003-01-01

224

The effect of taxol on Triticum preprophase root cells: preprophase microtubule band organization seems to depend on new microtubule assembly  

Microsoft Academic Search

Summary To examine whether preprophase microtubule band (PPB) organization occurs by rearrangement of pre-existing, or by assembly of new microtubules (Mts), we treated root cells ofTriticum turgidum with taxol, which stabilizes pre-existing Mts by slowing their depolymerization. With taxol early preprophase cells failed to form a normal PPB and PPB narrowing was prevented in cells that had already formed a

E. Panteris; P. Apostolakos; B. Galatis

1995-01-01

225

Differential effects of Paclitaxel on dendritic cell function  

PubMed Central

Background The potential utility of dendritic cells (DC) as cancer vaccines has been established in early trials in human cancers. The concomitant administration of cytotoxic agents and DC vaccines has been previously avoided due to potential immune suppression by chemotherapeutics. Recent studies show that common chemotherapy agents positively influence adaptive and innate anti-tumour immune responses. Results We investigated the effects of paclitaxel on human DC biology in vitro. DCs appear to sustain a significant level of resistance to paclitaxel and maintain normal viability at concentrations of up to 100 ?mol. In some cases this resistance against paclitaxel is significantly better than the level seen in tumour cell lines. Paclitaxel exposure led to a dose dependent increase in HLA class II expression equivalent to exposure to lipopolysaccharide (LPS), and a corresponding increase in proliferation of allogeneic T cells at the clinically relevant doses of paclitaxel. Increase in HLA-Class II expression induced by paclitaxel was not blocked by anti TLR-4 antibody. However, paclitaxel exposure reduced the endocytic capacity of DC but reduced the expression of key pro-inflammatory cytokines such as IL-12 and TNF?. Key morphological changes occurred when immature DC were cultured with 100 ?mol paclitaxel. They became small rounded cells with stable microtubules, whereas there were little effects on LPS-matured DC. Conclusions The effect of paclitaxel on human monocyte derived DC is complex, but in the clinical context of patients receiving preloaded and matured DC vaccines, its immunostimulatory potential and resistance to direct cytotoxicity by paclitaxel would indicate potential advantages to co-administration with vaccines.

2010-01-01

226

Acute Taxol nephrotoxicity: Histological and ultrastructural studies of mice kidney parenchyma  

PubMed Central

Taxol is a microtubule inhibitor drug widely used in treatment of many types of cancer. Nephrotoxicity is the most hazardous effect complicating chemotherapy in general and kidney functions must be monitored early during any chemotherapeutic course. The main objective of the present study was to investigate the effect of acute Taxol nephrotoxicity in mice. In the present study Taxol at different doses; MD, ID and MTD (0.6, 1.15 and 1.7 mg/kg), respectively, was given by intra-peritoneal route to 54 adult male mice with an average body weight of 20–25 g. Kidney samples was taken 6, 24, 48 h following administration, fixed in 10% neutral buffered formalin, paraffin sections 5 ?m thick were stained by haematoxylin and eosin and PAS and then examined for histological changes. Samples from animals treated by the maximum dose (MTD = 1.7 mg/kg) for 48 h were fixed in 3% gluteraldehyde in phosphate buffer (pH 7.4) and processed for transmission electron microscope. Taxol given for short duration was found to produce marked degenerative changes in kidney parenchyma even in minimum tolerated dose (MD = 0.6 mg/kg). Individual variations were observed regarding the degree of nephrotoxicity. There was marked loss of renal tubules epithelial lining, damage of brush border and formation of hyaline casts within the damaged tubules. The alterations were in the form of both necrotic and apoptotic changes in the kidney tubules. Focal atrophy of glomerular tufts was also observed. Vascular congestion and degenerative changes in renal blood vessels were occasionally evident in some samples. Ultrastructure study revealed damage of glomerular membrane. Proximal tubule showed loss of basal infoldings, damage of brush border, mitochondrial degeneration and nuclear changes. Distal tubules also showed demarked degenerative changes. Increased frequency of micronuclei proved that Taxol had genotoxic effects in mice bone marrow cells. In conclusion Taxol had nephrotoxic effect on mice kidney that must be considered during its use as a chemotherapeutic agent in human.

Rabah, Samar Omar

2010-01-01

227

Paclitaxel metabolism in rat and human liver microsomes is inhibited by phenolic antioxidants  

Microsoft Academic Search

Paclitaxel is an important, recently introduced anti-neoplastic drug. Paclitaxel metabolites are virtually inactive in comparison with the parent drug. The study investigated whether phenolic antioxidants could inhibit metabolic inactivation sufficiently to increase paclitaxel effects. Cytochrome P450 (CYP)-catalysed metabolism of paclitaxel was investigated in rat and human liver microsomes. In rat microsomes, paclitaxel was metabolised mainly to C3'-hydroxypaclitaxel (C3'-OHP), less to

Radka Václavíková; Stanislav Horský; Petr Šimek; Ivan Gut

2003-01-01

228

Relationships between the structures of taxol and baccatine III derivatives and their in vitro action on the disassembly of mammalian brain and Physarum amoebal microtubules.  

PubMed Central

The in vitro disassembly of microtubules from mammalian brain and Physarum is inhibited by various derivatives of taxol and baccatine III. Structure-activity relationships of the taxol derivatives were identical for both mammalian brain and Physarum microtubules. This observation suggests that the site of action of taxol has been preserved during the evolution of these two different eukaryotic lines. The substituent at C-13 of taxol was required to prevent disassembly of brain microtubules with or without microtubule-associated proteins. In contrast, both taxol and baccatine III prevented the disassembly of Physarum microtubules to the same extent, showing that the substituent at C-13 was not required in the interaction with Physarum tubulin. The different effects of baccatine III and taxol derivatives indicate that measuring the disassembly of microtubules from different organisms could be a useful parameter in the search for derivatives exhibiting antiparasitic activity.

Lataste, H; Senilh, V; Wright, M; Guenard, D; Potier, P

1984-01-01

229

Production, purification and characterization of taxol and 10DAB III from a new endophytic fungus Gliocladium sp. isolated from the Indian yew tree, Taxus baccata.  

PubMed

We have isolated endophytic fungi from Indian yew tree, Taxus baccata and then screened for taxol production. Out of the forty fungal cultures screened, one fungus Gliocladium sp. was found to produce taxol and 10DAB III (10 Deacetyl baccatin III). These compounds were purified by TLC, HPLC and characterized using UV-Spectroscopy, ESI-MS, MS/MS and proton NMR. One liter of Gliocladium sp. culture yielded 10 microg of taxol and 65 microg of 10 DAB III. The purified taxol from the fungus showed cytotoxicity towards cancer lines HL-60 (leukemia), A431 (epidermal carcinoma) and MCF-7 (breast cancer). PMID:19996685

Sreekanth, Dasari; Syed, Asad; Sarkar, Sampa; Sarkar, Dhiman; Santhakumari, B; Ahmad, Absar; Khan, Islam

2009-11-01

230

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

Microsoft Academic Search

Taxol triggers apoptosis in a variety of cancer cells, but it also upregulates cytoprotective proteins and\\/or pathways that\\u000a compromise its therapeutic efficacy. In this report, we found that Taxol treatment resulted in caspase-8-dependent apoptosis\\u000a in SKOV3 human ovarian cancer cells. Moreover, Taxol-induced apoptosis was associated with caspase-3 activation. Interestingly,\\u000a Taxol treatment upregulated ?-2,3-sialyltransferase (ST3Gal III) expression and forced expression of

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

2009-01-01

231

Paclitaxel nanoparticles for the potential treatment of brain tumors.  

PubMed

Despite the advances in tumor therapy, patients with primary brain tumors and brain metastases have a very poor prognosis. Low responses to chemotherapy are mainly attributed to impermeability of the blood-brain barrier to cytotoxic agents. Paclitaxel has been shown to be active against gliomas and various brain metastases. However, its use in treatment of brain tumors is limited due to low blood-brain barrier permeability and serious side effects associated with administration of the paclitaxel solvent, Cremophor EL. Lack of paclitaxel brain uptake is thought to be associated with the p-glycoprotein (p-gp) efflux transporter. In this work, paclitaxel (PX) was entrapped in novel cetyl alcohol/polysorbate nanoparticles. Paclitaxel nanoparticles (PX NPs) were characterized by means of size, short-term stability, drug entrapment efficiency, and release profile. The PX NP cytotoxicity profile was monitored using two different cell lines, U-118 and HCT-15. Brain uptake of PX NPs was evaluated using an in situ rat brain perfusion model. The results suggest that entrapment of paclitaxel in nanoparticles significantly increases the drug brain uptake and its toxicity toward p-glycoprotein expressing tumor cells. It was hypothesized that PX NPs could mask paclitaxel characteristics and thus limit its binding to p-gp, which consequently would lead to higher brain and tumor cell uptake of the otherwise effluxed drug. PMID:15380635

Koziara, Joanna M; Lockman, Paul R; Allen, David D; Mumper, Russell J

2004-09-30

232

Development of paclitaxel-TyroSpheres for topical skin treatment  

PubMed Central

A potential topical psoriasis therapy has been developed consisting of tyrosine-derived nanospheres (TyroSpheres) with encapsulated anti-proliferative paclitaxel. TyroSpheres provide enhancement of paclitaxel solubility (almost 4,000 times greater than PBS) by effective encapsulation and enable sustained, dose-controlled release over 72 hours under conditions mimicking skin permeation. TyroSpheres offer potential in the treatment of psoriasis, a disease resulting from over-proliferation of keratinocytes in the basal layer of the epidermis, by (a) enabling delivery of paclitaxel into the epidermis at concentrations >100 ng/cm2 of skin surface area and (b) enhancing the cytotoxicity of loaded paclitaxel to human keratinocytes (IC50 of paclitaxel-TyroSpheres was approximately 45% lower than that of free paclitaxel). TyroSpheres were incorporated into a gel-like viscous formulation to improve their flow characteristics with no impact on homogeneity, release or skin distribution of the payload. The findings reported here confirm that the TyroSpheres provide a platform for paclitaxel topical administration allowing skin drug localization and minimal systemic escape.

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

2012-01-01

233

Cordyceps sinensis Health Supplement Enhances Recovery from Taxol-Induced Leukopenia  

Microsoft Academic Search

This study aimed to evaluate the ability of the health food supplement Cordyceps sinensis (CS) to ameliorate suppressive effects of chemotherapy on bone marrow function as a model for cancer treatment. Mice were treated with Taxol (17 mg\\/kg body wt) one day before oral administration of a hot-water extract of CS (50 mg\\/kg daily) that was given daily for 3

WEI-CHUNG LIU; WEI-LING CHUANG; MIN-LUNG TSAI; JI-HONG HONG; WILLIAM H. MCBRIDE; CHI-SHIUN CHIANG

234

The induction of taxol production in the endophytic fungus— Periconia sp from Torreya grandifolia  

Microsoft Academic Search

  A Periconia sp was isolated from Torreya grandifolia (a relative of yew that does not synthesize taxol) near Huangshan National Park in the People’s Republic of China. This fungus,\\u000a not previously known as a tree endophyte, was isolated from the inner bark of a small lower limb. When freshly isolated from\\u000a the tree and placed in a semi-synthetic medium, the

J Y Li; R S Sidhu; E J Ford; D M Long; W M Hess; G A Strobel

1998-01-01

235

Preliminary assessment of the C13-side chain 2'-hydroxylase involved in Taxol biosynthesis  

SciTech Connect

The biosynthesis of the anticancer drug Taxol in yew (Taxus) species is thought to involve the preliminary formation of the advanced taxane diterpenoid intermediate baccatin III upon which the functionally important N-benzoyl phenylisoserinoyl side chain is subsequently assembled at the C13-O-position. In vivo feeding studies with Taxus tissues and characterization of the two transferases responsible for C13-side chain construction have suggested a sequential process in which an aminomutase converts {alpha}-phenylalanine to {beta}-phenylalanine which is then activated to the corresponding CoA ester and transferred to baccatin III to yield {beta}-phenylalanoyl baccatin III (i.e., N-debenzoyl-2'-deoxytaxol) that undergoes subsequent 2'-hydroxylation and N-benzoylation to afford Taxol. However, because the side chain transferase can utilize both {beta}-phenylalanoyl CoA and phenylisoserinoyl CoA in the C13-O-esterification of baccatin III, ambiguity remained as to whether the 2'-hydroxylation step occurs before or after transfer of the amino phenylpropanoyl moiety. Using cell-free enzyme systems from Taxus suspension cells, no evidence was found for the direct hydroxylation of {beta}-phenylalanine to phenylisoserine; however, microsomal preparations from this tissue appeared capable of the cytochrome P450-mediated hydroxylation of {beta}-phenylalanoyl baccatin III to phenylisoserinoyl baccatin III (i.e., N-debenzoyltaxol) as the penultimate step in the formation of Taxol and related N-substituted taxoids. These preliminary results, which are consistent with the proposed side chain assembly process, have clarified an important step of Taxol biosynthesis and set the foundation for cloning the responsible cytochrome P450 hydroxylase gene.

Long, Robert M. [Institute of Biological Chemistry, Washington State University, Pullman, WA 99164-6340 (United States); Croteau, Rodney [Institute of Biological Chemistry, Washington State University, Pullman, WA 99164-6340 (United States)]. E-mail: croteau@wsu.edu

2005-12-09

236

Taxol Production and Taxadiene Synthase Activity in Taxus canadensisCell Suspension Cultures  

Microsoft Academic Search

The cyclization of geranylgeranyl diphosphate to taxa-4(5),11(12)-diene represents the first committed, and a slow, step in the complex biosynthetic pathway leading to the anticancer drug Taxol. The cyclization enzyme, taxadiene synthase, has been previously purified from Pacific yew (Taxus brevifolia) stem and characterized, and the corresponding cDNA has been isolated. To better assess the role of taxadiene synthase in the

Mehri Hezari; Raymond E. B. Ketchum; Donna M. Gibson; Rodney Croteau

1997-01-01

237

Screening of taxol-producing endophytic fungi from Taxus chinensis var. mairei  

Microsoft Academic Search

A total of 38 endophytic fungus strains were isolated from Taxus chinensis var. mairei by the aseptic technique. Genomic DNA was extracted from isolated endophytic fungi and subjected to polymerase chain reaction\\u000a (PCR) analysis for the presence of the Taxus taxadiene synthase (TS) gene, a rate-limiting enzyme gene in the taxol biosynthetic pathway. Twelve out of 38 isolated endophytic fungus

X. Zhou; Z. Wang; K. Jiang; Y. Wei; J. Lin; X. Sun; K. Tang

2007-01-01

238

Cordyceps sinensis Health Supplement Enhances Recovery from Taxol-Induced Leukopenia  

PubMed Central

This study aimed to evaluate the ability of the health food supplement Cordyceps sinensis (CS) to ameliorate suppressive effects of chemotherapy on bone marrow function as a model for cancer treatment Mice were treated with Taxol (17 mg/kg body wt) one day before oral administration of a hot-water extract of CS (50 mg/kg daily) that was given daily for 3 weeks. White blood cell counts in peripheral blood of mice receiving Taxol were at 50% of normal levels on day 28 but had recovered completely in mice treated with CS. In vitro assays showed that CS enhanced the colony-forming ability of both granulocyte macrophage colony forming unit (GM-CFU) and osteogenic cells from bone marrow preparations and promoted the differentiation of bone marrow mesenchymal stromal cells into adipocytes, alkaline phosphatase–positive osteoblasts, and bone tissue. This result could be attributed to enhanced expression of Cbfa1 (core binding factor a) and BMP-2 (bone morphogenetic protein) with concurrent suppression of ODF (osteoclast differentiation factor/RANK [receptor activator of NF-?B]) ligand. In summary, CS enhances recovery of mice from leukopenia caused by Taxol treatment. It appears to do so by protecting both hematopoietic progenitor cells directly and the bone marrow stem cell niche through its effects on osteoblast differentiation.

Liu, Wei-Chung; Chuang, Wei-Ling; Tsai, Min-Lung; Hong, Ji-Hong; McBride, William H.; Chiang, Chi-Shiun

2009-01-01

239

Cordyceps sinensis health supplement enhances recovery from taxol-induced leukopenia.  

PubMed

This study aimed to evaluate the ability of the health food supplement Cordyceps sinensis (CS) to ameliorate suppressive effects of chemotherapy on bone marrow function as a model for cancer treatment. Mice were treated with Taxol (17 mg/kg body wt) one day before oral administration of a hot-water extract of CS (50 mg/kg daily) that was given daily for 3 weeks. White blood cell counts in peripheral blood of mice receiving Taxol were at 50% of normal levels on day 28 but had recovered completely in mice treated with CS. In vitro assays showed that CS enhanced the colony-forming ability of both granulocyte macrophage colony forming unit (GM-CFU) and osteogenic cells from bone marrow preparations and promoted the differentiation of bone marrow mesenchymal stromal cells into adipocytes, alkaline phosphatase-positive osteoblasts, and bone tissue. This result could be attributed to enhanced expression of Cbfa1 (core binding factor a) and BMP-2 (bone morphogenetic protein) with concurrent suppression of ODF (osteoclast differentiation factor/RANK [receptor activator of NF-kappaB]) ligand. In summary, CS enhances recovery of mice from leukopenia caused by Taxol treatment. It appears to do so by protecting both hematopoietic progenitor cells directly and the bone marrow stem cell niche through its effects on osteoblast differentiation. PMID:18367634

Liu, Wei-Chung; Chuang, Wei-Ling; Tsai, Min-Lung; Hong, Ji-Hong; McBride, William H; Chiang, Chi-Shiun

2008-04-01

240

Taxol biosynthesis: Taxane 13?-hydroxylase is a cytochrome P450-dependent monooxygenase  

PubMed Central

A central feature in the biosynthesis of Taxol is oxygenation at multiple positions of the taxane core structure, reactions that are considered to be mediated by cytochrome P450-dependent monooxygenases. A PCR-based differential display-cloning approach, using Taxus (yew) cells induced for Taxol production, yielded a family of related cytochrome P450 genes, one of which was assigned as a taxane 10?-hydroxylase by functional expression in yeast. The acquired clones that did not function in yeast were heterologously expressed by using the Spodoptera fugiperda-baculovirus-based system and were screened for catalytic capability by using taxa-4(20),11(12)-dien-5?-ol and its acetate ester as test substrates. This approach allowed identification of one of the cytochrome P450 clones (which bore 63% deduced sequence identity to the aforementioned taxane 10?-hydroxylase) as a taxane 13?-hydroxylase by chromatographic and spectrometric characterization of the corresponding recombinant enzyme product. The demonstration of a second relevant hydroxylase from the induced family of cytochrome P450 genes validates this strategy for elucidating the oxygenation steps of taxane diterpenoid (taxoid) metabolism. Additionally, substrate specificity studies with the available cytochrome P450 hydroxylases now indicate that there is likely more than one biosynthetic route to Taxol in yew species.

Jennewein, Stefan; Rithner, Christopher D.; Williams, Robert M.; Croteau, Rodney B.

2001-01-01

241

AFM Bio-Mechanical Investigation of the Taxol Treatment of Breast Cancer Cells  

NASA Astrophysics Data System (ADS)

Cancerous cells are known to be softer and easier to deform than normal cells. Changes in mechanical properties originate from the alteration of the actin cytoskeleton. The mechanism of cancer treatment using Taxol is related to the stabilization of microtubules. It has been shown that Taxol binds to polymerized tublin, stabilizes it against disassembly, and consequently inhibits cell division. An accurate quantitative study still lacks to relate the microtubule stabilizing effect with the cellular mechanical properties. We utilized our AFM to study changes in elastic properties of treated breast cancer cells. The AFM has several advantages for precise force measurements on a localized region with nanometer lateral dimension. In previous AFM studies, measurable contributions from the underlying hard substrate have been an obstacle to accurately determine the properties on thin samples. We modified our AFM tip to obtain the exact deformation profile as well as reducing the high stresses produced. We have probed depth profiles of mechanical properties of the taxol-treated and untreated cells by varying the indentation depth of the AFM-nanoindenting experiments.

Smith, Dylan; Patel, Dipika; Monjaraz, Fernando; Park, Soyeun

2009-10-01

242

A Phase II Study of the MDR Inhibitor Biricodar (INCEL, VX-710) and Paclitaxel in Women with Advanced Ovarian Cancer Refractory to Paclitaxel Therapy  

Microsoft Academic Search

Purpose. Incel (biricodar, VX-710) restores drug sensitivity to P-glycoprotein (MDR1) and multidrug-resistance-associated protein (MRP1) expressing cells. This phase II study evaluated the safety\\/tolerability, pharmacokinetics, and efficacy of VX-710 plus paclitaxel in women with advanced ovarian cancer refractory to prior paclitaxel therapy.Experimental design. Eligible patients had paclitaxel-refractory disease defined as progressive disease after a minimum of two cycles of paclitaxel (weekly

Michael V. Seiden; Kenneth D. Swenerton; Ursula Matulonis; Susan Campos; Peter Rose; Gerald Batist; Ene Ette; Varun Garg; Arlan Fuller; Matthew W. Harding; Danielle Charpentier

2002-01-01

243

A Case of Cystoid Macular Edema Associated with Paclitaxel Chemotherapy  

PubMed Central

We encountered a patient with cystoid macular edema (CME) secondary to paclitaxel use. A 57-year-old man presented with gradual decreased bilateral vision. His chemotherapeutic regimen consisted of bevacizumab, paclitaxel (175 mg/m2 for 5 months), and carboplatin. Optical coherence tomography imaging revealed bilateral CME greater than 500 µm. However, one year later, visual acuity was improved, best-corrected Snellen visual acuity was 40 / 80 in each eye, and CME was spontaneously improved. Our study confirmed that macular edema associated with paclitaxel use shows spontaneous resolution and improvement of visual acuity after a change of chemotherapeutic regimen.

Ham, Dong Sik; Lee, Joo Eun; Yun, Il Han

2012-01-01

244

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

PubMed

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

Soliman, Sameh S M; Raizada, Manish N

2013-01-22

245

Inhibition of infection of macrophages with Ehrlichia risticii by cytochalasins, monodansylcadaverine, and taxol.  

PubMed Central

The requirement of functions of clathrin, microfilaments, and microtubules in binding, internalization, proliferation, and spreading of Ehrlichia risticii in macrophages was studied. Monodansylcadaverine (MDC), which inhibits clustering and internalization of the ligand-receptor complexes into clathrin-coated vesicles; cytochalasin B or D, which depolymerizes microfilaments; and taxol, which binds and stabilizes polymerized microtubules, were found to prevent ehrlichial infection in murine peritoneal macrophages when they were present throughout the infection period. [35S]methionine-labeled ehrlichial binding to the macrophage was reduced by 0 to 22%; therefore, the binding was not the major point of inhibition. However, MDC, cytochalasin D, and taxol inhibited ehrlichial internalization into macrophages by 80, 58, and 32%, respectively. When MDC, cytochalasin B or D, or taxol was added immediately after internalization of E. risticii (3 h postinfection), ehrlichial replication in P388D1 cells was almost completely prevented. Also, all of these agents almost completely prevented ehrlichial spreading from P388D1 cells to THP-1 human monocytes. These agents were not found to be ehrlichiacidal when approximately 40%-infected P388D1 cells were treated for 2 days, although further intracellular proliferation was prevented. Furthermore, none of these compounds directly inhibited the metabolic activity of E. risticii, since 14CO2 production from L-[14C]glutamine by Percoll density gradient-purified host-cell-free E. risticii was not shown to be impaired. The action of taxol was probably due to impairment of the microtubule function since a microtubule-depolymerizing agent, colchicine, also inhibited intracellular proliferation of E. risticii. Neither reactive oxygen intermediates, nitric oxide, nor tumor necrosis factor alpha appeared to be involved in taxol-induced inhibition of E. risticii in macrophages. Thus, our findings indicate that ehrlichial internalization appears to take place by a mechanism that is more dependent on the functions of clathrin and less dependent on the functions of microfilaments or microtubules. Replication within macrophages and intercellular spreading appear to require clathrin, microfilaments, and microtubules. Consequently, alteration of these structures with inhibitors can result in complete prevention of infection.

Rikihisa, Y; Zhang, Y; Park, J

1994-01-01

246

Inhibitory Effect of Paclitaxel on Endothelial Cell Adhesion and Migration  

Microsoft Academic Search

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

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

2010-01-01

247

Sensitization of taxol-induced apoptosis by curcumin involves down-regulation of nuclear factor-kappaB and the serine\\/threonine kinase Akt and is independent of tubulin polymerization  

Microsoft Academic Search

Taxol is the best anticancer agent that has ever been isolated from plants, but its major disadvantage is its dose-limiting toxicity. In this study, we report with mechanism-based evidence that curcumin, a nontoxic food additive commonly used by the Indian population, sensitizes tumor cells more efficiently to the therapeutic effect of Taxol. A combination of 5 nm Taxol with 5

Smitha V Bava; Vineshkumar T Puliappadamba; Ayswaria Deepti; Asha Nair; Devarajan Karunagaran; Ruby John Anto

2005-01-01

248

Paclitaxel uptake and transport in Taxus cell suspension cultures  

PubMed Central

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

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

2012-01-01

249

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

Microsoft Academic Search

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

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

2007-01-01

250

Idiotypic Mimicry and the Assembly of a Supramolecular Structure: An Anti-Idiotypic Antibody that Mimics Taxol in its Tubulin-Microtubule Interactions  

Microsoft Academic Search

Taxol, originally extracted from the bark of the western yew, Taxus brevifolia, is reportedly the first of a new class of anti-cancer agents. It acts by promoting and irreversibly stabilizing microtubule assembly, thus interfering with the dynamic processes required for cell viability and multiplication. With the aim of using immunological techniques to study the mechanism of action of taxol, a

Jyh-Gang Leu; Bi-Xing Chen; Andrew W. Diamanduros; Bernard F. Erlanger

1994-01-01

251

Signal transduction pathway for oxidative burst and taxol production in suspension cultures of Taxus chinensis var. mairei induced by oligosaccharide from Fusarium oxysprum  

Microsoft Academic Search

Signal transduction pathway for oxidative burst and taxol production was studied in suspension cultures of Taxus chinensis var. mairei induced by oligosaccharide from Fusarium oxysprum. Suspension cells exhibited an oxidative burst approximately 4h after challenge with oligosaccharide. The secondary metabolism including accumulation of extracellular phenolics and taxol production were enhanced, while the alkalization of the outer medium and activity of

Ying-Jin Yuan; Chun Li; Zong-Ding Hu; Jin-Chuan Wu

2001-01-01

252

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

PubMed Central

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.

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

2013-01-01

253

Phototriggerable 2?,7-Caged Paclitaxel  

PubMed Central

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

Gropeanu, Radu A.; Baumann, Hella; Ritz, Sandra; Mailander, Volker; Surrey, Thomas; del Campo, Aranzazu

2012-01-01

254

High-performance liquid chromatography and micellar electrokinetic chromatography of taxol and related taxanes from bark and needle extracts of Taxus species.  

PubMed

High-performance liquid chromatography (HPLC) and micellar electrokinetic chromatography (MEKC) were applied for the separation of taxol, cephalomannine, and baccatin III in crude extracts from the needle and bark of Taxus species. The chromatogram of the bark extract was cleaner than that of the needle allowing a more reliable detection of taxol and cephalomannine in the bark extract. However, HPLC quantitation of taxol in the needle extract would be difficult due to coeluting taxinines. Nevertheless, this was not a problem in the MEKC experiment. In comparison to HPLC, MEKC offered baseline resolution of taxol from taxinines in the needle extract, less solvent waste, a smaller sample requirement, and the simultaneous detection of taxol, cephalomannine and baccatin III in a relatively simpler electrophoretic run. PMID:7952094

Chan, K C; Alvarado, A B; McGuire, M T; Muschik, G M; Issaq, H J; Snader, K M

1994-07-15

255

Taxol-induced growth arrest and apoptosis is associated with the upregulation of the Cdk inhibitor, p21WAF1/CIP1, in human breast cancer cells.  

PubMed

The anticancer agent, taxol, stabilizes tubulin polymerization, resulting in arrest at the G2/M phase of the cell cycle and apoptotic cell death. However, the molecular mechanism of this growth inhibition and apoptosis is poorly understood. In this study, we used MCF-7 and MDA-MB-231 human breast carcinoma cells which have different estrogen receptor (ER) and tumor suppressor p53 statuses to examine the mechanisms of taxol-induced growth inhibition and apoptosis. Treatment of the cells with taxol resulted in a time-dependent inhibition of cell viability, which was accompanied by an accumulation of cells at G2/M and the sub-G1 apoptotic region, determined by flow cytometric analysis. Furthermore, chromatin condensation, DNA ladder formation and proteolytic cleavage of poly(ADP-ribose) polymerase (PARP) in both cell lines were observed following treatment with taxol, indicating the occurrence of apoptotic cell death. Western blot analysis using whole cell lysates from MCF-7 and MDA-MB-231 cells treated with taxol demonstrated that taxol treatment inhibited expression of cyclin A and cyclin B1 proteins in a time-dependent manner. The inhibitory effects of taxol on cell growth and apoptosis induced by taxol were also associated with the downregulation of Wee1 kinase expression and a marked induction in the activity of the cyclin-dependent kinase inhibitor, p21WAF/CIP1. Furthermore, taxol elevated p21 promoter activity in both cell lines. These findings suggest that taxol-induced G2/M arrest and apoptosis in human breast carcinoma cells is mediated through the ER- and p53-independent upregulation of p21. PMID:23023313

Choi, Yung Hyun; Yoo, Young Hyun

2012-09-26

256

A Crucial Role of Caspase 3 and Caspase 8 in Paclitaxel-Induced Apoptosis  

Microsoft Academic Search

The anticancer drug paclitaxel is well known as an inhibitor of microtubule depolymerization, resulting in mitosis arrest. We investigated the mechanism underlying antitumor effects of paclitaxel on the lung adenocarcinoma cell line LC-2-AD. Less than 10 ?g\\/ml paclitaxel induced mitosis arrest upon LC-2-AD, followed by apoptosis, but more than 30 ?g\\/ml paclitaxel induced apoptosis without mitosis arrest. LC-2-AD with less

Haruki Oyaizu; Yasushi Adachi; Shigeru Taketani; Rikio Tokunaga; Shirou Fukuhara; Susumu Ikehara

1999-01-01

257

Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: Evidence for mitochondrial dysfunction  

Microsoft Academic Search

Paclitaxel chemotherapy frequently induces neuropathic pain during and often persisting after therapy. The mechanisms responsible for this pain are unknown. Using a rat model of paclitaxel-induced painful peripheral neuropathy, we have performed studies to search for peripheral nerve pathology. Paclitaxel-induced mechano-allodynia and mechano-hyperalgesia were evident after a short delay, peaked at day 27 and finally resolved on day 155. Paclitaxel-

Sarah J. L. Flatters; Gary J. Bennett

2006-01-01

258

Acetyl l-carnitine prevents and reduces paclitaxel-induced painful peripheral neuropathy  

Microsoft Academic Search

This study examines the potential efficacy of acetyl-l-carnitine (ALC) to prevent and treat paclitaxel-induced pain. Rats received four intraperitoneal (i.p.) injections of 2mg\\/kg paclitaxel on alternate days which, following a short delay induced marked mechanical hypersensitivity. Daily administration of ALC (50mg\\/kg and 100mg\\/kg; p.o.; concurrently with paclitaxel and for 14 days afterwards) prevented the development of paclitaxel-induced pain. This effect

Sarah J. L. Flatters; Wen-Hua Xiao; Gary J. Bennett

2006-01-01

259

Prediction of paclitaxel sensitivity by CDK1 and CDK2 activity in human breast cancer cells  

PubMed Central

Introduction Paclitaxel is used widely in the treatment of breast cancer. Not all tumors respond to this drug, however, and the characteristics that distinguish resistant tumors from sensitive tumors are not well defined. Activation of the spindle assembly checkpoint is required for paclitaxel-induced cell death. We hypothesized that cyclin-dependent kinase (CDK) 1 activity and CDK2 activity in cancer cells, which reflect the activation state of the spindle assembly checkpoint and the growth state, respectively, predict sensitivity to paclitaxel. Methods Cell viability assays and DNA and chromatin morphology analyses were performed in human breast cancer cell lines to evaluate sensitivity to paclitaxel and the cell cycle response to paclitaxel. We then examined the specific activities of CDK1 and CDK2 in these cell lines and in xenograft models of human breast cancer before and after paclitaxel treatment. Protein expression and kinase activity of CDKs and cyclins were analyzed using a newly developed assay system. Results In the cell lines, biological response to paclitaxel in vitro did not accurately predict sensitivity to paclitaxel in vivo. Among the breast cancer xenograft tumors, however, tumors with significantly increased CDK1 specific activity after paclitaxel treatment were sensitive to paclitaxel in vivo, whereas tumors without such an increase were resistant to paclitaxel in vivo. Baseline CDK2 specific activity was higher in tumors that were sensitive to paclitaxel than in tumors that were resistant to paclitaxel. Conclusions The change in CDK1 specific activity of xenograft tumors after paclitaxel treatment and the CDK2 specific activity before paclitaxel treatment are both associated with the drug sensitivity in vivo. Analysis of cyclin-dependent kinase activity in the clinical setting could be a powerful approach for predicting paclitaxel sensitivity.

Nakayama, Satoshi; Torikoshi, Yasuhiro; Takahashi, Takeshi; Yoshida, Tomokazu; Sudo, Tamotsu; Matsushima, Tomoko; Kawasaki, Yuko; Katayama, Aya; Gohda, Keigo; Hortobagyi, Gabriel N; Noguchi, Shinzaburo; Sakai, Toshiyuki; Ishihara, Hideki; Ueno, Naoto T

2009-01-01

260

The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces growth inhibition and enhances taxol-induced cell death in breast cancer  

Microsoft Academic Search

Purpose  The histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) enhances taxol-induced antitumor effects\\u000a against some human cancer cells. The aim of this study is to investigate whether SAHA can enhance taxol-induced cell death\\u000a against human breast cancer cells and to illustrate the mechanism in detail.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  A panel of eight human breast cancer cell lines and an immortalized human breast epithelial

Yi-kang Shi; Zhong-hua Li; Xi-qian Han; Ji-hu Yi; Zhen-hua Wang; Jing-li Hou; Cong-ran Feng; Qing-hong Fang; Hui-hui Wang; Peng-fei Zhang; Feng-shan Wang; Jie Shen; Peng Wang

2010-01-01

261

Target-specific cellular uptake of taxol-loaded heparin-PEG-folate nanoparticles.  

PubMed

To enhance site-specific intracellular delivery against folate receptor, heparin-PEG-folate (H-PEG-F) containing succinylated-heparin conjugated with folate via PEG 1000/3000 spacers has been prepared. Due to covalent strategy, H-PEG-F displays amphiphilic property, which is capable of entrapping a hydrophobic agent, like taxol, to form heparin-PEG-folate-taxol nanoparticles (H-PEG-F-T NPs) in aqueous solution. Hydrophobic agents can be entrapped within the core, while the H-PEG-F conjugates can stabilize the nanoparticles with exposing folate moieties on the surface. The structure of carrier and naoparticles has been characterized by(1)H NMR, and the content of folate and taxol has been quantitatively analyzed by UV method. The morphology and size of H-PEG-F-T NPs have been measured by field emission scanning electron microscopy (FESEM) and dynamic lighting scatter (DLS). All the NPs are in spherical shape and the sizes are less than 200 nm. The sizes of the NPs increases with increasing PEG segment length. By employing the flow cytomery method, the extent of cellular uptake has been comparatively evaluated under various conditions. The results of cellular uptake demonstrate that the cellular uptake of the carrier and the NPs is exceedingly higher for KB-3-1 cells (folate receptor overexpressing cell line) than for A549 cells (folate receptor deficiency cell line); H-PEG-F-T NPs show far greater extent of cellular uptake than that of H-PEG-F conjugates against A549 cells; when the content of folate is fixed at the same value, the extent of cellular uptake for the carrier and NPs ascends with the increase of PEG chain length against KB-3-1 cells. It suggests folate-receptor-mediated endocytosis and formation of nanoparticle and spacer length are considered to coaffect the cellular uptake efficiency of H-PEG-F-T NPs and H-PEG-F conjugates. Flow cytometry analysis depicts that KB-3-1 cells treated with H-PEG-F-T are arrested in the G(2)/M phase of the cell cycle, which states the similar inhibition mechanism as taxol. The strategy based on the formation of H-PEG-F-T NPs could be potentially applied for cancer cell targeted delivery of various therapeutic agents. PMID:21086982

Wang, Ying; Wang, Yiqing; Xiang, Jiannan; Yao, Kaitai

2010-11-18

262

Comparison of LC-UV and LC-MS-MS for the determination of taxol  

Microsoft Academic Search

Summary  The relative advantages of LC-UV and LC-MS-MS methodologies for taxol as applied to toxicokinetic and pharmacokinetic studies\\u000a is reviewed and some specific applications of the two methods used in our laboratories compared. The LC-MS-MS method was found\\u000a to be twenty-five times more sensitive than the LC-UV method. In essence where plasma concentrations are high and rapid turn\\u000a round of data

S. F. Baldrey; R. R. Brodie; G. R. Morris; E. H. Jenkins; S. T. Brookes

2002-01-01

263

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

NASA Astrophysics Data System (ADS)

Nanogels are promising carriers for the delivery of anti-cancer drugs for cancer therapy. We report in this study on a Janus nanogel system formed by mixing a prodrug of Taxol (PEGylated Taxol) and a copolymer of PLGA-PEG-PLGA. The Janus nanogels have good stability over months in aqueous solutions and the freeze-dried powder of nanogels can be re-dispersed instantly in aqueous solutions. The Janus nanogels show an enhanced inhibition effect on tumor growth in a mice breast cancer model probably due to the enhanced uptake of the nano-sized materials by the EPR effect. What is more, the nanogels can also serve as physical carriers to co-deliver other anti-cancer drugs such as doxorubicin to further improve the anti-cancer efficacy. The results obtained from H&E staining and TUNEL assay also support the observation of tumor growth inhibition. These results suggest the potential of this novel delivery system for cancer therapy.Nanogels are promising carriers for the delivery of anti-cancer drugs for cancer therapy. We report in this study on a Janus nanogel system formed by mixing a prodrug of Taxol (PEGylated Taxol) and a copolymer of PLGA-PEG-PLGA. The Janus nanogels have good stability over months in aqueous solutions and the freeze-dried powder of nanogels can be re-dispersed instantly in aqueous solutions. The Janus nanogels show an enhanced inhibition effect on tumor growth in a mice breast cancer model probably due to the enhanced uptake of the nano-sized materials by the EPR effect. What is more, the nanogels can also serve as physical carriers to co-deliver other anti-cancer drugs such as doxorubicin to further improve the anti-cancer efficacy. The results obtained from H&E staining and TUNEL assay also support the observation of tumor growth inhibition. These results suggest the potential of this novel delivery system for cancer therapy. Electronic supplementary information (ESI) available: Synthesis and characterization of compounds, dynamic time sweep, H&E result and body weight change of mice. See DOI: 10.1039/c3nr02937a

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

2013-09-01

264

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

PubMed Central

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

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

2009-01-01

265

RNA interference (RNAi) screening approach identifies agents that enhance paclitaxel activity in breast cancer cells  

Microsoft Academic Search

ABSTRACT: INTRODUCTION: Paclitaxel is a widely used drug in the treatment of patients with locally advanced and metastatic breast cancer. However, only a small portion of patients have a complete response to paclitaxel-based chemotherapy, and many patients are resistant. Strategies that increase sensitivity and limit resistance to paclitaxel would be of clinical use, especially for patients with triple-negative breast cancer

Joshua A Bauer; Fei Ye; Clayton B Marshall; Brian D Lehmann; Christopher S Pendleton; Yu Shyr; Carlos L Arteaga; Jennifer A Pietenpol

2010-01-01

266

Formulation and pharmacokinetic evaluation of a paclitaxel nanosuspension for intravenous delivery  

PubMed Central

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

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

2011-01-01

267

Oligosaccharides potentiate methyl jasmonate-induced production of paclitaxel in Taxus canadensis  

Microsoft Academic Search

The interdependence of methyl jasmonate (MJ) with chitin and chitosan derived elicitors in formation of paclitaxel was studied using plant cell suspension cultures of Taxus canadensis. Induction of paclitaxel biosynthesis was enhanced when MJ and elicitors were added 8 days after culture transfer compared to treatments in which only MJ or only elicitors were added. The enhancement of the paclitaxel

James C Linden; Muenduen Phisalaphong

2000-01-01

268

Ran suppresses paclitaxel-induced apoptosis in human glioblastoma cells.  

PubMed

Yeast-based functional screening of a human glioblastoma cDNA library identified ras-related nuclear protein (Ran) as a novel suppressor of Bcl-2-associated X protein (Bax), a pro-apoptotic member of the Bcl-2 family of proteins. Yeast cells that expressed human Ran were resistant to Bax-induced cell death. In U373MG glioblastoma cells, stable overexpression of Ran significantly attenuated apoptotic cell death induced by the chemotherapeutic agent paclitaxel. FACS analysis demonstrated that Ran is involved in paclitaxel-induced cell cycle arrest. Stable overexpression of Ran also markedly inhibited the phosphorylation of Bcl-2 by paclitaxel, and inhibited the translocation of Bax, the release of cytochrome c and activation of caspase-3. Paclitaxel-induced phosphorylation of c-JUN N-terminal kinase (JNK), but not p38, extracellular signal-regulated kinase and Akt, was markedly suppressed in U373MG cells that stably expressed Ran. These results suggest that Ran suppresses paclitaxel-induced cell death through the downregulation of JNK-mediated signal pathways. PMID:18690538

Woo, Im Sun; Jang, Han-Su; Eun, So Young; Kim, Hyo Jung; Ham, Sun Ah; Kim, Hye Jung; Lee, Jae Heun; Chang, Ki Churl; Kim, Jin-Hoi; Han, Chang Woo; Seo, Han Geuk

2008-10-01

269

Dual targeting folate-conjugated hyaluronic acid polymeric micelles for paclitaxel delivery.  

PubMed

A series of novel self-assembled hyaluronic acid derivatives (HA-C(18)) grafted with hydrophobic octadecyl moiety and further dual targeting folic acid-conjugated HA-C(18) (FA-HA-C(18)) were synthesized. With the increase in the degree of substitution of octadecyl group from 12.7% to 19.3%, the critical micellar concentration of HA-C(18) copolymers decreased from 37.3 to 10.0 ?g/mL. Paclitaxel (PTX) was successfully encapsulated into the hydrophobic cores of the HA-C(18) and FA-HA-C(18) micelles, with encapsulation efficiency as high as 97.3%. The physicochemical properties of the polymeric micelles were measured by DLS, TEM and DSC. Moreover, in vitro release behavior of PTX was investigated by dialysis bag method and PTX was released from micelles in a near zero-order sustained manner. In vitro antitumor activity tests suggested PTX-loaded HA-C(18) and FA-HA-C(18) micelles exhibited significantly higher cytotoxic activity against MCF-7 and A549 cells compared to Taxol at a lower PTX concentration. The cellular uptake experiments were conducted by quantitative assay of PTX cellular accumulation and confocal laser scanning microscopy imaging of coumarin-6 labeled HA-C(18) and FA-HA-C(18) micelles in folate receptor overexpressing MCF-7 cells. Folate and CD44 receptor competitive inhibition studies performed by fluorescence microscopy imaging suggested intracellular delivery of HA-C(18) and FA-HA-C(18) micelles were efficiently taken up via CD44 receptor-mediated endocytosis. The folate receptor-mediated endocytosis further enhanced internalized amounts of FA-HA-C(18) micelles in MCF-7 cells, as compared with HA-C(18) micelles. The internalization pathways of PTX-loaded HA-C(18) and FA-HA-C(18) micelles might include clathrin-mediated endocytosis, caveolae-mediated endocytosis and macropinocytosis. Therefore, the present study suggested that HA-C(18) and FA-HA-C(18) copolymers as biodegradable, biocompatible and cell-specific targetable nanostructure carriers, are promising nanosystems for cellular and intracellular targeting delivery of hydrophobic anticancer drugs. PMID:21945183

Liu, Yanhua; Sun, Jin; Cao, Wen; Yang, Jianhong; Lian, He; Li, Xin; Sun, Yinghua; Wang, Yongjun; Wang, Siling; He, Zhonggui

2011-09-16

270

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

PubMed Central

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.

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

2005-01-01

271

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

PubMed

Nanogels are promising carriers for the delivery of anti-cancer drugs for cancer therapy. We report in this study on a Janus nanogel system formed by mixing a prodrug of Taxol (PEGylated Taxol) and a copolymer of PLGA-PEG-PLGA. The Janus nanogels have good stability over months in aqueous solutions and the freeze-dried powder of nanogels can be re-dispersed instantly in aqueous solutions. The Janus nanogels show an enhanced inhibition effect on tumor growth in a mice breast cancer model probably due to the enhanced uptake of the nano-sized materials by the EPR effect. What is more, the nanogels can also serve as physical carriers to co-deliver other anti-cancer drugs such as doxorubicin to further improve the anti-cancer efficacy. The results obtained from H&E staining and TUNEL assay also support the observation of tumor growth inhibition. These results suggest the potential of this novel delivery system for cancer therapy. PMID:23982346

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

2013-09-26

272

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

PubMed Central

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

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

1994-01-01

273

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

PubMed

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

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

1994-10-25

274

Insulin-like growth factor 2 (IGF2) expression modulates Taxol resistance and is a candidate biomarker for reduced disease-free survival in ovarian cancer  

PubMed Central

Purpose This study was undertaken to examine the role of the insulin-like growth factor (IGF) signaling pathway in the response of ovarian cancer cells to Taxol and to evaluate the significance of this pathway in human epithelial ovarian tumors. Experimental design The effect of Taxol treatment on AKT activation in A2780 ovarian carcinoma cells was evaluated using antibodies specific for phosphorylated AKT. To study the drug-resistant phenotype, we developed a Taxol-resistant cell line, HEY-T30, derived from HEY ovarian carcinoma cells. IGF2 expression was measured by real-time PCR. An IGF1R inhibitor, NVP-AEW541, and IGF2 siRNA were used to evaluate the effect of IGF pathway inhibition on proliferation and Taxol sensitivity. IGF2 protein expression was evaluated by immunohistochemistry in 115 epithelial ovarian tumors, and analyzed in relation to clinical/pathologic factors using the Chi-square or Fisher’s exact tests. The influence of IGF2 expression on survival was studied with Cox regression. Results Taxol-induced AKT phosphorylation required IGF1R tyrosine kinase activity and was associated with upregulation of IGF2. Resistant cells had higher IGF2 expression compared with sensitive cells, and IGF pathway inhibition restored sensitivity to Taxol. High IGF2 tumor expression correlated with advanced stage (p<0.001) and tumor grade (p<0.01), and reduced disease-free survival (p<0.05). Conclusions IGF2 modulates Taxol resistance, and tumor IGF2 expression is a candidate prognostic biomarker in epithelial ovarian tumors. IGF pathway inhibition sensitizes drug-resistant ovarian carcinoma cells to Taxol. Such novel findings suggest that IGF2 represents a therapeutic target in ovarian cancer, particularly in the setting of Taxol resistance.

Huang, Gloria S.; Brouwer-Visser, Jurriaan; Ramirez, Marissa J.; Kim, Christine H.; Hebert, Tiffany M.; Lin, Juan; Arias-Pulido, Hugo; Qualls, Clifford R.; Prossnitz, Eric R.; Goldberg, Gary L.; Smith, Harriet O.; Horwitz, Susan Band

2010-01-01

275

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

Microsoft Academic Search

Taxol produces neuropathic pain with three distinct zones of involvement in the extremities. Most distally is an area of on-going pain and proximal to this is a zone of sensory disturbance but not overt pain. These two areas were confined in all but one case to the glabrous skin of the hands and\\/or feet. More proximal is an area not

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

2004-01-01

276

Comparative in vitro cytotoxicity of taxol and Taxotere against cisplatin-sensitive and-resistant human ovarian carcinoma cell lines  

Microsoft Academic Search

Using the sulforhodamine B assay, we compared the cytotoxic properties of the novel microtubule agent taxol and the semi-synthetic related compound Taxotere in nine human ovarian-carcinoma cell lines, including three pairs of cell lines rendered resistant to cisplatin or carboplatin. In addition, the cytotoxicity of the commonly used anticancer drugs cisplatin and adriamycin and the topoisomerase II inhibitor etoposide was

Lloyd R. Kelland; George Abel

1992-01-01

277

Monitoring Response to Convection-enhanced Taxol Delivery in Brain Tumor Patients Using Diffusion-weighted Magnetic Resonance Imaging1  

Microsoft Academic Search

Convection-enhanced drug delivery (CEDD) is a novel approach to enhance the delivery of drugs directly into brain tumors. We have used diffusion-weighted MRI (DWMRI) to monitor the effects of intratumoral CEDD in three brain tumor patients treated with Taxol. Clear changes in the images and the water diffusion parameters were observed shortly after the initiation of treatment. Initially, a bright

Yael Mardor; Yiftach Roth; Zvi Lidar; Tali Jonas; Raphael Pfeffer; Stephan E. Maier; Meir Faibel; Dvora Nass; Moshe Hadani; Arie Orenstein; Jack S. Cohen; Zvi Ram

278

Separation of 7-xylosyl-10-deacetyl paclitaxel and 10-deacetylbaccatin III from the remainder extracts free of paclitaxel using macroporous resins  

Microsoft Academic Search

The separation and enrichment of 10-deacetylbaccatin III (10-DAB III) and 7-xylosyl-10-deacetyl paclitaxel were studied on seven macroporous resins with special structures. The performance of 7-xylosyl-10-deacetyl paclitaxel and 10-DAB III on macroporous resins including AB-8, ADS-17, ADS-21, ADS-31, ADS-8, H1020 and NKA-II was compared according to their adsorption and desorption properties. AB-8 provided a much higher adsorption capacity for 7-xylosyl-10-deacetyl paclitaxel

Yujie Fu; Yuangang Zu; Shuangming Li; Rui Sun; Thomas Efferth; Wei Liu; Shougang Jiang; Hao Luo; Ying Wang

2008-01-01

279

Safety and Efficacy of the Multidrug Resistance Inhibitor Incel (Biricodar; VX-710) in Combination with Paclitaxel for Advanced Breast Cancer Refractory to Paclitaxel  

Microsoft Academic Search

Purpose: VX-710 (biricodar, Incel) restores drug sensi- tivity to P-glycoprotein (MDR1) and multidrug resistance- associated protein (MRP1)-expressing cells. This Phase II study evaluated the safety\\/tolerability, pharmacokinetics, and efficacy of VX-710 plus paclitaxel in women with locally advanced or metastatic breast cancer who were refractory to prior paclitaxel therapy. Experimental Design: Eligible patients had paclitaxel- refractory disease defined as progressive disease

Deborah Toppmeyer; Andrew D. Seidman; Michael Pollak; Christy Russell; Katherine Tkaczuk; Shailendra Verma; Beth Overmoyer; Varun Garg; Ene Ette; Matthew W. Harding; George D. Demetri

2002-01-01

280

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

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

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

2010-01-01

281

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

NASA Astrophysics Data System (ADS)

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

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

2010-08-01

282

Quantitative Proteomic Analysis of Ovarian Cancer Cells Identified Mitochondrial Proteins Associated with Paclitaxel Resistance  

PubMed Central

Paclitaxel has been widely used as an anti-mitotic agent in chemotherapy for a variety of cancers and adds substantial efficacy as the first-line chemotherapeutic regimen for ovarian cancers. However, the frequent occurrence of paclitaxel resistance limits its function in long-term management. Despite abundant clinical and cellular demonstration of paclitaxel resistant tumors, the molecular mechanisms leading to paclitaxel resistance are poorly understood. Using genomic approaches, we have previously identified an association between a BTB/POZ gene, Nac1, and paclitaxel resistance in ovarian cancer. The experiments presented here have applied multiple quantitative proteomic methods to identify protein changes associated with paclitaxel resistance and Nac1 function. The SKOV-3 ovarian serous carcinoma cell line, which has inducible expression of dominant negative Nac1, was used to determine the paclitaxel treatment associated changes in the presence and absence of functional Nac1. Quantitative proteomic analyses were performed using iTRAQ labeling and mass spectrometry. Two label-free quantitative proteomic methods: LC-MS and spectral count were used to increase confidence of proteomic quantification. A total of 1371 proteins were quantified by at least one of the quantitative proteomic methods. Candidate proteins related to paclitaxel and NAC1 function were identified in this study. Go analysis of the protein changes identified upon paclitaxel resistance revealed that cell component enrichment related to mitochondria. Moreover, tubulin and mitochondrial proteins were the major cellular components with changes associated with paclitaxel treatment. This suggests that mitochondria may play a role in paclitaxel resistance.

Tian, Yuan; Tan, Aik-Choon; Sun, Xiaer; Olson, Matthew T; Xie, Zhi; Jinawath, Natini; Chan, Daniel W.; Shih, Ie-Ming; Zhang, Zhen; Zhang, Hui

2010-01-01

283

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

PubMed Central

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

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

2008-01-01

284

Functionalized nanospheres for targeted delivery of paclitaxel.  

PubMed

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

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

2013-06-20

285

Taxol and LPS Modulation of c-kit and nm23 Expression in Macrophages and Normal vs. Malignant Breast Cancer Cell Lines.  

National Technical Information Service (NTIS)

Apart from its well characterized anti-mitotic effects, Taxol shares with bacterial lipopolysaccharide (LPS) the capacity to elicit microtubule-independent, intracellular signaling in murine macrophages leading to expression of many genes. This IDEA grant...

S. N. Vogel

1999-01-01

286

Ifosfamide Plus Paclitaxel Extends Life for Patients With Uterine Carcinosarcoma  

Cancer.gov

Women with a rare, aggressive form of uterine cancer who were treated with the drugs ifosfamide and paclitaxel lived a median of five months longer than women who were treated with ifosfamide alone, according to the Feb. 10, 2007, Journal of Clinical Oncology.

287

Paclitaxel and Cisplatin Combination Chemotherapy in Recurrent Epithelial Ovarian Cancer  

Microsoft Academic Search

The objective of this study was to assess the efficacy of chemotherapy in recurrent epithelial ovarian cancer using the sequential combination of 24-hr paclitaxel followed by cisplatin. All patients presenting to the Department of Gynecologic Oncology at Roswell Park Cancer Institute between April 1993 and May 1995 with recurrent epithelial ovarian cancer were offered enrollment in a prospective trial utilizing

Jeffrey M. Goldberg; M. Steven Piver; Ronald E. Hempling; Fernando O. Recio

1996-01-01

288

Taxol induces caspase-independent cytoplasmic vacuolization and cell death through endoplasmic reticulum (ER) swelling in ASTC-a-1 cells  

Microsoft Academic Search

High concentration of taxol was found to induce programmed cell death (PCD) and cytoplasm vacuolization in human lung adenocarcinoma (ASTC-a-1) cells. To elucidate the relationship between the PCD and cytoplasm vacuolization, confocal fluorescence microscopy was performed on the cytoplasm vacuolization, endoplasmic reticulum (ER) and mitochondria swelling after taxol treatment in living cells. erRFP plasmid was used to probe the ER

Tong-sheng Chen; Xiao-ping Wang; Lei Sun; Long-xiang Wang; Da Xing; Martin Mok

2008-01-01

289

Biosynthesis of Taxol: Enzymatic Acetylation of 10-Deacetylbaccatin-III to Baccatin-III in Crude Extracts from Roots of Taxus baccata  

Microsoft Academic Search

The biosynthesis of taxol is a multistep process. One intermediate reaction is the acetylation of 10-deacetylbaccatin-III (10-DAB) to baccatin-III, an assumed precursor of taxol. Here we describe the cell free acetylation of 10-DAB in crude extracts from roots ofTaxus baccatasaplings using14C- or3H-labeled acetyl-coenzyme A as the acetyl donor. The reaction is strictly dependent on the addition of 10-DAB and is

Rainer Zocher; Wolfram Weckwerth; Christine Hacker; Bettina Kammer; Till Hornbogen; Dietrich Ewald

1996-01-01

290

Taxol, an anticancer drug produced by an endophytic fungus Bartalinia robillardoides Tassi, isolated from a medicinal plant, Aegle marmelos Correa ex Roxb  

Microsoft Academic Search

Taxol is an important anticancer drug widely used in the clinic. An endophytic fungus Bartalinia robillardoides (strain AMB-9) was isolated from Aegle marmelos, a medicinal plant and screened for taxol production. The fungus was identified based on the morphology of the fungal culture\\u000a and the characteristics of the spores. This fungus was grown in MID liquid medium and analyzed chromatographically

V. Gangadevi; J. Muthumary

2008-01-01

291

Kinetics of taxol production and nutrient use in suspension cultures of Taxus cuspidata in shake flasks and a Wilson-type bioreactor  

Microsoft Academic Search

Suspension cultures of Taxus cuspidata were grown in shake flasks and Wilson-type reactors where bubbled air provided both agitation and mixing. Taxol titers of 22 mg l?1 were achieved for both configurations in 20 days for a volumetric productivity of 1.1 mg l?1 day?1. This productivity is many-fold higher than reported for other Taxus sp. suspension cultures. Taxol was released

Luis J. Pestchanker; Susan C. Roberts; Michael L. Shuler

1996-01-01

292

Purification and Characterization of Taxa4(5),11(12)-diene Synthase from Pacific Yew ( Taxus Brevifolia) that Catalyzes the First Committed Step of Taxol Biosynthesis  

Microsoft Academic Search

The first step in the biosynthesis of taxol in Pacific yew (Taxus brevifolia) is the cyclization of the universal diterpene precursor geranylgeranyl pyrophosphate to taxa-4(5),11(12)-diene. This parent olefin of the taxane diterpenoids is then elaborated to taxol and related compounds by a complex series of reactions involving oxidations and side-chain acylations. Cyclization activity is located principally in yew stem bark

M. Hezari; N. G. Lewis; R. Croteau

1995-01-01

293

The final acylation step in Taxol biosynthesis: Cloning of the taxoid C13-side-chain N-benzoyltransferase from Taxus  

Microsoft Academic Search

The formation of several acyl groups and an amide group of Taxol is catalyzed by regioselective CoA thioester-dependent acyltransferases. Several full-length acyltransferase sequences, obtained from a cDNA library constructed from mRNA isolated from Taxus cuspidata cells induced for Taxol production with methyl jasmonate, were individually expressed in Escherichia coli, from which a cDNA clone encoding a 3'-N-debenzoyl- 2'-deoxytaxol N-benzoyltransferase was

Kevin Walker; Robert Long; Rodney Croteau

2002-01-01

294

Preparation, characterization and in vitro cytotoxicity of paclitaxel-loaded sterically stabilized solid lipid nanoparticles.  

PubMed

In an effort to develop an alternative formulation of paclitaxel suitable for parenteral administration, paclitaxel-loaded sterically stabilized solid lipid nanoparticles (SLNs) were prepared, characterized and examined for in vitro cytotoxicity. The SLNs, comprising trimyristin (TM) as a solid lipid core and egg phosphatidylcholine and pegylated phospholipid as stabilizers, were prepared using a hot homogenization method. Regardless of paclitaxel loading, the particle sizes and zeta potentials of the prepared SLNs were around 200nm and -38mV, respectively, suggesting that they would be suitable as a parenteral formulation. Cryo-scanning electron microscopy showed that the SLNs were homogeneous and spherical in shape, while differential scanning calorimetry measurement of the melting peak revealed that the TM exists as a solid in our formulation. Paclitaxel was loaded to the solid cores at a w/w ratio of 6%. Gel column chromatography showed that paclitaxel co-eluted with the phospholipids, indicating that paclitaxel was incorporated in the SLNs. An in vitro drug release study showed that paclitaxel was released from the SLNs in a slow but time-dependent manner. Furthermore, treatment of the OVCAR-3 human ovarian cancer cell line and the MCF-7 breast cancer cell line with paclitaxel-loaded SLNs yielded cytotoxicities comparable to those of a commercially available Cremophor EL-based paclitaxel formulation. These results collectively suggest that our optimized SLN formulation may have a potential as alternative delivery system for parenteral administration of paclitaxel. PMID:17257668

Lee, Mi-Kyung; Lim, Soo-Jeong; Kim, Chong-Kook

2007-01-10

295

Paclitaxel loaded nanosponges: in-vitro characterization and cytotoxicity study on MCF-7 cell line culture.  

PubMed

Beta cyclodextrin (?-CD) based nanosponges were synthesized and paclitaxel inclusion complex with nanosponges were prepared using techniques of inclusion complex formation. The paclitaxel nanosponge's complexes were evaluated for their release. The nanosponges complexes were also evaluated using DSC, FTIR, and NMR techniques for confirmation of inclusion complex formation between paclitaxel and nanosponges. Particle size and morphology of paclitaxel nanosponge's complex were estimated using SEM, TEM and dynamic light scattering techniques. The particle sizes were found out to be in range of 400 to 600 nm. Cytotoxic efficacy of paclitaxel nanosponge complex was determined against MCF-7 cells and paclitaxel nanosponge's complex was found to be cytotoxic and more effective against this cell line. PMID:21235471

Ansari, Khalid A; Torne, Satyen J; Vavia, Pradeep R; Trotta, Francesco; Cavalli, Roberta

2011-03-01

296

[Distribution and variation of paclitaxel and cephalomannine contents in wild Taxus cuspidata].  

PubMed

Paclitaxel and cephalomannine contents in wild Taxus cuspidata were determined by HPLC. The results indicated that paclitaxel and cephalomannine contents in T. cuspidate at the sunny side were slightly higher than that at the shadow side in the current-year and biennial branches. Paclitaxel and cephalomannine contents had no obvious regularity in leaves. Paclitaxel and cephalomannine contents were both the highest in the bark, then in the current-year branches, lower in the current-year leaves, and the lowest in the fruits. There were no remarkable correlation between stem diameter and paclitaxel and cephalomannine contents in the current-year branches and leaves. Significant difference was observed among samples collected in different period, and higher paclitaxel and cephalomannine concentrations were detected at the dormancy stage than that at the flower and fruit stages. PMID:21585029

Chang, Zui; Guo, Na; Liu, Tong; Zhou, Zhiqiang; Wang, Yang

2011-02-01

297

[nab-Paclitaxel. Clinical value of an innovative taxane-containing formulation].  

PubMed

Nanoparticle-albumin bound paclitaxel (nab-paclitaxel) represents an innovative taxane-containing formulation lacking any critical solvents with minimal risks for any hypersensitivity reactions as well as perspectives for dose escalation as a consequence. Preclinical data indicated an increase of drug accumulation in tumor tissues via nab-paclitaxel administration which appears to be related to direct interaction with albumin-binding proteins including stromal SPARC. Phase III study results revealed clinically relevant advantages regarding efficacy and tolerability associated with nab-paclitaxel compared to conventional docetaxel and paclitaxel in patients with metastatic breast cancer. Further experience may encourage its use in other tumor entities including NSCLC, ovarian and pancreatic carcinoma as well as melanoma. As a consequence, the development of algorithms is ongoing in order to be able to select patients in more detail who will particularly benefit from nab-paclitaxel treatment. PMID:23379109

Lipp, Hans-Peter

2013-01-01

298

Phase I Study of Pazopanib in Combination with Weekly Paclitaxel in Patients with Advanced Solid Tumors  

PubMed Central

Purpose. To evaluate the maximum tolerated regimen (MTR), dose-limiting toxicities, and pharmacokinetics of pazopanib, an oral small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, in combination with paclitaxel. Patients and Methods. Pazopanib was given daily with weekly paclitaxel on days 1, 8, and 15 every 28 days. Dose levels of pazopanib (mg/day)/paclitaxel (mg/m2) were 400/15, 800/15, 800/50, and 800/80. An expanded cohort was enrolled at the MTR. Plasma samples were collected to evaluate the effect of pazopanib, an inhibitor of cytochrome P450 (CYP)3A4, on the pharmacokinetics of paclitaxel, a CYP3A4 and CYP2C8 substrate. Results. Of 26 enrolled patients, 17 were treated at the MTR of 800 mg pazopanib and 80 mg/m2 paclitaxel. Dose-limiting toxicities included a grade 3 abscess and grade 2 hyperbilirubinemia. Other toxicities included elevated liver transaminases and diarrhea. Six patients (23%) had partial responses and 15 patients (58%) had stable disease. Administration of 800 mg pazopanib resulted in a 14% lower paclitaxel clearance and a 31% higher paclitaxel maximal concentration than with administration of paclitaxel alone at 15, 50, and 80 mg/m2. At the MTR, coadministration of 800 mg pazopanib and 80 mg/m2 paclitaxel resulted in a 26% higher geometric mean paclitaxel area under the curve. Conclusion. Pazopanib, at a dose of 800 mg daily, can be safely combined with a therapeutic dose of paclitaxel at 80 mg/m2 when administered on days 1, 8, and 15, every 28 days. The observed greater plasma concentrations of paclitaxel given concurrently with pazopanib suggest that pazopanib is a weak inhibitor of CYP3A4 and CYP2C8.

Dowlati, Afshin; Jones, Suzanne F.; Infante, Jeffrey R.; Nishioka, Jennifer; Fang, Lei; Hodge, Jeffrey P.; Gainer, Shelby D.; Arumugham, Thangam; Suttle, A. Benjamin; Dar, Mohammed M.; Lager, Joanne J.; Burris, Howard A.

2010-01-01

299

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

PubMed Central

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.

Wang, Yingzhe; Teng, Quincy; Tan, Chalet

2013-01-01

300

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

Microsoft Academic Search

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

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

2010-01-01

301

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

Microsoft Academic Search

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

Yasushi Shintani; Toshimasa Tanaka; Yukimasa Nozaki

1997-01-01

302

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

PubMed Central

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.

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

2013-01-01

303

Taxol-induced microtubule asters in mitotic extracts of Xenopus eggs: requirement for phosphorylated factors and cytoplasmic dynein  

Microsoft Academic Search

Taxol, a microtubule stabilizing drug, in- duces the formation of numerous microtubule asters in the cytoplasm of mitotic cells (De Brabander, M., G. Geuens, R. Nuydens, R. Willebrords, J. DeMey. 1981. Proc. Natl. Acad. Sci. USA. 78:5608-5612). The cen- ter of these asters share with spindle poles some char- acteristics such as the presence of centrosomal mate- rial and calmodulin.

Fulvia Verde; Jean-Marc Berre; Claude Antony; Eric Karsenti

1991-01-01

304

Production of Taxol® and baccatin III by a selected Taxus baccata callus line and its derived cell suspension culture  

Microsoft Academic Search

Small callus pieces excised from a selected 1-year-old stable callus line of Taxus baccata were grown on B5 solid medium supplemented with either phenylalanine (1 mM) or the elicitor compound VSO4 (0.05 or 0.1 mM). Under these conditions, callus growth and the production of Taxol® and baccatin III were tested during 8 weeks of culture. Growth was enhanced by the

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

1999-01-01

305

Overexpression of a 10-deacetylbaccatin III-10 ?- O -acetyltransferase gene leads to increased taxol yield in cells of Taxus chinensis  

Microsoft Academic Search

Taxus chinensis suspension cells were transformed by the Agrobacterium-mediated transformation method to overexpress the dbat gene coding for 10-deacetylbaccatin III-10 ?-O-acetyltransferase, a key enzyme for taxol biosynthesis. A. tumefaciens strain LBA4404 harboring either pCAMBIA1303 or the recombinant plasmid p1303-SdbatN was used. Both plasmids harbored the hygromycin phosphotransferase gene (hptII) and gusA-mgfp5 gene as selectable markers, but the latter plasmid also

Peng Zhang; Shu-Tao Li; Ting-Ting Liu; Chun-Hua Fu; Peng-Peng Zhou; Chun-Fang Zhao; Long-Jiang Yu

2011-01-01

306

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

PubMed Central

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.

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

307

Acute transient encephalopathy following paclitaxel treatment in an adolescent with a recurrent suprasellar germinoma.  

PubMed

Paclitaxel is an antineoplastic agent that is used in the treatment of a variety of solid tumors. Dose-limiting side effects of myelosuppression and peripheral neuropathy are well known. Paclitaxel has minimal penetration of the blood-brain barrier and central nervous system side effects are rare. However, transient encephalopathy following paclitaxel infusion has been described in adults but not in children. We present the case of a 14-year-old female with a recurrent suprasellar germinoma who developed an acute encephalopathy 4-6 hr following paclitaxel infusion. PMID:16991134

Rook, James; Rosser, Tena; Fangusaro, Jason; Finlay, Jonathan

2008-03-01

308

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

NASA Astrophysics Data System (ADS)

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.

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

2013-03-01

309

Overcoming paclitaxel resistance in uterine endometrial cancer using a COX-2 inhibitor.  

PubMed

Cyclooxygenase (COX)-2 inhibitors have been reported to potentially modulate the resistance of cancer cells to chemotherapeutic drugs by affecting multidrug resistance 1 (MDR1) expression. In the present study, we investigated the association between COX-2 and MDR1 expression in endometrial cancers and evaluated the effects of the COX-2 inhibitor, etodolac, in combination with paclitaxel on paclitaxel-resistant endometrial cancer cells. The relationship between COX-2 and MDR1 mRNA expression was examined by quantitative PCR in 36 endometrial cancer specimens. The paclitaxel-resistant cell line OMC-2P was established from OMC-2 cells. Paclitaxel (1 µg/ml) with or without etodolac (10 µg/ml) was added to OMC-2 and OMC-2P cells, and COX-2 and MDR1 mRNA expression levels were examined. The concentration of prostaglandin E2 (PGE2) in the supernatant of each cell line was examined by enzyme-linked immunosorbent assay. The function of MDR1 was determined by intracellular accumulation of rhodamine 123 using flow cytometry, and the concentration of intracellular paclitaxel was determined by high-performance liquid chromatography. We found a positive relationship between COX-2 and MDR1 mRNA expression in endometrial cancer. Both COX-2 mRNA expression and PGE2 production were elevated in resistant OMC-2P cells when compared to non-resistant OMC-2 cells. Additionally, MDR1 mRNA expression was markedly upregulated in OMC-2P cells. In OMC-2 cells, COX-2 and MDR1 mRNA levels were significantly upregulated by paclitaxel treatment and downregulated by co-administration with etodolac. In OMC-2P cells, COX-2 mRNA expression was also significantly upregulated by paclitaxel treatment and tended to be downregulated by co-administration with etodolac. Moreover, co-administration of paclitaxel and etodolac suppressed the induction of MDR1 mRNA. Rhodamine 123 efflux was increased in OMC-2P cells when compared to the efflux in the OMC-2 cells and was increased in response to paclitaxel treatment. Co-administration of paclitaxel and etodolac in both cell lines resulted in decreased rhodamine 123 efflux. The actual concentration of intracellular paclitaxel in OMC-2P cells was significantly lower than that in OMC-2 cells treated with paclitaxel alone and was significantly increased after co-administration of paclitaxel and etodolac. These findings suggest that paclitaxel resistance may be associated with COX-2 and MDR1 expression in cancer cells. Co-administration of COX-2 inhibitors and paclitaxel may have a key role in modulating or overcoming paclitaxel resistance in endometrial cancers. PMID:24100466

Hasegawa, Kiyoshi; Ishikawa, Kunimi; Kawai, Satoshi; Torii, Yutaka; Kawamura, Kyoko; Kato, Rina; Tsukada, Kazuhiko; Udagawa, Yasuhiro

2013-10-08

310

Development and application of a validated gradient elution HPLC method for simultaneous determination of 5-fluorouracil and paclitaxel in dissolution samples of 5-fluorouracil\\/paclitaxel-co-eluting stents  

Microsoft Academic Search

The combined use of 5-fluorouracil and paclitaxel is common in clinical trials. However, there are few methods for simultaneous determination of 5-fluorouracil and paclitaxel; most reported approaches can only quantitate either 5-fluorouracil or paclitaxel. This paper proposes a new gradient elution HPLC method for simultaneous determination of 5-fluorouracil and paclitaxel using a photodiode array detector, C18 column (250mm×4.6mm, 5?m) with

Weiluan Chen; Yuanyuan Shen; Haojun Rong; Lei Lei; Shengrong Guo

311

Design, Synthesis, and Biological Evaluation of New Paclitaxel Analogs With the Ability to Evade Efflux by P-Glycoprotein.  

National Technical Information Service (NTIS)

Paclitaxel, a cytotoxic agent originally isolated fro the bark of the Pacific Yew, has been developed as an effective chemotherapeutic drug, Sadly however, the treatment of cancer with paclitaxel often results in the development of drug resistance. Furthe...

B. J. Turunen G. I. Georg

2004-01-01

312

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

PubMed Central

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

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

2013-01-01

313

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

PubMed

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

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

2013-08-13

314

Reduction of Paclitaxel-induced Peripheral Neuropathy with Glutamine1  

Microsoft Academic Search

Purpose: Dose-limiting toxicity of many newer chemo- therapeutic agents is peripheral neuropathy. Prior attempts to reduce this side effect have been unsuccessful. We report on the possible successful reduction of peripheral neuropa- thy with glutamine administration after high-dose pacli- taxel. Experimental Design: Patients entered a high-dose chemotherapy protocol in which the first high-dose cycle was paclitaxel at 825 mg\\/m2 given

Linda Vahdat; Kyriakos Papadopoulos; Dale Lange; Shelby Leuin; Elizabeth Kaufman; Diana Donovan; Deborah Frederick; Emilia Bagiella; Amy Tiersten; Gwen Nichols; Thomas Garrett; David Savage; Karen Antman; Charles S. Hesdorffer; Casilda Balmaceda

2001-01-01

315

Treatment of HIV-associated Kaposi's sarcoma with paclitaxel  

Microsoft Academic Search

We investigated whether paclitaxel was active in AIDS-associated Kaposi's sarcoma. We gave 135 mg\\/m2 intravenously over 3 hours every 21 days. Follow-up is available on the first 20 patients, most of whom had advanced Kaposi's sarcoma and severe immuno-compromise. Neutropenia was the most frequent dose-limiting toxic effect; novel toxic effects included late fevers, rash, and eosinophilia. Creatinine increased in 2

M. W. Saville; J. Lietzau; J. M. Pluda; W. H. Wilson; R. W. Humphrey; E. Feigel; S. M. Steinberg; S. Broder; R. Yarchoan; J. Odom; I. Feuerstein

1995-01-01

316

Cystoid macular edema induced by nab-paclitaxel.  

PubMed

Cystoid macular edema (CME) is a rare complication of taxane-based chemotherapy. We encountered a patient who developed CME during treatment with nab-paclitaxel for metastatic breast cancer. Early detection of this disease enables continuation of appropriate treatment without reducing the quality of life for patients with end-stage disease. Physicians should be aware of this potential adverse effect, and should make changes to the treatment of patients as soon as possible. PMID:22592399

Tanaka, Yuko; Bando, Hiroko; Hara, Hisato; Ito, Yasuaki; Okamoto, Yoshifumi

2012-05-17

317

Targeting of albumin-embedded paclitaxel nanoparticles to tumors  

Microsoft Academic Search

We have used tumor-homing peptides to target abraxane, a clinically approved paclitaxel-albumin nanoparticle, to tumors in mice. The targeting was accomplished with two peptides, CREKA and LyP-1 (CGNKRTRGC). Fluorescein (FAM)-labeled CREKA-abraxane, when injected intravenously into mice bearing MDA-MB-435 human cancer xenografts, accumulated in tumor blood vessels, forming aggregates that contained red blood cells and fibrin. FAM-LyP-1-abraxane co-localized with extravascular islands

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

2009-01-01

318

Topotecan and Gemcitabine in Platinum\\/Paclitaxel-Resistant Ovarian Cancer  

Microsoft Academic Search

24 patients were enrolled into a phase I–II study conducted to determine the maximum tolerated doses of topotecan-gemcitabine in sequential combination and the response rate in platinum\\/paclitaxel resistant ovarian cancer patients. A total of 83 courses are evaluable, with a median number of three cycles administered per patients (range 2–7). Topotecan was administered on days 1–5 by 30 min i.v.

Stefano Greggi; M. Giovanna Salerno; Giuseppe D’Agostino; Gabriella Ferrandina; Domenica Lorusso; Luigi Manzione; Salvatore Mancuso; Giovanni Scambia

2001-01-01

319

Orally Bioavailable Tubulin Antagonists for Paclitaxel-Refractory Cancer  

PubMed Central

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.

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

320

Paclitaxel production by plant-cell-culture technology.  

PubMed

Plant cells catalyze multiple-step reactions of secondary metabolite biosynthesis, and selectively synthesize chiral compounds with polycyclic structures. Taking advantage of this characteristic, we studied the production of the anticancer drug paclitaxel, which is currently produced in limited supply. Callus culture investigations indicate that woody plant medium supplemented with 10(-5) mol L(-1) 1-naphthylacetic acid and without the NH4+ -type ion is the best condition for growth of the callus. The accumulation of paclitaxel and related taxanes in Taxus plants is thought to be a biological response to specific external stimuli. Several signal transducers were screened; taxane biosynthesis was strongly promoted by methyl jasmonate (MeJA) and silver thiosulfate (STS) as an anti-ethylene compound. Of ten taxane-type diterpenoids isolated from T. baccata suspension-cultured cells treated with MeJA, five have a phenylisoserine side-chain at the C-13 position of the taxane skeleton. Time-course analysis revealed two regulatory steps in taxane biosynthesis: the taxane-ring formation step and the acylation step of the C-13 position. Methyl jasmonate promoted the formation of the taxane-ring. The production of paclitaxel reached a maximum level of 295 mg L(-1) in a large-scale culture of T. x media cells using a two-stage process. PMID:15217102

Tabata, Homare

2004-01-01

321

Ascorbic acid alleviates toxicity of paclitaxel without interfering with the anticancer efficacy in mice.  

PubMed

Paclitaxel is used extensively as a chemotherapeutic agent against a broad range of tumors but often leads to the early termination of treatment due to severe toxic side effects. In this study, we hypothesized that ascorbic acid could reduce the toxic side effects without interfering with the anticancer effect of paclitaxel. To demonstrate this, we examined the effect of the combinational treatment of ascorbic acid and paclitaxel using H1299 (a non-small cell lung cancer cell line) and BALB/c mice implanted with or without sarcoma 180 cancer cells. In H1299 cells, the anticancer effects of the combinational treatment with paclitaxel and ascorbic acid were up to 1.7-foldhigher than those of single-agent paclitaxel treatment. In addition, it was shown that the viability of the HEL299 normal cells was up to 1.6-fold higher with the combinational treatment than with paclitaxel treatment alone. In vivo mouse experiments also showed that mice co-treated with paclitaxel and ascorbic acid did not exhibit the typical side effects induced by paclitaxel, such as a reduction in the numbers of white blood cells and red blood cells and the level of hemoglobin (P < .05). The analysis of cancer-related gene expression by quantitative real-time polymerase chain reaction and immunohistochemistry revealed that the combinational treatment suppressed cancer cell multiplication. Taken together, these results suggest that combinational chemotherapy with ascorbic acid and paclitaxel not only does not block the anticancer effects of paclitaxel but also alleviates the cytotoxicity of paclitaxel in vivo and in vitro. PMID:23176798

Park, Jin-Hee; Davis, Keith R; Lee, Gunsup; Jung, Manyong; Jung, Yuchul; Park, Jungan; Yi, Sang-Yeop; Lee, Myung-Ah; Lee, Sukchan; Yeom, Chang-Hwan; Kim, Jin

2012-10-26

322

Synthesis, physico-chemical and biological characterization of a paclitaxel macromolecular prodrug.  

PubMed

Paclitaxel was attached to poly(hydroxyethylaspartamide) via a succinic spacer arm by a two-step protocol: (1) synthesis of 2'-O-succinyl-paclitaxel; (2) synthesis of PHEA-2'-O-succinyl-paclitaxel. The 2'-O-succinyl-paclitaxel derivative and the macromolecular conjugate were characterized by UV, IR, NMR and mass spectrometry analysis. The reaction yields were over 95% and the purity of products over 98%. Paclitaxel release and degradation from 2'-O-succinyl-paclitaxel occurred at a faster rate at pH 5.5 than 7.4. After 30 h of incubation at pH 5.5 and 7.4 the released free paclitaxel was about 40 and 20%, respectively. In plasma both drug release and degradation were found to occur at a higher rate than in buffer at pH 7.4 suggesting that an enzymatic mechanism could be involved. The paclitaxel release and degradation from PHEA-2'-O-succinyl-paclitaxel were negligible at pH 5.5 and 7.4 and very slow in plasma. Investigation carried out using murine myeloid cell line showed that the polymeric prodrug maintains partial pharmacological activity of paclitaxel. The DL50 of the conjugate (over 40 ng/ml) as compared to free paclitaxel (about 1 ng/ml) was correlated to the slow drug release. Finally a pharmacokinetic study carried out by intravenous inoculation of the macromolecular prodrug to mice demonstrated that the polymer conjugation modify dramatically the in vivo fate of the drug. The conjugate disappeared from the bloodstream much more quickly as compared to both free drug and naked polymer. Massive accumulation of bioconjugate in the liver (80% of the dose) was found to persist throughout 1 week. PMID:15207549

Cavallaro, G; Licciardi, M; Caliceti, P; Salmaso, S; Giammona, G

2004-07-01

323

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

PubMed

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

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

2011-11-21

324

Therapeutic angiogenesis inhibits or rescues chemotherapy-induced peripheral neuropathy: taxol- and thalidomide-induced injury of vasa nervorum is ameliorated by VEGF.  

PubMed

Toxic neuropathy represents an important clinical problem in the use of the chemotherapeutic substances Taxol and thalidomide. Sensory neuropathy has a high incidence, lacks an effective treatment and is the dose-limiting factor for these drugs. The pathogenic basis of these neuropathies is unknown. We investigated the hypothesis that the experimental toxic neuropathies from Taxol and thalidomide results from destruction of vasa nervorum and can be reversed by the administration of an angiogenic cytokine. In animal models of Taxol- and thalidomide-induced neuropathy, nerve blood flow has been attenuated and the number of vasa nervorum has been reduced. Intramuscular gene transfer of naked plasmid DNA encoding VEGF-1 administered in parallel with Taxol injections completely inhibited deterioration of nerve function and diminution of the peripheral nerve vasculature. Gene therapy in animals with established Taxol- or thalidomide-induced neuropathies resulted in recovery of vascularity and improved nerve electrophysiology. These findings implicate microvascular damage as the basis for toxic neuropathy and suggest that angiogenic growth factors may constitute a novel treatment for this disorder. PMID:17164777

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

2007-01-01

325

A flow cytometry method to quantitate internalized immunotoxin shows Taxol synergistically increases cellular immunotoxin uptake  

PubMed Central

Cancer cells within solid tumors live in a unique microenvironment containing barriers impairing the penetration of antibodies, immunoconjugates and immunotoxins. SS1P is an immunotoxin composed of the Fv portion of a mesothelinspecific antibody fused to a bacterial toxin and is now undergoing Phase II testing in mesothelioma. We describe a new approach to study the targeting process of SS1P in tumors. A flow cytometry-based method (FC method) was developed to quantify the uptake of SS1P by individual tumor cells, and a gel filtration assay was developed to study shed mesothelin (sMSLN), a barrier for SS1P therapy. The cellular uptake of SS1P in tumor cells peaked several hours after blood SS1P was cleared, reflecting the underlining intra-tumor distribution process of SS1P independent of its blood supply. With this approach, we demonstrated Taxol improved the penetration of SS1P in the tumor, associated with a reduced sMSLN barrier in tumor extracellular fluid. Our study provides a mechanistic basis for the combined use of SS1P with cytotoxic drugs and helps explain the increased anti-tumor activity when chemotherapy and antibody-based therapies are combined. We also showed that the FC method can quantify the tumor cell uptake of Herceptin and an immunotoxin targeting HER2/neu.

Zhang, Yujian; Hansen, Johanna; Xiang, Laiman; Kawa, Seiji; Onda, Masanori; Ho, Mitchell; Hassan, Raffit; Pastan, Ira

2009-01-01

326

Conformational changes in tubulin in GMPCPP and GDP-taxol microtubules observed by cryoelectron microscopy  

PubMed Central

Microtubules are dynamic polymers that stochastically switch between growing and shrinking phases. Microtubule dynamics are regulated by guanosine triphosphate (GTP) hydrolysis by ?-tubulin, but the mechanism of this regulation remains elusive because high-resolution microtubule structures have only been revealed for the guanosine diphosphate (GDP) state. In this paper, we solved the cryoelectron microscopy (cryo-EM) structure of microtubule stabilized with a GTP analogue, guanylyl 5?-?,?-methylenediphosphonate (GMPCPP), at 8.8-Å resolution by developing a novel cryo-EM image reconstruction algorithm. In contrast to the crystal structures of GTP-bound tubulin relatives such as ?-tubulin and bacterial tubulins, significant changes were detected between GMPCPP and GDP-taxol microtubules at the contacts between tubulins both along the protofilament and between neighboring protofilaments, contributing to the stability of the microtubule. These findings are consistent with the structural plasticity or lattice model and suggest the structural basis not only for the regulatory mechanism of microtubule dynamics but also for the recognition of the nucleotide state of the microtubule by several microtubule-binding proteins, such as EB1 or kinesin.

Yajima, Hiroaki; Ogura, Toshihiko; Nitta, Ryo; Okada, Yasushi; Sato, Chikara

2012-01-01

327

Beyond taxol: microtubule-based treatment of disease and injury of the nervous system.  

PubMed

Contemporary research has revealed a great deal of information on the behaviours of microtubules that underlie critical events in the lives of neurons. Microtubules in the neuron undergo dynamic assembly and disassembly, bundling and splaying, severing, and rapid transport as well as integration with other cytoskeletal elements such as actin filaments. These various behaviours are regulated by signalling pathways that affect microtubule-related proteins such as molecular motor proteins and microtubule severing enzymes, as well as a variety of proteins that promote the assembly, stabilization and bundling of microtubules. In recent years, translational neuroscientists have earmarked microtubules as a promising target for therapy of injury and disease of the nervous system. Proof-of-principle has come mainly from studies using taxol and related drugs to pharmacologically stabilize microtubules in animal models of nerve injury and disease. However, concerns persist that the negative consequences of abnormal microtubule stabilization may outweigh the positive effects. Other potential approaches include microtubule-active drugs with somewhat different properties, but also expanding the therapeutic toolkit to include intervention at the level of microtubule regulatory proteins. PMID:23811322

Baas, Peter W; Ahmad, Fridoon J

2013-06-27

328

Recent population decline and selection shape diversity of taxol-related genes.  

PubMed

Taxanes are defensive metabolites produced by Taxus species (yews) and used in anticancer therapies. Despite their medical interest, patterns of natural diversity in taxane-related genes are unknown. We examined variation at five main genes of Taxus baccata in the Iberian Peninsula, a region where unique yew genetic resources are endangered. We looked at several gene features and applied complementary neutrality tests, including diversity/divergence tests, tests solely based on site frequency spectrum (SFS) and Zeng's compound tests. To account for specific demography, microsatellite data were used to infer historical changes in population size based on an Approximate Bayesian Computation (ABC) approach. Polymorphism-divergence tests pointed to positive selection for genes TBT and TAT and balancing selection for DBAT. In addition, neutrality tests based on SFS found that while a recent reduction in population size may explain most statistics' values, selection may still be in action in genes TBT and DBAT, at least in some populations. Molecular signatures on taxol genes suggest the action of frequent selective waves with different direction or intensity, possibly related to varying adaptive pressures produced by the host-enemy co-evolution on defence-related genes. Such natural selection processes may have produced taxane variants still undiscovered. PMID:22574693

Burgarella, C; Navascués, M; Zabal-Aguirre, M; Berganzo, E; Riba, M; Mayol, M; Vendramin, G G; González-Martínez, S C

2012-05-10

329

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

PubMed

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

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

2011-03-23

330

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

PubMed

The present study examines the acute, sub-acute toxicity, and cytotoxicity of paclitaxel elastic liposomal formulation in comparison to a marketed Cremophor EL (polyoxyethylated castor oil):ethanol (1:1, v/v) based formulation. In the previous study, Cremophor EL free paclitaxel elastic liposomal formulation was developed and characterized. Cytotoxicity of formulation was evaluated by MTT assay using A549 cell lines. Percentage intracellular uptake of paclitaxel elastic liposomal and marketed formulation was determined using a fluorescence activating cell sorting assay (FACS) and fluorescence microscopy techniques. Single and repeated dose toxicity measurement showed no mortality, hematological, biochemical, or histopathological changes up to a dose of 120?mg/kg for paclitaxel elastic liposomal formulation, in comparison the marketed formulation showed toxicity at a dose of 40?mg/kg. Maximum tolerated dose (MTD) for paclitaxel elastic liposomal and marketed formulation was found to be 160?mg/kg and 40?mg/kg, respectively. Results of FACS analysis showed a 94.6?±?2.5% intracellular uptake of fluorescence marker acridine orange (AO) loaded in elastic liposomes; in comparison the AO solution showed only a 19.8?±?1.1% uptake. Paclitaxel elastic liposomal formulation seems to be a better alternative for safe and effective delivery of paclitaxel. This study proves the safety and higher intracellular uptake of paclitaxel elastic liposomal formulation. PMID:22074176

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

2011-11-10

331

Paclitaxel: Ein Chemotherapeutikum zur Restenoseprophylaxe? Experimentelle Untersuchungen in vitro und in vivo  

Microsoft Academic Search

Summary Paclitaxel, a potent anti-tumor agent, shifts the cytoskeleton equilibrium towards assembly of altered and extraordinarily stable microtubules. These cellular modifications lead to reduced proliferation, migration, and signal transduction. It is highly lipophilic, which promotes a rapid cellular uptake, and has a long-lasting effect in the cell due to the structural alteration of the cytoskeleton. This makes paclitaxel a promising

C. Herdeg; M. Oberhoff; D. I. Siegel-Axel; A. Baumbach; A. Blattner; A. Küttner; S. Schröder; K. R. Karsch

2000-01-01

332

Lipid nanocarriers improve paclitaxel transport throughout human intestinal epithelial cells by using vesicle-mediated transcytosis  

Microsoft Academic Search

The use of lipid nanocapsules (LNCs) has enabled an improvement of the oral bioavailability of paclitaxel (Ptx). However, mechanisms that support this recent observation are not yet understood. By focusing on the well defined in vitro Caco-2 model, the purpose of this study was to evaluate the transport of LNCs across a model intestinal barrier. Firstly, four sizes of paclitaxel

E. Roger; F. Lagarce; E. Garcion; J.-P. Benoit

2009-01-01

333

Paclitaxel-incorporated nanoparticles of hydrophobized polysaccharide and their antitumor activity.  

PubMed

The aim of this study was to characterize paclitaxel-incorporated polysaccharide nanoparticles and evaluate their antitumor activity in vitro and in vivo. Pullulan was hydrophobically modified using acetic anhydride to make the paclitaxel-incorporated nanoparticles. Pullulan acetate (PA) was used to encapsulate paclitaxel using the nanoprecipitation method. The particles had spherical shapes under electron microscopy with sizes <100 nm. The sizes of paclitaxel-incorporated nanoparticles increased to >100 nm, and higher drug feeding induced higher particle size and drug content. Initial drug burst release was observed until 2 days and then the drug was continuously released over 1 week. Intrinsic cytotoxicity of empty PA nanoparticles was tested with RAW264.7 macrophage cells for biocompatibilty. The viability of RAW264.7 cells was >93% at all concentrations of empty PA nanoparticles, indicating that the PA nanoparticles are not acutely cytotoxic to normal human cells. The nanoparticles showed lower antitumor activity in vitro against HCT116 human colon carcinoma cells than that of paclitaxel itself, indicating the sustained release properties of nanoparticles. An in vivo study using HCT116 human colon carcinoma-bearing mice showed that paclitaxel-incorporated PA nanoparticles reduced tumor growth more than that of paclitaxel itself. These results indicate that PA paclitaxel-incorporated nanoparticles are a promising candidate for antitumor drug delivery. PMID:22561793

Lee, Sang Joon; Hong, Gun-Young; Jeong, Young-Il; Kang, Mi-Sun; Oh, Jong-Suk; Song, Chae-Eun; Lee, Hyun Chul

2012-04-23

334

Paclitaxel inhibits killing by murine cytotoxic T lymphocytes in vivo but not in vitro  

Microsoft Academic Search

To kill antigen-specific target cells (TCs), cytotoxic T lymphocytes (CTLs) reorganise their microtubule cytoskeleton to deliver lytic granules to the TCs. We used two drugs that stabilise microtubules, paclitaxel and peloruside, to determine how the stabilising microtubule network affects CTL function in vitro and in vivo. In vitro, neither paclitaxel nor peloruside inhibited antigen-specific killing, lytic granule delivery to the

Marcus James Robinson; Franca Ronchese; John H Miller; Anne Camille La Flamme; AC La Flamme

2010-01-01

335

A large-scale purification of paclitaxel from cell cultures of Taxus chinensis  

Microsoft Academic Search

A large-scale purification method was developed for producing paclitaxel, to guarantee high purity and yield from plant cell cultures. The complete method for mass production was a simple and efficient procedure, for the isolation and purification of paclitaxel from the biomass of Taxus chinensis, consisting of solvent extraction, synthetic adsorbent treatment, and two steps of precipitation, followed by two steps

Sang-Hyun Pyo; Heung-Bok Park; Bong-Kyu Song; Byung-Hee Han; Jin-Hyun Kim

2004-01-01

336

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

PubMed Central

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.

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

2012-01-01

337

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

PubMed Central

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

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

2011-01-01

338

Acetyl-L-carnitine prevents and reduces paclitaxel-induced painful peripheral neuropathy.  

PubMed

This study examines the potential efficacy of acetyl-L-carnitine (ALC) to prevent and treat paclitaxel-induced pain. Rats received four intraperitoneal (i.p.) injections of 2 mg/kg paclitaxel on alternate days which, following a short delay induced marked mechanical hypersensitivity. Daily administration of ALC (50 mg/kg and 100 mg/kg; p.o.; concurrently with paclitaxel and for 14 days afterwards) prevented the development of paclitaxel-induced pain. This effect was long lasting, for at least 3 weeks after the last dose of ALC. In a separate experiment, daily administration of ALC (100 mg/kg; p.o.; for 10 days) to rats with established paclitaxel-induced pain produced an analgesic effect. This effect dissipated shortly after ALC treatment was withdrawn. We conclude that ALC may be useful in the prevention and treatment of chemotherapy-induced painful peripheral neuropathy. PMID:16406309

Flatters, Sarah J L; Xiao, Wen-Hua; Bennett, Gary J

2006-01-06

339

Successful treatment by adding duloxetine to pregabalin for peripheral neuropathy induced by Paclitaxel.  

PubMed

Although paclitaxel is a commonly used anticancer drug, peripheral neuropathy may develop as a side effect. Worsening of the symptoms with time may cause patients who receive paclitaxel to give up their chemotherapy. Duloxetine, a serotonin- and norepinephrine-reuptake inhibitor, has been used to treat peripheral neuropathic pain. We report the case of a 68-year-old man with gastric cancer, who underwent gastrectomy and then received 8 cycles of chemotherapy involving weekly administrations of paclitaxel. Under this paclitaxel treatment, he complained of severe peripheral neuropathy, leading to a diminished quality of life. Following treatment with a combination of duloxetine and pregabalin, a remission of his symptoms was achieved. Duloxetine plus pregabalin therapy may be useful for the peripheral neuropathy induced by paclitaxel. PMID:23064035

Takenaka, Motoyasu; Iida, Hiroki; Matsumoto, Shigemi; Yamaguchi, Shinobu; Yoshimura, Noritaka; Miyamoto, Maki

2012-10-11

340

A fullerene-paclitaxel chemotherapeutic: synthesis, characterization, and study of biological activity in tissue culture.  

PubMed

A fullerene-paclitaxel conjugate has been synthesized as a slow-release drug for aerosol liposome delivery of paclitaxel for lung cancer therapy. The conjugate was designed to release paclitaxel via enzymatic hydrolysis and subsequently has shown a half-life of release of 80 min in bovine plasma. A liposome formulation of the conjugate has been prepared using dilauroylphosphatidylcholine (DLPC), and its IC50 is virtually identical to the IC50 for a paclitaxel-DLPC formulation in human epithelial lung carcinoma A549 cells. With both clinically relevant kinetics of hydrolysis and significant cytotoxicity in tissue culture, the conjugate holds promise for enhanced therapeutic efficacy of paclitaxel in vivo. PMID:16144396

Zakharian, Tatiana Y; Seryshev, Alexander; Sitharaman, Balaji; Gilbert, Brian E; Knight, Vernon; Wilson, Lon J

2005-09-14

341

Separation of 7-xylosyl-10-deacetyl paclitaxel and 10-deacetylbaccatin III from the remainder extracts free of paclitaxel using macroporous resins.  

PubMed

The separation and enrichment of 10-deacetylbaccatin III (10-DAB III) and 7-xylosyl-10-deacetyl paclitaxel were studied on seven macroporous resins with special structures. The performance of 7-xylosyl-10-deacetyl paclitaxel and 10-DAB III on macroporous resins including AB-8, ADS-17, ADS-21, ADS-31, ADS-8, H1020 and NKA-II was compared according to their adsorption and desorption properties. AB-8 provided a much higher adsorption capacity for 7-xylosyl-10-deacetyl paclitaxel and 10-DAB III than other resins, and its adsorption data fitted well to the Langmuir and Freundlich isotherm. According to the adsorption and desorption capacities and the adsorption isotherms, AB-8 demonstrated a remarkable capability for the preparative separation of 7-xylosyl-10-deacetyl paclitaxel and 10-DAB III from the remainder extracts free of paclitaxel. In order to optimize parameters of separation, dynamic adsorption and desorption experiments were carried out on the columns packed with AB-8 resin. The optimal conditions were: the processing volume 15 BV; concentrations of 7-xylosyl-10-deacetyl paclitaxel and 10-DAB III in feed solution 0.0657 mg/mL and 0.1494 mg/mL; flow rate 1 mL/min; temperature 35 degrees C. The gradient elution program was as follows: 30% ethanol for 3 BV, then 80% of ethanol for 6 BV, flow rate 1 mL/min. After the AB-8 resin treatment, the contents of 7-xylosyl-10-deacetyl paclitaxel and 10-DAB III in the product had increased from 0.053% and 0.2% to 3.34% and 1.69%, which were 62.43-fold and 8.54-fold of those in the untreated extracts, respectively, and the recoveries of 7-xylosyl-10-deacetyl paclitaxel and 10-DAB III were 85.85% and 52.78%. The performance achieved good separation and higher recovery of 7-xylosyl-10-deacetyl paclitaxel and 10-DAB III from remainder extracts free of paclitaxel by using AB-8 resin. It is a fast and effective method for the separation and enrichment of 7-xylosyl-10-deacetyl paclitaxel and 10-DAB III. PMID:18054030

Fu, Yujie; Zu, Yuangang; Li, Shuangming; Sun, Rui; Efferth, Thomas; Liu, Wei; Jiang, Shougang; Luo, Hao; Wang, Ying

2007-11-17

342

Regulatory Polymorphisms in ?-Tubulin IIa Are Associated with Paclitaxel-Induced Peripheral Neuropathy  

PubMed Central

Purpose Peripheral neuropathy is the dose-limiting toxicity of paclitaxel, a chemotherapeutic drug widely used to treat several solid tumors such as breast, lung, and ovary. The cytotoxic effect of paclitaxel is mediated through ?-tubulin binding in the cellular microtubules. In this study, we investigated the association between paclitaxel neurotoxicity risk and regulatory genetic variants in ?-tubulin genes. Experimental Design We measured variation in gene expression of three ?-tubulin isotypes (I, IVb, and IIa) in lymphocytes from 100 healthy volunteers, sequenced the promoter region to identify polymorphisms putatively influencing gene expression and assessed the transcription rate of the identified variants using luciferase assays. To determine whether the identified regulatory polymorphisms were associated with paclitaxel neurotoxicity, we genotyped them in 214 patients treated with paclitaxel. In addition, paclitaxel-induced cytotoxicity in lymphoblastoid cell lines was compared with ?-tubulin expression as measured by Affymetrix exon array. Results We found a 63-fold variation in ?-tubulin IIa gene (TUBB2A) mRNA content and three polymorphisms located at ?101, ?112, and ?157 in TUBB2A promoter correlated with increased mRNA levels. The ?101 and ?112 variants, in total linkage disequilibrium, conferred TUBB2A increased transcription rate. Furthermore, these variants protected from paclitaxel-induced peripheral neuropathy [HR, 0.62; 95% confidence interval (CI), 0.42–0.93; P = 0.021, multivariable analysis]. In addition, an inverse correlation between TUBB2A and paclitaxel-induced apoptosis (P = 0.001) in lymphoblastoid cell lines further supported that higher TUBB2A gene expression conferred lower paclitaxel sensitivity. Conclusions This is the first study showing that paclitaxel neuropathy risk is influenced by polymorphisms regulating the expression of a ?-tubulin gene.

Leandro-Garcia, Luis J.; Leskela, Susanna; Jara, Carlos; Green, Henrik; Avall-Lundqvist, Elisabeth; Wheeler, Heather E.; Dolan, M. Eileen; Inglada-Perez, Lucia; Maliszewska, Agnieszka; de Cubas, Aguirre A.; Comino-Mendez, Inaki; Mancikova, Veronika; Cascon, Alberto; Robledo, Mercedes; Rodriguez-Antona, Cristina

2013-01-01

343

Up-regulation of cdc2 protein during paclitaxel-induced apoptosis.  

PubMed

Microtubule damages induced by paclitaxel inhibit proteasome-dependent degradation of cyclin B, resulting in a sustained activation of cyclin B/cdc2 kinase and a cell cycle arrest in mitosis. It has been previously shown that this kinase activity is also required for paclitaxel-induced apoptosis. We found here that paclitaxel increased cdc2 mRNA and protein levels and led to an accumulation of cdc2 in the active dephosphorylated form in NIH-OVCAR-3 cells. The addition of cycloheximide inhibited the paclitaxel-induced increase in cdc2 protein level, further indicating that paclitaxel stimulates cdc2 synthesis. This increase in cdc2 synthesis is a consequence of paclitaxel-induced arrest in mitosis. Indeed, dual analysis of DNA and cdc2 protein contents indicated that cdc2 up-regulation occurred in cells arrested with a G2/M DNA content. Furthermore, no up-regulation of cdc2 protein was observed when paclitaxel-treated cells were prevented from entering mitosis by treatment with purvalanol A, a cyclin-dependent kinase (CDK) inhibitor, or stimulated to exit mitosis with 2-AP, a non-specific kinase inhibitor. In addition, when paclitaxel-induced apoptosis was inhibited by Bcl-2 over-expression, cdc2 up-regulation did not occur, leading to a lower level of activation of the cyclin B/cdc2 complex. Taken together, these results indicated that paclitaxel-induced cdc2 protein synthesis participates in a positive feedback loop designed to increase the activity of cyclin B/cdc2 kinase and thus may play a role in paclitaxel-induced apoptosis. PMID:10956385

Chadebech, P; Truchet, I; Brichese, L; Valette, A

2000-09-15

344

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

PubMed

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

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

2002-09-13

345

A phase II study of paclitaxel, carboplatin, and hyperfractionated radiation therapy for locally advanced inoperable non–small-cell lung cancer (a Vanderbilt cancer center affiliate network study)  

Microsoft Academic Search

Purpose: We conducted a prospective phase II study to determine the response rate, toxicity, and survival rate of concurrent weekly paclitaxel, carboplatin, and hyperfractionated radiation therapy (paclitaxel\\/carboplatin\\/HFX RT) followed by 2 cycles of paclitaxel and carboplatin for locally advanced unresectable non-small cell lung cancer (NSCLC). The weekly paclitaxel and carboplatin regimen was designed to optimize the radiosensitizing properties of paclitaxel

Hak Choy; Russell F Devore; Kenneth R Hande; Lester L Porter; Paul Rosenblatt; Furhan Yunus; Larry Schlabach; Clyde Smith; Yu Shyr; David H Johnson

2000-01-01

346

Action of taxol on mitosis: modification of microtubule arrangements and function of the mitotic spindle in Haemanthus endosperm  

PubMed Central

We have studied the effect of taxol on mitosis in Haemanthus endosperm. Immuno-Gold Stain (IGS), a new immunocytochemical method (17), was used to visualize microtubules (MTs) in the light microscope. Observations on MT arrangements were correlated with studies in vivo. Chromosome movements are affected in all stages of mitosis which progresses over at least 10(4) range of taxol concentrations. The three most characteristic effects on MTs are: (a) enhancement of the lateral associations between MTs, seen especially during the reorganization of the polar region of the spindle, (b) promotion of MT assembly, leading to the formation of additional MTs in the spindle and MT arrays in the cytoplasm, and (c) an increase in MT stability, demonstrated in their increased cold resistance. In this report, the emphasis is on the primary, immediate effects, occurring in the first 30 min of taxol action. Effects are detected after a few mins, are reversible, and are concentration/time dependent. The spindle and phragmoplast are remarkably modified due to the enhancement of lateral associations of MTs and the formation of abundant nonkinetochore and polar, asterlike MTs. The equatorial region of the interzone in anaphase may be entirely depleted of MTs, and the spindle may break perpendicular to the spindle axis. Mitosis is completed in these conditions, providing evidence for the motile autonomy of each half-spindle. Trailing chromosome arms in anaphase are often stretched and broken. Chromosome fragments are transported away from the polar regions, i.e., in the direction opposite to that expected (5, 6). This supplies the first direct evidence of pushing by elongating MTs in an anastral higher plant spindle. These observations draw attention to the relation between the lateral association of MT ends to assembly/disassembly and to the role of such an interaction in spindle function and organization.

1983-01-01

347

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

PubMed

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

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

2013-08-12

348

Cloning, heterologous expression, and characterization of a phenylalanine aminomutase involved in Taxol biosynthesis.  

PubMed

Biosynthesis of the N-benzoyl phenylisoserinoyl side chain of the anticancer drug Taxol starts with the conversion of 2S-alpha-phenylalanine to 3R-beta-phenylalanine by phenylalanine aminomutase (PAM). A gene cloning approach was based on the assumption that PAM would resemble the well known plant enzyme phenylalanine ammonia lyase. A phenylalanine ammonia lyase-like sequence acquired from a Taxus cuspidata cDNA library was expressed functionally in Escherichia coli and confirmed as the target aminomutase that is virtually identical to the recombinant enzyme and clone from Taxus chinensis, acquired recently by a reverse genetics approach (Bristol-Myers Squibb (August 14, 2003) U. S. Patent WO 03/066871 A2). The full-length cDNA has an open reading frame of 2094 base pairs and encodes a protein of 698 residues with a calculated molecular mass of 76,530 Da. The recombinant mutase has a pH optimum of 8.5, a k(cat) value of 0.015 s(-1), and a K(m) of 45 +/- 8 microm for 2S-alpha-phenylalanine. The stereochemical mechanism of PAM involves the removal and interchange of the pro-3S hydrogen and the amino group, which rebonds at C-3 with retention of configuration. The recombinant enzyme appears to catalyze both the forward and reverse reactions with specificity for both 2S-alpha-phenylalanine and 3S- or 3R-beta-phenylalanine substrates, respectively, whereas the related phenylpropanoids 2S-aminocyclohexanepropanoic acid, 2R-alpha-phenylalanine, and 2S-alpha-tyrosine are not converted to their beta-isomers by the mutase. PMID:15494399

Walker, Kevin D; Klettke, Karin; Akiyama, Takumi; Croteau, Rodney

2004-10-19

349

Enhanced cellular association of paclitaxel delivered in chitosan-PLGA particles.  

PubMed

We have previously demonstrated that the cellular association, cytotoxicity, and in vivo anti-tumor efficacy of paclitaxel are significantly greater when delivered in PLGA microparticles compared to nanoparticles. The purpose of this research is to test the hypothesis that mucoadhesive chitosan promotes adhesion of PLGA particles to mucus on the tumor epithelium, resulting in enhanced cellular association and cytotoxicity of paclitaxel. PLGA particles containing paclitaxel or Bodipy(®) were prepared and chitosan was either adsorbed or chemically conjugated to the particle surface. The cellular association and cytotoxicity of paclitaxel in 4T1 cells was determined. A 4-10 fold increase in cellular association of paclitaxel was observed when chitosan was adsorbed or conjugated to the PLGA particles. Chitosan-conjugated PLGA microparticles were most cytotoxic with an IC(50) value of 0.77 ?M. Confocal microscopy demonstrated that chitosan-PLGA microparticles adhered to the surface of 4T1 cells. Pretreatment of either 4T1 cells or chitosan-PLGA particles with mucin resulted in significant increase in cellular association of paclitaxel. A linear correlation was established between theoretical amount of chitosan used and experimentally determined amount of chitosan adsorbed or conjugated to PLGA nanoparticles. In conclusion, cellular association and cytotoxicity of paclitaxel was significantly enhanced when delivered in chitosan-PLGA particles. PMID:21356285

Chakravarthi, Sudhir S; Robinson, Dennis H

2011-02-26

350

Phase II and pharmacokinetic study of paclitaxel therapy for unresectable hepatocellular carcinoma patients.  

PubMed Central

Hepatocellular carcinoma (HCC) is a common lethal disease in Asia and there is no effective chemotherapy. Identification of new effective drugs in the treatment of inoperable HCC is urgently need. This is a phase II clinical study to investigate the efficacy, toxicity and pharmacokinetics of paclitaxel in HCC patients. Twenty patients with measurable, unresectable HCC, normal serum bilirubin, normal bone marrow and renal functions were studied. Paclitaxel 175 mg m(-2) was given intravenously over 3 h every 3 weeks. No complete or partial responses were observed. Five patients had stable disease. Major treatment toxicities (grade 3-4) were neutropenia (25%), thrombocytopenia (15%), infection (10%) and allergy (10%). Treatment-related deaths occurred in two patients. The median survival was 12 weeks (range 1-36). Paclitaxel is metabolized by the liver and the pharmacokinetics of paclitaxel in cancer patients with liver involvement or impairment may be important clinically. Pharmacokinetic study was completed in 13 HCC patients. The paclitaxel area under the curve was significantly increased (P < 0.02), clearance decreased (P < 0.02) and treatment-related deaths increased (P = 0.03) in patients with hepatic impairment. In conclusion, paclitaxel in this dose and schedule has no significant anti-cancer effect in HCC patients. Paclitaxel should be used with caution in cancer patients with liver impairment.

Chao, Y.; Chan, W. K.; Birkhofer, M. J.; Hu, O. Y.; Wang, S. S.; Huang, Y. S.; Liu, M.; Whang-Peng, J.; Chi, K. H.; Lui, W. Y.; Lee, S. D.

1998-01-01

351

Hyaluronic acid-paclitaxel conjugate micelles: synthesis, characterization, and antitumor activity.  

PubMed

Chemical conjugates of paclitaxel and hyaluronic acid (HA) were synthesized by utilizing a novel HA solubilization method in a single organic phase. Hydrophilic HA was completely dissolved in anhydrous DMSO with addition of poly(ethylene glycol) (PEG) by forming nanocomplexes. Paclitaxel was then chemically conjugated to HA in the DMSO phase via an ester linkage without modifying extremely hydrophilic HA. A series of HA-paclitaxel conjugates with different conjugation percentages were synthesized and characterized. HA-paclitaxel conjugates self-assembled in aqueous solution to form nanosized micellar aggregates, as characterized by dynamic light scattering (DLS), atomic force microscopy (AFM), and transmission electron microscopy (TEM). An intact form of paclitaxel was regenerated from HA-paclitaxel conjugate micelles at acidic pH conditions. HA-paclitaxel conjugate micelles exhibited more pronounced cytotoxic effect for HA receptor overexpressing cancer cells than for HA receptor deficient cells, suggesting that they can be potentially utilized as tumor-specific nanoparticulate therapeutic agents. PMID:18481885

Lee, Hyukjin; Lee, Kyuri; Park, Tae Gwan

2008-05-16

352

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

PubMed

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

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

2006-11-23

353

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

PubMed

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

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

2012-06-01

354

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

PubMed

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

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

355

Paclitaxel is only a weak radiosensitizer of human cervical carcinoma cell lines.  

PubMed

Two human squamous cell cervical carcinoma cell lines, C-33A (HTB 31) and MS751 (HTB 34), were exposed to either paclitaxel alone or paclitaxel for 24 hr followed by graded doses of Cs-137 radiation. Each was then analyzed for both clonogenic survival and alterations to cell cycle progression. No radiosensitization or affect on the cell cycle was seen using 1 x 10(-9) M paclitaxel. Each line was equally sensitive to the drug with approximately 50% cell lethality seen after 1 x 10(-8) M of paclitaxel. This concentration of paclitaxel also produced substantial G2M arrest, seen immediately after drug exposure and lasting up to 2 days. Gamma radiation delivered during the time of G2M arrest showed only a small degree of radiosensitization by paclitaxel for the relatively radioresistant MS751 line at 4 Gy (SF4 = 16.0 +/- 3.2% --> 5.7 +/- 1.1%, P = 0.049) but no sensitization using radiation doses of conventional fraction size [sensitizer enhancement ratios 1.1 (0.80-1.40) and 1.3 (0.95-1.65) for the C-33A and MS751 cell lines, respectively]. It is concluded that paclitaxel produces only a modest radiosensitization effect, indicating that this compound will have limited benefit as a radiosensitizer for the treatment of cervical cancer. PMID:8631547

Erlich, E; McCall, A R; Potkul, R K; Walter, S; Vaughan, A

1996-02-01

356

Adverse drug reaction profile of nanoparticle versus conventional formulation of paclitaxel: An observational study  

PubMed Central

Objectives: Conventional polyethoxylated castor oil (PCO)-based paclitaxel is associated with major adverse drug reactions (ADRs). Nanoxel, a nanoparticle-based formulation, may improve its tolerability by removing the need for PCO vehicle, and also permit its use in a higher dose. We conducted intensive monitoring of the ADR profile of Nanoxel in comparison with conventional paclitaxel in a public tertiary care set-up. Materials and Methods: ADR data were collected from 10 patients receiving Nanoxel and 10 age-matched controls receiving conventional paclitaxel in this longitudinal observational study, conducted in a medical oncology ward over 18 months. Severity was graded as per US National Cancer Institute Common Terminology Criteria for Adverse Events. Results: The groups had comparable demography at baseline. The median disease duration and per cycle median dose of paclitaxel were greater in the Nanoxel arm. Total 119 ADRs were noted with Nanoxel and 123 with conventional paclitaxel. Of these, 25 (21.0%, 95% CI 13.69–28.33%) in the Nanoxel and 20 (16.2%, 95% CI 9.74–22.78%) in paclitaxel group were of grade 3/4 severity. Common events included myalgia, nausea, anemia, paresthesia, alopecia, diarrhea, and vomiting with Nanoxel, and paresthesia, anemia, myalgia, anorexia, alopecia, vomiting, diarrhea, stomatitis, and nausea with paclitaxel. Of the less common events (<5%), grade 2 or 3 arthralgia was seen exclusively with Nanoxel while motor neuropathy with muscular weakness was more frequent and severe with conventional paclitaxel. Hypersensitivity reactions were not encountered in either arm, although no antiallergy premedication was employed for Nanoxel. Conclusions: Despite its ADR profile being statistically comparable to conventional paclitaxel, this observational study suggests that Nanoxel tolerability could be better, considering that a significantly higher dose was employed. This hypothesis needs confirmation through an interventional study.

Brahmachari, Ballari; Hazra, Avijit; Majumdar, Anup

2011-01-01

357

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

PubMed

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

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

2011-03-13

358

RNA interference (RNAi) screening approach identifies agents that enhance paclitaxel activity in breast cancer cells  

PubMed Central

Introduction Paclitaxel is a widely used drug in the treatment of patients with locally advanced and metastatic breast cancer. However, only a small portion of patients have a complete response to paclitaxel-based chemotherapy, and many patients are resistant. Strategies that increase sensitivity and limit resistance to paclitaxel would be of clinical use, especially for patients with triple-negative breast cancer (TNBC). Methods We generated a gene set from overlay of the druggable genome and a collection of genomically deregulated gene transcripts in breast cancer. We used loss-of-function RNA interference (RNAi) to identify gene products in this set that, when targeted, increase paclitaxel sensitivity. Pharmacological agents that targeted the top scoring hits/genes from our RNAi screens were used in combination with paclitaxel, and the effects on the growth of various breast cancer cell lines were determined. Results RNAi screens performed herein were validated by identification of genes in pathways that, when previously targeted, enhanced paclitaxel sensitivity in the pre-clinical and clinical settings. When chemical inhibitors, CCT007093 and mithramycin, against two top hits in our screen, PPMID and SP1, respectively, were used in combination with paclitaxel, we observed synergistic growth inhibition in both 2D and 3D breast cancer cell cultures. The transforming growth factor beta (TGF?) receptor inhibitor, LY2109761, that targets the signaling pathway of another top scoring hit, TGF?1, was synergistic with paclitaxel when used in combination on select breast cancer cell lines grown in 3D culture. We also determined the relative paclitaxel sensitivity of 22 TNBC cell lines and identified 18 drug-sensitive and four drug-resistant cell lines. Of significance, we found that both CCT007093 and mithramycin, when used in combination with paclitaxel, resulted in synergistic inhibition of the four paclitaxel-resistant TNBC cell lines. Conclusions RNAi screening can identify druggable targets and novel drug combinations that can sensitize breast cancer cells to paclitaxel. This genomic-based approach can be applied to a multitude of tumor-derived cell lines and drug treatments to generate requisite pre-clinical data for new drug combination therapies to pursue in clinical investigations.

2010-01-01

359

Design and Synthesis of (+)-Discodermolide-Paclitaxel Hybrids Leading to Enhanced Biological Activity1  

PubMed Central

Potential binding modes of (+)-discodermolide at the paclitaxel binding site of tubulin have been identified by computational studies based on earlier structural and SAR data. Examination of the prospective binding modes reveal that the aromatic pocket occupied by the paclitaxel side-chain is unoccupied by (+)-discodermolide. Based on these findings, a small library of (+)-discodermolide-paclitaxel hybrids have been designed and synthesized. Biological evaluation reveals a two- to eight- fold increase in antiproliferative activity compared to the parent molecule using the A549 and MCF-7 cancer cell lines.

Smith, Amos B.; Sugasawa, Keizo; Atasoylu, Onur; Yang, Chia-Ping Huang; Horwitz, Susan Band

2011-01-01

360

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

PubMed

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

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

2013-05-02

361

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

PubMed

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

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

2013-03-21

362

Doxorubicin and paclitaxel loaded microbubbles for ultrasound triggered drug delivery  

PubMed Central

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

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

2011-01-01

363

Semi-Synthesis and In-Vitro Anticancer Evaluation of Derivatives of a New Microtubule Poison with a Taxol-Like Mechanism.  

National Technical Information Service (NTIS)

In prior research we had discovered a steroid-like molecule with antimicrotubule activity of the Taxol-like mechanism of action from a tropical ornamental plant. There are only a few molecules known that have this type of activity. One of these is clinica...

T. Hemscheidt

2002-01-01

364

Taxol: quantitative internuclear proton-proton distances in CDCl3 solution from nOe data: 2D nmr ROESY buildup rates at 500 MHz.  

PubMed

Quantitative nmr internuclear proton-proton distance measurements obtained by observation of the initial buildup rates of nOe's in 2D ROESY spectra of taxol [1] in CDCl3 are reported. A comparison to the X-ray crystal structure of taxotere [2] is made, and the results are discussed in terms of previous studies of structure-activity relationships. PMID:1359020

Hilton, B D; Chmurny, G N; Muschik, G M

1992-08-01

365

Molecular dynamic simulations of the tubulin-human gamma synuclein complex: structural insight into the regulatory mechanism involved in inducing resistance against Taxol.  

PubMed

Members of the synuclein family (?, ? and ? synucleins) are intrinsically disordered in nature and play a crucial role in the progression of various neurodegenerative disorders and cancers. The association of ?Syn with both BubR1 as well as microtubule subunits renders resistance against various anti-cancer drugs. However, the structural aspects underlying drug resistance have not been explored. In this study, the mechanism involved in the association between ?Syn and microtubule subunits (??Tub) was investigated and the results reveal a strong interaction between ?Syn and the tail regions of ??Tub. Complexation of ?Syn induces conformational rearrangements in the nucleotide binding loops (NBL), interdomain and tail regions of both ? and ?Tub. Moreover, in ?Tub, the massive displacement observed in M and S loops significantly alters the binding site of microtubule targeting drugs like Taxol. The resulting weak association between Taxol and ?Tub of the ?Syn-??Tub complex was confirmed by molecular dynamic simulation studies. In addition, the effect of Taxol on NBL, M and S loops of ??Tub, is reversed in the presence of ?Syn. These results clearly indicate that the presence of ?Syn annulled the allosteric regulation imposed by Taxol on the ??Tub complex as well as preventing the binding of microtubule targeting drugs, which eventually leads to the development of resistance against these drugs in cancer cells. PMID:23532302

Panneerselvam, Manivel; Muthu, Kannan; Jayaraman, Muthukumaran; Sridharan, Upasana; Jenardhanan, Pranitha; Ramadas, Krishna

2013-03-27

366

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

PubMed

In this study, a total of 25 endophytic fungi were successfully isolated from the inner bark of Taxus baccata grown in Iran by the aseptic technique. Genomic DNA was extracted from isolated endophytic fungi and subjected to polymerase chain reaction (PCR) analysis for the presence of the Taxus taxadiene synthase (ts) gene, which encodes the enzyme catalyzing the first committed step of taxol biosynthesis. Four of 25 isolated endophytic fungi isolates showed PCR positive for the ts gene. Subsequently, taxol and 10-deacetylbaccatin III (10-DAB III) were extracted from culture filtrates and mycelia of the PCR positive isolates and analyzed by high-performance liquid chromatography and mass spectrometry. The analysis showed that one isolate (SBU-16) produced taxol (6.9 ± 0.2 ?g L(-1) ) and its intermediate compound, 10-DAB III (2.2 ± 0.1 ?g L(-1) ). The isolate SBU-16 was identified as Stemphylium sedicola SBU-16, according to its morphological characteristics as well as the internal transcribed spacer nuclear rDNA gene sequence analysis. Interestingly, this is the first report of the genus Stemphylium as a taxol-producing taxon. PMID:22211912

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

2012-01-10

367

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

NASA Astrophysics Data System (ADS)

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

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

2011-12-01

368

SIRT6 modulates paclitaxel and epirubicin resistance and survival in breast cancer.  

PubMed

In this study, we report the identification of a novel role of SIRT6 in both epirubicin and paclitaxel resistance in breast cancer. We found that SIRT6 protein levels are elevated in paclitaxel- and epirubicin-resistant MCF-7 cells compared with the parental sensitive cells. SIRT6 knockout and depletion sensitized cells to both paclitaxel and epirubicin treatment, whereas SIRT6 ectopic overexpression led to increased resistance to paclitaxel and epirubicin. Moreover, our data suggest that SIRT6 could be mediating epirubicin resistance through enhancing the DNA repair response to epirubicin-induced DNA damage. Clonogenic assays also revealed that mouse embryonic fibroblasts (MEFs) lacking SIRT6 have decreased long-term viability in response to epirubicin. The tumour suppressor FOXO3a increases its levels of acetylation in MEFs depleted of SIRT6, whereas its induction by epirubicin is attenuated in breast cancer cells overexpressing SIRT6. Further cell viability studies demonstrate that deletion of FOXO1/3/4 in MEFs can confer sensitivity to both paclitaxel and epirubicin, suggesting that SIRT6 reduces paclitaxel and epirubicin sensitivity, at least in part, through modulating FOXO acetylation and expression. Consistently, immunohistochemical analysis of 118 breast cancer patient samples revealed that high SIRT6 nuclear staining is significantly associated with poorer overall survival (P = 0.018; Kaplan-Meier analysis). Multivariate Cox analysis demonstrated that nuclear SIRT6 staining remained associated with death after correcting for tumour stage and lymph-node involvement (P = 0.033). Collectively, our data suggest that SIRT6 has a role in paclitaxel and epirubicin sensitivity via targeting FOXO proteins and that SIRT6 could be a useful biomarker and therapeutic target for paclitaxel- and epirubicin-resistant cancer. PMID:23514751

Khongkow, Mattaka; Olmos, Yolanda; Gong, Chun; Gomes, Ana R; Monteiro, Lara J; Yagüe, Ernesto; Cavaco, Tania B; Khongkow, Pasarat; Man, Ellen P S; Laohasinnarong, Sasiwan; Koo, Chuay-Yeng; Harada-Shoji, Narumi; Tsang, Janice W-H; Coombes, R Charles; Schwer, Bjoern; Khoo, Ui-Soon; Lam, Eric W-F

2013-03-20

369

Weekly oral paclitaxel as first-line treatment in patients with advanced gastric cancer  

Microsoft Academic Search

Background: Pharmacokinetic study has shown that co-administration of cyclosporin A (CsA), which acts as a P-glycoprotein (P-gp) and CYP-3A blocker, resulted in an 8-fold increase in the systemic exposure of oral paclitaxel. Two doses of oral paclitaxel on 1 day in combination with CsA resulted in higher systemic exposure than single dose administration. Patients and methods: In this phase II

C. M. F. Kruijtzer; H. Boot; J. H. Beijnen; H. L. Lochs; F. X. Parnis; A. S. T. Planting; J. M. G. Pelgrims; R. Williams; R. A. A. Mathôt; H. Rosing; M. E. Schot; H. van Tinteren; J. H. M. Schellens

2003-01-01

370

Preventing Paclitaxel-Induced Peripheral Neuropathy: A Phase II Trial of Vitamin E Supplementation  

Microsoft Academic Search

A randomized, controlled trial was performed to assess the efficacy and safety of vitamin E supplementation for prophylaxis against paclitaxel-induced peripheral neuropathy (PIPN). Thirty-two patients undergoing six courses of paclitaxel-based chemotherapy were randomly assigned to receive either chemotherapy with vitamin E (300mg twice a day, Group I) or chemotherapy without vitamin E supplementation (Group II). A detailed neurological examination and

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

2006-01-01

371

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

Microsoft Academic Search

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

R. T. Liggins; H. M. Burt

2002-01-01

372

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

PubMed Central

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.

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

2012-01-01

373

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

Microsoft Academic Search

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

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

374

Paclitaxel Induces Vascular Endothelial Growth Factor Expression through Reactive Oxygen Species Production  

Microsoft Academic Search

The antineoplastic drug paclitaxel is known to block cells in the G2\\/M phase of the cell cycle through stabilization of microtubules. The development of paclitaxel resistance in tumors is one of the most significant obstacles to successful therapy. Vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1 (HIF-1) are important regulators of neovascularization. HIF-1 regulates VEGF expression at the transcriptional

Hyun Sun Kim; Jin Mi Oh; Dong Hoon Jin; Kyu-Hwan Yang; Eun-Yi Moon

2008-01-01

375

Superior Antitumor Activity of Nanoparticle Albumin-Bound Paclitaxel in Experimental Gastric Cancer  

PubMed Central

Gastric cancer is the second common cause of cancer related death worldwide and lacks highly effective treatment for advanced disease. Nab-paclitaxel is a novel microtubule-inhibitory cytotoxic agent that has not been tested in gastric cancer as of yet. In this study, human gastric cancer cell lines AGS, NCI-N87 and SNU16 were studied. Nab-paclitaxel inhibited cell proliferation with an IC50 of 5 nM in SNU16, 23 nM in AGS and 49 nM in NCI-N87 cells after 72-hour treatment, which was lower than that of oxaliplatin (1.05 ?M to 1.51 ?M) and epirubicin (0.12 ?M to 0.25 ?M). Nab-paclitaxel treatment increased expression of the mitotic-spindle associated phospho-stathmin irrespective of the baseline total or phosphorylated stathmin level, and induced mitotic cell death as confirmed through increased expression of cleaved-PARP and caspase-3. After a two-week nab-paclitaxel, oxaliplatin or epirubicin treatment, the average in vivo local tumor growth inhibition rate was 77, 17.2 and 21.4 percent, respectively (p?=?0.002). Effects of therapy on tumoral proliferative and apoptotic indices corresponded with tumor growth inhibition data, while expression of phospho-stathmin also increased in tissues. There was an increase in median animal survival after nab-paclitaxel treatment (93 days) compared to controls (31 days, p?=?0.0007), oxaliplatin (40 days, p?=?0.0007) or to docetaxel therapy (81 days, p?=?0.0416). The strong antitumor activity of nab-paclitaxel in experimental gastric cancer supports such microtubule-inhibitory strategy for clinical application. Nab-paclitaxel benefits were observed independent from phosphorylated stathmin expression at baseline, putting into question the consideration of nab-paclitaxel use in gastric cancer based on this putative biomarker.

Zhang, Changhua; Awasthi, Niranjan; Schwarz, Margaret A.; Hinz, Stefan; Schwarz, Roderich E.

2013-01-01

376

Treatment of Coronary In-Stent Restenosis with a Paclitaxel-Coated Balloon Catheter  

Microsoft Academic Search

Background Treatment of coronary in-stent restenosis is hampered by a high incidence of recur- rent in-stent restenosis. We assessed the efficacy and safety of a paclitaxel-coated bal- loon in this setting. Methods We enrolled 52 patients with in-stent restenosis in a randomized, double-blind, mul- ticenter trial to compare the effects of a balloon catheter coated with paclitaxel (3 ?g per

Bruno Scheller; Christoph Hehrlein; Wolfgang Bocksch; Wolfgang Rutsch; Dariush Haghi; Ulrich Dietz; Michael Böhm; Ulrich Speck

2010-01-01

377

Superior antitumor activity of nanoparticle albumin-bound paclitaxel in experimental gastric cancer.  

PubMed

Gastric cancer is the second common cause of cancer related death worldwide and lacks highly effective treatment for advanced disease. Nab-paclitaxel is a novel microtubule-inhibitory cytotoxic agent that has not been tested in gastric cancer as of yet. In this study, human gastric cancer cell lines AGS, NCI-N87 and SNU16 were studied. Nab-paclitaxel inhibited cell proliferation with an IC50 of 5 nM in SNU16, 23 nM in AGS and 49 nM in NCI-N87 cells after 72-hour treatment, which was lower than that of oxaliplatin (1.05 ?M to 1.51 ?M) and epirubicin (0.12 ?M to 0.25 ?M). Nab-paclitaxel treatment increased expression of the mitotic-spindle associated phospho-stathmin irrespective of the baseline total or phosphorylated stathmin level, and induced mitotic cell death as confirmed through increased expression of cleaved-PARP and caspase-3. After a two-week nab-paclitaxel, oxaliplatin or epirubicin treatment, the average in vivo local tumor growth inhibition rate was 77, 17.2 and 21.4 percent, respectively (p?=?0.002). Effects of therapy on tumoral proliferative and apoptotic indices corresponded with tumor growth inhibition data, while expression of phospho-stathmin also increased in tissues. There was an increase in median animal survival after nab-paclitaxel treatment (93 days) compared to controls (31 days, p?=?0.0007), oxaliplatin (40 days, p?=?0.0007) or to docetaxel therapy (81 days, p?=?0.0416). The strong antitumor activity of nab-paclitaxel in experimental gastric cancer supports such microtubule-inhibitory strategy for clinical application. Nab-paclitaxel benefits were observed independent from phosphorylated stathmin expression at baseline, putting into question the consideration of nab-paclitaxel use in gastric cancer based on this putative biomarker. PMID:23460921

Zhang, Changhua; Awasthi, Niranjan; Schwarz, Margaret A; Hinz, Stefan; Schwarz, Roderich E

2013-02-27

378

In vitro evaluation of dose-response curve for paclitaxel in breast cancer  

Microsoft Academic Search

Background  The dose-response curve for anticancer agents cannot be evaluated by studying patients directly. To investigate individual\\u000a differences in the dose-response curve for paclitaxel in breast cancer, we utilized the histoculture drug response assay (HDRA)\\u000a technique. as]Materials and Methods: Twenty specimens obtained from breast cancer patients who underwent surgical resection\\u000a were used in this study. The inhibition rates of paclitaxel at

Tatsuya Yoshimasu; Shoji Oura; Issei Hirai; Takeshi Tamaki; Yozo Kokawa; Fuminori Ota; Rie Nakamura; Yukio Shimizu; Mitsumasa Kawago; Yoshimitsu Hirai; Koma Naito; Megumi Kiyoi; Hirokazu Tanino; Yoshitaka Okamura; Tomoko Furukawa

2007-01-01

379

Overexpression of centrosomal protein Nlp confers breast carcinoma resistance to paclitaxel.  

PubMed

Nlp (ninein-like protein), an important molecule involved in centrosome maturation and spindle formation, plays an important role in tumorigenesis and its abnormal expression was recently observed in human breast and lung cancers. In this study, the correlation between overexpression of Nlp and paclitaxel chemosensitivity was investigated to explore the mechanisms of resistance to paclitaxel and to understand the effect of Nlp upon apoptosis induced by chemotherapeutic agents. Nlp expression vector was stably transfected into breast cancer MCF-7 cells. With Nlp overexpression, the survival rates, cell cycle distributions and apoptosis were analyzed in transfected MCF-7 cells by MTT test and FCM approach. The immunofluorescent assay was employed to detect the changes of microtubule after paclitaxel treatment. Immunoblotting analysis was used to examine expression of centrosomal proteins and apoptosis associated proteins. Subsequently, Nlp expression was retrospectively examined with 55 breast cancer samples derived from paclitaxel treated patients. Interestingly, the survival rates of MCF-7 cells with Nlp overexpressing were higher than that of control after paclitaxel treatment. Nlp overexpression promoted G2-M arrest and attenuated apoptosis induced by paclitaxel, which was coupled with elevated Bcl-2 protein. Nlp expression significantly lessened the microtubule polymerization and bundling elicited by paclitaxel attributing to alteration on the structure or dynamics of ?-tubulin but not on its expression. The breast cancer patients with high expression of Nlp were likely resistant to the treatment of paclitaxel, as the response rate in Nlp negative patients was 62.5%, whereas was 58.3 and 15.8% in Nlp (+) and Nlp (++) patients respectively (p = 0.015). Nlp expression was positive correlated with those of Plk1 and PCNA. These findings provide insights into more rational chemotherapeutic regimens in clinical practice, and more effective approaches might be developed through targeting Nlp to increase chemotherapeutic sensitivity. PMID:22353935

Zhao, Weihong; Song, Yongmei; Xu, Binghe; Zhan, Qimin

2012-02-01

380

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

Microsoft Academic Search

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

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

2009-01-01

381

Gemcitabine plus Paclitaxel as First-Line Chemotherapy for Patients with Advanced Breast Cancer  

Microsoft Academic Search

Objectives: To assess the efficacy and tolerability of gemcitabine and paclitaxel as first-line treatment in advanced breast cancer. Methods: Patients with histologically confirmed metastatic or metastatic plus locally advanced breast cancer received gemcitabine 1,200 mg\\/m2 on days 1 and 8 and paclitaxel 175 mg\\/m2 on day 1 every 21 days for 8 cycles. Results: From December 1999 to August 2001,

Carlos Delfino; Graciela Caccia; Luis Riva Gonzáles; Elizabeth Mickiewicz; Jeannette Rodger; Luis Balbiani; Daniel Flores Morales; Alberto Zori Comba; Celia Brosio

2004-01-01

382

Cannabidiol Prevents the Development of Cold and Mechanical Allodynia in Paclitaxel-Treated Female C57Bl6 Mice  

PubMed Central

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

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

2011-01-01

383

Low-dose paclitaxel synergizes with oncolytic adenoviruses via mitotic slippage and apoptosis in ovarian cancer  

PubMed Central

The microtubule-stabilizing drug paclitaxel has activity in relapsed ovarian cancer. dl922-947, an oncolytic adenovirus with a 24-bp deletion in E1A CR2, replicates selectively within and lyses cells with a dysregulated Rb pathway and has efficacy in ovarian cancer. In the aggressive A2780CP xenograft, combination treatment with weekly dl922-947 and paclitaxel has significantly greater efficacy than either treatment alone and can produce complete tumor eradication in some animals. We investigated the mechanisms of paclitaxel's synergy with dl922-947 in ovarian cancer. The host-cell microtubule network is grossly rearranged and stabilized following adenovirus infection, but paclitaxel does not increase this significantly. Paclitaxel does not synergize by increasing infectivity, viral protein expression or virus release. However, destabilizing the microtubule network with nocodazole reduces viral exit, revealing a novel microtubule-dependent pathway for non-lytic adenoviral exit. dl922-947 can override multiple cell cycle checkpoints but induces cell death by a non-apoptotic mechanism. In combination, dl922-947 and low-dose paclitaxel induces aberrant, multipolar mitoses, mitotic slippage and multinucleation, triggering an apoptotic cell death.

Ingemarsdotter, C K; Baird, S K; Connell, C M; Oberg, D; Hallden, G; McNeish, I A

2010-01-01

384

Antitumor activity and molecular dynamics simulations of paclitaxel-laden triazine dendrimers.  

PubMed

The antitumor activities of triazine dendrimers bearing paclitaxel, a well-known mitotic inhibitor, are evaluated in SCID mice bearing human prostate cancer xenografts. To increase the activity of a first generation prodrug 1 that contained twelve paclitaxel molecules tethered via an ester linkage, the new construct described here, prodrug 2, tethers paclitaxel with linkers containing both an ester and disulfide. While PEGylation is necessary for solubility, and may improve biocompatibility and increase plasma half-life, it increases the heterogeneity of the sample with an average of eight to nine PEG chains (2 kDa each) incorporated. The heterogeneous population of PEGylated materials was used without fractionation based on models obtained from molecular dynamics simulations. Three models were examined; hexaPEGylated, nonaPEGylated, and dodecaPEGylated constructs. Intravenous delivery of prodrug 2 was performed by single, double or triple dosing regimes with doses spaced by one week. The doses varied from 50 mg of paclitaxel/kg to 200 mg of paclitaxel/kg. Tumor growth arrest and regression was observed over the 10-week treatment period without mortality for mice treated with the 50 mg of paclitaxel/kg treated three times. PMID:22260328

Lim, Jongdoo; Lo, Su-Tang; Hill, Sonia; Pavan, Giovanni M; Sun, Xiankai; Simanek, Eric E

2012-02-03

385

miR135a contributes to paclitaxel resistance in tumor cells both in vitro and in vivo  

Microsoft Academic Search

Cancer cell resistance to paclitaxel continues to be a major clinical problem. In this study, we utilized microRNA (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

A Holleman; I Chung; R R Olsen; B Kwak; A Mizokami; N Saijo; A Parissenti; Z Duan; E E Voest; B R Zetter

2011-01-01

386

Phase I Study of JM216 (an Oral Platinum Analogue) in Combination with Paclitaxel in Patients with Advanced Malignancies  

Microsoft Academic Search

This phase I study wasconducted to determine the dose limitingtoxicity, maximum tolerated doses, andrecommended phase II doses of thecombination of JM-216 and paclitaxel. Patients received paclitaxel intravenouslyover one hour on day 1 of each cycle. OralJM-216 was administered on days 1–5starting after the paclitaxel infusion. Cycles were repeated every 21 days. Patients were accrued at nine differentdosing combinations. JM-216 doses

Suzanne Jones; John Hainsworth; Howard A. Burris; Dana Thompson; Eric Raefsky; Valerie Johnson; Sharon Calvert; Cecile Bulanhagui; David Lebwohl; F. Anthony Greco

2002-01-01

387

Low-dose paclitaxel modulates tumour fibrosis in gastric cancer  

PubMed Central

Various treatments have been used for peritoneal dissemination, which is the most common mode of metastasis in gastric cancer, but sufficiently good clinical outcomes have not yet been obtained because of the presence of rich fibrous components and acquired drug resistance. Epithelialmesenchymal transition (EMT) is one of the major causes of tissue fibrosis and transforming growth factor-? (TGF-?) has a pivotal function in the progression of EMT. Smad proteins play an important role in the TGF-? signalling pathway. The TGF-?/Smad signalling pathway can be modulated by stabilising microtubules with paclitaxel (PTX). Here, we investigated whether paclitaxel can modulate TGF-?/Smad signalling in human peritoneal methothelial cells (HPMCs). To determine the cytostatic concentrations of antineoplastic agents in HPMCs, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed using PTX, 5-fluorouracil and cisplatin. The minimum concentration that caused significant inhibition of TGF-?1-induced morphological changes in human peritoneal methothelial cells on pre-treatment with PTX was 5 nM at 48 h (cell viability: 87.1±1.5%, P<0.01). The TGF-? signalling cascade and the status of various fibrous components were evaluated by immunofluorescence staining, real-time quantitative PCR and western blotting. TGF-? signalling induced morphological changes, ?-SMA expression and collagen I synthesis in HPMCs and PTX treatment suppressed these EMT-like changes. Moreover, PTX treatment markedly suppressed Smad2 phosphorylation. These data suggest that at a low-dose, PTX can significantly suppress the TGF-?/Smad signalling pathway by inhibiting Smad2 phosphorylation in the human peritoneum and that this can reduce stromal fibrosis.

TSUKADA, TOMOYA; FUSHIDA, SACHIO; HARADA, SHINICHI; TERAI, SHIROH; YAGI, YASUMICHI; KINOSHITA, JUN; OYAMA, KATSUNOBU; TAJIMA, HIDEHIRO; NINOMIYA, ITASU; FUJIMURA, TAKASHI; OHTA, TETSUO

2013-01-01

388

Randomized Phase II Trial of weekly paclitaxel alone versus trastuzumab plus weekly paclitaxel as first-line therapy of patients with Her2 positive advanced breast cancer  

Microsoft Academic Search

Background  A randomized Phase II study evaluated the activity of weekly paclitaxel versus its combination with trastuzumab for treatment\\u000a of patients with advanced breast cancer overexpressing HER-2.\\u000a \\u000a \\u000a \\u000a Patients and methods  Among 124 patients randomized, 123 are assessable for toxicity and 118 for response. Patients received weekly paclitaxel single\\u000a agent (80 mg\\/m2) or combined with trastuzumab (4 mg\\/kg loading dose, then weekly 2 mg\\/kg). HER-2 overexpression

Giampietro Gasparini; Massimo Gion; Luigi Mariani; Paola Papaldo; Diana Crivellari; Gianfranco Filippelli; Alessandro Morabito; Vittorio Silingardi; Francesco Torino; Antonella Spada; Matelda Zancan; Livia De Sio; Antonio Caputo; Francesco Cognetti; Antonio Lambiase; Dino Amadori

2007-01-01

389

Gender differences in paclitaxel-induced neuropathic pain behavior and analgesic response in rats  

PubMed Central

Background Females show greater sensitivity than males to several modalities of experimental pain. However, the gender differences in paclitaxel-induced neuropathic pain have not been studied. The current study examined the gender differences in neuropathic pain behavior and the effect of analgesics in a paclitaxel-induced neuropathic pain model in rats. Methods Neuropathic pain was induced by intraperitoneal injection of paclitaxel (2 mg/kg) on 4 alternate days in Sprague-Dawley rats of both genders. Mechanical allodynia was measured using a von Frey filament. The gender differences in analgesic responses were determined after administration of morphine (2 or 5 mg/kg), ketamine (2 or 5 mg/kg), or combined morphine (2 mg/kg) and ketamine (2 mg/kg). Results Paclitaxel induced mechanical allodynia, which began to manifest on day 4, peaked within 10 days, and plateaued for at least 2 months after the first paclitaxel injection. No gender difference in the manifestation of mechanical allodynia was observed. A 2 mg/kg dose of ketamine increased the mechanical threshold only in males. The 5 mg/kg dose of ketamine significantly increased the mechanical threshold in both genders. Morphine (2 and 5 mg/kg) dose-dependently increased the mechanical thresholds in both genders. The 2 mg/kg dose of ketamine enhanced the antinociceptive effect of 2 mg/kg morphine only in females. Conclusions No gender difference in paclitaxel-induced neuropathic pain or analgesic response to ketamine or morphine was observed in Sprague-Dawley rats. Low dose ketamine enhanced the analgesic effect of morphine on paclitaxel-induced mechanical allodynia but only in female rats.

Hwang, Boo-Young; Kim, Eun-Soo; Kim, Chul-Hong; Kwon, Jae-Young

2012-01-01

390

Cellular senescence induced by aberrant MAD2 levels impacts on paclitaxel responsiveness in vitro  

PubMed Central

Background: The mitotic arrest deficiency protein 2 (MAD2) is a key component of the mitotic spindle assembly checkpoint, monitoring accurate chromosomal alignment at the metaphase plate before mitosis. MAD2 also has a function in cellular senescence and in a cell's response to microtubule inhibitory (MI) chemotherapy exemplified by paclitaxel. Methods: Using an siRNA approach, the impact of MAD2 down-regulation on cellular senescence and paclitaxel responsiveness was investigated. The endpoints of senescence, cell viability, migration, cytokine expression, cell cycle analysis and anaphase bridge scoring were carried out using standard approaches. Results: We show that MAD2 down-regulation induces premature senescence in the MCF7 breast epithelial cancer cell line. These MAD2-depleted (MAD2?) cells are also significantly replicative incompetent but retain viability. Moreover, they show significantly higher levels of anaphase bridges and polyploidy compared to controls. In addition, these cells secrete higher levels of IL-6 and IL-8 representing key components of the senescence-associated secretory phenotype (SASP) with the ability to impact on neighbouring cells. In support of this, MAD2? cells show enhanced migratory ability. At 72?h after paclitaxel, MAD2? cells show a significant further induction of senescence compared with paclitaxel naive controls. In addition, there are significantly more viable cells in the MAD2? MCF7 cell line after paclitaxel reflecting the observed increase in senescence. Conclusion: Considering that paclitaxel targets actively dividing cells, these senescent cells will evade cytotoxic kill. In conclusion, compromised MAD2 levels induce a population of senescent cells resistant to paclitaxel.

Prencipe, M; Fitzpatrick, P; Gorman, S; Mosetto, M; Klinger, R; Furlong, F; Harrison, M; O'Connor, D; Roninson, I B; O'Sullivan, J; McCann, A

2009-01-01

391

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

PubMed

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

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

2013-07-18

392

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

PubMed

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

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

2009-10-27

393

Schedule-dependent antagonism of paclitaxel and cisplatin in human gastric and ovarian carcinoma cell lines in vitro.  

PubMed

Paclitaxel has demonstrated broad clinical activity in a variety of malignancies both alone and in combination with other chemotherapeutic agents. The in vitro cytotoxicity of paclitaxel and cisplatin alone, in combination and in sequence, were evaluated against established human gastric and ovarian carcinoma cell lines using 2-h drug exposure. The combination of cisplatin and paclitaxel was found to be additive or even synergistic when paclitaxel was given 24 h prior to cisplatin as demonstrated by isobologram analysis. However, when both drugs were given simultaneously or when cisplatin was given prior to paclitaxel, a strong antagonistic interaction was observed. This antagonism was evident for up to 72 h after a 2-h exposure to cisplatin. Pretreatment with cisplatin caused no alteration in [3H]paclitaxel uptake in HM2 gastric carcinoma cells, but resulted in decreased intracellular retention of paclitaxel. Since cisplatin treatment led to a reduction in cellular glutathione content in these cells and reduced levels of glutathione have been associated with protection against cytotoxicity of paclitaxel, cells were pretreated with L-buthionine sulfoximine (L-BSO). However, depletion of glutathione had no influence on the activity of paclitaxel. A significant accumulation of cells in S-phase was observed 24 h after cisplatin, which resolved after 48 h and resulted in a pronounced increase of G2M phase. These data demonstrate that the interactions of paclitaxel and cisplatin are highly schedule-dependent and applications of cisplatin simultaneously with or prior to paclitaxel may result in pronounced antagonism. These findings could have implications for the design of further clinical protocols. PMID:7695986

Vanhoefer, U; Harstrick, A; Wilke, H; Schleucher, N; Walles, H; Schröder, J; Seeber, S

1995-01-01

394

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

Microsoft Academic Search

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

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

2005-01-01

395

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

Microsoft Academic Search

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

Alphonse G.. Taghian; Sherif I. Assaad; Andrzej Niemierko; Scott R. Floyd; Simon N. Powell

2005-01-01

396

SPARC Expression Correlates with Tumor Response to Albumin-Bound Paclitaxel in Head and Neck Cancer Patients  

PubMed Central

SPARC up-regulation is a poor prognostic factor in head and neck cancer. It was hypothesized that because of a SPARC-albumin interaction, tumoral SPARC facilitates the accumulation of albumin in the tumor and increases the effectiveness of albumin-bound paclitaxel (nab-paclitaxel). This hypothesis was tested by correlating the response to nab-paclitaxel and SPARC tumor expression in a retrospective analysis of a 60-patient clinical study of nab-paclitaxel as monotherapy against head and neck cancer. Sixteen tumor specimens were available for analysis. There were 11 responders (CR/PR) and 5 nonresponders (SD/PD) among the 16 nab-paclitaxel-treated patients (12/16 SPARC-positive, 75%). Response to nab-paclitaxel was higher for SPARC-positive patients (10/12, 83%) than SPARC-negative patients (1/4, 25%). The SPARC-negative patients exhibited significantly lower response than the overall response rate among all 60 patients (1/4, 25% vs 45/60, 75%). Although preliminary, data are supportive of the hypothesis that SPARC overexpression may correlate with response to nab-paclitaxel. If confirmed in larger studies, treatment with nab-paclitaxel may convert a poor prognosis SPARC-positive patient population into a group with better clinical outcomes.

Desai, Neil; Trieu, Vuong; Damascelli, Bruno; Soon-Shiong, Patrick

2009-01-01

397

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

PubMed Central

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.

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

2012-01-01

398

A phase II study of paclitaxel and capecitabine as a first-line combination chemotherapy for advanced gastric cancer  

Microsoft Academic Search

Paclitaxel and capecitabine, which have distinct mechanisms of action and toxicity profiles, have each shown high activity as single agents in gastric cancer. Synergistic interaction between these two drugs was suggested by taxane-induced upregulation of thymidine phosphorylase. We, therefore, evaluated the antitumour activity and toxicities of paclitaxel and capecitabine as first-line therapy in patients with advanced gastric cancer (AGC). Patients

H J Kang; H M Chang; T W Kim; M-H Ryu; H-J Sohn; J H Yook; S T Oh; B S Kim; J-S Lee; Y-K Kang

2008-01-01

399

Paclitaxel resistance is associated with switch from apoptotic to autophagic cell death in MCF7 breast cancer cells  

Microsoft Academic Search

Taxanes remain first line chemotherapy in management of metastatic breast cancer and have a key role in epithelial ovarian cancer, with increasingly common use of weekly paclitaxel dosing regimens. However, their clinical utility is limited by the development of chemoresistance. To address this, we modelled in vitro paclitaxel resistance in MCF-7 cells. We show that at clinically relevant drug doses,

G M A Ajabnoor; T Crook; H M Coley

2012-01-01

400

Synergistic Interaction of Paclitaxel and Curcumin with Cyclodextrin Polymer Complexation in Human Cancer Cells.  

PubMed

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

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

2013-06-13

401

Thermoreversible liposomal poloxamer gel for the delivery of paclitaxel: dose proportionality and hematological toxicity studies.  

PubMed

The currently existing treatment modalities of cancer suffer from a major drawback of systemic toxicity, which results from high systemic drug exposure. Delivery of chemotherapeutic agents by delivery systems that alleviate systemic side effects but at the same time provide therapeutic advantage by controlling tumor growth exists as a viable option. To achieve this objective, a thermo reversible poloxamer gel containing paclitaxel incorporated in liposomes was formulated at three dose loadings. These paclitaxel loaded formations were injected subcutaneously (s.c.) in Sprague Dawley rats. Blood samples collected at various time points were used in the determination of drug concentration as well as white blood cell and neutrophil counts for the estimation of systemic toxicity of the formulation. Absorption of paclitaxel after s.c. injection occurred slowly with prominence of absorption phase in plasma profile, suggesting presence of flip-flop pharmacokinetics. In spite of increase in dose of paclitaxel administered, no statistically significant increase in plasma levels and pharmacokinetic parameters occurred. Further, no significant increase in hematological toxicity was observed with increased drug exposure to animals. These results show that liposomal poloxamer gels reduce systemic toxicity of paclitaxel even at high doses; and thus, can serve as an effective delivery system for alleviating body burden of this toxic chemotherapeutic agent. PMID:18604987

Dhanikula, R S; Dhanikula, A B; Panchagnula, R

2008-06-01

402

Insights into the binding of paclitaxel to human serum albumin: multispectroscopic studies.  

PubMed

The interaction of paclitaxel with human serum albumin (HSA) was studied using fluorescence, resonance light scattering, ultraviolet-visible, circular dichroism and Fourier transform infrared spectroscopy at pH 7.4. Fluorescence data revealed that the fluorescence quenching of HSA by paclitaxel was a static quenching procedure. Time-resolved fluorescence data also confirmed the quenching mode, which present a constant decay time of about 5 ns. The binding sites were approximately 1 and the binding constant suggested a weak association (324/M at 298 K), which is helpful for the release of the drug to targeted organs. The thermodynamic parameters, ?G(?), ?H° and ?S° were calculated as - 1.06 × 10(4) J/mol, 361 J/mol per K and 9.7 × 10(4) J/mol respectively at 298 K, suggesting that binding was spontaneous and was driven mainly by hydrophobic interactions. The binding distance between HSA and paclitaxel was determined to be 2.23 nm based on the Förster theory. Analysis of circular dichroism, ultraviolet-visible, three-dimensional fluorescence, Fourier transform infrared and resonance light scattering spectra demonstrated that HSA conformation was slightly altered in the presence of paclitaxel and dimension of the individual HSA molecules were larger after interacting with paclitaxel. These results were confirmed by a molecular docking study. PMID:23674486

Yang, Xiuli; Ye, Zuowu; Yuan, Yong; Zheng, Zaoqian; Shi, Jiana; Ying, Yin; Huang, Ping

2013-05-15

403

Paclitaxel induces apoptosis in Saos-2 cells with CD95L upregulation and Bcl-2 phosphorylation.  

PubMed

We examined the effect of paclitaxel on human osteoblastic cells Saos-2 to determine if paclitaxel can affect proliferation and apoptosis. We used a p53-negative cell line in order to mimic the loss of function frequently observed at the clinical level. Paclitaxel induced cell death in a dose- and time-dependent manner. Marked nuclear condensation and fragmentation of chromatin were observed by Hoechst 33258 stain, DNA ladder formation, electron microscopy, and flow cytometry at concentrations as low as 100 nM, a concentration which can be achieved by infusion in human plasma. At 100 nM, paclitaxel induced a G2 arrest at 8 h of treatment. The cells then continued to accumulate in G2 until 72 h when the percentage of apoptotic events reached 54%. At the molecular level, Bcl-2 protein was phosphorylated at 16 h and PARP protein was cleaved, indicating the activation of caspase-3-like proteases. Caspase inhibitors Z-VAD-FMK and Z-DEVD-FMK rescued Saos-2 cells from paclitaxel-induced apoptosis. CD95 expression was constantly high, while CD95L showed a threefold increase in expression. This suggests that, following the G2 arrest, apoptosis is induced through the CD95/CD95L system. PMID:10502406

Pucci, B; Bellincampi, L; Tafani, M; Masciullo, V; Melino, G; Giordano, A

1999-10-10

404

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

PubMed

The principal purpose of this study was to evaluate relationships between paclitaxel plasma steady-state concentration (Css) and both disease outcome and toxicity in patients with non-small cell lung cancer (NSCLC) treated with paclitaxel and cisplatin in an Eastern Cooperative Oncology Group (ECOG) Phase III study E5592. Chemotherapy-naive patients with stage IIIb and IV NSCLC were randomized to treatment with either 75 mg/m2 cisplatin i.v. on day 1 and 100 mg/m2 etoposide i.v. on days 1-3 (EC arm) or 75 mg/m2 cisplatin i.v. combined with either a low dose of paclitaxel (135 mg/m2, 24-h i.v. infusion; PC arm) or a higher dose of paclitaxel (250 mg/m2 i.v., 24-h i.v. infusion) with granulocyte colony-stimulating factor (PCG arm). End-of-24-h-infusion paclitaxel concentrations, which have been demonstrated to be nearly equal to CssS on this schedule, were obtained during the first and second courses in patients on the PC and PCG arms. Relationships between the average paclitaxel Css (Css,avg) and the best response to treatment, time to treatment failure (TTF), survival, and worst grade of leukopenia and neurotoxicity were evaluated by univariate analysis. A multivariate model was used to assess the influence of paclitaxel Css in conjunction with other potentially relevant patient variables that may affect disease outcome, including the paclitaxel treatment arm, age, sex, performance status, weight loss during the previous 6 months, and disease stage. Paclitaxel Css in both courses 1 and 2 were obtained in 71 patients treated with PC and 75 patients treated with PCG. Although Css,avgS in patients treated with PC and PCG were significantly different (median, 0.32 versus 0.81 micromol/liter; P < 0.0001), response rates were not (33.8 versus 26.7%; P = 0.3719). In addition, there were no differences between the PC and PCG arms in TTF (median, 5.1 versus 5.5 months, P = 0.6201) or survival (median, 11.6 versus 11.3 months, P = 0.7173). Combined analysis of paclitaxel concentrations from both treatment arms revealed no significant difference in paclitaxel Css,avg between responders and nonresponders [median, 0.40 (range, 0.16-1.6) micromol/liter versus 0.55 (range, 0.11-3.6)], and Css,avgS were similar in patients segregated according to whether they had a complete response, partial response, stable disease, or progressive disease as their best response to treatment (P = 0.7612). In addition, the relationship between Css,avg and TTF was weak (r2 = 0.00003, P = 0.94), as was the relationship between Css,avg and survival (P = 0.1267). With regard to the principal toxicities, neither the propensity to develop neuromuscular and neurosensory toxicity nor the worst grade of these adverse effects were related to Css,avg (P = 0.5000 and 0.2033, respectively); however, the relationship between Css,avg and the worst grade of leukopenia experienced was marginally significant (P = 0.0796). In a multivariate model, neither the combined effect of relevant demographic and stratification variables nor paclitaxel Css,avg predicted for either response (P = 0.1544) or TTF (P = 0.2574), whereas the combined effect of all covariates predicted for survival (P = 0.0249). With regard to individual covariates, a lower disease stage (stage IIIb) was the only significant positive determinant of response (P = 0.0173), female sex was the only significant favorable predictor for TTF (P = 0.0195), and a lower ECOG performance status (= 0) was the only significant positive determinant of survival (P = 0.0121) in the multivariate model. In summary, paclitaxel Css,avg was not a determinant of response, TTF, or survival in patients with advanced NSCLC treated with paclitaxel as a 24-h i.v. infusion combined with cisplatin. On the basis of both the clinical and pharmacodynamic results of E5592, there is no compelling reason to treat patients with advanced NSCLC with paclitaxel on a 24-h i.v. schedule at doses of > 135 mg/m2 in combination with cisplatin, although highe PMID:10213211

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

1999-04-01

405

CGK733 enhances multinucleated cell formation and cytotoxicity induced by taxol in Chk1-deficient HBV-positive hepatocellular carcinoma cells.  

PubMed

Hepatocellular carcinoma (HCC) is one of the most deadly human cancers. Chronic hepatitis B virus (HBV) infection is one of the predominant risk factors associated with the development of HCC and complicates the treatment of HCC. In this study, we demonstrate that a HBV-positive HCC cell line HepG2.2.15, was more resistant to chemotherapy agents than its parental HBV-negative cell line HepG2. HBV-positive HCC cells exhibited defective Chk1 phosphorylation and increased chromosomal instability. CGK733, a small molecule inhibitor reportedly targeting the kinase activities of ATM and ATR, significantly enhanced taxol-induced cytotoxicity in HBV-positive HepG2.2.15 cells. The mechanism lies in CGK733 triggers the formation of multinucleated cells thus promotes the premature mitotic exit of taxol-induced mitotic-damaged cells through multinucleation and mitotic catastrophe in HBV-positive HepG2.2.15 cells. These results suggest that CGK733 could potentially reverse the taxol resistance in HBV-positive HCC cells and may suggest a novel strategy to treat HBV-infected HCC patients. PMID:22564734

Wang, Huan; Zuo, Bin; Wang, Haibin; Ren, Laifeng; Yang, Peng; Zeng, Ming; Duan, Dan; Liu, Cong; Li, Mingyuan

2012-04-30