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1

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

2

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

3

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

4

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

5

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

6

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

7

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

8

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

9

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

10

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

11

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

12

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

13

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

14

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

15

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

16

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

17

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

18

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

19

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

20

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

21

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

22

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

23

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

24

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

25

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

26

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

27

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

28

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

29

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

30

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

31

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

32

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

33

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

34

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

35

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

36

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

37

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

38

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

39

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

40

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

41

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

42

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

43

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

44

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

45

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

46

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

47

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

48

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

49

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

50

(-)-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

51

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

52

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

53

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

54

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

55

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

56

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

57

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

58

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

59

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

60

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

61

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

62

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

63

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.

64

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

65

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

66

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

67

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

68

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

69

[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

70

[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

71

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

72

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

73

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

74

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

75

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

76

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

77

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

78

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

79

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

80

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

81

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

82

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

83

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

84

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

85

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

86

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

87

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

88

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

89

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

90

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

91

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

92

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

93

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

94

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

95

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

96

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

97

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

98

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

99

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

100

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

101

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

102

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

103

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

104

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

105

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

106

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

107

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

108

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

109

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

110

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

111

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

112

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

113

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

114

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

115

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

116

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

117

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

118

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

119

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

120

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

121

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

122

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

123

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

124

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

125

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

126

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

127

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

128

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

129

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

130

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

131

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

132

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

133

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

134

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

135

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

136

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

137

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

138

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

139

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

140

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

141

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

142

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

143

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

144

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

145

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

146

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

147

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

148

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

149

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

150

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

151

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

152

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

153

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

154

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

155

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

156

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

157

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

158

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

159

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

160

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

161

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

162

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

163

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

164

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

165

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

166

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

167

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

168

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

169

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

170

Influence on intestinal mucous permeation of paclitaxel of absorption enhancers and dosage forms based on electron spin resonance spectroscopy.  

PubMed

The aim of this paper is to investigate the permeation mechanism of the hydrophobic drug, paclitaxel in intestinal membranes of mice in relation to enhancers and preparation factors. The alteration fluidity of lipid and protein in mucous membrane were determined using electron spin resonance (ESR) when the membrane was treated with several enhancers including Pluronic F68, polyethylene glycol (PEG), Brij78 and lecithin. At the same time, the enhanced permeation of paclitaxel across the intestinal intercellular membrane of stratum corneum was studied for three formulations: inclusion complex, microemulsion and injection. The results showed that use of paclitaxel-hydroxypropyl-beta-cyclodextrin inclusion complexation and of paclitaxel microemulsion as vehicle and PEG 1500 as enhancer could significantly increase the permeation kinetics of paclitaxel in a fluid diffusion study. The effect on absorption characteristics of enhancing permeation of this hydrophobic drug in the intestinal mucosa was considered in the light of the change in membrane fluid. PMID:17557746

Zhang, X N; Xu, J; Tang, L H; Gong, J; Yan, X Y; Zhang, Q

2007-05-01

171

Praziquantel Synergistically Enhances Paclitaxel Efficacy to Inhibit Cancer Cell Growth  

PubMed Central

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

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

2012-01-01

172

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

PubMed Central

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

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

2013-01-01

173

Paclitaxel-loaded lipid nanoparticles prepared by solvent injection or ultrasound emulsification.  

PubMed

Lipid nanoparticles were fabricated as an injectable carrier system for paclitaxel. The components for the lipid matrix were based on phospholipids, and sucrose fatty acid ester was used as an emulsifier. Formulation prepared with solvent injection has a slightly larger particle size (187.6 nm) than the formulation (147.7 nm) prepared with ultrasound emulsification. Differential scanning calorimetry results indicated that paclitaxel entrapped in the lipid nanoparticles existed in an amorphous state in the lipid matrix. In vitro drug release was rather slow; only 12.5-16.5% of the drug released from the formulations within 14 days. Lipid nanoparticles demonstrated their potential as a promising pharmaceutical formulation of paclitaxel. PMID:17012121

Arica Yegin, Betül; Benoît, Jean-Pierre; Lamprecht, Alf

2006-10-01

174

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

175

PAM50 proliferation score as a predictor of weekly paclitaxel benefit in breast cancer.  

PubMed

To identify a group of patients who might benefit from the addition of weekly paclitaxel to conventional anthracycline-containing chemotherapy as adjuvant therapy of node-positive operable breast cancer. The predictive value of PAM50 subtypes and the 11-gene proliferation score contained within the PAM50 assay were evaluated in 820 patients from the GEICAM/9906 randomized phase III trial comparing adjuvant FEC to FEC followed by weekly paclitaxel (FEC-P). Multivariable Cox regression analyses of the secondary endpoint of overall survival (OS) were performed to determine the significance of the interaction between treatment and the (1) PAM50 subtypes, (2) PAM50 proliferation score, and (3) clinical and pathological variables. Similar OS analyses were performed in 222 patients treated with weekly paclitaxel versus paclitaxel every 3 weeks in the CALGB/9342 and 9840 metastatic clinical trials. In GEICAM/9906, with a median follow up of 8.7 years, OS of the FEC-P arm was significantly superior compared to the FEC arm (unadjusted HR = 0.693, p = 0.013). A benefit from paclitaxel was only observed in the group of patients with a low PAM50 proliferation score (unadjusted HR = 0.23, p < 0.001; and interaction test, p = 0.006). No significant interactions between treatment and the PAM50 subtypes or the various clinical-pathological variables, including Ki-67 and histologic grade, were identified. Finally, similar OS results were obtained in the CALGB data set, although the interaction test did not reach statistical significance (p = 0.109). The PAM50 proliferation score identifies a subset of patients with a low proliferation status that may derive a larger benefit from weekly paclitaxel. PMID:23423445

Martín, Miguel; Prat, Aleix; Rodríguez-Lescure, Alvaro; Caballero, Rosalía; Ebbert, Mark T W; Munárriz, Blanca; Ruiz-Borrego, Manuel; Bastien, Roy R L; Crespo, Carmen; Davis, Carole; Rodríguez, César A; López-Vega, José M; Furió, Vicente; García, Ana M; Casas, Maribel; Ellis, Matthew J; Berry, Donald A; Pitcher, Brandelyn N; Harris, Lyndsay; Ruiz, Amparo; Winer, Eric; Hudis, Clifford; Stijleman, Inge J; Tuck, David P; Carrasco, Eva; Perou, Charles M; Bernard, Philip S

2013-02-20

176

Akt Phosphorylation at Ser473 Predicts Benefit of Paclitaxel Chemotherapy in Node-Positive Breast Cancer  

PubMed Central

Purpose We tested the hypothesis that Akt-Ser473 phosphorylation (pAkt) predicts benefit from the sequential addition of paclitaxel to adjuvant doxorubicin plus cyclophosphamide (AC) chemotherapy in patients with node-positive breast cancer participating in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-28 trial. Patients and Methods Primary tumors from the NSABP B-28 trial tissue microarray were available from 1,581 of 3,060 patients who were randomly assigned to receive either four cycles of AC alone or followed by four cycles of paclitaxel. Immunohistochemistry and quantitative analysis of pAkt were performed at the National Cancer Institute blinded to clinical outcome. Association between pAkt and clinical outcome was assessed using multivariate Cox modeling adjusting for age, tumor size, number of positive nodes, tumor grade, estrogen receptor status, and human epidermal growth factor receptor 2 status. Results With a median follow-up of 9.1 years, there were no differences in disease-free survival (adjusted hazard ratio [HR], 1.02; P = .81) or overall survival (HR, 0.97; P = .80) with and without receiving paclitaxel among 975 patients with pAkt-negative tumors. In 606 patients with pAkt-positive tumors, the sequential addition of paclitaxel resulted in a 26% improvement in disease-free survival (HR, 0.74; P = .02) or a 20% improvement in overall survival (HR, 0.80; P = .17). Conclusion pAkt significantly predicts disease-free benefit from the sequential addition of paclitaxel to AC chemotherapy in patients with node-positive breast cancer. Patients with pAkt-negative breast tumors do not appear to benefit from the addition of paclitaxel.

Yang, Sherry X.; Costantino, Joseph P.; Kim, Chungyeul; Mamounas, Eleftherios P.; Nguyen, Dat; Jeong, Jong-Hyeon; Wolmark, Norman; Kidwell, Kelley; Paik, Soonmyung; Swain, Sandra M.

2010-01-01

177

[The advance in synthetic biology: towards a microbe-derived paclitaxel intermediates].  

PubMed

The synthetic biology matures to promote the heterologous biosynthesis of the well-known drug paclitaxel that is one of the most important and active chemotherapeutic agents for the first-line clinical treatment of cancer. This review focuses on the construction and regulation of the biosynthetic pathway of paclitaxel intermediates in both Escherichia coli and Saccharomyces cerevisiae. In particular, the review also features the early efforts to design and overproduce taxadiene and the bottleneck of scale fermentation for producing the intermediates. PMID:23672014

Wang, Wei; Yang, Yan; Zheng, Xiao-Dong; Huang, Shu-Qiong; Guo, Lei; Kong, Jian-Qiang; Cheng, Ke-Di

2013-02-01

178

Variants in the SLCO1B3 Gene: Interethnic Distribution and Association with Paclitaxel Pharmacokinetics  

Microsoft Academic Search

To explore retrospectively the relationships between paclitaxel pharmacokinetics and three known, non-synonymous single-nucleotide polymorphisms (SNPs) in SLCO1B3, the gene encoding organic anion transporting polypeptide (OATP)1B3. Accumulation of [3H]paclitaxel was studied in Xenopus laevis oocytes injected with cRNA of Oatp1b2, OATP1A2, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, and NTCP. The 334T>G (Ser112Ala), 699G>A (Met233Ile), and 1564G>T (Gly522Cys) loci of SLCO1B3 were screened

N F Smith; S Marsh; T J Scott-Horton; A Hamada; S Mielke; K Mross; W D Figg; J Verweij; H L McLeod; A Sparreboom

2007-01-01

179

Cytarabine and paclitaxel exhibit different cell-cycle specificities in different cell growing status  

Microsoft Academic Search

Objective  To investigate the cell-cycle specificites of cytarabine and paclitaxel in different growing status of target cell.\\u000a \\u000a \\u000a \\u000a Methods  Using flow cytometry, we tested the cell-cycle specificities of cytarabine and paclitaxel on acute lymphocte leukemia cell\\u000a line Molt-4 in different growing status and on clinical acute lymphocyte leukemia specimens in vitro as well as in leukemia patients in vivo.\\u000a \\u000a \\u000a \\u000a Results  Cytarabine induced S phase

Peng Zhang; Yi Zhou; Deding Tao; Jianfeng Zhou; Jianping Gong

2006-01-01

180

Treatment of small coronary arteries with a paclitaxel-coated balloon catheter  

Microsoft Academic Search

Background  Treatment of lesions in small coronary arteries by percutaneous transluminal coronary intervention is limited by a high recurrence\\u000a rate. We assessed the use of a paclitaxel-coated balloon in this indication.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  One-hundred eighteen patients with stenoses in small coronary vessels were treated by a paclitaxel-coated balloon (3 ?g\\/mm2). The main inclusion criteria encompassed diameter stenosis of ?70% and ?22 mm in length with

Martin Unverdorben; Franz X. Kleber; Hubertus Heuer; Hans-Reiner Figulla; Christian Vallbracht; Matthias Leschke; Bodo Cremers; Stefan Hardt; Michael Buerke; Hanns Ackermann; Michael Boxberger; Ralf Degenhardt; Bruno Scheller

2010-01-01

181

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.  

PubMed

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, C?? column (250 mm × 4.6 mm, 5 ?m) with methanol and 0.5% H?PO? aqueous solution as the mobile phase components. The injection volume was 50 ?l and the column temperature was maintained at 30 °C. The method was validated according to USP Category I requirements. The validation characteristics included system suitability, linearity, analytical range, LOD, LOQ, accuracy, precision, specificity, stability, ruggedness and robustness. The calibration curves exhibited linear concentration ranges of 0.2-40 ?g/ml for 5-fluorouracil and 1.5-150 ?g/ml for paclitaxel with correlation coefficients larger than 0.99990. The lower limits of quantitation were 2 ng/ml for 5-fluorouracil and 0.75 ?g/ml for paclitaxel, respectively. The intra and inter-day precision and accuracy were found to be well within acceptable limits (i.e., 5%). The results demonstrate that this method is reliable, reproducible and suitable for simultaneous quantitation of the two drugs in the release media of 5-fluorouracil/paclitaxel-co-eluting stents. PMID:22075374

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

2011-10-15

182

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

PubMed Central

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

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

2012-01-01

183

Paclitaxel production using co-culture of Taxus suspension cells and paclitaxel-producing endophytic fungi in a co-bioreactor  

Microsoft Academic Search

The co-culture of the suspension cells of Taxus chinensis var. mairei and its endophytic fungi, Fusarium mairei, in a 20-L co-bioreactor was successfully established for paclitaxel production. The co-bioreactor consists of two-unit tanks\\u000a (10 L each) with a repairable separate membrane in the center, culturing Taxus suspension cells in one tank and growing fungi in another. By optimizing the co-culture conditions,

Yong-Cheng Li; Wen-Yi Tao; Long Cheng

2009-01-01

184

Front-line paclitaxel-vinorelbine versus paclitaxel-carboplatin in patients with advanced non-small-cell lung cancer: a randomized phase III trial  

Microsoft Academic Search

Purpose: This randomized phase III trial of advanced or metastatic non-small-cell lung cancer (NSCLC) was designed to compare a standard treatment such as carboplatin (CRP)- paclitaxel (PCT) with a new combination, vinorelbine (VRL)- PCT—two agents acting in microtubules. Patients and methods: Three hundred and sixty patients (stage IIIa, IIIb and IV) were included and evaluated for response rate, survival and

G. P. Stathopoulos; M. Veslemes; N. Georgatou; D. Antoniou; P. Giamboudakis; K. Katis; D. Tsavdaridis; S. K. Rigatos; I. Dimitroulis; S. Bastani; S. Loukides; K. Vergos; K. Marossis; T. Grigoratou; E. Kalatzi; M. Charalambatou; A. Paspalli; P. Michalopoulou; M. Stoka; A. Gerogianni

2004-01-01

185

A phase II randomised clinical trial comparing cisplatin, paclitaxel and ifosfamide with cisplatin, paclitaxel and epirubicin in newly diagnosed advanced epithelial ovarian cancer: long-term survival analysis.  

PubMed

To test the feasibility and efficacy of epirubicin and ifosfamide added to first-line chemotherapy with cisplatin and paclitaxel in a phase II randomised clinical trial. Patients with histologically proven epithelial ovarian cancer were randomly assigned to receive first-line polychemotherapy with cisplatin/paclitaxel/epirubicin (CEP) or cisplatin/paclitaxel/ifosfamide (CIP) for six cycles every 21 days. Two hundred and eight patients were randomised between the two treatment arms and the median number of cycles per patient was six. Toxicity was predominantly haematological with both regimens; however, anaemia, leucopaenia, neutropaenic fever and use of granulocyte colony-stimulating factors and transfusion were significantly more frequent in the CIP treatment arm. Response rates were 85% (95% confidence interval (CI) 77-93%) in the CIP arm and 90% (95% CI 84-96%) in the CEP arm; complete response rates were 48 and 52%. After a median follow-up of 82 months, median overall survival (OS) was 51 and 65 months; 5-year survival rates were respectively 43 and 50%. In this clinical trial, both regimens showed good efficacy, but toxicity was heavier with the CIP regimen. Considering that more than 50% of patients were suboptimally debulked after the first surgery, OS seems to be longer than is commonly reported. This unexpected finding might be a consequence of the close surgical surveillance and aggressive chemotherapeutic approach. PMID:18253120

Fruscio, R; Colombo, N; Lissoni, A A; Garbi, A; Fossati, R; Ieda', N; Torri, V; Mangioni, C

2008-02-05

186

A phase II randomised clinical trial comparing cisplatin, paclitaxel and ifosfamide with cisplatin, paclitaxel and epirubicin in newly diagnosed advanced epithelial ovarian cancer: long-term survival analysis  

PubMed Central

To test the feasibility and efficacy of epirubicin and ifosfamide added to first-line chemotherapy with cisplatin and paclitaxel in a phase II randomised clinical trial. Patients with histologically proven epithelial ovarian cancer were randomly assigned to receive first-line polychemotherapy with cisplatin/paclitaxel/epirubicin (CEP) or cisplatin/paclitaxel/ifosfamide (CIP) for six cycles every 21 days. Two hundred and eight patients were randomised between the two treatment arms and the median number of cycles per patient was six. Toxicity was predominantly haematological with both regimens; however, anaemia, leucopaenia, neutropaenic fever and use of granulocyte colony-stimulating factors and transfusion were significantly more frequent in the CIP treatment arm. Response rates were 85% (95% confidence interval (CI) 77–93%) in the CIP arm and 90% (95% CI 84–96%) in the CEP arm; complete response rates were 48 and 52%. After a median follow-up of 82 months, median overall survival (OS) was 51 and 65 months; 5-year survival rates were respectively 43 and 50%. In this clinical trial, both regimens showed good efficacy, but toxicity was heavier with the CIP regimen. Considering that more than 50% of patients were suboptimally debulked after the first surgery, OS seems to be longer than is commonly reported. This unexpected finding might be a consequence of the close surgical surveillance and aggressive chemotherapeutic approach.

Fruscio, R; Colombo, N; Lissoni, A A; Garbi, A; Fossati, R; Ieda', N; Torri, V; Mangioni, C

2008-01-01

187

IVUS-guided rotational atherectomy for unexpandable paclitaxel-eluting stent: A case report and review of literature.  

PubMed

We describe a patient suffering from late stent thrombosis in a paclitaxel-eluting stent which had an underexpanded ring due to the three-hundred-sixty-degree circumferential calcified plaque. Intravascular ultrasound (IVUS) revealed rotational atherectomy could successfully ablate both the metallic ring and the calcified ring. The ablated segment was scaffolded with a new paclitaxel-eluting stent, well expanded and documented by IVUS. To our knowledge, this is the first case report of stent ablation for an unexpanded paclitaxel-eluting stent. From the Medline index, there were only six case reports of stent ablation. We review and summarize the operation details of stent ablation from these reports. PMID:24133508

Ku, Po-Ming; Huang, Tsuei-Yuen; Chen, Zhih-Cherng; Woo, Max; Hung, Jui-Sung

2013-09-01

188

IVUS-guided rotational atherectomy for unexpandable paclitaxel-eluting stent: A case report and review of literature  

PubMed Central

We describe a patient suffering from late stent thrombosis in a paclitaxel-eluting stent which had an underexpanded ring due to the three-hundred-sixty-degree circumferential calcified plaque. Intravascular ultrasound (IVUS) revealed rotational atherectomy could successfully ablate both the metallic ring and the calcified ring. The ablated segment was scaffolded with a new paclitaxel-eluting stent, well expanded and documented by IVUS. To our knowledge, this is the first case report of stent ablation for an unexpanded paclitaxel-eluting stent. From the Medline index, there were only six case reports of stent ablation. We review and summarize the operation details of stent ablation from these reports.

Ku, Po-Ming; Huang, Tsuei-Yuen; Chen, Zhih-Cherng; Woo, Max; Hung, Jui-Sung

2013-01-01

189

Angiogenesis Inhibition in the in Vivo Antineoplastic Effect of Manumycin and Paclitaxel against Anaplastic Thyroid Carcinoma  

Microsoft Academic Search

Our laboratory has investigated the anticancer effects of combined manumycin (a farnesyltransferase inhibitor) and paclitaxel (a micro- tubule inhibitor) against anaplastic thyroid carcinoma (ATC). In this study we reported the in vivo efficacy of this combination against ATC cells and the lack of toxicity of this treatment in mice. We observed that manumycin-treated tumors looked paler than both control and

GUANGPU XU; JINGXUAN PAN; CHARLES MARTIN; SAI-CHING JIM YEUNG

2010-01-01

190

Paclitaxel augments cytotoxic effect of photodynamic therapy using verteporfin in gastric and bile duct cancer cells.  

PubMed

Photodynamic therapy (PDT) shows a limited antitumor effect in treating gastrointestinal tumors because of improper light penetration or insufficient photosensitizer uptake. The aim of this study was to evaluate the cytotoxic effect of PDT combined with paclitaxel on in vitro cancer cells. In vitro photodynamic therapy was performed in gastric cancer cells (NCI-N87) and bile duct cancer cells (YGIC-6B) using verteporfin (2 ug mL(-1)) and a PTH light source (1 000 W, Oriel Co.) with 665-675 nm narrow band pass filter. Cytotoxicity was compared using the MTT assay between cancer cells treated with PDT alone or pretreated with paclitaxel (IC(25)). Apoptotic changes were evaluated using DAPI staining, DNA fragmentation analysis, Annexin V-FITC apoptosis assay, cell cycle analysis, and western blots for cytochrome c, Bax, and Bid. The PDT-induced cytotoxicity was potentiated by pretreating with low dose paclitaxel (P < 0.001). The enhanced cytotoxicity was due to an augmented apoptotic response mediated by exaggerated cytochrome c released from mitochondria, without Bax or Bid activation. These results show that paclitaxel pretreatment enhances PDT-mediated cancer therapy. PMID:18597023

Park, Seungwoo; Hong, Sung Pil; Oh, Tae Yoon; Bang, Seungmin; Chung, Jae Bock; Song, Si Young

2008-05-15

191

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

192

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

193

Microtubule Interactions with Chemically Diverse Stabilizing Agents: Thermodynamics of Binding to the Paclitaxel Site Predicts Cytotoxicity  

Microsoft Academic Search

Summary The interactions of microtubules with most com- pounds described as stabilizing agents have been studied. Several of them (lonafarnib, dicumarol, lutein, and jatrophane polyesters) did not show any stabilizing effect on microtubules. Taccalonolides A and E show paclitaxel-like effects in cells, but they were not able to modulate in vitro tubulin assembly or to bind micro- tubules, which suggests

Rubén M. Buey; Isabel Barasoain; Evelyn Jackson; Arndt Meyer; Paraskevi Giannakakou; Ian Paterson; Susan Mooberry; José M. Andreu; J. Fernando Díaz

2005-01-01

194

Molecular Description of Evolving Paclitaxel Resistance in the SKOV-3 Human Ovarian Carcinoma Cell Line1  

Microsoft Academic Search

Ovarian cancer is currently the most lethal gynecological malignancy in the United States. Although effective therapies exist, the acquisition of multidrug resistance within persisting tumor cells renders curative ther- apies elusive for the majority of women with ovarian cancer. In an attempt to better define the evolution of paclitaxel resistance, three SKOV-3 sublines were selected during successive rounds of exposure

Diana E. Lamendola; Zhenfeng Duan; Rushdia Z. Yusuf; Michael V. Seiden

2003-01-01

195

Hepatocyte Growth Factor Sensitizes Human Ovarian Carcinoma Cell Lines to Paclitaxel and Cisplatin  

Microsoft Academic Search

The hepatocyte growth factor (HGF) receptor, encoded by the MET oncogene, is expressed in 70% of human ovarian carcinomas and over- expressed in 30% of cases. Because HGF is known to protect cells from apoptosis, we investigated whether receptor expression modifies ovarian cancer cell response to chemotherapy. The apoptotic effect of the front- line chemotherapeutic drugs paclitaxel and cisplatin on

Andrea Rasola; Sergio Anguissola; Norma Ferrero; Daniela Gramaglia; Antonella Maffe; Piera Maggiora; Paolo M. Comoglio; M. Flavia Di Renzo

2004-01-01

196

Activity of Gemcitabine in Patients with Advanced Ovarian Cancer: Responses Seen Following Platinum and Paclitaxel  

Microsoft Academic Search

Thirty-eight women with epithelial ovarian cancer were treated with gemcitabine, a new antimetabolite. All had previously received platinum, and 27 had also received paclitaxel. Four patients had a partial response giving a response rate of 13% in assessable patients (n= 31) and 11% for all patients entered. Additionally, 6 patients had stable disease with >50% reduction in CA-125 for at

Jeremy D. Shapiro; Michael J. Millward; Danny Rischin; Michael Michael; Vicki Walcher; Prudence A. Francis; Guy C. Toner

1996-01-01

197

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

Microsoft Academic Search

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

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

1999-01-01

198

Formulation Optimization of Paclitaxel Carried by PEGylated Emulsions Based on Artificial Neural Network  

Microsoft Academic Search

Purpose. To develop paclitaxel carried by injectable PEGylated emulsions, an artificial neural network (ANN) was used to optimize the formulation—which has a small particle size, high entrapment efficiency, and good stability—and to investigate the role of each ingredient in the emulsion.

Tianyuan Fan; Kozo Takayama; Yoshiyuki Hattori; Yoshie Maitani

2004-01-01

199

Raman confocal microscopy and AFM combined studies of cancerous cells treated with Paclitaxel  

Microsoft Academic Search

Paclitaxel interferes with the normal function of microtubule breakdown, induces apoptosis in cancer cells and sequesters free tubulin. As this drug acts also on other cell mechanisms it is important to monitor its accumulation in the cell compartments. The intracellular spreading of the drug was followed using a WITEC 300R confocal Raman microscope equipped with a CCD camera. Hence Atomic

L. Derely; P.-Y. Collart Dutilleul; Sylvain Michotte de Welle; V. Szabo; C. Gergely; F. J. G. Cuisinier

2011-01-01

200

Inhibition of neointimal hyperplasia in vascular grafts by sustained perivascular delivery of paclitaxel  

Microsoft Academic Search

Inhibition of neointimal hyperplasia in vascular grafts by sustained perivascular delivery of paclitaxel.BackgroundNeointimal hyperplasia occurs commonly at the anastomoses of arteriovenous grafts for chronic hemodialysis, causing stenosis and occlusion. Antiproliferative drugs may be effective in inhibiting hyperplasia, but local drug delivery would be required to minimize systemic side effects. We examined the feasibility of local drug delivery to inhibit neointimal

TAKAHISA MASAKI; RAMESH RATHI; GAYLEN ZENTNER; John K. Leypoldt; Syed F. Mohammad; Gregory L. Burns; LI LI; SERGEY ZHUPLATOV; THANIT CHIRANANTHAVAT; SEUNG-JUNG KIM; STEVEN KERN; JOHN HOLMAN; SUNG WAN KIM; Alfred K. Cheung

2004-01-01

201

Weekly nab-Paclitaxel in Metastatic Breast Cancer - Summary and Results of an Expert Panel Discussion.  

PubMed

Taxanes are regarded as the most effective single agents in the treatment of metastatic breast cancer (MBC). For conventional taxanes, crucial toxicities and impairments in clinical efficacy are related to solvents necessary because of the agents' hydrophobicity. The mandatory premedication with corticosteroids causes additional side effects. Nab-paclitaxel is a solvent-free colloidal suspension of paclitaxel and human serum albumin that exploits the physiological transport properties of albumin. It is registered as monotherapy with a recommended dose of 260 mg/m(2) every 3 weeks for the treatment of patients with MBC, who have failed a first-line treatment of metastatic disease and for whom a standard anthracycline treatment is not indicated. Clinical evidence is available for the registered 3-weekly administration and for alternative weekly schedules in first and further lines of therapy of patients with MBC. During an advisory board meeting, a group of 8 German breast cancer experts reviewed the clinical data of nab-paclitaxel in MBC and discussed how nab-paclitaxel could be used in clinical practice on the basis of the current data. PMID:22740801

Jackisch, Christian; Lück, Hans-Joachim; Untch, Michael; Bischoff, Joachim; Müller, Volkmar; Schmidt, Marcus; Thill, Marc; Kiechle, Marion

2012-04-16

202

In vivo prevention of arterial restenosis with paclitaxel-encapsulated targeted lipid-polymeric nanoparticles  

PubMed Central

Following recent successes with percutaneous coronary intervention (PCI) for treating coronary artery disease (CAD), many challenges remain. In particular, mechanical injury from the procedure results in extensive endothelial denudation, exposing the underlying collagen IV-rich basal lamina, which promotes both intravascular thrombosis and smooth muscle proliferation. Previously, we reported the engineering of collagen IV-targeting nanoparticles (NPs) and demonstrated their preferential localization to sites of arterial injury. Here, we develop a systemically administered, targeted NP system to deliver an antiproliferative agent to injured vasculature. Approximately 60-nm lipid–polymeric NPs were surface functionalized with collagen IV-targeting peptides and loaded with paclitaxel. In safety studies, the targeted NPs showed no signs of toxicity and a ?3.5-fold improved maximum tolerated dose versus paclitaxel. In efficacy studies using a rat carotid injury model, paclitaxel (0.3 mg/kg or 1 mg/kg) was i.v. administered postprocedure on days 0 and 5. The targeted NP group resulted in lower neointima-to-media (N/M) scores at 2 wk versus control groups of saline, paclitaxel, or nontargeted NPs. Compared with sham-injury groups, an ?50% reduction in arterial stenosis was observed with targeted NP treatment. The combination of improved tolerability, sustained release, and vascular targeting could potentially provide a safe and efficacious option in the management of CAD.

Chan, Juliana M.; Drum, Chester L.; Bronson, Roderick T.; Golomb, Gershon; Langer, Robert; Farokhzad, Omid C.

2011-01-01

203

Effect of Paclitaxel Local Delivery on Neointimal Formation after Endothelial Denudation of the Rat Carotid Artery  

Microsoft Academic Search

Background and Objectives:Mechanisms of restenosis following successful coronary angioplasty (PTCA are known as vascular smooth muscle cells (VSMCs proliferation and migration, elastic recoil or vascular wall remodeling. Paclitaxel whose effect on the stabilization of microtubles leads to cell death is highly lipophilic, permitting easy pass through cell membrane, and has a long-term antiproliferative effect. This study was performed to evaluate

Myeong-Chan Cho; Nam Joo Kwak; Hainan Piao; Tae Jin Youn

204

Ultrasound activated paclitaxel delivery in mice using a combined therapy and imaging probe system  

Microsoft Academic Search

Localized therapeutic effects of an experimental therapeutic agent on a mouse MC38 tumor model were evaluated using a combined ultrasound therapy and imaging probe system (TIPS). With ultrasound activated paclitaxel delivery, the tumor growth is substantially retarded for at least 3 days. The therapeutic effect of ultrasound is statistically significant (p=0.03) within one day after treatment but gradually decreases with

William T. Shi; Marcel Böhmer; Muzaffer Celebi; Annemieke van Wamel; Chien Ting Chin; Ceciel Chlon; Alexander L. Klibanov; Christopher S. Hall

2008-01-01

205

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

PubMed Central

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

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

2012-01-01

206

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

PubMed

Angiosarcomas are rare, aggressive vascular malignancies of endothelial cell differentiation. Kasabach-Merritt syndrome is a rare condition defined by the association of thrombocytopenia and consumption coagulopathy with specific vascular tumors, such as tufted angioma or kaposiform hemangioendothelioma. We report here two cases of angiosarcomas complicated by a Kasabach-Merritt syndrome and their outcome after treatment with paclitaxel. PMID:23980686

Grellety, Thomas; Italiano, Antoine

2013-09-01

207

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

PubMed Central

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

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

2006-01-01

208

Digitoxin activates EGR1 and synergizes with paclitaxel on human breast cancer cells  

PubMed Central

Background: Numerous studies have suggested that digitalis derivatives promise to be superior to existing adjuvant therapy for breast cancer as to effects and side-effects. In the present study, we have used gene expression analysis to determine the molecular action of digitoxin on breast cancer cells and assessed digitoxin’s ability to synergize with the chemotherapy agent paclitaxel with respect to inhibition of cell proliferation Materials and Methods: We treated (Her2 overexpressing, ER low) MDA-MB-453 human breast cancer cells with digitoxin at four doses {20 ng/ml (26 nM) to 1 ?g/ml} and collected RNA at 6 h and 24 h for gene expression analysis. To examine the effects on ER positive cells, we treated MCF7 cells with digitoxin at 1 ?g/ml and collected RNA for RT-PCR analysis. In addition, we assayed the growth inhibitory effect of low doses of digitoxin combined with paclitaxel and determined combination index values. Results: To reveal primary effects, we examined digitoxin’s effect 6 h post-treatment with the highest dose, 1?g/ml, and found upregulation of the stress response genes EGR-1 and NAB2, lipid biosynthetic genes and the tumor suppressor gene p21, and downregulation of the mitotic cell cycle gene CDC16 and the replication gene PolR3B. RT-PCR analysis validated effects on stress response, apoptotic and cell cycle genes on MDA-MB-453 and MCF7 cells. Western blot analysis confirmed induction of EGR1 protein at 1 h and ATF3 at 24 h. Paclitaxel, as well as digitoxin, inhibited the in vitro activity of the purified Na+-K+-ATPase; digitoxin enhanced the growth inhibitory effects of paclitaxel on Her2 overexpressing breast cancer cells. Conclusions: Our studies show the potential of digitoxin to prevent and treat breast cancer and indicate that the combination of digitoxin and paclitaxel is a promising treatment for ER negative breast cancer. These findings are the first to alert physicians to the possible dangers to patients who take a combination of digitoxin and paclitaxel. The potential dangers ensuing when paclitaxel and digitoxin are combined are dependent on the dose of digitoxin.

Einbond, Linda Saxe; Wu, Hsan-au; Su, Tao; Chang, Tangel; Panjikaran, Maya; Wang, Xiaomei; Goldsberry, Sarah

2010-01-01

209

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

PubMed Central

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

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

2011-01-01

210

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

PubMed Central

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

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

2011-01-01

211

Adjuvant treatment of breast cancer patients with 1–3 positive lymph nodes: vinorelbine plus epirubicin; vinorelbine plus epirubicin sequential followed up by paclitaxel; epirubicin plus cyclophosphamide; epirubicin plus cyclophosphamide sequential followed up by paclitaxel. A phase II study  

Microsoft Academic Search

Purpose. The efficacy of anthracyclin-containing adjuvant chemotherapy of node-positive breast cancer can be further improved by adding sequential paclitaxel (T). There is also clinical evidence that replacing cyclophosphamide (C) with vinorelbin (V) might further reduce toxicity. In order to assess the safety of these options, we initiated a clinical cohort study of epirubicin\\/cyclophoshamide and epirubicin\\/vinorelbine with or without sequential paclitaxel.Method.

D. Elling; H. Eggemann; S. Kümmel; P. Breitbach; A. Kohls; G. Morack; H. Schlosser; J. Krocker

2003-01-01

212

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

PubMed

Targeted drug delivery using nanocrystalline materials delivers the drug at the diseased site. This increases the efficacy of the drug in killing the cancer cells. Surface modifications were done to target the drug to a particular receptor on the cell surface. This paper reports synthesis of hydroxyapatite and titanium dioxide nanoparticles and modification of their surface with polyethylene glycol (PEG) followed by folic acid (FA). Paclitaxel, an anticancer drug, is attached to functionalized hydroxyapatite and titanium dioxide nanoparticles. The pure and functionalised nanoparticles are characterised with XRD, TEM and UV spectroscopy. Anticancer analysis was carried out in DEN induced hepatocarcinoma animals. Biochemical, hematological and histopathological analysis show that the surface modified paclitaxel attached nanoparticles have an higher anticancer activity than the pure paclitaxel and surface modified nanoparticles without paclitaxel. This is due to the targeting of the drug to the folate receptor in the cancer cells. PMID:23615724

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

2013-08-01

213

The Stent-Eluting Drugs Sirolimus and Paclitaxel Suppress Healing of the Endothelium by Induction of Autophagy  

PubMed Central

Clinical studies have indicated that the stent-eluting drugs sirolimus and paclitaxel impact restenosis; however, it is still elusive how these drugs affect the vascular endothelium at the molecular and cellular levels. The purpose of this study was to determine whether sirolimus and paclitaxel induce molecular and cellular alterations in the vascular endothelium. Endothelial regrowth was assessed in human aortic endothelial cells and rat aortic endothelium. Molecular and cellular alterations were analyzed in human aortic endothelial cells by Western blot analysis, transmission electron microscopy, and immunofluorescence staining. Green fluorescent protein-LC3 mice were used to analyze autophagic endothelium. Here, we show that sirolimus and paclitaxel differentially induce self-digesting autophagy in vascular endothelial cells with changes in expression of LC3B, p53, and Bcl-2, considerably suppressing re-endothelialization and revascularization. These results suggest that phenotypic alteration in the endothelium by sirolimus or paclitaxel might affect the rates of late stent thrombosis, myocardial infarction, and mortality.

Hayashi, Shin-ichiro; Yamamoto, Akitsugu; You, Fukka; Yamashita, Kentaro; Ikegame, Yuka; Tawada, Masahiro; Yoshimori, Tamotsu; Shimizu, Shigeomi; Nakashima, Shigeru

2009-01-01

214

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

PubMed

The purpose of this study was to investigate the effect of paclitaxel in combination with 20(s)-ginsenoside Rg3 on its anti-tumour effect in nude mice. In the Caco-2 transport assay, the apparent permeability from the apical side to the basal side (P(app)) (A-B) and P(app) (B-A) of paclitaxel were measured when co-incubated with different concentrations of 20(s)-ginsenoside Rg3. The results indicated that the penetration of paclitaxel through the Caco-2 monolayer from the apical side to the basal side was facilitated by 20(s)-ginsenoside Rg3 in a concentration-dependent manner. Meanwhile, 20(s)-ginsenoside Rg3 inhibited P-glycoprotein (P-gp), and the maximum inhibition was achieved at 80 µM (p < 0.05). The pharmacokinetic parameters of paclitaxel after oral co-administration of paclitaxel (40 mg/kg) with various doses of 20(s)-ginsenoside Rg3 in rats were investigated by an in vivo pharmacokinetic experiment. The results showed that the AUC of paclitaxel co-administered with 20(s)-ginsenoside Rg3 was significantly higher (p < 0.001 at 10 mg/kg) compared with the control. The relative bioavailability (RB) % of paclitaxel with 20(s)-ginsenoside Rg3 was 3.4-fold (10 mg/kg) higher than that of the control. The effect of paclitaxel orally co-administered with 20(s)-ginsenoside Rg3 against human tumour MCF-7 xenografts in nude mice was also evaluated. Paclitaxel (20 mg/kg) co-administered with 20(s)-ginsenoside Rg3 (10 mg/kg) exhibited an effective anti-tumour activity with the relative tumor growth rate (T/C) values of 39.36% (p <0.05). The results showed that 20(s)-ginsenoside Rg3 enhanced the oral bioavailability of paclitaxel in rats and improved the anti-tumour activity in nude mice, indicating that oral co-administration of paclitaxel with 20(s)-ginsenoside Rg3 could provide an effective strategy in addition to the established i.v. route. PMID:22898996

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

2012-09-21

215

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

Microsoft Academic Search

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

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

2000-01-01

216

Antitumour activity of ANG1005, a conjugate between paclitaxel and the new brain delivery vector Angiopep-2  

PubMed Central

Background and purpose: Paclitaxel is highly efficacious in the treatment of breast, head and neck, non-small cell lung cancers and ovarian carcinoma. For malignant gliomas, paclitaxel is prevented from reaching its target by the presence of the efflux pump P-glycoprotein (P-gp) at the blood–brain barrier. We investigated the utilization of a new drug delivery system to increase brain delivery of paclitaxel. Experimental approach: Paclitaxel molecules were conjugated to a brain peptide vector, Angiopep-2, to provide a paclitaxel–Angiopep-2 conjugate named ANG1005. We determined the brain uptake capacity, intracellular effects and antitumour properties of ANG1005 in vitro against human tumour cell lines and in vivo in human xenografts. We then determined ANG1005 activity on brain tumours with intracerebral human tumour models in nude mice. Key results: We show by in situ brain perfusion that ANG1005 enters the brain to a greater extent than paclitaxel and bypasses the P-gp. ANG1005 has an antineoplastic potency similar to that of paclitaxel against human cancer cell lines. We also demonstrate that ANG1005 caused a more potent inhibition of human tumour xenografts than paclitaxel. Finally, ANG1005 administration led to a significant increase in the survival of mice with intracerebral implantation of U87 MG glioblastoma cells or NCI-H460 lung carcinoma cells. Conclusions and implications: These results demonstrate the antitumour potential of a new drug, ANG1005, and establish that conjugation of anticancer agents with the Angiopep-2 peptide vector could increase their efficacy in the treatment of brain cancer.

Regina, A; Demeule, M; Che, C; Lavallee, I; Poirier, J; Gabathuler, R; Beliveau, R; Castaigne, J-P

2008-01-01

217

Phase III Randomized Trial of Docetaxel-Carboplatin Versus Paclitaxel-Carboplatin as First-line Chemotherapy for Ovarian Carcinoma  

Microsoft Academic Search

Background: Chemotherapy with a platinum agent and a taxane (paclitaxel) is considered the standard of care for treatment of ovarian carcinoma. We compared the com- bination of docetaxel- carboplatin with the combination of paclitaxel- carboplatin as first-line chemotherapy for stage Ic-IV epithelial ovarian or primary peritoneal can- cer. Methods: We randomly assigned 1077 patients to receive docetaxel at 75 mg\\/m2

Paul A. Vasey; Gordon C. Jayson; Alan Gordon; Hani Gabra; Rob Coleman; Ronnie Atkinson; David Parkin; James Paul; Andrea Hay; Stan B. Kaye

2004-01-01

218

In vitro and in vivo evaluation of the safety and stability of the TAXUS ® Paclitaxel-Eluting Coronary Stent  

Microsoft Academic Search

Functional aspects of the styrene-b-isobutylene-b-styrene triblock copolymer (SIBS) which is incorporated into a drug-eluting\\u000a stent (DES) coating are described. The SIBS copolymer is employed on the TAXUS® Paclitaxel-Eluting Coronary Stent as a carrier for paclitaxel (PTx). Optical and scanning electron microscopic analysis of\\u000a stents explanted from rabbit and porcine models after 2 years and 6 months, respectively, showed that the SIBS coating

Mark Boden; Robert Richard; Marlene C. Schwarz; Steve Kangas; Barbara Huibregtse; James J. Barry

2009-01-01

219

Intra-articular treatment of arthritis with microsphere formulations of paclitaxel: biocompatibility and efficacy determinations in rabbits  

Microsoft Academic Search

Objectives:To assess the biocompatibility of controlled release microspheres prepared from different polymeric biomaterials in various size ranges in rabbit synovial joints and based on these data, design and evaluate the efficacy of an intra-articular, paclitaxel-loaded microspheres formulation in rabbit models of arthritis. Methods:Paclitaxel-loaded microspheres of poly(lactide-co-glycolide) (PLGA), poly(L-lactic acid) (PLA) and poly(caprolactone) (PCL) were prepared in different size ranges and

R. T. Liggins; T. Cruz; W. Min; L. Liang; W. L. Hunter; H. M. Burt

2004-01-01

220

Co-administration of perifosine with paclitaxel synergistically induces apoptosis in ovarian cancer cells: More than just AKT inhibition  

Microsoft Academic Search

Here we report an oral alkylphospholipid perifosine dramatically sensitizes chemo-resistant ovarian cancer cells to paclitaxel induced cell death and apoptosis in vitro. We found that co-administration perifosine with paclitaxel in human ovarian cancer cells led to the inhibition of AKT\\/mTOR complex 1 (mTORC1), a marked increase in ceramide and reactive oxygen species (ROS) production, and a striking increase in the

Hui Sun; Teng Yu; Jinchao Li

2011-01-01

221

A Dose Escalation Study of the Biweekly Administration of Paclitaxel, Oxaliplatin and Capecitabine in Patients with Advanced Solid Tumors  

Microsoft Academic Search

Purpose: To determine the dose-limiting toxicities (DLTs) and the maximum-tolerated doses of the paclitaxel, oxaliplatin (LOHP) and capecitabine combination in patients with advanced solid tumors. Patients and Methods: Patients received escalating doses of paclitaxel (starting dose 100 mg\\/m2) and LOHP (starting dose 40 mg\\/m2) on days 1 and 15 and capecitabine (starting dose 800 mg\\/m2\\/day) on days 1–7 and 15–21

Zacharenia Saridaki; Vasiliki Bozionelou; Nikolaos Kentepozidis; Athanasios Kotsakis; Nikolaos Vardakis; Antonia Kalykaki; Ioannis Gioulbasanis; Athanasios Karampeazis; Lambros Vamvakas; Vassilis Georgoulias; Dimitris Mavroudis

2007-01-01

222

Paclitaxel with Cisplatin as Salvage Treatment for Patients with Previously Treated Advanced Transitional Cell Carcinoma of the Urothelial Tract  

Microsoft Academic Search

BACKGROUND: This study was performed to evaluate the safety and efficacy of paclitaxel with cisplatin as salvage therapy in patients previously treated with gemcitabine and cisplatin (G\\/C) for advanced tran- sitional cell carcinoma (TCC) of the urothelial tract. METHODS: Twenty-eight patients with metastatic or locally advanced TCC who had received prior G\\/C chemotherapy were enrolled. All patients received paclitaxel (175

Ji Eun Uhm; Ho Yeong Lim; Won Seog Kim; Han Yong Choi; Hyun Moo Lee; Byeong-Bae Park; Won Ki Kang

2007-01-01

223

Cellular Uptake and In Vitro Drug Release Studies on Paclitaxel-Loaded Poly(caprolactone)-Grafted Dextran Copolymeric Nanoparticles  

Microsoft Academic Search

Biodegradable and biocompatible polymers play a key role to provide a solution for sustained chemotherapy, when engineered\\u000a to nanostructure. One such effort has been put forward to engineer self-assembled poly(caprolactone)-grafted dextran (PGD)\\u000a core–shell micellar vehicle for anticancer drug (paclitaxel) and presented in this study. Paclitaxel-loaded PGD nanoparticles\\u000a (NPs) were prepared by a modified oil\\/water emulsion method and characterized by laser

P. Prabu; Atul A. Chaudhari; J. A. Ko; N. Dharmaraj; S. Y. Park; H. Y. Kim; M. S. Khil

2009-01-01

224

Paclitaxel and baccatin III production induced by methyl jasmonate in free and immobilized cells of Taxus baccata  

Microsoft Academic Search

The effects of 100 and 200 ?M methyl jasmonate (MJA) on cell proliferation and paclitaxel and baccatin III production were\\u000a investigated in free and alginate immobilized cells of Taxus baccata growing in a selected product formation culture medium. The greatest accumulation of paclitaxel (13.20 mg dm?3) and baccatin III (4.62 mg dm?3) occurred when 100 ?M MJA was added to

M. Bonfill; S. Bentebibel; E. Moyano; J. Palazón; R. Eibl; M. T. Piñol

2007-01-01

225

Phase 2 Trial of Paclitaxel Polyglumex with Capecitabine for Metastatic Breast Cancer.  

PubMed

BACKGROUND:: Capecitabine and paclitaxel are established effective treatments, alone and combined with other cytotoxic and targeted agents, for metastatic breast cancer (MBC). Paclitaxel polyglumex (a macromolecular conjugate of paclitaxel bound to poly-L-glutamic acid) has potential advantages over conventional paclitaxel, including little alopecia, short infusion time with no premedication, enhanced tumor permeability/retention effect, and improved tolerability. We therefore examined tolerability and efficacy of paclitaxel polyglumex with capecitabine in patients with MBC. PATIENTS AND METHODS:: This was a single-stage phase 2 study, with interim analysis conducted with endpoints of tumor response, adverse events (toxicities), time to progression, and overall survival. The main eligibility criteria were: age >18 years, no prior MBC chemotherapy, Eastern Cooperative Oncology Group performance score <2, disease measurable by RECIST criteria, no HER2 overexpression or amplification, no brain metastases or peripheral sensory neuropathy. Treatment consisted of paclitaxel polyglumex (135 mg/m) by intravenous infusion on day 1+capecitabine (825 mg/m) orally twice daily on days 1 to 14, repeated on a 3-week cycle. Forty-one evaluable patients were required to test the null hypothesis that the complete and partial tumor response rate (CR+PR) was at the most 40% against the alternative of at least 60%. Paclitaxel polyglumex+capecitabine would be considered promising in this population if ?21 responses were observed among first 41 evaluable patients. RESULTS:: Forty-eight patients were enrolled between April 2006 and April 2007; all patients were evaluable. The median number of treatment cycles administered was 6. Eighteen patients [38%; 95% confidence interval (CI), 24%-53%] had a confirmed tumor response (2 CR, 16 PR) by RECIST criteria. Fifteen (38%; 95% CI, 23%-53%) responses occurred in first 41 patients, falling short of prespecified goal of 21 responses. Median duration of tumor response was 13.2 months. Three of the responders were progression free at last follow-up with a median follow-up of 43 months. Median progression-free survival was 5.1 months (95% CI, 4.0-7.6 mo). Six-month progression-free survival was 42% (95% CI, 30%-58%). Median dose level administered was paclitaxel polyglumex (135 mg/m) and capecitabine (825 mg/m) for cycles 1 to 7. Most common severe (grade 3/4) toxicities (at least possibly related to study drug) were: leukopenia 9 (19%), neutropenia 8 (17%), neurosensory 4 (8%), skin reaction-hand/foot 4 (8%), and dyspnea 2 (4%). Forty-six percent (22/47) of patients experienced grade ?3 toxicity and 8% (4/48) experienced grade ?4 toxicity. No alopecia was reported. CONCLUSIONS:: Although the trial failed to reach goal of 21 confirmed tumor responses among the first 41 evaluable patients, paclitaxel polyglumex and capecitabine is well tolerated and effective in MBC. PMID:23211220

Northfelt, Donald W; Allred, Jacob B; Liu, Heshan; Hobday, Timothy J; Rodacker, Mark W; Lyss, Alan P; Fitch, Tom R; Perez, Edith A

2012-12-01

226

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

PubMed Central

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

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

2011-01-01

227

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

PubMed

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

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

2013-09-12

228

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

PubMed Central

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

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

2013-01-01

229

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

230

Phase III trial comparing paclitaxel poliglumex vs docetaxel in the second-line treatment of non-small-cell lung cancer  

Microsoft Academic Search

Paclitaxel poliglumex (PPX), a macromolecule drug conjugate linking paclitaxel to polyglutamic acid, reduces systemic exposure to peak concentrations of free paclitaxel. Patients with non-small-cell lung cancer (NSCLC) who had received one prior platinum-based chemotherapy received 175 or 210 mg m?2 PPX or 75 mg m?2 docetaxel. The study enrolled 849 previously treated NSCLC patients with advanced disease. Median survival (6.9

L Paz-Ares; H Ross; M O'Brien; A Riviere; U Gatzemeier; J Von Pawel; E Kaukel; L Freitag; W Digel; H Bischoff; R García-Campelo; N Iannotti; P Reiterer; I Bover; J Prendiville; A J Eisenfeld; F B Oldham; B Bandstra; J W Singer; P Bonomi

2008-01-01

231

Molecular subtypes of breast cancer in relation to paclitaxel response and outcomes in women with metastatic disease: results from CALGB 9342  

Microsoft Academic Search

INTRODUCTION: The response to paclitaxel varies widely in metastatic breast cancer. We analyzed data from CALGB 9342, which tested three doses of paclitaxel in women with advanced disease, to determine whether response and outcomes differed according to HER2, hormone receptor, and p53 status. METHODS: Among 474 women randomly assigned to paclitaxel at a dose of 175, 210, or 250 mg\\/m2,

Lyndsay N Harris; Gloria Broadwater; Nancy U Lin; Alexander Miron; Stuart J Schnitt; David Cowan; Jonathan Lara; Ira Bleiweiss; Donald Berry; Matthew Ellis; Daniel F Hayes; Eric P Winer; Lynn Dressler

2006-01-01

232

Dose-Dense Sequential Adriamycin-Paclitaxel-Cyclophosphamide Chemotherapy Is Well Tolerated and Safe in High-Risk Early Breast Cancer  

Microsoft Academic Search

Objective: The feasibility of dose-dense sequential adjuvant chemotherapy with Adriamycin, paclitaxel and cyclophosphamide was evaluated. Methods: Fifty-five high-risk breast cancer patients were enrolled. The following chemotherapy schedule was used: 4 × Adriamycin ? 4 × paclitaxel ? 4 × cyclophosphamide, q 2 weeks (Adriamycin, 60 mg\\/m2; paclitaxel, 200 mg\\/m2 over 3 h, and cyclophosphamide, 800 mg\\/m2). Results: The dose intensity

Zsuzsanna Kahan; Gabriella Uhercsak; Rozalia Hajnal-Papp; Krisztina Boda; Laszlo Thurzo

2005-01-01

233

Adjuvant dose-dense doxorubicin plus cyclophosphamide followed by dose-dense nab -paclitaxel is safe in women with early-stage breast cancer: a pilot study  

Microsoft Academic Search

Every-2-week (dose-dense) adjuvant doxorubicin (A) plus cyclophosphamide (C) followed by paclitaxel is a safe and effective\\u000a adjuvant chemotherapy regimen. Every-3-week nab-paclitaxel is safe and more effective at 50% higher dose than every-3-week paclitaxel in metastatic breast cancer (BC). This\\u000a study evaluated the safety of adjuvant dose-dense AC followed by dose-dense nab-paclitaxel for early-stage BC. Women with operable, histologically confirmed BC

Nicholas Robert; Lea Krekow; Chris Stokoe; Alicia Clawson; Jose Iglesias; Joyce O’Shaughnessy

2011-01-01

234

Heparin–Paclitaxel Conjugates Using Mixed Anhydride as Intermediate: Synthesis, Influence of Polymer Structure on Drug Release, Anticoagulant Activity and In Vitro Efficiency  

Microsoft Academic Search

Purpose  The heparin–paclitaxel conjugates using amino acid as linker (HD2), with low anticoagulant activity, the similar anticancer activity as paclitaxel, offer great potential for further investigation.\\u000a \\u000a \\u000a \\u000a Methods  Two types of heparin–paclitaxel conjugates (HD) have been developed, in which O-acetylated heparin as carrier conjugates with paclitaxel by direct ester bond (HD1) and by inserting different amino acids as spacers, including valine, leucine, and

Ying Wang; Dingcheng Xin; Kaijian Liu; Jiannan Xiang

2009-01-01

235

Activity- and schedule-dependent interactions of paclitaxel, etoposide and hydroperoxy-ifosfamide in cisplatin-sensitive and -refractory human ovarian carcinoma cell lines.  

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 a 2 h exposure to paclitaxel, hydroperoxy-ifosfamide and etoposide alone, in combination and in sequence, was evaluated against established cisplatin-sensitive and cisplatin-refractory human ovarian carcinoma cell lines using isobologram analysis. The combinations of either paclitaxel-hydroperoxy-ifosfamide or paclitaxel-etoposide were found to be additive or synergistic when the drugs were given simultaneously or when paclitaxel was given 24 h before hydroperoxy-ifosfamide or etoposide respectively. However, when etoposide or hydroperoxy-ifosfamide were given before paclitaxel, antagonistic interactions were observed. With regard to etoposide this antagonism was evident for up to 24 h. In agreement with our data with the schedule-dependent interactions of paclitaxel and cisplatin in human gastric and ovarian carcinoma cell lines, these data demonstrate that the interactions of paclitaxel, etoposide and hydroperoxy-ifosfamide are also highly schedule dependent and applications of etoposide or ifosfamide before paclitaxel may result in pronounced antagonism. These findings could have implications for the design of further clinical protocols. PMID:8688325

Klaassen, U; Harstrick, A; Schleucher, N; Vanhoefer, U; Schröder, J; Wilke, H; Seeber, S

1996-07-01

236

Activity- and schedule-dependent interactions of paclitaxel, etoposide and hydroperoxy-ifosfamide in cisplatin-sensitive and -refractory human ovarian carcinoma cell lines.  

PubMed Central

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 a 2 h exposure to paclitaxel, hydroperoxy-ifosfamide and etoposide alone, in combination and in sequence, was evaluated against established cisplatin-sensitive and cisplatin-refractory human ovarian carcinoma cell lines using isobologram analysis. The combinations of either paclitaxel-hydroperoxy-ifosfamide or paclitaxel-etoposide were found to be additive or synergistic when the drugs were given simultaneously or when paclitaxel was given 24 h before hydroperoxy-ifosfamide or etoposide respectively. However, when etoposide or hydroperoxy-ifosfamide were given before paclitaxel, antagonistic interactions were observed. With regard to etoposide this antagonism was evident for up to 24 h. In agreement with our data with the schedule-dependent interactions of paclitaxel and cisplatin in human gastric and ovarian carcinoma cell lines, these data demonstrate that the interactions of paclitaxel, etoposide and hydroperoxy-ifosfamide are also highly schedule dependent and applications of etoposide or ifosfamide before paclitaxel may result in pronounced antagonism. These findings could have implications for the design of further clinical protocols.

Klaassen, U.; Harstrick, A.; Schleucher, N.; Vanhoefer, U.; Schroder, J.; Wilke, H.; Seeber, S.

1996-01-01

237

In Vitro assessment of the utility of stearyl triphenyl phosphonium modified liposomes in overcoming the resistance of ovarian carcinoma Ovcar-3 cells to paclitaxel.  

PubMed

Paclitaxel loaded in liposomes modified with stearyl triphenyl phosphonium (STPP) showed improved mitochondrial colocalization and cytotoxicity in a paclitaxel resistant cell line. The improvement in cytotoxicity was not solely due to the increased accumulation of paclitaxel in mitochondria but also due to the specific toxicity of STPP towards the resistant cell line. Mechanistic studies revealed that the cytotoxicity of STPP was associated with a decrease in mitochondrial membrane potential and other hallmarks related to caspase-independent cell death (CICD). This specific toxicity of STPP towards the paclitaxel resistant cell line was also maintained in three-dimensional in vitro spheroid cultures. PMID:23123917

Solomon, Melani A; Shah, Anee A; D'Souza, Gerard G M

2012-11-01

238

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

PubMed Central

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

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

2012-01-01

239

Pharmacokinetics and tissue distribution of PGG–paclitaxel, a novel macromolecular formulation of paclitaxel, in nu\\/nu mice bearing NCI460 lung cancer xenografts  

Microsoft Academic Search

Purpose  PGG–PTX is a water-soluble formulation of paclitaxel (PTX), made by conjugating PTX to poly(l-?-glutamylglutamine) acid (PGG) via ester bonds, that spontaneously forms a nanoparticle in aqueous environments. The purpose\\u000a of this study was to compare the pharmacokinetics and tissue distribution of PTX following injection of either free PTX or\\u000a PGG–PTX in mice.\\u000a \\u000a \\u000a \\u000a Experimental design  Both [3H]PTX and PGG–[3H]PTX were administered as

Xinghe Wang; Gang Zhao; Sang Van; Nan Jiang; Lei Yu; David Vera; Stephen B. Howell

2010-01-01

240

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

PubMed Central

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

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

2000-01-01

241

[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

242

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

NASA Astrophysics Data System (ADS)

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

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

2013-02-01

243

Confocal Raman data analysis enables identifying apoptosis of MCF-7 cells caused by anticancer drug paclitaxel  

NASA Astrophysics Data System (ADS)

Confocal Raman microscopy is a noninvasive, label-free imaging technique used to study apoptosis of live MCF-7 cells. The images are based on Raman spectra of cells components, and their apoptosis is monitored through diffusion of cytochrome c in cytoplasm. K-mean clustering is used to identify mitochondria in cells, and correlation analysis provides the cytochrome c distribution inside the cells. Our results demonstrate that incubation of cells for 3 h with 10 ?M of paclitaxel does not induce apoptosis in MCF-7 cells. On the contrary, incubation for 30 min at a higher concentration (100 ?M) of paclitaxel induces gradual release of the cytochrome c into the cytoplasm, indicating cell apoptosis via a caspase independent pathway.

Salehi, Hamideh; Middendorp, Elodie; Panayotov, Ivan; Dutilleul, Pierre-Yves Collard; Vegh, Attila-Gergely; Ramakrishnan, Sathish; Gergely, Csilla; Cuisinier, Frederic

2013-05-01

244

Paclitaxel coated balloons for coronary artery interventions: a comprehensive review of preclinical and clinical data.  

PubMed

After the "mechanical era" in interventional cardiology (represented by balloon angioplasty and bare metal stent implantation), arrived the "local dispensing" era, began with the intracoronary delivery of antithrombotic or antirestenotic drugs. However, even drug eluting stents have some pitfalls and cannot be used in all clinical subsets. In this article we will review the significant data on the paclitaxel-coated balloons for the treatment of coronary artery disease. Particularly, we will review the rationale of this new treatment strategy, the preclinical data and will focus on available clinical studies in humans. After the initial boost of the paclitaxel coated balloons with the Paccocath technology in in-stent restenotic lesions, the experimentation of newer devices in native coronary arteries raised some concerns on their efficacy and safety. We will comment on this topic trying to understand the reasons of this failure, and will discuss on possible future developments and applications for these devices for the treatment of coronary artery disease. PMID:21955612

Cortese, Bernardo; Bertoletti, Alessandra

2011-09-28

245

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

246

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

PubMed Central

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

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

2001-01-01

247

Herbal medicine Shakuyaku-kanzo-to reduces paclitaxel-induced painful peripheral neuropathy in mice  

Microsoft Academic Search

ObjectivesPaclitaxel is widely used in cancer chemotherapy for the treatment of solid tumors such as breast, ovarian and lung cancer. However, it sometimes induces moderate to severe muscle pain, and impairs the patients’ quality of life. An appropriate method for relieving this pain is not well established. Shakuyaku-kanzo-to, a herbal medicine, is known to relieve menstrual pain, muscle spasm, and

Takao Hidaka; Tomoko Shima; Kiyofumi Nagira; Masahiro Ieki; Takafumi Nakamura; Yukiko Aono; Yasushi Kuraishi; Takashi Arai; Shigeru Saito

2009-01-01

248

Profound and persistent painful paclitaxel peripheral neuropathy in a premenopausal patient  

PubMed Central

The authors herein report the case of a 35-year-old woman undergoing adjuvant therapy for node positive breast cancer, who presented with short and rapidly progressive history of bilateral lower limb symptoms of peripheral neuropathy following therapy with paclitaxel. MRI of her neural axis revealed no leptomeningeal enhancement or focal metastatic lesions. Neurophysiological tests favoured toxic sensory axonal polyneuropathy. She remains symptomatic following discontinuation of therapy 20 months ago, and is under review with pain management.

Quintyne, K I; Mainstone, P; McNamara, B; Boers, P; Wallis, F; Gupta, R K

2011-01-01

249

Assessment of Paclitaxel Induced Sensory Polyneuropathy with "Catwalk" Automated Gait Analysis in Mice  

PubMed Central

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

Endres, Matthias

2013-01-01

250

Assessment of Paclitaxel induced sensory polyneuropathy with "catwalk" automated gait analysis in mice.  

PubMed

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

Huehnchen, Petra; Boehmerle, Wolfgang; Endres, Matthias

2013-10-15

251

Paclitaxel-loaded Pluronic nanoparticles formed by a temperature-induced phase transition for cancer therapy  

Microsoft Academic Search

We prepared nanoparticles by a temperature-induced phase transition in a mixture of Pluronic F-68 and liquid PEG (polyethylene glycol, molecular weight: 400) containing paclitaxel (PTX) with a fast, simple, continuous and solvent-free process. The liquid PEG is used as solubilizer of PTX and the polymer for the encapsulation of PTX is composed of Pluronic F-68. At the phase transition temperature,

Keun Sang Oh; Ji Yung Song; Sun Hang Cho; Bum Suk Lee; Sang Yoon Kim; Kwangmeyung Kim; Hyesung Jeon; Ick Chan Kwon; Soon Hong Yuk

2010-01-01

252

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

Microsoft Academic Search

In an effort to develop an alternative formulation of paclitaxel (PTX) suitable for intravenous administration, PTX-loaded\\u000a sterically stabilized solid lipid nanoparticles (SLNs) were prepared and their pharmacokinetics and biodistribution were investigated.\\u000a The pegylated SLNs were comprised of trimyristin (TM) as a solid lipid core and egg phosphatidylcholine and pegylated phospholipid\\u000a as stabilizers. The prepared pegylated TM-SLNs containing PTX exhibited monodispersed

Rihua Li; Jae Soon Eun; Mi-Kyung Lee

2011-01-01

253

Phase II Trial of Cetuximab With or Without Paclitaxel in Patients With Advanced Urothelial Tract Carcinoma  

PubMed Central

Purpose The benefit of salvage chemotherapy is modest in metastatic urothelial cancer. We conducted a randomized, noncomparative phase II study to measure the efficacy of cetuximab with or without paclitaxel in patients with previously treated urothelial cancer. Patients and Methods Patients with metastatic urothelial cancer who received one line of chemotherapy in the perioperative or metastatic setting were randomly assigned to 4-week cycles of cetuximab 250 mg/m2 with or without paclitaxel 80 mg/m2 per week. We used early progression as an indicator of futility. Either arm would close if seven of the initial 15 patients in that arm progressed at the first disease evaluation at 8 weeks. Results We enrolled 39 evaluable patients. The single-agent cetuximab arm closed after nine of the first 11 patients progressed by 8 weeks. The combination arm completed the full accrual of 28 patients, of whom 22 patients (78.5%) had visceral disease. Twelve of 28 patients had progression-free survival greater than 16 weeks. The overall response rate was 25% (95% CI, 11% to 45%; three complete responses and four partial responses). The median progression-free survival was 16.4 weeks (95% CI, 12 to 25.1 weeks), and the median overall survival was 42 weeks (95% CI, 30.4 to 78 weeks). Treatment-related grade 3 and 4 adverse events that occurred in at least two patients were rash (six cases), fatigue (five cases), and low magnesium (three cases). Conclusion Although it had limited activity as a single agent, cetuximab appears to augment the antitumor activity of paclitaxel in previously treated urothelial cancers. The cetuximab and paclitaxel combination merits additional study to establish its role in the treatment of urothelial cancers.

Wong, Yu-Ning; Litwin, Samuel; Vaughn, David; Cohen, Seth; Plimack, Elizabeth R.; Lee, James; Song, Wei; Dabrow, Michael; Brody, Marion; Tuttle, Holly; Hudes, Gary

2012-01-01

254

Paclitaxel with cisplatin in concurrent chemoradiotherapy for locally advanced nasopharyngeal carcinoma  

Microsoft Academic Search

The aim of this study was to evaluate the efficacy and the toxicity of paclitaxel and cisplatin in patients in concurrent\\u000a radiotherapy for locally advanced nasopharyngeal carcinoma, and to see whether such a regime would be better tolerated than\\u000a high dose cisplatin plus fluoracil in Chinese patients. Thirty-one patients with locally advanced nasopharyngeal carcinoma\\u000a were enrolled. Patients were scheduled to

Xia-Yun He; Chao-Su Hu; Hong-Mei Ying; Yong-Ru Wu; Guo-Pei Zhu; Tai-Fu Liu

2010-01-01

255

Visualization and comparison of drug effects after local paclitaxel delivery with different catheter types  

Microsoft Academic Search

Background: The microtubule stabilizing compound paclitaxel has proved to have potent antiproliferative effects on smooth muscle cells\\u000a both in vitro and in vivo. It induces cellular modifications that result in reduced proliferation, migration and signal transduction\\u000a by shifting the cellular microtubule equilibrium towards assembly. We therefore reasoned that a visualization of the altered\\u000a cytoskeleton could enable an evaluation of the

Christian Herdeg; Martin Oberhoff; Andreas Baumbach; Andreas Blattner; Axel Küttner; Stephen Schröder; Karl K. Haase; Karl R. Karsch

1999-01-01

256

Sirolimus- versus Paclitaxel-Eluting Stent Implantation for Unprotected Left Main Coronary Artery Stenosis  

Microsoft Academic Search

We performed this study in order to compare the immediate and mid-term outcomes of sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES) in lesions of the unprotected left main coronary artery (LMCA). We assessed 54 patients from 5 centers who had undergone unprotected LMCA stenting (35 SES and 19 PES). The procedural success rates were 100 and 95%, respectively, in the

Sang Hak Lee; Young-Guk Ko; Yangsoo Jang; Hyuck Moon Kwon; Seung-Hwan Lee; Jung Han Yoon; Si Hoon Park; Byung Ok Kim; Dong Woon Jeon; Joo Young Yang; Seung-Ki Ryu

2005-01-01

257

Application of Paclitaxel-Eluting Metal Stents in Renal Artery of Pig Model  

Microsoft Academic Search

Background and Purpose: Recent reports concerning coronary, carotid, and femoral vasculature have pro- posed the use of drug-eluting metal stents (MS) to improve clinical and angiographic outcomes. Based on these reports, we used paclitaxel-eluting MS within an animal renal artery lumen and compared the results with those using a bare-metal stent. Materials and Methods: The experimental model in this study

Theodore Voudoukis; Evangelos N. Liatsikos; George C. Kagadis; Nicolaos Christeas; Nicolaos Flaris; Konstantinos Katsanos; Constantinos Costantinides; Petros Perimenis; Chrisoula D. Scopa; Kriton S. Filos; George C. Nikiforidis; Dimitrios Alexopoulos; Dimitrios Siablis

2007-01-01

258

Blends of Paclitaxel with POSS-Based Biodegradable Polyurethanes: Morphology, Miscibility, and Specific Interactions  

Microsoft Academic Search

The morphology, miscibility, and specific interactions of paclitaxel (PTx) with a family of polyhedral oligosilsesquioxane (POSS)-based biodegradable thermoplastic polyurethanes (POSS TPUs) were investigated systematically using wide-angle X-ray diffraction (WAXD), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR). These POSS TPUs incorporate an alternating multiblock structure formed by POSS hard segments and the soft segments composed of polylactide\\/caprolactone copolymer

Qiongyu Guo; Pamela T. Knight; Jian Wu; Patrick T. Mather

2010-01-01

259

Drug-eluting stents show delayed healing: paclitaxel more pronounced than sirolimus  

Microsoft Academic Search

Aims To understand wound healing after drug-eluting stents (DES) placement in humans, we studied the histology of in-stent restenosis (ISR) tissue obtained by atherectomy from bare metal stents (BMS) and DES in comparison with de novo atherosclerosis. Methods and results The tissue was retrieved from ISR in ten sirolimus-eluting stents (SES) and nine paclitaxel-eluting stents (PES), six BMS, and nine

Heleen M. M. van Beusekom; Francesco Saia; Jaap D. Zindler; Pedro A. Lemos; Stijn L. Swager-ten Hoor; Maarten A. H. van Leeuwen; Pim J. de Feijter; Patrick W. Serruys; Willem J. van der Giessen

260

A phase I and pharmacokinetic study of NK105, a paclitaxel-incorporating micellar nanoparticle formulation  

Microsoft Academic Search

This phase I study was designed to examine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), the recommended dose (RD) for phase II, and the pharmacokinetics of NK105, a new polymeric micelle carrier system for paclitaxel (PTX). NK105 was administered as a 1-h intravenous infusion every 3 weeks, without antiallergic premedication. The starting dose was 10 mg m?2, and

T Hamaguchi; K Kato; H Yasui; C Morizane; M Ikeda; H Ueno; K Muro; Y Yamada; T Okusaka; K Shirao; Y Shimada; H Nakahama; Y Matsumura

2007-01-01

261

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

262

Visual evoked potentials findings in course of paclitaxel doxorubicin combination chemotherapy  

Microsoft Academic Search

The case of a 63 year-old woman affected by advanced breast cancer is reported. Chemotherapy with paclitaxel (200 mg\\/m2) and doxorubicin (60 mg\\/m2) every three weeks was given for 8 cycles. The patient progressively developed a sensory-motor neuropathy of axonal type. After the 6th chemotherapy cycle the patient complained of subjective visual symptoms without a relevant reduction of visual acuity.

Vidmer Scaioli; Augusto Caraceni; Cinzia Martini; Elena Palazzini; Emiliana Tarenzi; Fabio Fulfaro; Elisabetta Munzone

1995-01-01

263

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

PubMed

Prodigiosin is a bacterial metabolite with potent anticancer activity, which is attributed to its proapoptotic effect selectively active in malignant cells. Still, the molecular mechanisms whereby prodigiosin induces apoptosis remain largely unknown. In particular, the role of survivin, a vital inhibitor of apoptosis, in prodigiosin-induced apoptosis has never been addressed before and hence was the primary goal of this study. Our results showed that prodigiosin dose-dependently induced down-regulation of survivin in multiple breast carcinoma cell lines, including MCF-7, T-47D and MDA-MB-231. This down-regulation is mainly regulated at the level of transcription, as prodigiosin reduced the levels of both survivin mRNA and survivin promoter activity but failed to rescue survivin expression when proteasome-mediated degradation is abolished. Importantly, overexpression of survivin rendered cells more resistant to prodigiosin, indicating an essential role of survivin down-regulation in prodigiosin-induced apoptosis. In addition, we found that prodigiosin synergistically enhanced cell death induced by paclitaxel, a chemotherapy drug known to up-regulate survivin that in turn confers its own resistance. This paclitaxel sensitization effect of prodigiosin is ascribed to the lowering of survivin expression, because prodigiosin was shown to counteract survivin induction by paclitaxel and, notably, the sensitization effect was severely abrogated in cells that overexpress survivin. Taken together, our results argue that down-regulation of survivin is an integral component mediating prodigiosin-induced apoptosis in human breast cancer cells, and further suggest the potential of prodigiosin to sensitize anticancer drugs, including paclitaxel, in the treatment of breast cancer. PMID:19133282

Ho, Tsing-Fen; Peng, Yu-Ta; Chuang, Show-Mei; Lin, Shin-Chang; Feng, Bo-Lin; Lu, Chien-Hsing; Yu, Wan-Ju; Chang, Jo-Shu; Chang, Chia-Che

2008-12-24

264

Enhanced paclitaxel production induced by the combination of elicitors in cell suspension cultures of Taxus chinensis  

Microsoft Academic Search

Taxus chinensis suspension cells were cultured in the modified Gamborg's B5 medium. Addition of 50 mg chitosan l-1, 60 µM methyl jasmonate and 30 µM Ag+ resulted in the greatest paclitaxel production, at 25 mg l-1 in the cultures, being almost 40 times higher than that of the control culture, 10 times higher than that of the culture exposed to

C. H. Zhang; X. G. Mei; L. Liu; L. J. Yu

2000-01-01

265

Long Circulating Lectin Conjugated Paclitaxel Loaded Magnetic Nanoparticles: A New Theranostic Avenue for Leukemia Therapy  

Microsoft Academic Search

Amongst all leukemias, Bcr-Abl positive chronic myelogenous leukemia (CML) confers resistance to native drug due to multi drug resistance and also resistance to p53 and fas ligand pathways. In the present study, we have investigated the efficacy of microtubule stabilizing paclitaxel loaded magnetic nanoparticles (pac-MNPs) to ascertain its cytotoxic effect on Bcr-Abl positive K562 cells. For active targeted therapy, pac-MNPs

Abhalaxmi Singh; Fahima Dilnawaz; Sanjeeb Kumar Sahoo

2011-01-01

266

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

Microsoft Academic Search

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

Jingwei Xie; Chi-Hwa Wang

2006-01-01

267

Albumin-bound formulation of paclitaxel (Abraxane® ABI-007) in the treatment of breast cancer  

PubMed Central

Breast cancer is the most common type of malignancy diagnosed in women. In the metastatic setting this disease is still uncurable. Taxanes represent an important class of antitumor agents which have proven to be fundamental in the treatment of advanced and early-stage breast cancer, but the clinical advances of taxanes have been limited by their highly hydrophobic molecular status. To overcome this poor water solubility, lipid-based solvents have been used as a vehicle, and new systemic formulations have been developed, mostly for paclitaxel, which are Cremophor-free and increase the circulation time of the drug. ABI-007 is a novel, albumin-bound, 130-nm particle formulation of paclitaxel, free from any kind of solvent. It has been demonstrated to be superior to an equitoxic dose of standard paclitaxel with a significantly lower incidence of toxicities in a large, international, randomized phase III trial. The availability of new drugs, such as Abraxane®, in association with other traditional and non-traditional drugs (new antineoplastic agents and targeted molecules), will give the oncologist many different effective treatment options for patients in this setting.

Miele, Evelina; Spinelli, Gian Paolo; Miele, Ermanno; Tomao, Federica; Tomao, Silverio

2009-01-01

268

In vivo evaluation of lipid nanocapsules as a promising colloidal carrier for paclitaxel.  

PubMed

Paclitaxel-loaded lipid nanocapsules (PX-LNC) exhibit interesting in vitro characteristics with improved antitumoral activity compared with free PX formulation. Biodistribution studies were realized with the use of (14)C-trimyristin ((14)C-TM) or (14)C-phosphatidylcholine ((14)C-PC) whereas antitumoral activity of PX-LNC formulations was based on the animal survival in a chemically induced hepatocellular carcinoma (HCC) model in Wistar rats. Blood concentration-time profiles for both labeled (14)C-TM-LNC and (14)C-PC-LNC were similar; the t(1/2) and MRT values (over 2h and close to 3h, respectively, for both formulations) indicated the long circulating properties of the LNC carrier with a slow distribution and elimination phase. Survival curves of paclitaxel treated groups showed a statistical significant difference compared to the control survival curve (P=0.0036 and 0.0408). Animals treated with 4x 70 mg/m(2) of PX-LNC showed the most significant increase in mean survival times compared to the controls (IST(mean) 72%) and cases of long-term survivors were preferentially observed in the PX-LNC treated group (37.5%; 3/8). These results demonstrate the great interest to use LNC as drug delivery system for paclitaxel, permitting with an equivalent therapeutic efficiency to avoid the use of excipients such as polyoxyethylated castor oil for its formulation. PMID:17646066

Lacoeuille, F; Hindre, F; Moal, F; Roux, J; Passirani, C; Couturier, O; Cales, P; Le Jeune, J J; Lamprecht, A; Benoit, J P

2007-06-19

269

Chemosensitizing activities of cyclotides from Clitoria ternatea in paclitaxel-resistant lung cancer cells  

PubMed Central

Cyclotides comprise a family of circular mini-peptides that have been isolated from various plants and have a wide range of bioactivities. Previous studies have demonstrated that cyclotides have antitumor effects and cause cell death by membrane permeabilization. The present study aimed to evaluate the cytotoxicity and chemosensitizing activities of cyclotides from Clitoria ternatea in paclitaxel-resistant lung cancer cells. In this study, a total of seven cyclotides were selected for colorimetric cell viability assay (MTT assay) to evaluate their anticancer and chemosensitizing activities in the lung cancer cell line A549 and its sub-line A549/paclitaxel. Results suggested that certain cyclotides had significant anticancer and chemosensitizing abilities; such cyclotides were capable of causing multi-fold decreases in the half maximal inhibitory concentration (IC50) value of cliotides in the presence of paclitaxel. More importantly, their bioactivities were found to be correlated with their net charge status. In conclusion, cyclotides from C. ternatea have potential in chemosensitization application.

SEN, ZHANG; ZHAN, XIAO KAI; JING, JIN; YI, ZHANG; WANQI, ZHOU

2013-01-01

270

Analysis of aggregate size as a process variable affecting paclitaxel accumulation in Taxus suspension cultures  

PubMed Central

Plant cell aggregates have long been implicated in affecting cellular metabolism in suspension culture, yet the rigorous characterization of aggregate size as a process variable and its effect on bioprocess performance has not been demonstrated. Aggregate fractionation and analysis of biomass-associated product is commonly used to assess the effect of aggregation, but we establish that this method is flawed under certain conditions and does not necessarily agree with comprehensive studies of total culture performance. Leveraging recent advances to routinely measure aggregate size distributions, we developed a simple method to manipulate aggregate size and evaluate its effect on the culture as a whole, and found that Taxus suspension cultures with smaller aggregates produced significantly more paclitaxel than cultures with larger aggregates in two cell lines over a range of aggregate sizes, and where biomass accumulation was equivalent prior to elicitation with methyl jasmonate. T. cuspidata P93AF cultures with mean aggregate sizes of 690 ?m and 1100 ?m produced 22 mg/L and 11 mg/L paclitaxel, respectively, a 2-fold increase for smaller aggregates, and T. cuspidata P991 cultures with mean aggregate sizes of 400 ?m and 840 ?m produced 6 mg/L and 0.3 mg/L paclitaxel, respectively, an increase of 20-fold for smaller aggregates. These results demonstrate the importance of validating experiments aimed at a specific phenomenon with total process studies, and provide a basis for treating aggregate size as a targeted process variable for rational control strategies.

Kolewe, Martin E.; Henson, Michael A.; Roberts, Susan C.

2013-01-01

271

Long Circulating Lectin Conjugated Paclitaxel Loaded Magnetic Nanoparticles: A New Theranostic Avenue for Leukemia Therapy  

PubMed Central

Amongst all leukemias, Bcr-Abl positive chronic myelogenous leukemia (CML) confers resistance to native drug due to multi drug resistance and also resistance to p53 and fas ligand pathways. In the present study, we have investigated the efficacy of microtubule stabilizing paclitaxel loaded magnetic nanoparticles (pac-MNPs) to ascertain its cytotoxic effect on Bcr-Abl positive K562 cells. For active targeted therapy, pac-MNPs were functionalized with lectin glycoprotein which resulted in higher cellular uptake and lower IC50 value suggesting the efficacy of targeted delivery of paclitaxel. Both pac-MNPs and lectin conjugated pac-MNPs have a prolonged circulation time in serum suggesting increased bioavailability and therapeutics index of paclitaxel in vivo. Further, the molecular mechanism pertaining to pac-induced cytotoxicity was analyzed by studying the involvement of different apoptotic pathway proteins by immunoblotting and quantitative PCR. Our study revealed simultaneous activation of JNK pathway leading to Bcr-Abl instability and the extrinsic apoptotic pathway after pac-MNPs treatment in two Bcr-Abl positive cell lines. In addition, the MRI data suggested the potential application of MNPs as imaging agent. Thus our in vitro and in vivo results strongly suggested the pac-MNPs as a future prospective theranostic tool for leukemia therapy.

Singh, Abhalaxmi; Dilnawaz, Fahima; Sahoo, Sanjeeb Kumar

2011-01-01

272

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

PubMed

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

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

2012-01-19

273

Selective cyclooxygenase inhibitors increase paclitaxel sensitivity in taxane-resistant ovarian cancer by suppressing P-glycoprotein expression  

PubMed Central

Objective The purpose of this study was to investigate whether selective cyclooxygenase (COX) inhibitors promote paclitaxel-induced apoptosis in taxane-resistant ovarian cancer cells by suppressing MDR1/P-glycoprotein (P-gp) expression. Methods Taxane-resistant ovarian cancer cells were cultured with paclitaxel alone or combined with a selective COX inhibitors. The expression patterns of MDR1/P-gp and the ability of COX inhibitors to inhibit growth of taxane-resistant ovarian cancer cells were measured. The efficacy of prostaglandin E2 (PGE2) supplementation was measured to evaluate the mechanisms involved in suppressing MDR1 gene expression. Results P-gp was upregulated in taxane-resistant ovarian cancer cells compared to paired paclitaxel-sensitive ovarian cancer cells. An 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that selective COX inhibitors significantly enhanced the cytotoxic effects of paclitaxel in taxane-resistant ovarian cancer cells via a prostaglandin-independent mechanism. These increased apoptotic effects were further verified by measuring an increased percentage of cells in sub-G1 stage using flow cytometry. Selective COX inhibitors suppressed MDR1 and P-gp expression. Moreover, combined treatment with paclitaxel and selective COX inhibitors increased poly (ADP-ribose) polymerase (PARP) cleavage in taxane-resistant ovarian cancer cells. Conclusion Selective COX inhibitors significantly promote paclitaxel-induced cell death in taxane-resistant ovarian cancer cells in a prostaglandin-independent manner. COX inhibitors could be potent therapeutic tools to promote paclitaxel sensitization of taxane-resistant ovarian cancers by suppressing MDR1/P-gp, which is responsible for the efflux of chemotherapeutic agents.

Lee, Jung-Pil; Hahn, Ho-Suap; Hwang, Soo-Jin; Choi, Ji-Young; Lee, In-Ho

2013-01-01

274

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

PubMed Central

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

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

2011-01-01

275

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

276

Nab-paclitaxel for first-line treatment of patients with metastatic breast cancer and poor prognostic factors: a retrospective analysis.  

PubMed

Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) has demonstrated clinical benefit in metastatic breast cancer (MBC) in a randomized phase III trial versus paclitaxel (CA012; N = 454) and in a randomized phase II trial versus docetaxel (CA024; N = 300). This retrospective analysis examines whether patients with poor prognostic factors demonstrate similar outcomes to the intent-to-treat (ITT) populations in these trials. This retrospective analysis evaluated the efficacy and safety of previously untreated patients with MBC with the following poor prognostic factors: visceral dominant metastases and short disease-free interval (DFI; ?2 years). In CA012 (n = 186 first-line patients), nab-paclitaxel demonstrated a significantly higher overall response rate (ORR) versus paclitaxel in patients with visceral dominant metastases (42 vs. 23 %; P = 0.022), whereas the higher ORR for nab-paclitaxel in patients with a short DFI (43 vs. 33 %; P = NS) was not statistically significant. In CA024, a significantly higher ORR for nab-paclitaxel 150 mg/m(2) versus docetaxel was observed in patients with visceral dominant metastases (76 vs. 37 %; P < 0.001). No significant differences in ORR were observed in patients with a short DFI. Although progression-free survival (PFS) and overall survival showed trends similar to ORR, statistical significance was only achieved for comparisons of PFS in patients with visceral dominant metastases in CA024 (13.1 months for nab-paclitaxel 150 mg/m(2) vs. 7.8 months for docetaxel [P = 0.019] and 7.5 months for nab-paclitaxel 100 mg/m(2) [P = 0.010]). Safety results were similar to previous reports of the ITT populations. nab-Paclitaxel demonstrated similar efficacy in patients with poor prognostic factors as in the ITT populations of these two trials. In each trial, ORR was significantly higher for nab-paclitaxel versus the comparator taxane among patients with visceral dominant metastases. PMID:23563958

O'Shaughnessy, Joyce; Gradishar, William J; Bhar, Paul; Iglesias, Jose

2013-04-06

277

Safety of nanoparticle albumin-bound paclitaxel administered to breast cancer patients with clinical contraindications to paclitaxel or docetaxel: Four case reports  

PubMed Central

Taxanes, including paclitaxel (PTX) and docetaxel (DOC), are poorly soluble in water due to their hydrophobic properties and thus, require solvents. However, use of these solvents has been associated with toxic responses, including a hypersensitivity reaction (HSR). Nanoparticle albumin-bound paclitaxel (nab-PTX) is a novel formulation of PTX, which allows reconstitution of the agent with a saline solution instead of solvents and administration without premedication for HSRs. The current study reports the safe administration of nab-PTX to four breast cancer patients considered clinically to have contraindications to PTX or DOC. Two of the patients had previously experienced HSRs to PTX or DOC and the other two patients had contraindications to steroids as a premedication for HSRs, since one patient suffered from diabetes and the other was a carrier of the hepatitis B virus. All 4 patients were safely administered nab-PTX. In conclusion, administration of nab-PTX appears to be effective for patients that have previously experienced HSRs to other taxanes or in those with contraindications to steroids.

KIMURA, KOSEI; TANAKA, SATORU; IWAMOTO, MITSUHIKO; FUJIOKA, HIROYA; TAKAHASHI, YUKO; SATO, NAYUKO; TERASAWA, RISA; TOMINAGA, TOMO; IKARI, AYANA; UCHIYAMA, KAZUHISA

2013-01-01

278

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

PubMed

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

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

2011-02-14

279

Paclitaxel plus Carboplatin Chemotherapy for Primary Peritoneal Carcinoma: A Study of 22 Cases and Comparison with Stage III–IV Ovarian Serous Carcinoma  

Microsoft Academic Search

The aim of this study was to assess the clinical characteristics and outcome of patients with either primary peritoneal carcinoma (PPC) or ovarian serous carcinoma (OSC) treated with paclitaxel plus carboplatin chemotherapy. We retrospectively identified 22 PPC patients and 55 stage III–IV OSC patients treated between 2002 and 2007. After exploratory laparotomy, all patients received paclitaxel and carboplatin every 3

R. Kawaguchi; Y. Tanase; S. Haruta; A. Nagai; S. Yoshida; N. Furukawa; H. Ooi; K. Kobayashi

2012-01-01

280

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

Microsoft Academic Search

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

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

2000-01-01

281

Mechanisms of the Synergistic Interaction between the Bisphosphonate Zoledronic Acid and the Chemotherapy Agent Paclitaxel in Breast Cancer Cells in vitro  

Microsoft Academic Search

Breast cancer patients often receive both paclitaxel and zoledronic acid as part of their treatment, and these drugs are reported to have synergistic effects on the induction of apoptosis of breast cancer cells in vitro. We have found that the synergistic interaction is drug sequence dependent, with maximal levels of apoptosis achieved when cells are treated with paclitaxel followed by

H. L. Neville-Webbe; C. A. Evans; R. E. Coleman; I. Holen

2006-01-01

282

Effects of local intracoronary paclitaxel delivery using the Remedy transport catheter on neointimal hyperplasia after stent implantation in a porcine model  

Microsoft Academic Search

PurposeTo assess the effects of local paclitaxel delivery using the Remedy catheter on neointimal hyperplasia in a porcine model and compare these results to commercially available BMS and biodegradable polymer-coated paclitaxel-eluting stents (BP-PES).

Krzysztof Milewski; Aleksander Zurakowski; Jacek Pajak; Lukasz Liszka; Marcin Debinski; Piotr P. Buszman; Motaz Abu Samra; Piotr Dominek; Michael S. Aboodi; Grzegorz L. Kaluza; Pawel Buszman

2011-01-01

283

Phase 2 Trial of Single Agent Ifosfamide\\/Mesna in Patients with Platinum\\/Paclitaxel Refractory Ovarian Cancer Who Have Not Previously Been Treated with an Alkylating Agent  

Microsoft Academic Search

Ifosfamide has been shown to possess modest activity in patients with platinum\\/cyclophosphamide refractory ovarian cancer. Current standard initial chemotherapy for ovarian cancer does not include an alkylating agent (paclitaxel substituting for cyclophosphamide). To evaluate the activity of ifosfamide in patients with refractory ovarian cancer who had not previously received an alkylating agent, 21 patients with platinum\\/paclitaxel refractory disease were treated

Maurie Markman; Alexander Kennedy; Gregory Sutton; Jean Hurteau; Kenneth Webster; Gertrude Peterson; Barbara Kulp; Jerome Belinson

1998-01-01

284

Crosstalk between autophagy and apoptosis in the regulation of paclitaxel-induced cell death in v-Ha-ras-transformed fibroblasts.  

PubMed

The previous studies by this author group has shown that paclitaxel, a mitotic inhibitor used in breast cancer chemotherapy, inhibits cell growth via induction of Raf-1-dependent apoptosis. In this article, the role of autophagy in paclitaxel anticancer action was investigated using v-Ha-ras-transformed NIH 3T3 cells. Paclitaxel induced a notable increase in the number of fluorescent particles labeled with monodansylcadaverine (MDC), a specific marker for autophagic vacuoles. MDC-labeled vacuoles clearly exhibited the fluorescent-tagged LC3 in cells transiently overexpressing GFP-LC3 (a protein that associates with autophagosome membranes). However, autophagy inhibition with 3-methyladenine (3-MA) failed to rescue v-Ha-ras-transformed NIH 3T3 cells from paclitaxel-induced cell death. More interestingly, the apoptosis inhibition by overexpression of the X-linked inhibitor of apoptosis (XIAP) did not fully block the cell death by paclitaxel, implying that apoptosis inhibition might accelerate the autophagic components of the paclitaxel response. Conversely, Raf-1 shRNA expression protected against paclitaxel-induced cell death through the simultaneous inhibition of both autophagy and apoptosis. These results suggest that both autophagy and apoptosis act as cooperative partners to induce cell death in v-Ha-ras-transformed NIH 3T3 cells treated with paclitaxel. PMID:21069434

Eum, Ki-Hwan; Lee, Michael

2010-11-11

285

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

286

A Phase I dose-escalation study of the VEGFR inhibitor tivozanib hydrochloride with weekly paclitaxel in metastatic breast cancer.  

PubMed

Tivozanib is a potent selective tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. This Phase Ib study investigated the safety/tolerability, pharmacokinetics (PK), and activity of tivozanib with weekly paclitaxel in metastatic breast cancer (MBC). MBC patients with no prior VEGFR TKI treatment received daily oral tivozanib (3 weeks on, 1 week off) with weekly paclitaxel 90 mg/m(2). Standard 3 + 3 dose escalation was used; tivozanib cohorts (C) included C1 0.5 mg, C2 1.0 mg, and C3 1.5 mg. Assessments included Response Evaluation Criteria in Solid Tumors response, PK, and vascular function. Eighteen patients enrolled. Toxicities in >20 % of patients included fatigue, alopecia, nausea, diarrhea, peripheral sensory neuropathy, and hypertension. Grade 3/4 toxicities in >15 % of patients included fatigue and neutropenia. Maximum tolerated dose was tivozanib 1.5 mg with paclitaxel 90 mg/m(2). Four patients withdrew because of toxicity and one due to progressive disease. Thirteen patients were evaluable for response: four (30.8 %) had confirmed partial response; four had stable disease ?6 months (30.8 %). PK data suggest no influence of paclitaxel on tivozanib concentrations. Tivozanib plus weekly paclitaxel was tolerable at all dose levels, supporting their combination at full dose. Activity in this small population was encouraging. PMID:23868188

Mayer, Erica L; Scheulen, M E; Beckman, J; Richly, H; Duarte, A; Cotreau, M M; Strahs, A L; Agarwal, S; Steelman, L; Winer, E P; Dickler, M N

2013-07-19

287

Modulation of MDR1 and MRP3 Gene Expression in Lung Cancer Cells after Paclitaxel and Carboplatin Exposure.  

PubMed

Carboplatin-paclitaxel is a reference regimen in the treatment of locally advanced or disseminated non-small cell lung cancer (NSCLC). This paper discusses the multidrug resistance developed with this drug combination, which is one of the major obstacles to successful treatment. In order to understand and overcome the drug resistance pattern of NSCLC after carboplatin plus paclitaxel exposure, levels of mRNA expression of multidrug resistance 1 (MDR1) and multidrug resistance-associated protein 3 (MRP3) were investigated in primary NSCLC cell lines (A-549 and A-427) and a metastasis-derived NSCLC cell line (NODO). Our results showed that exposure of the three NSCLC lines to plasma concentrations of paclitaxel (5 ?M) produced an increase in MDR1 expression, while MRP3 showed no alteration in expression. By contrast, the same cells exposed to carboplatin plasma concentrations (30 ?M) showed overexpression of MRP3. In these cells, MDR1 showed no expression changes. Interestingly, the combination of both paclitaxel and carboplatin caused increased expression of the MDR1 drug resistance gene rather than the individual treatments. These results suggest that carboplatin and paclitaxel may induce drug resistance mediated by MDR1 and MRP3, which may be enhanced by the simultaneous use of both drugs. PMID:23443122

Melguizo, Consolación; Prados, Jose; Luque, Raquel; Ortiz, Raúl; Caba, Octavio; Alvarez, Pablo J; Gonzalez, Beatriz; Aranega, Antonia

2012-12-05

288

Paclitaxel and filgrastim for hematopoietic progenitor cell mobilization in patients with hematologic malignancies after failure of a prior mobilization regimen.  

PubMed

Paclitaxel and G-CSF have been evaluated for HPC mobilization in breast cancer and found to have tolerable toxicity with a predictable time to initiate leukapheresis. However, this approach has not been reported in patients with hematologic malignancies failing prior mobilization. We report a case-series of 26 adults given paclitaxel and G-CSF for HPC mobilization after failure of an initial mobilization. Patients received paclitaxel 250 mg/m(2) followed by G-CSF 10-16 mcg/kg/day. Compared to the initial regimen, paclitaxel mobilization produced greater CD34+ cell yields (median 1.53 x 10(6) CD34+ cells/kg vs. 0.79 x 10(6) CD34+ cells/kg, p = 0.004). Seventy-six percent of patients initiated leukapheresis on day 8, the remainder on day 9 or 10. Three patients developed febrile neutropenia resulting in one death prior to leukapheresis. Overall, 73% of patients proceeded with autologous HPC transplant. This case-series suggests paclitaxel may be an option for HPC mobilization in patients failing prior regimens. PMID:18067011

McKibbin, Trevor; Burzynski, Julianna; Greene, Rebecca; Ochoa-Bayona, Jose; Tsai, T W; Callander, Natalie; Freytes, Cesar

2007-12-01

289

Modulation of MDR1 and MRP3 Gene Expression in Lung Cancer Cells after Paclitaxel and Carboplatin Exposure  

PubMed Central

Carboplatin-paclitaxel is a reference regimen in the treatment of locally advanced or disseminated non-small cell lung cancer (NSCLC). This paper discusses the multidrug resistance developed with this drug combination, which is one of the major obstacles to successful treatment. In order to understand and overcome the drug resistance pattern of NSCLC after carboplatin plus paclitaxel exposure, levels of mRNA expression of multidrug resistance 1 (MDR1) and multidrug resistance-associated protein 3 (MRP3) were investigated in primary NSCLC cell lines (A-549 and A-427) and a metastasis-derived NSCLC cell line (NODO). Our results showed that exposure of the three NSCLC lines to plasma concentrations of paclitaxel (5 ?M) produced an increase in MDR1 expression, while MRP3 showed no alteration in expression. By contrast, the same cells exposed to carboplatin plasma concentrations (30 ?M) showed overexpression of MRP3. In these cells, MDR1 showed no expression changes. Interestingly, the combination of both paclitaxel and carboplatin caused increased expression of the MDR1 drug resistance gene rather than the individual treatments. These results suggest that carboplatin and paclitaxel may induce drug resistance mediated by MDR1 and MRP3, which may be enhanced by the simultaneous use of both drugs.

Melguizo, Consolacion; Prados, Jose; Luque, Raquel; Ortiz, Raul; Caba, Octavio; Alvarez, Pablo J.; Gonzalez, Beatriz; Aranega, Antonia

2012-01-01

290

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

291

Paclitaxel as Neoadjuvant Therapy for High Grade Angiosarcoma of the Spleen: a Brief Report and Literature Review  

PubMed Central

Introduction: Splenic angiosarcoma is a rare tumor with only a few cases reported in the literature. Surgical resection offers the best chance of cure for this aggressive neoplasm but is often precluded by infiltration of the tumor to surrounding critical structures. We report a case of a locally advanced angiosarcoma rendered operable by treatment with Paclitaxel monotherapy. Case presentation: A 69 year old female presented with a high grade splenic angiosarcoma, considered inoperable due to the extent of local spread. She received three cycles of single agent Paclitaxel and underwent a successful resection of the tumor. Conclusion: Chemotherapy options for splenic angiosarcoma are not well studied. Paclitaxel as monotherapy is a useful therapeutic option in down staging tumors, facilitating surgical resection and merits further study in clinical trials.

Vakkalanka, Bhanu; Milhem, Mohammed

2010-01-01

292

Cellular aggregation is a key parameter associated with long term variability in paclitaxel accumulation in Taxus suspension cultures.  

PubMed

Plant cell cultures provide a renewable source for synthesis and supply of commercially valuable plant-derived products, particularly for secondary metabolites. However, instability in product yields over multiple passages has hampered the efficient and sustainable use of this technology. Paclitaxel accumulation in Taxus cell suspension culture was quantified over multiple passages and correlated to mean aggregate size, extracellular sugar level, ploidy, and cell cycle distribution. Paclitaxel levels varied approximately 6.9-fold over the six-month timeframe investigated. Of all of the parameters examined, only mean aggregate size correlated with paclitaxel accumulation, where a significant negative correlation (r = - 0.75, p < 0.01) was observed. These results demonstrate the relevance of measuring, and potentially controlling, aggregate size during long term culture passages, particularly for plant suspensions where industrially relevant secondary metabolites are not pigmented to enable rapid culture selection. PMID:23439858

Patil, Rohan A; Kolewe, Martin E; Roberts, Susan C

2012-10-01

293

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

PubMed

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

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

2009-03-23

294

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

PubMed

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

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

2012-03-29

295

Comparison of Cell Death-inducing Effect of Novel Taxane SB-T-1216 and Paclitaxel in Breast Cancer Cells  

PubMed Central

Background In this study, the effect of novel taxane SB-T-1216 and paclitaxel were compared on drug-sensitive MDA-MB-435 and drug-resistant NCI/ADR-RES human breast cancer cells. Materials and Methods Cell growth and survival were evaluated after 96-hour incubation with tested concentrations of taxanes. The effect on the formation of microtubule bundles was assessed employing fluorescence microscopy and on the cell cycle employing flow cytometric analysis. The activity of caspases was assessed employing commercial colorimetric kits. Results The IC50 (concentration resulting in 50% of living cells in comparison with the control) of SB-T-1216 in drug-sensitive cells was 0.6 nM versus 1 nM for paclitaxel. However, the IC50 of SB-T-1216 in drug-resistant cells was 1.8 nM versus 300 nM for paclitaxel. Both SB-T-1216 and paclitaxel at death-inducing concentrations induced the formation of microtubule bundles in drug-sensitive as well as drug-resistant cells. Cell death induced in drug-sensitive and drug-resistant cells by paclitaxel was associated with the accumulation of cells in the G2/M phase. On the contrary, cell death induced by SB-T-1216 took place without the accumulation of cells in the G2/M phase but with a decreased number of G1 cells and the accumulation of hypodiploid cells. Both SB-T-1216 and paclitaxel activated caspase-3, caspase-9, caspase-2 and caspase-8 in drug-sensitive as well as drug-resistant cells. Conclusion Cell death induced by both paclitaxel and novel taxane SB-T-1216 in breast cancer cells is associated with caspase activation and with the formation of interphase microtubule bundles. Novel taxane SB-T-1216, but not paclitaxel, seems to be capable of inducing cell death without the accumulation of cells in the G2/M phase.

KOVAR, JAN; EHRLICHOVA, MARIE; SMEJKALOVA, BARBORA; ZANARDI, ILARIA; OJIMA, IWAO; GUT, IVAN

2010-01-01

296

Preclinical efficacy studies of a novel nanoparticle-based formulation of paclitaxel that out-performs Abraxane  

Microsoft Academic Search

Purpose  Poly-(?-l-glutamylglutamine)–paclitaxel (PGG–PTX) is a novel polymer-based formulation of paclitaxel (PTX) in which the PTX is linked\\u000a to the polymer via ester bonds. PGG–PTX is of interest because it spontaneously forms very small nanoparticles in plasma.\\u000a In mouse models, PGG–PTX increased tumor exposure to PTX by 7.7-fold relative to that produced by PTX formulated in Cremophor.\\u000a In this study, the efficacy

Zhongling Feng; Gang Zhao; Lei Yu; David Gough; Stephen B. Howell

2010-01-01

297

Toxicological Study and Efficacy of Blank and Paclitaxel-Loaded Lipid Nanocapsules After i.v. Administration in Mice  

Microsoft Academic Search

Purpose  Lipid nanocapsules (LNCs) are solvent-free drug nanocarriers permitting entrapment of paclitaxel and increasing its antitumoural\\u000a effect in animal models after i.v. injection. The tolerance and efficacy of LNCs after repeated dose i.v. administration were assessed in mice. The maximum tolerated dose (MTD) and 50% lethal dose (LD50) were studied.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  Paclitaxel-loaded LNC formulation was given i.v. at the dose of 12 mg\\/kg

José Hureaux; Frédéric Lagarce; Frédéric Gagnadoux; Marie-Christine Rousselet; Valérie Moal; Thierry Urban; Jean-Pierre Benoit

2010-01-01

298

[Efficacy and tolerability of controlled-release oxycodone against nab-paclitaxel-induced musculoskeletal pain in breast cancer patients].  

PubMed

Paclitaxel therapy often causes musculoskeletal pain, and some clinical studies have indicated that this pain is due to nerve injury, rather than muscle or joint lesion. We report four clinical cases in which controlled-release oxycodone improved pain intensity in breast cancer patients with severe musculoskeletal pain caused by nab-paclitaxel therapy. In each case, oxycodone was well-tolerated and the symptoms of peripheral neuropathy were quite mild, indicating that oxycodone exhibited a preventive or therapeutic effect on peripheral neuropathy. Therefore, oxycodone may have favorable efficacy and tolerability against cancer therapy-related pain with a neuropathic element in breast cancer patients. PMID:23986044

Inoue, Kenichi; Ohkubo, Fumie; Nagai, Shigenori; Tsuboi, Miki; Kubo, Kazuyuki; Kurozumi, Ken; Hayashi, Yuji; Matsumoto, Hiroshi; Takei, Hiroyuki

2013-08-01

299

A phase I and pharmacokinetic study of weekly paclitaxel and carboplatin in patients with metastatic esophageal cancer  

Microsoft Academic Search

PURPOSE: To determine the maximum-tolerated dose, toxicity profile, and\\u000a pharmacokinetics of a fixed dose of paclitaxel followed by increasing\\u000a doses of carboplatin, given weekly to patients with advanced esophageal or\\u000a gastric junction cancer. EXPERIMENTAL DESIGN: Paclitaxel was administered\\u000a on day 1 as a 1-h infusion at a fixed dose of 100 mg\\/m(2) followed by a\\u000a 1-h infusion of carboplatin targeting

M. B. Polee; A. Sparreboom; F. A. L. M. Eskens; R. Hoekstra; Schaaf van de J; J. Verweij; G. Stoter; Gaast van der A

2004-01-01

300

Phase II Study of Carboplatin and Paclitaxel in Advanced Thymoma and Thymic Carcinoma  

PubMed Central

Purpose The purpose of this study was to evaluate the impact of carboplatin and paclitaxel in patients with advanced previously untreated thymoma and thymic carcinoma. Patients and Methods We conducted a prospective multicenter study in patients with unresectable thymoma (n = 21) or thymic carcinoma (n = 23). Patients were treated with carboplatin (area under the curve, 6) plus paclitaxel (225 mg/m2) every 3 weeks for a maximum of six cycles. The primary end point of this trial was to evaluate the objective response rate. Results From February 2001 through January 2008, 46 patients were enrolled. Thirteen patients had grade 4 or greater toxicity, mostly neutropenia. Using RECIST (Response Evaluation Criteria in Solid Tumors) 1.0 criteria, three complete responses (CRs) and six partial responses (PRs; objective response rate [ORR], 42.9%; 90% CI, 24.5% to 62.8%) were observed in the thymoma cohort; 10 patients had stable disease. For patients with thymic carcinoma, no CRs and five PRs (ORR, 21.7%; 90% CI, 9.0% to 40.4%) were observed; 12 patients had stable disease. Progression-free survival (PFS) was 16.7 (95% CI, 7.2 to 19.8) and 5.0 (95% CI, 3.0 to 8.3) months for thymoma and thymic carcinoma cohorts, respectively. To date, only seven patients (33.3%) with thymoma have died, compared with 16 patients (69.6%) with thymic carcinoma. Median survival time was 20.0 months (95% CI, 5.0 to 43.6 months) for patients with thymic carcinoma, but it has not been reached for patients with thymoma. Conclusion Carboplatin plus paclitaxel has moderate clinical activity for patients with thymic malignancies, but this seems less than expected with anthracycline-based therapy. Patients with thymic carcinoma have poorer PFS and overall survival than patients with thymoma.

Lemma, Girum L.; Lee, Ju-Whei; Aisner, Seena C.; Langer, Corey J.; Tester, William J.; Johnson, David H.; Loehrer, Patrick J.

2011-01-01

301

Inherent and acquired resistance to paclitaxel in hepatocellular carcinoma: molecular events involved.  

PubMed

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

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

2013-04-16

302

BNP7787-mediated modulation of paclitaxel- and cisplatin-induced aberrant microtubule protein polymerization in vitro.  

PubMed

Taxane and platinum drugs are important agents in the treatment of cancer and have shown activity against a variety of tumors, including ovarian, breast, and lung cancer, either as single agents or in combination with other chemotherapy drugs. However, a serious and prevalent side effect of taxane (docetaxel and all formulations/derivatives of paclitaxel) and platinum (cisplatin, carboplatin, and oxaliplatin) agents is dose-limiting chemotherapy-induced peripheral neuropathy (CIPN). CIPN can result in treatment delays, dose modifications, and, in severe cases, discontinuation of chemotherapy. Consequently, effective treatments for CIPN are needed. Dimesna (BNP7787; Tavocept; disodium 2,2'-dithio-bis-ethanesulfonate) is an investigational drug that is undergoing international clinical development as a treatment that is coadministered with first-line taxane and platinum combination chemotherapy in patients with inoperable advanced primary adenocarcinoma of the lung. BNP7787 is currently being developed with the objective of increasing the survival of cancer patients receiving taxane- and/or cisplatin-based chemotherapy. Additional data indicate that BNP7787 may also protect against common and serious chemotherapy-induced toxicities, including chemotherapy-induced anemia, nausea, emesis, nephrotoxicity, and neuropathy, without interfering with antitumor activity of the chemotherapeutic agent(s). Studies herein show that BNP7787 prevents aberrant microtubule protein (MTP) polymerization that is caused by exposure of MTP to paclitaxel or cisplatin. BNP7787 modulates paclitaxel-induced hyperpolymerization of MTP in a dose-dependent manner, and mesna, an in vivo metabolite of BNP7787, protects against time-dependent cisplatin-induced inactivation of MTP. We propose that interactions between BNP7787 and MTP may play a role in BNP7787-mediated protection against CIPN. PMID:20807779

Parker, Aulma R; Petluru, Pavankumar N; Wu, Meizhen; Zhao, Min; Kochat, Harry; Hausheer, Frederick H

2010-08-31

303

Paclitaxel, carboplatin, and trastuzumab in a neo-adjuvant regimen for HER2-positive breast cancer.  

PubMed

To evaluate a nonanthracycline-containing regimen consisting of 24 weekly administrations of paclitaxel, carboplatin, and trastuzumab as neo-adjuvant therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Patients with stage II or III breast cancer, including inflammatory disease, with HER2 overexpression (immunohistochemistry and/or fluorescent in situ hybridization) were treated with 24 weekly administrations of paclitaxel 70 mg/m(2) , carboplatin AUC = 3 mg/mL/minute, and trastuzumab 2 mg/kg (loading dose 4 mg/kg). In cycles 7, 8, 15, 16, 23, and 24, only trastuzumab was given. The primary end point was pathologic complete response (pCR) in both breast and axilla. Of 61 evaluable patients, 61% had stage II disease and 75% were node-positive. The median NRI (Neoadjuvant Response Index, a measure of the degree of downstaging by chemotherapy) of all patients was 0.86. Twenty-seven (44%) had a NRI of 1.0, which corresponds to pCR in breast and lymph nodes. The most commonly reported grade 3/4 toxicities were neutropenia (72%) and thrombocytopenia (36%). Dose reduction was necessary in 51% of the patients. A weekly carboplatin-paclitaxel-trastuzumab neo-adjuvant regimen is highly active in HER2-positive breast cancer with an acceptable toxicity profile. A multicenter phase 2 trial has recently reached its accrual target and will serve as a basis for a subsequent randomized phase 3 study comparing this regimen to a similar regimen preceded by anthracyclines. PMID:23682812

Sonke, Gabe S; Mandjes, Ingrid A; Holtkamp, Marjo J; Schot, Margaret; van Werkhoven, Erik; Wesseling, Jelle; Vrancken Peeters, Marie-Jeanne; Rodenhuis, Sjoerd; Linn, Sabine C

2013-05-20

304

Sequence dependent antitumour efficacy of the vascular disrupting agent ZD6126 in combination with paclitaxel  

PubMed Central

The clinical success of small-molecule vascular disrupting agents (VDAs) depends on their combination with conventional therapies. Scheduling and sequencing remain key issues in the design of VDA–chemotherapy combination treatments. This study examined the antitumour activity of ZD6126, a microtubule destabilising VDA, in combination with paclitaxel (PTX), a microtubule-stabilising cytotoxic drug, and the influence of schedule and sequence on the efficacy of the combination. Nude mice bearing MDA-MB-435 xenografts received weekly cycles of ZD6126 (200?mg?kg?1 i.p.) administered at different times before or after PTX (10, 20, and 40?mg?kg?1 i.v.). ZD6126 given 2 or 24?h after PTX showed no significant benefit, a result that was attributed to a protective effect of PTX against ZD6126-induced vascular damage and tumour necrosis, a hallmark of VDA activity. Paclitaxel counteracting activity was reduced by distancing drug administrations, and ZD6126 given 72?h after PTX potentiated the VDA's antitumour activity. Schedules with ZD6126 given before PTX improved therapeutic activity, which was paralleled by a VDA-induced increase in cell proliferation in the viable tumour tissue. Paclitaxel given 72?h after ZD6126 yielded the best response (50% tumours regressing). A single treatment with ZD6126 followed by weekly administration of PTX was sufficient to achieve a similar response (57% remissions). These findings show that schedule, sequence and timing are crucial in determining the antitumour efficacy of PTX in combination with ZD6126. Induction of tumour necrosis and increased proliferation in the remaining viable tumour tissue could be exploited as readouts to optimise schedules and maximise therapeutic efficacy.

Martinelli, M; Bonezzi, K; Riccardi, E; Kuhn, E; Frapolli, R; Zucchetti, M; Ryan, A J; Taraboletti, G; Giavazzi, R

2007-01-01

305

Sequence dependent antitumour efficacy of the vascular disrupting agent ZD6126 in combination with paclitaxel.  

PubMed

The clinical success of small-molecule vascular disrupting agents (VDAs) depends on their combination with conventional therapies. Scheduling and sequencing remain key issues in the design of VDA-chemotherapy combination treatments. This study examined the antitumour activity of ZD6126, a microtubule destabilising VDA, in combination with paclitaxel (PTX), a microtubule-stabilising cytotoxic drug, and the influence of schedule and sequence on the efficacy of the combination. Nude mice bearing MDA-MB-435 xenografts received weekly cycles of ZD6126 (200 mg kg(-1) i.p.) administered at different times before or after PTX (10, 20, and 40 mg kg(-1) i.v.). ZD6126 given 2 or 24 h after PTX showed no significant benefit, a result that was attributed to a protective effect of PTX against ZD6126-induced vascular damage and tumour necrosis, a hallmark of VDA activity. Paclitaxel counteracting activity was reduced by distancing drug administrations, and ZD6126 given 72 h after PTX potentiated the VDA's antitumour activity. Schedules with ZD6126 given before PTX improved therapeutic activity, which was paralleled by a VDA-induced increase in cell proliferation in the viable tumour tissue. Paclitaxel given 72 h after ZD6126 yielded the best response (50% tumours regressing). A single treatment with ZD6126 followed by weekly administration of PTX was sufficient to achieve a similar response (57% remissions). These findings show that schedule, sequence and timing are crucial in determining the antitumour efficacy of PTX in combination with ZD6126. Induction of tumour necrosis and increased proliferation in the remaining viable tumour tissue could be exploited as readouts to optimise schedules and maximise therapeutic efficacy. PMID:17848949

Martinelli, M; Bonezzi, K; Riccardi, E; Kuhn, E; Frapolli, R; Zucchetti, M; Ryan, A J; Taraboletti, G; Giavazzi, R

2007-09-11

306

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

Microsoft Academic Search

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

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

2008-01-01

307

Hyaluronic acid–paclitaxel: effects of intraperitoneal administration against CD44(+) human ovarian cancer xenografts  

Microsoft Academic Search

Purpose  Hyaluronan (HA)-receptors (mainly CD44 and RHAMM) are overexpressed in a wide variety of cancers including ovarian tumors,\\u000a and HA-bioconjugates have been developed to enhance selective entry of cytotoxic drugs into HA receptor-expressing cancerous\\u000a cells. Here, we evaluated the potential application of a new HA-paclitaxel bioconjugate, ONCOFID-P, for intraperitoneal (IP)\\u000a treatment of ovarian cancer.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  In vitro cytotoxic effect of ONCOFID-P was

Ilaria De Stefano; Alessandra Battaglia; Gian Franco Zannoni; Maria Grazia Prisco; Andrea Fattorossi; Daniele Travaglia; Silvia Baroni; Davide Renier; Giovanni Scambia; Cristiano Ferlini; Daniela Gallo

2011-01-01

308

Acquired factor VIII inhibitors: case reports of paclitaxel and penicillin-induced entities.  

PubMed

Acquired hemophilia A is an uncommon but potentially life-threatening clinical entity mediated by specific autoantibodies direct against coagulation factor VIII. It may be associated with a number of conditions such as solid malignancies, autoimmune diseases, lymphoproliferative disorders, and drugs. Early recognition of this entity is necessary to avoid a delay in treatment, which might lead to serious complications including severe bleeding and death. Hereby, we report a case of acquired hemophilia A caused by a commonly used drug, penicillin, as well as the first reported case, to our knowledge, of acquired Factor VIII inhibitor secondary to paclitaxel. PMID:19696661

El-Osta, Hazem; Reddy, Pavan; Deutsch, Jeremy M

2009-12-01

309

[A case of intraperitoneal paclitaxel administration in a gastric cancer patient with severely impaired renal function].  

PubMed

This study was designed to evaluate the pharmacokinetics and toxicity of paclitaxel, administered via an intraperitoneal route for a gastric cancer patient with renal dysfunction. The patient was a woman in her 50's, who had been diagnosed with severe renal dysfunction but no treatment history was known. She complained of dyspnea for a large quantity of ascites and was urgently hospitalized. It was diagnosed as gastric cancer with peritoneal dissemination. At this hospital, PTX was administered weekly intraperitoneally through an infusion port without complication. This result suggested that intraperitoneal PTX chemotherapy for a patient with renal dysfunction was a safe treatment. PMID:16315928

Ohbu, Masahide; Maruyama, Michio; Miyawaki, Yutaka; Tamura, Nobuko; Koide, Ayaki; Hasegawa, Kumi; Maruyama, Shouji; Takashima, Itaru; Ebuchi, Masakazu

2005-10-01

310

The formulation of aptamer-coated paclitaxel–polylactide nanoconjugates and their targeting to cancer cells  

Microsoft Academic Search

Paclitaxel–polylactide (Ptxl–PLA) conjugate nanoparticles, termed as nanoconjugates (NCs), were prepared through Ptxl\\/(BDI)ZnN(TMS)2 (BDI = 2-((2,6-diisopropylphenyl)-amido)-4-((2,6-diisopropylphenyl)-imino)-2-pentene)-mediated controlled polymerization of lactide (LA) followed by nanoprecipitation. Nanoprecipitation of Ptxl–PLA resulted in sub-100 nm NCs with monomodal particle distributions and low polydispersities. The sizes of Ptxl–PLA NCs could be precisely controlled by using appropriate water-miscible solvents and by controlling the concentration of Ptxl–PLA during nanoprecipitation. Co-precipitation of a

Rong Tong; Linda Yala; Timothy M. Fan; Jianjun Cheng

2010-01-01

311

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

312

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

PubMed

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

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

2013-05-01

313

Modified Paclitaxel-loaded Nanoparticles for Inhibition of Hyperplasia in a Rabbit Arterial Balloon Injury Model  

Microsoft Academic Search

Purpose  This study tested the possibility of localized intravascular infusion of positive charged paclitaxel-loaded nanoparticles\\u000a (NPs) to better prevent neointimal formation in a rabbit carotid artery injury model.\\u000a \\u000a \\u000a \\u000a Materials and Methods  NPs were prepared by oil–water emulsion\\/solvent evaporation technique using biodegradable poly (lactide-co-glycolide) (PLGA).\\u000a A cationic surfactant, didodecyldimethylammonium bromide (DMAB), was absorbed on the NP surface by electrostatic attraction\\u000a between positive and

Lin Mei; Hongfan Sun; Xu Jin; Dunwan Zhu; Rui Sun; Minfang Zhang; Cunxian Song

2007-01-01

314

Antitumor effect of paclitaxel is mediated by inhibition of myeloid-derived suppressor cells and chronic inflammation in the spontaneous melanoma model.  

PubMed

The antitumor effects of paclitaxel are generally attributed to the suppression of microtubule dynamics resulting in defects in cell division. New data demonstrated that in ultralow noncytotoxic concentrations, paclitaxel modulated in immune cells in vitro the activity of small Rho GTPases, the key regulators of intracellular actin dynamics. However, the immunomodulatory properties of paclitaxel in vivo have not been evaluated. In this study, using the ret transgenic murine melanoma model, which mimics human cutaneous melanoma, we tested effects of ultralow noncytotoxic dose paclitaxel on functions of myeloid-derived suppressor cells (MDSCs), chronic inflammatory mediators, and T cell activities in the tumor microenvironment in vivo. Administration of paclitaxel significantly decreased accumulation and immunosuppressive activities of tumor-infiltrating MDSCs without alterations of the bone marrow hematopoiesis. This was associated with the inhibition of p38 MAPK activity, TNF-? and production, and S100A9 expression in MDSCs. The production of mediators of chronic inflammation in the tumor milieu also was diminished. Importantly, reduced tumor burden and increased animal survival upon paclitaxel application was mediated by the restoration of CD8 T cell effector functions. We suggest that the ability of paclitaxel in a noncytotoxic dose to block the immunosuppressive potential of MDSCs in vivo represents a new therapeutic strategy to downregulate immunosuppression and chronic inflammation in the tumor microenvironment for enhancing the efficacy of concomitant anticancer therapies. PMID:23359505

Sevko, Alexandra; Michels, Tillmann; Vrohlings, Melissa; Umansky, Ludmila; Beckhove, Philipp; Kato, Masashi; Shurin, Galina V; Shurin, Michael R; Umansky, Viktor

2013-01-28

315

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

SciTech Connect

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

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

2006-02-01

316

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

PubMed

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

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

2007-01-01

317

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

PubMed Central

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

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

2012-01-01

318

The use of submicron\\/nanoscale PLGA implants to deliver paclitaxel with enhanced pharmacokinetics and therapeutic efficacy in intracranial glioblastoma in mice  

Microsoft Academic Search

Pharmacokinetics and therapeutic efficacy of submicron\\/nanoscale, intracranial implants were evaluated for treating malignant glioblastoma in mice. 9.1% (w\\/w) paclitaxel-loaded polylactide-co-glycolide (PLGA) nanofiber discs (F3) were fabricated and characterized for morphology and size distribution. Along with F3, three other formulations, 9.1% (w\\/w) paclitaxel-loaded PLGA submicron-fiber discs (F2), 16.7% (w\\/w) paclitaxel-loaded PLGA microspheres entrapped in hydrogel matrices (H80 and M80) were intracranially

Sudhir H. Ranganath; Yilong Fu; Davis Y. Arifin; Irene Kee; Lin Zheng; How-Sung Lee; Pierce K.-H. Chow; Chi-Hwa Wang

2010-01-01

319

The enthalpies and kinetic of dissolution of diterpenoid derivative—paclitaxel in aqueous NaCl solutions at 309.5 K  

NASA Astrophysics Data System (ADS)

The enthalpies of dissolution of paclitaxel in normal saline were measured using a RD496-2000 Calvet Microcalorimeter at 309.65 K under atmospheric pressure. The differential enthalpy (?dif H m ) and molar enthalpy (?sol H m) of dissolution of paclitaxel innormal saline were determined. The corresponding kinetic equation described the dissolution process was elucidated to be d?/ dt = 10-3.57(1 - a)1.15. Moreover, the half-life, ?sol H m , ?sol G m and ?sol S m of the dissolution process were also obtained. This work will provide a potential reference for the clinical application of paclitaxel.

Chen, Qi; Zhao, Weiwei; Pu, Xiaohua

2013-08-01

320

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

Microsoft Academic Search

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

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

2008-01-01

321

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

PubMed

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

Ami, Nozomi; Okamoto, Kazuo; Oshima, Hidehiko

2012-04-28

322

Paclitaxel-PHBV nanoparticles and their toxicity to endometrial and primary ovarian cancer cells.  

PubMed

This report is an integrated study to include the molecular simulation, physicochemical characterization and biological analysis of a paclitaxel-loaded PHBV nanoparticle that demonstrates uptake, release and cytotoxicity in cancer cell lines. Taking this nanoparticle one step closer to its use in a clinical setting, we demonstrate that it causes significant cell death in primary cultures of stage IIIc serous ovarian cancer cells isolated from six patients. Molecular simulations revealed a high affinity of paclitaxel for the water-polymer interface, thus the drug is delivered only when the polymer near it is degraded. The Fourier transform infrared spectroscopy suggests the formation of a short-lived crystalline phase, also observed in the CG simulations, and transmission electron microscopy revealed branched structures on the surface of particles, which disappeared after 4 days. Biological analyses indicated that these particles have a 48-h window of toxicity protection, allowing for the endocytosis of the particle by the cells; this finding was corroborated by confocal microscopy and flow cytometry. The low cost to synthesize PHBV using microorganisms and the potential chemical modifications of the polymer make it attractive for inexpensive, large-scale pharmaceutical production. PMID:23465827

Vilos, Cristian; Morales, Francisco A; Solar, Paula A; Herrera, Natalia S; Gonzalez-Nilo, Fernando D; Aguayo, Daniel A; Mendoza, Hegaly L; Comer, Jeffrey; Bravo, Maria L; Gonzalez, Pamela A; Kato, Sumie; Cuello, Mauricio A; Alonso, Catalina; Bravo, Erasmo J; Bustamante, Eva I; Owen, Gareth I; Velasquez, Luis A

2013-03-05

323

Phase II study of high-dose paclitaxel in platinum-refractory epithelial ovarian cancer.  

PubMed

The purposes of this study were to determine the efficacy of paclitaxel, using a dose of 200 mg/m2 intravenous continuous infusion over 24 hours every three weeks in the treatement of platinum-refractory epithelial ovarian cancer (EOC) and to evaluate the toxicities. Eligibility criteria included: histologically proven EOC, platinum resistance, measurable disease, Zubrod performance status grade 0-2, expected survival of > 3 months and adequate hematological function. Response was assessed at three-cycle intervals or earlier if required. Twenty-one patients were recruited in this study. The response rate was 52% (2 CR, 9 PR) with a median duration of response of six months. The median progression-free interval was eight months and the median survival was 12 months. Leukopenia was the predominant toxic effect. Eighty-six percent of patients required granulocyte-colony stimulation factor (G-CSF). All patients had alopecia grade 3. In conclusion, high-dose paclitaxel is active in platinum-refractory EOC with manageable toxicities. PMID:11214622

Wilailak, S; Tresukosol, D; Linasmita, V; Termrungruanglert, W

2000-01-01

324

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

325

[An effective weekly paclitaxel administration for gastric cancer with malignant ascites--a case report].  

PubMed

A 71 year-old woman underwent total gastrectomy for advanced gastric cancer of p stage IV (pathological findings: por1 type 3 pT3, pN3 (12p: 1/1, 16b1 int: 3/3, 16b1 lat: 2/2), P1, CY1, H0) in March 2002. She was treated with the double modulation therapy of MTX/CDDP/5-FU intraperitoneally after the surgery. After leaving the hospital, she was carrying out the chemotherapy with MTX/5-FU continually. In August 2002, she became hospitalized once again because an appetite decrease and diarrhea appeared. CT of abdomen showed that malignant ascites had obviously accumulated, and she was admitted. Because it was conceivable in all cases of an inflammation by the chemical stimulation that originated in an anticancer drug, we suspended the intraperitoneal chemotherapy. Paclitaxel 90 mg/body administration was started intravenously on a weekly basis from the end of the same month. Those symptoms improved and she was discharged from the hospital, and was continued the paclitaxel administration. In CT of the abdomen that was taken in November in 2002, malignant ascites had obviously been decreasing and disappeared completely after that. PMID:16315930

Koide, Ayaki; Maruyama, Michio; Hasegawa, Kumi; Miyawaki, Yutaka; Tamura, Nobuko; Ohbu, Masahide; Maruyama, Shoji; Takashima, Itaru; Ebuchi, Masakazu

2005-10-01

326

Targeted nanoparticles that deliver a sustained, specific release of paclitaxel to irradiated tumors  

PubMed Central

To capitalize on the response of tumor cells to ionizing radiation, we developed a controlled-release nanoparticle drug delivery system using a targeting peptide that recognizes a radiation-induced cell surface receptor. Phage display biopanning identified Gly-Ile-Arg-Leu-Arg-Gly (GIRLRG) as a peptide that selectively recognizes tumors responding to ionizing radiation. Membrane protein extracts of irradiated glioma cells identified glucose-regulated protein GRP78 as the receptor target for GIRLRG. Antibodies to GRP78 blocked the binding of GIRLRG in vitro and in vivo. Conjugation of GIRLRG to a sustained-release nanoparticle drug delivery system yielded increased paclitaxel concentration and apoptosis in irradiated breast carcinomas for up to three weeks. Compared to controls, a single administration of the GIRLRG-targeted nanoparticle drug delivery system to irradiated tumors delayed the in vivo tumor tripling time by 55 days (P=0.0001) in MDA-MB-231, and 12 days in GL261 (P<0.005). This targeting agent combines a novel recombinant peptide with a paclitaxel encapsulating nanoparticle that specifically targets irradiated tumors, increasing apoptosis and tumor growth delay in a manner superior to known chemotherapy approaches.

Passarella, Ralph J.; Spratt, Daniel E.; van der Ende, Alice E.; Phillips, John G.; Wu, Hongmei; Sathiyakumar, Vasanth; Zhou, Li; Hallahan, Dennis E.; Harth, Eva; Diaz, Roberto

2010-01-01

327

[Carcinosarcoma of the ovary treated with paclitaxel and carboplatin chemotherapy - a report of 4 cases].  

PubMed

Ovarian carcinosarcoma is a rare gynecologic malignancy that tends to develop in elderly women. This tumor consists of both carcinomatous and sarcomatous components and is associated with a poor prognosis. Because of its rarity, the optimal chemotherapeutic regimen to treat this tumor is yet to be determined. We report 4 cases of ovarian carcinosarcoma treated with paclitaxel/carboplatin(PC)therapy. The median age was 67 years(range, 64-72 years). Two patients with stage II c disease underwent a primary debulking surgery; one had microscopic residual and the other had<1 cm residual disease, and both patients received adjuvant PC therapy. In 2 other patients, a stage III patient and a stage IV patient, a partial response was achieved with neoadjuvant chemotherapy. They underwent an interval debulking surgery(residual disease<1 cm in both patients)followed by additional PC therapy. Recurrence developed in 3 patients except for 1 stage II c patient with microscopic residual disease. These 3 recurrences developed in the pelvis. Progression-free survival ranged 3-15 months; in the stage II c patient, disease progressed during adjuvant PC therapy. Overall survival of the 3 patients with recurrence ranged 6- 41 months. In conclusion, paclitaxel and carboplatin chemotherapy is an effective regimen for ovarian carcinosarcoma, although the duration of response is relatively short. PMID:24047791

Otsuka, Isao; Takaya, Hisamitsu; Takagi, Kiyotaka; Tanaka, Ayuko; Kaseki, Hanako; Izuta, Chinatsu; Sato, Maya; Matsuura, Takuto; Suzuki, Yosuke

2013-09-01

328

Effects of Paclitaxel on EGFR Endocytic Trafficking Revealed Using Quantum Dot Tracking in Single Cells  

PubMed Central

Paclitaxel (PTX), a chemotherapeutic drug, affects microtubule dynamics and influences endocytic trafficking. However, the mechanism and the dynamics of altered endocytic trafficking by paclitaxel treatment in single living cells still remain elusive. By labeling quantum dots (QDs) to the epidermal growth factor (EGF), we continuously tracked the endocytosis and post-endocytic trafficking of EGF receptors (EGFRs) in A549 cells for a long time interval. A single-cell analysis method was introduced to quantitatively study the dynamics of endocytic trafficking. Compared with the control cells, the velocity of directed motion was reduced by 30% due to the suppression of high speed movements of EGF-QDs along the microtubules in PTX-treated cells. The endocytic trafficking in PTX-treated cells was mainly via super-diffusive mode of motion, whereas in control cells, it was mostly via sub-diffusive mode of motion. Moreover, PTX shortened endosomal trafficking and prevented EGF-QDs from moving to the perinuclear area via the rapid delivery of EGF-QDs into the peripheral lysosomes. The present study may shed light on the mechanism of the effect of PTX on the treatment of lung cancer.

Li, Hui; Duan, Zhao-Wen; Xie, Ping; Liu, Yu-Ru; Wang, Wei-Chi; Dou, Shuo-Xing; Wang, Peng-Ye

2012-01-01

329

Molecular dynamics of paclitaxel encapsulated by salicylic acid-grafted chitosan oligosaccharide aggregates.  

PubMed

Chitosan oligosaccharide (COS) derivatives have attracted significant interest in drug delivery systems because of their well-known low toxicity, excellent biocompatibility, and biodegradability. Paclitaxel-loaded nanoparticles based on salicylic acid-grafted chitosan oligosaccharide (COS/SA) were synthesized and characterized. Then, in order to understand the mechanism of the actions of the paclitaxel (PTX) encapsulated by COS/SA, all-atom molecular dynamics simulations were performed to analyze the aggregation of COS/SA molecules. The van der Waals and hydrophobic interactions are the major driving forces for the drug encapsulation process. Electrostatic and hydrogen-bonding interactions also play helpful roles in the COS/SA aggregation. Analyses of the radial distribution function and solvent accessible surface area indicate that the COS/SA nanoparticles are highly hydrosoluble and that the nanoparticles can significantly enhance the aqueous solubility of a hydrophobic drug. Different drug loading systems are also investigated in this work, and the best theoretical drug loading is found to be 10% (w/w). The present work provides insights into the mechanism of the atomic structures of drug-loaded polymeric nanoparticles and presents new perspective for the design of drug delivery systems with desirable properties. PMID:23219327

Wang, Xiao-Ying; Zhang, Ling; Wei, Xiao-Hong; Wang, Qi

2012-12-06

330

[Administration of nab-paclitaxel for 9 metastatic breast cancer patients].  

PubMed

Nab-paclitaxel was administered to 9 patients with refractory advanced or recurrent breast cancer from 1 to 8 times(median 4)triweekly. The median cumulative dose was 775mg/m2(range 260-2, 000), and the median delivered dose intensity was 66. 7mg/m2/week(range 58. 3-86. 7). The response to treatment was CR in one patient, PR in 2 patients, SD in one patient, and PD in 4 patients. In one patient, treatment had to be suspended because of grade 3 peripheral neuropathy. The clinical benefit was 33%. All 4 PD patients were administered other salvage treatments and are alive. Adverse events included 6 case of neutropenia(grade 3-4 in 4 cases), grade 3 AST/ALT elevations in one patient, grade 3 myalgia in one patient. No case of febrile neutropenia was seen. All reactions were under control except for one patient with grade 3 peripheral neuropathy. Concurrent trastuzumab administration was safe also. In conclusion, nab-paclitaxel could be administered safely, and may contribute to the treatment of refractory advanced or recurrent breast cancer. PMID:22790043

Sakaguchi, Koichi; Mizuta, Naruhiko; Imai, Aya; Nakatsukasa, Katsuhiko; Morita, Midori; Soushi, Mari; Taguchi, Tetsuya

2012-07-01

331

Tumor targeting effects of a novel modified paclitaxel-loaded discoidal mimic high density lipoproteins.  

PubMed

Abstract Objective: Monocholesterylsuccinate (CHS)-modified paclitaxel-loaded discoidal reconstituted high density lipoproteins (cP-d-rHDL) as novel biomimetic nanocarriers that were developed for tumor targeting delivery to avoid unexpected drug leakage from discoidal reconstituted high density lipoproteins (d-rHDL) during remodeling process associated with lecithin-cholesterol acyltransferase (LCAT). Methods: Their in vitro characterizations and biomimetic properties, simultaneously tumor distribution and pharmacodynamics in tumor bearing mice were elaborately investigated. Results. In vitro characterization results showed that cP-d-rHDL had nano-size diameter, high negative zeta potential and high entrapment efficiency (EE). Furthermore, morphology study indicated that cP-d-rHDL did not remodel in the presence of LCAT, compared with that of paclitaxel-loaded d-rHDL (P-d-rHDL, not modified). And cellular uptake, together with cytotoxicity toward tumor cells of cP-d-rHDL was not affected after interaction with LCAT. Tumor distribution and pharmacodynamics tests revealed that cP-d-rHDL possessed specific targeting property and anti-tumor efficacy. Conclusion: cP-d-rHDL served to restrain remodeling process and drug leakage, at the same time reinforce the targeting effect, and could act as a potential drug delivery system for cancer therapy. PMID:24079327

Wang, Ji; Jia, Junting; Liu, Jianping; He, Hongliang; Zhang, Wenli; Li, Zhenghua

2013-09-30

332

Molecular evolution of paclitaxel biosynthetic genes TS and DBAT of Taxus species.  

PubMed

Evolutionary patterns of sequence divergence were analyzed in genes from the conifer genus Taxus (yew), encoding paclitaxel biosynthetic enzymes taxadiene synthase (TS) and 10-deacetylbaccatin III-10 beta-O-acetyltransferase (DBAT). N-terminal fragments of TS, full-length DBAT and internal transcribed spacer (ITS) were amplified from 15 closely related Taxus species and sequenced. Premature stop codons were not found in TS and DBAT sequences. Codon usage bias was not found, suggesting that synonymous mutations are selectively neutral. TS and DBAT gene trees are not consistent with the ITS tree, where species formed monophyletic clades. In fact, for both genes, alleles were sometimes shared across species and parallel amino acid substitutions were identified. While both TS and DBAT are, overall, under purifying selection, we identified a number of amino acids of TS under positive selection based on inference using maximum likelihood models. Positively selected amino acids in the N-terminal region of TS suggest that this region might be more important for enzyme function than previously thought. Moreover, we identify lineages with significantly elevated rates of amino acid substitution using a genetic algorithm. These findings demonstrate that the pattern of adaptive paclitaxel biosynthetic enzyme evolution can be documented between closely related Taxus species, where species-specific taxane metabolism has evolved recently. PMID:18327645

Hao, Da Cheng; Yang, Ling; Huang, Beili

2008-03-08

333

Disruption of HepG2 cell adhesion by gold nanoparticle and Paclitaxel disclosed by in situ QCM measurement  

Microsoft Academic Search

Cell adhesion is a crucial issue for cytotoxicity or anticancer effectiveness for tumor cells. However, how both nanoparticles and drugs affect cell adhesion has not yet been defined. Herein, we report for the first time that gold nanoparticles and Paclitaxel can disrupt adhesion, as well as enhance apoptosis of HepG2 cell individually and synergistically, as observed by in situ measurement

Xiao-Lan Wei; Zhi-Hong Mo; Biao Li; Jin-Min Wei

2007-01-01

334

In vitro mutagenicity and blood compatibility of paclitaxel and curcumin in poly (DL-lactide-co-glicolide) films.  

PubMed

Curcumin is considered to be a potential component for drug-eluting stents due to its anti-inflammatory properties. In this study we compared the mutagenicity and blood compatibility of curcumin to first generation drug eluting stent components: paclitaxel and sirolimus. The Ames test was used to assess mutagenicity. Blood compatibility was tested by measuring platelet activation and fibrinogen adsorption on poly (DL-lactide-co-glycolide, PLGA) films. We discovered that there was no significant increase in the number of revertants/plate following treatment with curcumin (up to 0.5mg/plate) or sirolimus (up to 0.5 ?g/plate). However, a significant induction in the frequency of bacterial his(+) revertant colonies by paclitaxel at concentrations of 0.02, 0.05, 0.1, 0.2 and 0.5 ?g/plate was observed. We also discovered a significant reduction in platelet activation by PLGA films containing 30% and 50% by weight curcumin. A similar reduction in platelet activation was also observed for PLGA films containing 1% by weight paclitaxel. In addition, we observed an increase of fibrinogen adsorption to PLGA-films containing curcumin. This would compromise the potential use of curcumin as a component of drug-eluting stents. Moreover, our data challenges the current view that paclitaxel does not significantly induce mutagenesis. PMID:23108037

Vieira, Iara Lucia Barbosa Fernandes; de Souza, Debora Cristina Passos; da Silva Coelho, Liliane; Chen, Lee Chen; Guillo, Lidia Andreu

2012-10-26

335

Tumor therapy with a urokinase plasminogen activator-activated anthrax lethal toxin alone and in combination with paclitaxel.  

PubMed

PA-U2, an engineered anthrax protective antigen that is activated by urokinase was combined with wildtype lethal factor in the treatment of Colo205 colon adenocarcinoma in vitro and B16-BL6 mouse melanoma in vitro and in vivo. This therapy was also tested in combination with the small molecule paclitaxel, based on prior reports suggesting synergy between ERK1/2 inhibition and chemotherapeutics. Colo205 was sensitive to PA-U2/LF while B16-BL6 was not. For the combination treatment of B16-BL6, paclitaxel showed a dose response in vitro, but cells remained resistant to PA-U2/LF even in the presence of paclitaxel. In vivo, each therapy slowed tumor progression, and an additive effect between the two was observed. Since LF targets tumor vasculature while paclitaxel is an antimitotic, it is possible the agents were acting against different cells in the stroma, precluding a synergistic effect. The engineered anthrax toxin PA-U2/LF warrants further development and testing, possibly in combination with an antiangiogenesis therapy such as sunitinib or sorafinib. PMID:22843210

Wein, Alexander N; Liu, Shihui; Zhang, Yi; McKenzie, Andrew T; Leppla, Stephen H

2012-07-28

336

Determination of Paclitaxel Distribution in Solid Tumors by Nano-Particle Assisted Laser Desorption Ionization Mass Spectrometry Imaging  

PubMed Central

A sensitive, simple and reproducible protocol for nanoparticle-assisted laser desorption/ionization mass spectrometry imaging technique is described. The use of commercially available TiO2 nanoparticles abolishes heterogeneous crystallization, matrix background interferences and enhances signal detection, especially in the low mass range. Molecular image normalization was based on internal standard deposition on tissues, allowing direct comparison of drug penetration and distribution between different organs and tissues. The method was applied to analyze the distribution of the anticancer drug paclitaxel, inside normal and neoplastic mouse tissue sections. Spatial resolution was good, with a linear response between different in vivo treatments and molecular imaging intensity using therapeutic drug doses. This technique distinguishes the different intensity of paclitaxel distribution in control organs of mice, such as liver and kidney, in relation to the dose. Animals treated with 30 mg/kg of paclitaxel had half of the concentration of those treated with 60 mg/kg. We investigated the spatial distribution of paclitaxel in human melanoma mouse xenografts, following different dosage schedules and found a more homogeneous drug distribution in tumors of mice given repeated doses (5×8 mg/kg) plus a 60 mg/kg dose than in those assigned only a single 60 mg/kg dose. The protocol can be readily applied to investigate anticancer drug distribution in neoplastic lesions and to develop strategies to optimize and enhance drug penetration through different tumor tissues.

Zucchetti, Massimo; Pretto, Francesca; Carra, Andrea; D'Incalci, Maurizio; Giavazzi, Raffaella; Davoli, Enrico

2013-01-01

337

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

338

Weekly administration of paclitaxel attenuated rectal stenosis caused by multiple peritoneal recurrence 8 years after the resection of gastric carcinoma  

Microsoft Academic Search

We report a patient with rectal stenosis caused by peritoneal recurrence 8 years after a curative resection of advanced stage gastric carcinoma; the recurrence was effectively treated with the weekly administration of paclitaxel. The patient was a 66-year-old Japanese woman who was admitted to our hospital complaining of abdominal pain and frequent bowel movements. She had undergone total gastrectomy, due

Yoichi Sakurai; Ikuo Yoshida; Shuhei Tonomura; Wakana Sakai; Yasuko Nakamura; Hiroki Imazu; Toshiki Matsubara; Masahiro Ochiai

2003-01-01

339

Weekly administration of paclitaxel attenuated rectal stenosis caused by multiple peritoneal recurrence 8 years after the resection of gastric carcinoma.  

PubMed

We report a patient with rectal stenosis caused by peritoneal recurrence 8 years after a curative resection of advanced stage gastric carcinoma; the recurrence was effectively treated with the weekly administration of paclitaxel. The patient was a 66-year-old Japanese woman who was admitted to our hospital complaining of abdominal pain and frequent bowel movements. She had undergone total gastrectomy, due to advanced-stage gastric carcinoma with extensive lymph node metastasis, 8 years before, and had taken an oral anticancer agent, fluoropyrimidine, for 4 years after the operation. Colonofiberscopy performed on admission revealed circumferential rectal stenosis located 10 cm from the anal verge. Barium enema study demonstrated extensive poor expansion of the upper and lower rectum and irregularity of the descending colon. Abdominal computed tomography (CT) scanning revealed wall thickening in the rectum and descending colon. These findings were compatible with rectal stenosis caused by the peritoneal recurrence of gastric carcinoma. Weekly administration of paclitaxel was started. The abdominal symptoms soon disappeared when the second cycle of paclitaxel was completed, and they have not appeared since then. The rectal stenosis was attenuated, as confirmed by imaging analyses. Weekly paclitaxel has been effective for more than 13 months, suggesting that the patient is in a state of tumor dormancy of recurrent gastric carcinoma. PMID:14716519

Sakurai, Yoichi; Yoshida, Ikuo; Tonomura, Shuhei; Sakai, Wakana; Nakamura, Yasuko; Imazu, Hiroki; Matsubara, Toshiki; Ochiai, Masahiro

2003-01-01

340

Biodistribution, Radiation Dose Estimates, and In Vivo Pgp Modulation Studies of 18F-Paclitaxel in Nonhuman Primates  

Microsoft Academic Search

Multidrug resistance (MDR) associated with increased expres- sion and function of the P-glycoprotein (Pgp) efflux pump often causes chemotherapeutic failure in cancer. To provide insight into both the dynamics of the pump and the effects of MDR, we radiolabeled paclitaxel, a substrate for the Pgp pump, with 18F to study MDR in vivo with PET. We obtained biodistribution and radiation

Karen A. Kurdziel; Dale O. Kiesewetter; Richard E. Carson; William C. Eckelman; Peter Herscovitch

341

Expression of dbat and dbtnbt genes involved in paclitaxel biosynthesis during the growth cycle of Taxus baccata L. callus cultures.  

PubMed

The time-course of expression of dbat and dbtnbt genes involved in the later steps of paclitaxel biosynthesis and the intracellular taxane accumulation were investigated through a 64-day subculture interval of VI/M1 and VI/M2 Taxus baccata callus cultures. HPLC proved traces of baccatin III and an intracellular content of paclitaxel up to 90 microg/g DW. The steady-state of the respective gene transcripts was measured by quantitative real-time RT-PCR. The expression profile of dbat and dbtnbt genes was slightly different and varied within the subculture. The highest level of dbat expression was detected 24 h after inoculation followed by a decrease in both cultures. In contrast with dbat no substantially high expression of the dbtnbt gene after inoculation was observed. The impact of the conditions during inoculation on gene expression is discussed. Although the increase in transcriptional activity of both genes positively correlated with callus growth, the intracellular accumulation of paclitaxel varied during subculture with the maximum in the stationary (VI/M1) or at the end of the linear (VI/M2) phase. The increase of the steady-state mRNA level of the dbtnbt gene was followed by paclitaxel accumulation with a delay of approx. 28 (VI/M1) and 14 days (VI/M2). PMID:19040113

Katkovcinová, Zuzana; Lázárová, Martina; Brunáková, Katarína; Kosuth, Ján; Cellárová, Eva

342

Top-down and bottom-up approaches in production of aqueous nanocolloids of low solubility drug paclitaxel.  

PubMed

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

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

2011-03-25

343

Symptomatic and neurophysiological responses of paclitaxel- or cisplatin-induced neuropathy to oral acetyl- l-carnitine  

Microsoft Academic Search

Acetyl-l-carnitine (ALC) improves non-oncological neuropathies. We tested oral ALC (1 g tid) for 8 weeks in 25 patients with neuropathy grade ?3 (common toxicity criteria – CTC) during paclitaxel or cisplatin therapy, or grade ?2 persisting for at least three months after discontinuing the drugs. An independent neurologist assessed patients before and after ALC. All patients except one reported symptomatic

Giulia Bianchi; Giordano Vitali; Augusto Caraceni; Sabrina Ravaglia; Giuseppe Capri; Sante Cundari; Claudio Zanna; Luca Gianni

2005-01-01

344

Functional deficits in peripheral nerve mitochondria in rats with paclitaxel- and oxaliplatin-evoked painful peripheral neuropathy.  

PubMed

Cancer chemotherapeutics like paclitaxel and oxaliplatin produce a dose-limiting chronic sensory peripheral neuropathy that is often accompanied by neuropathic pain. The cause of the neuropathy and pain is unknown. In animal models, paclitaxel-evoked and oxaliplatin-evoked painful peripheral neuropathies are accompanied by an increase in the incidence of swollen and vacuolated mitochondria in peripheral nerve axons. It has been proposed that mitochondrial swelling and vacuolation are indicative of a functional impairment and that this results in a chronic axonal energy deficiency that is the cause of the neuropathy's symptoms. However, the significance of mitochondrial swelling and vacuolation is ambiguous and a test of the hypothesis requires a direct assessment of the effects of chemotherapy on mitochondrial function. The results of such an assessment are reported here. Mitochondrial respiration and ATP production were measured in rat sciatic nerve samples taken 1-2 days after and 3-4 weeks after induction of painful peripheral neuropathy with paclitaxel and oxaliplatin. Significant deficits in Complex I-mediated and Complex II-mediated respiration and significant deficits in ATP production were found for both drugs at both time points. In addition, prophylactic treatment with acetyl-l-carnitine, which inhibited the development of paclitaxel-evoked and oxaliplatin-evoked neuropathy, prevented the deficits in mitochondrial function. These results implicate mitotoxicity as a possible cause of chemotherapy-evoked chronic sensory peripheral neuropathy. PMID:21907196

Zheng, Huaien; Xiao, Wen Hua; Bennett, Gary J

2011-08-30

345

Paclitaxel-Based Chemotherapy for Advanced Pancreatic Cancer after Gemcitabine-Based Therapy Failure: A Case Series of 5 Patients  

PubMed Central

Background/Objectives Gemcitabine (GEM) is a gold-standard chemotherapy agent for advanced pancreatic cancer. Because of the malignant character of the disease, nearly all patients show disease progression despite treatment with GEM-based chemotherapy; therefore, second-line chemotherapy may be beneficial for these patients. We report a retrospective analysis of 5 patients with advanced pancreatic cancer, treated with a paclitaxel-containing regimen as second-, third- or fourth-line chemotherapy after various therapies, such as a GEM-based regimen, S-1 regimen, and chemoradiation. We retrospectively analyzed the efficacy and adverse events, and evaluated the paclitaxel-containing regimens. A review of the literature is also discussed. Results The median overall survival from the start of salvage therapy was 10.7 months. The disease control rate of the paclitaxel-containing regimen according to RECIST criteria was 60%, including complete response in 0 patients, partial response in 3, and stable disease in 2. Two patients had malignant ascites at the start of this salvage therapy, and in both of them the ascites and clinical complaints improved. Grade 3 and 4 hematological adverse events were observed in 2 patients and 1 patient, respectively. Conclusion Salvage paclitaxel-based therapy could be beneficial to advanced pancreatic cancer patients who maintain good performance status after several chemotherapy failures.

Igarashi, Hisato; Ito, Tetsuhide; Hisano, Terumasa; Fujimori, Nao; Niina, Yusuke; Yasuda, Mikihiko; Kaku, Toyoma; Matsuo, Susumu; Oono, Takamasa; Yoshinaga, Masahiro; Sakai, Hiroyuki; Takayanagi, Ryoichi

2011-01-01

346

AFM-Detected Apoptotic Changes in Morphology and Biophysical Property Caused by Paclitaxel in Ishikawa and HeLa Cells  

PubMed Central

The apoptosis of cancer cells is associated with changes in the important cell properties including morphology, surface roughness and stiffness. Therefore, the changes in morphology and biophysical properties can be a good way of evaluating the anticancer activity of a drug. This study examined the effect of paclitaxel on the properties of Ishikawa and HeLa cells using atomic force microscopy (AFM), and the relationship between the changes in morphology and the biophysical properties and apoptosis was discussed. The viability and proliferation of the cells were analyzed using the methylthiazol tetrazolium (MTT) method and a TUNEL assay to confirm cellular apoptosis due to a paclitaxel treatment. AFM observations clearly showed the apoptotic morphological and biophysical changes in Ishikawa and HeLa cells. After the paclitaxel treatment, the cell membrane was torn and holed, the surface roughness was increased, and the stiffness was decreased. These changes were observed more apparently after a 24 h treatment and in Ishikawa cells compared to HeLa cells. The MTT and TUNEL assays results revealed the Ishikawa cells to be more sensitive to paclitaxel than HeLa cells and definite apoptosis occurred after a 24 h treatment. These results showed good agreement with the AFM results. Therefore, research on the morphological and biophysical changes by AFM in cancer cells will help to evaluate the anticancer activities of the drugs.

Park, Eun Kuk; Jung, Min-Hyung; Yoon, Kyung-Sik; Park, Hun-Kuk

2012-01-01

347

No-Reflow Phenomenon During Treatment of Coronary In-Stent Restenosis With a Paclitaxel-Coated Balloon Catheter  

PubMed Central

Drug-eluting balloon (DEB) with angioplasty a paclitaxel-coated balloon catheter is an effective treatment option in patients with in-stent restenosis (ISR) after a drug-eluting stent (DES). We describe a case in which 'no-reflow' phenomenon developed after DEB angioplasty of a DES ISR lesion. Coronary flow was restored after intracoronary administration of nicorandil.

Chung, Han-Hee; Jung, Mi-Hyang; Yang, Hae-Kyung; Park, Kyung-Seon; Yoo, Ki-Dong

2012-01-01

348

Inhibition of paclitaxel and baccatin III accumulation by mevinolin and fosmidomycin in suspension cultures of Taxus baccata  

Microsoft Academic Search

To achieve a better understanding of the metabolism and accumulation of paclitaxel and baccatin III in cell cultures of Taxus, inhibitors of the early steps in the terpenoid pathway were applied to a cell suspension culture of Taxus baccata: fosmidomycin as an inhibitor of the non-mevalonate branch of the pathway, and mevinolin as an inhibitor of the mevalonate branch. Synthesis

Javier Palazón; Rosa M. Cusidó; Mercedes Bonfill; Carmen Morales; M. Teresa Piñol

2003-01-01

349

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

PubMed Central

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

2012-01-01

350

ss3 integrin modulates transforming growth factor beta induced (TGFBI) function and paclitaxel response in ovarian cancer cells  

PubMed Central

Background The extracellular matrix (ECM) has a key role in facilitating the progression of ovarian cancer and we have shown recently that the secreted ECM protein TGFBI modulates the response of ovarian cancer to paclitaxel-induced cell death. Results We have determined TGFBI signaling from the extracellular environment is preferential for the cell surface ?vß3 integrin heterodimer, in contrast to periostin, a TGFBI paralogue, which signals primarily via a ß1 integrin-mediated pathway. We demonstrate that suppression of ß1 integrin expression, in ß3 integrin-expressing ovarian cancer cells, increases adhesion to rTGFBI. In addition, Syndecan-1 and ?4 expression is dispensable for adhesion to rTGFBI and loss of Syndecan-1 cooperates with the loss of ß1 integrin to further enhance adhesion to rTGFBI. The RGD motif present in the carboxy-terminus of TGFBI is necessary, but not sufficient, for SKOV3 cell adhesion and is dispensable for adhesion of ovarian cancer cells lacking ß3 integrin expression. In contrast to TGFBI, the carboxy-terminus of periostin, lacking a RGD motif, is unable to support adhesion of ovarian cancer cells. Suppression of ß3 integrin in SKOV3 cells increases resistance to paclitaxel-induced cell death while suppression of ß1 integrin has no effect. Furthermore, suppression of TGFBI expression stimulates a paclitaxel resistant phenotype while suppression of fibronectin expression, which primarily signals through a ß1 integrin-mediated pathway, increases paclitaxel sensitivity. Conclusions Therefore, different ECM components use distinct signaling mechanisms in ovarian cancer cells and in particular, TGFBI preferentially interacts through a ß3 integrin receptor mediated mechanism to regulate the response of cells to paclitaxel-induced cell death.

2012-01-01

351

p27kip1 overexpression promotes paclitaxel-induced apoptosis in pRb-defective SaOs-2 cells.  

PubMed

p27kip1 is a cyclin-dependent kinase (CDK) inhibitor, which controls several cellular processes in strict collaboration with pRb. We evaluated the role of p27kip1 in paclitaxel-induced apoptosis in the pRb-defective SaOs-2 cells. Following 48 h of exposure of SaOs-2 cells to 100 nM paclitaxel, we observed an increase in p27kip1 expression caused by the decrease of the ubiquitin-proteasome activity. Such increase was not observed in SaOs-2 cells treated with the caspase inhibitors Z-VAD-FMK, suggesting that p27kip1 enhancement at 48 h is strictly related to apoptosis. Finally, we demonstrated that SaOs-2 cells transiently overexpressing the p27kip1 protein are more susceptible to paclitaxel-induced apoptosis than SaOs-2 cells transiently transfected with the empty vector. Indeed, after 48 h of paclitaxel treatment, 41.8% of SaOs-2 cells transiently transfected with a pcDNA3-p27kip1 construct were Annexin V-positive compared to 30.6% of SaOs-2 cells transfected with the empty vector (P < 0.05). In conclusion, we demonstrated that transfection of the pRb-defective SaOs-2 cells with the p27kip1 gene via plasmid increases their susceptibility to paclitaxel-induced apoptosis. The promoting effect of p27kip1 overexpression on apoptosis makes p27kip1 and proteasomal inhibitors interesting tools for therapy in patients with pRb-defective cancers. PMID:16598766

Gabellini, Chiara; Pucci, Bruna; Valdivieso, Paola; D'Andrilli, Giuseppina; Tafani, Marco; De Luca, Antonio; Masciullo, Valeria

2006-08-15

352

Phase I trial of hepatic arterial infusion of nanoparticle albumin-bound paclitaxel: toxicity, pharmacokinetics, and activity.  

PubMed

Because liver involvement in patients with metastatic cancer has limited options and poor outcomes, we conducted a phase I study to determine the safety, activity, and pharmacokinetic characteristics of hepatic arterial infusion of nanoparticle albumin-bound paclitaxel (HAI nab-paclitaxel). Cohorts of three patients having predominant hepatic metastases received HAI nab-paclitaxel at three dose levels (180, 220, and 260 mg/m(2), respectively) infused for more than 1 hour every 3 weeks (3 + 3 design). Some patients participated in comparative pharmacokinetic studies (i.v. vs. HAI), receiving their first course i.v., to determine peak concentrations and effect of first-pass hepatic extraction compared with subsequent courses administered by HAI. The highest dose level was expanded to determine the safety and activity of HAI nab-paclitaxel. Thirty-eight patients were treated. There were no dose-limiting toxicities at doses up to 260 mg/m(2). Common adverse events included alopecia, fatigue, myelosuppresion, nausea, and vomiting. Three patients had stable disease for 4 or more months and 2 patients (1 of 12 with breast cancer and 1 of 1 with cervical cancer) achieved a partial response lasting for 5 and 15 months, respectively. Peak concentrations were lower (?50%) with greater hepatic extraction of drug (?42%) following HAI than i.v. infusion based on area under the curve comparison of drug exposure. HAI nab-paclitaxel showed partial hepatic extraction. At doses 260 mg/m(2) or less given for 1 hour every 3 weeks, the treatment was well-tolerated and showed activity in advanced cancer patients with predominant liver metastases. PMID:21571911

Fu, Siqing; Naing, Aung; Moulder, Stacy L; Culotta, Kirk S; Madoff, David C; Ng, Chaan S; Madden, Timothy L; Falchook, Gerald S; Hong, David S; Kurzrock, Razelle

2011-05-13

353

Enhanced Oral Absorption of Paclitaxel in a Novel Self-Microemulsifying Drug Delivery System with or Without Concomitant Use of P-Glycoprotein Inhibitors  

Microsoft Academic Search

Purpose. The objective of this study was to evaluate the pharmacokinetics of paclitaxel in a novel self-microemulsifying drug delivery system (SMEDDS) for improved oral administration with or without P-glycoprotein (P-gp) inhibitors.

Shicheng Yang; R. Neslihan Gursoy; Gregory Lambert; Simon Benita

2004-01-01

354

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

PubMed Central

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

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

2006-01-01

355

Paclitaxel and vinorelbine, evoked the release of substance P from cultured rat dorsal root ganglion cells through different PKC isoform-sensitive ion channels.  

PubMed

Many patients suffer from serious adverse effects including respiratory distress and pulmonary edema during and after chemotherapy with paclitaxel or vinorelbine. These effects appear to be due to the activation of neurokinin-1 receptors. The present study investigated the influences of paclitaxel and vinorelbine on the substance P (sP) release from cultured dorsal root ganglion (DRG) cells using a radioimmunoassay. Both paclitaxel and vinorelbine evoked sP release in a dose- and time-dependent manner within 60 min at a concentration range of 0.1-10 microM. The sP release levels induced by the two drugs were attenuated by pretreatment with the protein kinase Cs (PKCs) inhibitors (bisindolylmaleimide I and Gö6976). Moreover, the paclitaxel- or vinorelbine-induced sP release was diminished in the absence of extracellular Ca2+ or the presence of LaCl3 (an extracellular Ca2+ influx blocker). A Ca2+ imaging assay further indicated that both paclitaxel and vinorelbine gradually increased the intracellular Ca2+ concentration, and these increases lasted for at least 15 min and were suppressed by Gö6976. Paclitaxel caused the membrane translocation of only PKCbeta within 10 min after stimulation, whereas vinorelbine induced the translocation of both PKCalpha and beta. The paclitaxel- and vinorelbine-induced sP release levels were separately inhibited by ruthenium red (a transient receptor potential (TRP) channel blocker) and gabapentin (an inhibitor of voltage-gated Ca2+ channels (VGCCs)). These findings suggest that paclitaxel and vinorelbine evoke the sP release from cultured DRG cells by the extracellular Ca2+ influx through TRP channels activated by PKCbeta and VGCCs activated by both PKCalpha and beta, respectively. PMID:19376141

Miyano, Kanako; Tang, He-Bin; Nakamura, Yoki; Morioka, Norimitsu; Inoue, Atsuko; Nakata, Yoshihiro

2009-04-17

356

Effect of paclitaxel on vascular endothelial growth factor (VEGF) and interleukin (IL)-8 in serum of patients with recurrent ovarian cancer: a comparison of weekly vs triweekly regimens  

Microsoft Academic Search

Antiangiogenic scheduling of cancer chemotherapeutics has been increasingly recognized to be a potential application of the paclitaxel in cancer therapy. The purpose of this study is to confirm antiangiogenic effects of weekly low-dose paclitaxel in recurrent ovarian carcinoma. Measurements of serum vascular endothelial cell growth factor (VEGF) and interleukin (IL)-8 were performed using enzyme-linked immunosorbent assay (ELISA) kits. Serum was

Keiko Saito; Yoshihiro Kikuchi; Kazuyuki Fujii; Tsunekazu Kita; Kenichi Furuya

2006-01-01

357

Phase II study of weekly paclitaxel and trastuzumab in anthracycline- and taxane-pretreated patients with HER2-overexpressing metastatic breast cancer  

Microsoft Academic Search

Synergism between anti-HER2 monoclonal antibody (trastuzumab) and paclitaxel has been shown in vitro and in vivo. In previous experiences, weekly administration of trastuzumab and paclitaxel has shown significant activity in metastatic breast cancer. In this phase II study, we evaluated the activity and the toxicity of this weekly regimen in anthracycline- and taxane-pretreated patients with HER2-overexpressing metastatic breast cancer. Between

S Gori; M Colozza; A M Mosconi; E Franceschi; C Basurto; R Cherubini; A Sidoni; A Rulli; C Bisacci; V De Angelis; L Crinò; M Tonato

2004-01-01

358

Proteinase-activated receptor 2 sensitizes transient receptor potential vanilloid 1, transient receptor potential vanilloid 4, and transient receptor potential ankyrin 1 in paclitaxel-induced neuropathic pain  

Microsoft Academic Search

Paclitaxel chemotherapy is limited by a long-lasting painful neuropathy that lacks an effective therapy. In this study, we tested the hypothesis that paclitaxel may release mast cell tryptase, which activates protease-activated receptor 2 (PAR2) and, subsequently, protein kinases A and C, resulting in mechanical and thermal (both heat and cold) hypersensitivity. Correlating with the development of neuropathy after repeated administration

Y. Chen; C. Yang; Z. J. Wang

2011-01-01

359

The effects of opioid receptor antagonists on electroacupuncture-produced anti-allodynia\\/hyperalgesia in rats with paclitaxel-evoked peripheral neuropathy  

Microsoft Academic Search

Research supports the effectiveness of acupuncture for conditions such as chronic low back and knee pain. In a five-patient pilot study the modality also improved the symptoms of chemotherapy-induced neuropathic pain. Using an established rat model of paclitaxel-induced peripheral neuropathy, we evaluated the effect of electroacupuncture (EA) on paclitaxel-induced hyperalgesia and allodynia that has not been studied in an animal

Xianze Meng; Yu Zhang; Aihui Li; Jiajia Xin; Lixing Lao; Ke Ren; Brian M. Berman; Ming Tan; Rui-Xin Zhang

2011-01-01

360

Weekly regimen of epirubicin and paclitaxel as second-line chemotherapy in patients with metastatic transitional cell carcinoma of urothelial tract: results of a phase II study  

Microsoft Academic Search

Until recently, there was no standard second-line treatment for advanced urothelial carcinoma. Although included in first-line\\u000a regimens, role of anthracyclines was never investigated as second-line therapy. Single-agent paclitaxel showed modest results\\u000a in this setting. The purpose of this study was to assess the efficacy and toxicity of concomitant weekly administration of\\u000a epirubicin plus paclitaxel in patients with metastatic urothelial carcinoma

Antonio Rozzi; Margherita Salerno; Francesca Bordin; Ferdinando De Marco; Stefano Di Nicola; Gaetano Lanzetta

361

Potentiation of paclitaxel-induced apoptosis by the novel cyclin-dependent kinase inhibitor NU6140: a possible role for survivin down-regulation.  

PubMed

Cyclin-dependent kinases (CDK) play a crucial role in the control of the cell cycle. Aberrations in the control of cell cycle progression occur in the majority of human malignancies; hence, CDKs are promising targets for anticancer therapy. Here, we define the cellular effects of the novel CDK inhibitor NU6140, alone or in association with paclitaxel, with respect to inhibition of cell proliferation and cell cycle progression and induction of apoptosis in HeLa cervical carcinoma cells and in comparison with purvalanol A. Both CDK inhibitors induced a concentration-dependent cell cycle arrest at the G(2)-M phase and an increase in the apoptotic rate, with a concomitant down-regulation of the antiapoptotic protein survivin, a member of the inhibitors of apoptosis protein family. Notably, the addition of NU6140 to paclitaxel-treated cells resulted in markedly increased cytotoxic effect and apoptotic response in comparison with the paclitaxel-purvalanol A combination (86 +/- 11% and 37 +/- 8%, respectively). Similarly, the extent of caspase-9 and caspase-3 activation in paclitaxel-NU6140-treated cells was approximately 4-fold higher than after the paclitaxel-purvalanol A combination. Moreover, an almost complete abrogation of the expression of the active, Thr(34)-phosphorylated form of survivin was observed in cells exposed to the paclitaxel-NU6140 combination. A synergistic effect of the paclitaxel-NU6140 combination, as a consequence of survivin inhibition and increased activation of caspase-9 and caspase-3, was also observed in OAW42/e ovarian cancer line but not in the derived OAW42/Surv subline ectopically expressing survivin. Results from this study indicate that NU6140 significantly potentiates the apoptotic effect of paclitaxel, with inhibition of survivin expression/phosphorylation as the potential mechanism. PMID:16170024

Pennati, Marzia; Campbell, Allyson J; Curto, Maria; Binda, Mara; Cheng, Yuzhu; Wang, Lan-Zeng; Curtin, Nicola; Golding, Bernard T; Griffin, Roger J; Hardcastle, Ian R; Henderson, Andrew; Zaffaroni, Nadia; Newell, David R

2005-09-01

362

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

363

Effects of Silibinin, Inhibitor of CYP3A4 and P-Glycoprotein in vitro, on the Pharmacokinetics of Paclitaxel after Oral and Intravenous Administration in Rats  

Microsoft Academic Search

Silibinin, a flavonoid, is an inhibitor of P-glycoprotein (P-gp)-mediated efflux transporters, and its oxidative metabolism is catalyzed by CYP3A4. The purpose of this study was to investigate the effect of oral silibinin on the bioavailability and pharmacokinetics of orally and intravenously administered paclitaxel in rats. The pharmacokinetic parameters of paclitaxel were determined in rats after oral (40 mg\\/kg) or intravenous

Chong-Ki Lee; Jun-Shik Choi

2010-01-01

364

A multi-center phase II study of sequential paclitaxel and bryostatin-1 (NSC 339555) in patients with untreated, advanced gastric or gastroesophageal junction adenocarcinoma  

Microsoft Academic Search

Summary  \\u000a Purpose: Protein Kinase C (PKC), involved in transmembrane signaling of cell surface receptors, promotes carcinogenesis and tumor\\u000a progression. Bryostatin-1 competes with PKC for phorbol esters (tumor promoters), thus inhibiting tumor progression. Bryostatin-1\\u000a also increases cytotoxicity of paclitaxel in a sequential fashion. We studied sequential paclitaxel and bryostatin-1 in patients\\u000a with untreated, advanced gastric adenocarcinoma. Methods: Patients with histologic proof

Jaffer A. Ajani; Yixing Jiang; Josephine Faust; Baochong B. Chang; Linus Ho; James C. Yao; Steven Rousey; Shaker Dakhil; Richard C. Cherny; Catherine Craig; Archie Bleyer

2006-01-01

365

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

Microsoft Academic Search

Summary  Poor aqueous solubility limits the therapeutic index of paclitaxel as an anti-cancer drug. Synthesis of soluble prodrugs of\\u000a paclitaxel, or conjugation of the drug to macromolecular carriers have been reported to increase its water-solubility. Macromolecular\\u000a drug carriers have an added advantage of targeting the drug to the tumor site due to the abnormal tumor blood and lymphatic\\u000a vasculature. This study

Shama Moktan; Claudia Ryppa; Felix Kratz; Drazen Raucher

366

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

Microsoft Academic Search

Prophylactic treatment with acetyl-l-carnitine (ALCAR) prevents the neuropathic pain syndrome that is evoked by the chemotherapeutic agent, paclitaxel. The paclitaxel-evoked pain syndrome is associated with degeneration of the intraepidermal terminal arbors of primary afferent neurons, with the activation of cutaneous Langerhans cells, and with an increased incidence of swollen and vacuolated axonal mitochondria in A-fibers and C-fibers. Previous work suggests

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

2008-01-01

367

Non-Polymer-Based Paclitaxel-Coated Coronary Stents for the Treatment of Patients With De Novo Coronary Lesions Angiographic Follow-Up of the DELIVER Clinical Trial  

Microsoft Academic Search

Background—Paclitaxel, a microtubule-stabilizing compound with potent antitumor activity, has been shown to inhibit smooth muscle cell proliferation and migration. The DELIVER trial was a prospective, randomized, blinded, multicenter clinical evaluation of the non-polymer-based paclitaxel-coated ACHIEVE stent compared with the stainless steel Multi-Link (ML) PENTA stent. Methods and Results—A total of 1043 patients with focal de novo coronary lesions, 25 mm

Alexandra J. Lansky; Ricardo A. Costa; Gary S. Mintz; Yoshihiro Tsuchiya; Mark Midei; David A. Cox; Charles O'Shaughnessy; Robert A. Applegate; Louis A. Cannon; Michael Mooney; Anthony Farah; Mark A. Tannenbaum; Steven Yakubov; Dean J. Kereiakes; S. Chiu Wong; Barry Kaplan; Ecaterina Cristea; Gregg W. Stone; Martin B. Leon; William D. Knopf; William W. O'Neill

2011-01-01

368

Phase III trial comparing paclitaxel poliglumex vs docetaxel in the second-line treatment of non-small-cell lung cancer.  

PubMed

Paclitaxel poliglumex (PPX), a macromolecule drug conjugate linking paclitaxel to polyglutamic acid, reduces systemic exposure to peak concentrations of free paclitaxel. Patients with non-small-cell lung cancer (NSCLC) who had received one prior platinum-based chemotherapy received 175 or 210 mg m(-2) PPX or 75 mg m(-2) docetaxel. The study enrolled 849 previously treated NSCLC patients with advanced disease. Median survival (6.9 months in both arms, hazard ratio=1.09, P=0.257), 1-year survival (PPX=25%, docetaxel=29%, P=0.134), and time to progression (PPX=2 months, docetaxel=2.6 months, P=0.075) were similar between treatment arms. Paclitaxel poliglumex was associated with significantly less grade 3 or 4 neutropenia (P<0.001) and febrile neutropenia (P=0.006). Grade 3 or 4 neuropathy (P<0.001) was more common in the PPX arm. Patients receiving PPX had less alopecia and did not receive routine premedications. More patients discontinued due to adverse events in the PPX arm compared to the docetaxel arm (34 vs 16%, P<0.001). Paclitaxel poliglumex and docetaxel produced similar survival results but had different toxicity profiles. Compared with docetaxel, PPX had less febrile neutropenia and less alopecia, shorter infusion times, and elimination of routine use of medications to prevent hypersensitivity reactions. Paclitaxel poliglumex at a dose of 210 mg m(-2) resulted in increased neurotoxicity compared with docetaxel. PMID:18475293

Paz-Ares, L; Ross, H; O'Brien, M; Riviere, A; Gatzemeier, U; Von Pawel, J; Kaukel, E; Freitag, L; Digel, W; Bischoff, H; García-Campelo, R; Iannotti, N; Reiterer, P; Bover, I; Prendiville, J; Eisenfeld, A J; Oldham, F B; Bandstra, B; Singer, J W; Bonomi, P

2008-05-13

369

Phase III trial comparing paclitaxel poliglumex vs docetaxel in the second-line treatment of non-small-cell lung cancer  

PubMed Central

Paclitaxel poliglumex (PPX), a macromolecule drug conjugate linking paclitaxel to polyglutamic acid, reduces systemic exposure to peak concentrations of free paclitaxel. Patients with non-small-cell lung cancer (NSCLC) who had received one prior platinum-based chemotherapy received 175 or 210?mg?m?2 PPX or 75?mg?m?2 docetaxel. The study enrolled 849 previously treated NSCLC patients with advanced disease. Median survival (6.9 months in both arms, hazard ratio=1.09, P=0.257), 1-year survival (PPX=25%, docetaxel=29%, P=0.134), and time to progression (PPX=2 months, docetaxel=2.6 months, P=0.075) were similar between treatment arms. Paclitaxel poliglumex was associated with significantly less grade 3 or 4 neutropenia (P<0.001) and febrile neutropenia (P=0.006). Grade 3 or 4 neuropathy (P<0.001) was more common in the PPX arm. Patients receiving PPX had less alopecia and did not receive routine premedications. More patients discontinued due to adverse events in the PPX arm compared to the docetaxel arm (34 vs 16%, P<0.001). Paclitaxel poliglumex and docetaxel produced similar survival results but had different toxicity profiles. Compared with docetaxel, PPX had less febrile neutropenia and less alopecia, shorter infusion times, and elimination of routine use of medications to prevent hypersensitivity reactions. Paclitaxel poliglumex at a dose of 210?mg?m?2 resulted in increased neurotoxicity compared with docetaxel.

Paz-Ares, L; Ross, H; O'Brien, M; Riviere, A; Gatzemeier, U; Von Pawel, J; Kaukel, E; Freitag, L; Digel, W; Bischoff, H; Garcia-Campelo, R; Iannotti, N; Reiterer, P; Bover, I; Prendiville, J; Eisenfeld, A J; Oldham, F B; Bandstra, B; Singer, J W; Bonomi, P

2008-01-01

370

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

PubMed Central

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

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

2005-01-01

371

The enhancement of Raf1 kinase activity by knockdown of Spry2 is associated with high sensitivity to paclitaxel in v-Ha -ras -transformed NIH 3T3 fibroblasts  

Microsoft Academic Search

We previously demonstrated that the downregulation of Raf-1 kinase may contribute to the development of acquired resistance\\u000a in paclitaxel-resistant cells. In this study, we determine whether the sensitivities of parental and its v-Ha-ras-transformed NIH 3T3 cells to paclitaxel were dependent on Raf-1 kinase activity. Paclitaxel sensitivity of v-Ha-ras-transformed cells was found to be significantly higher than that of its parental

Jun-Ho Ahn; Ki-Hwan Eum; Michael Lee

2009-01-01

372

A prospective evaluation of the safety and efficacy of the TAXUS Element paclitaxel-eluting coronary stent system for the treatment of de novo coronary artery lesions: Design and statistical methods of the PERSEUS clinical program  

Microsoft Academic Search

BACKGROUND: Paclitaxel-eluting stents decrease angiographic and clinical restenosis following percutaneous coronary intervention compared to bare metal stents. TAXUS Element is a third-generation paclitaxel-eluting stent which incorporates a novel, thinner-strut, platinum-enriched metal alloy platform. The stent is intended to have enhanced radiopacity and improved deliverability compared to other paclitaxel-eluting stents. The safety and efficacy of the TAXUS Element stent are being

Dominic J Allocco; Louis A Cannon; Amy Britt; John E Heil; Andrey Nersesov; Scott Wehrenberg; Keith D Dawkins; Dean J Kereiakes

2010-01-01

373

Paclitaxel loaded carrier based biodegradable polymeric implants: Preparation and in vitro characterization  

PubMed Central

The objective of this study was to develop paclitaxel (PTX) loaded poly(?-caprolactone) (PCL) based tiny implants. ?-Cyclodextrin (?-CD) and polyethylene glycol (PEG 6000) were used to enhance solubility and release of the drug in the phosphate buffer saline pH 7.4. Implants were evaluated in terms of color, shape, thickness, surface area, weight, drug content. Developed implants were characterized for their surface morphology (SEM analysis), drug physical state by thermal analysis (DSC studies), crystalline nature (XRD studies) and drug excipients compatibility (FT-IR spectroscopy). Macroscopically all the tiny implants were white in color and cylindrical in shape with smooth surfaces. PTX was entrapped within implants in the polymeric amorphous form. In vitro drug release studies showed prolonged and controlled release of PTX with zero order and Korsmeyer–Peppas model being exhibited. Excipients and method of preparation did not affect chemical stability of PTX.

Hiremath, Jagadeesh G.; Khamar, Nirav S.; Palavalli, Subhash G.; Rudani, Chetan G.; Aitha, Rajeshkumar; Mura, Prasanthkumar

2012-01-01

374

PLGA nanoparticles codeliver paclitaxel and Stat3 siRNA to overcome cellular resistance in lung cancer cells  

PubMed Central

Background: Effective cancer chemotherapy remains an important issue in cancer treatment, and signal transducer and activator of transcription-3 (Stat3) activation leads to cellular resistance of anticancer agents. Polymers are ideal vectors to carry both chemotherapeutics and small interfering ribonucleic acid (siRNA) to enhance antitumor efficacy. In this paper, poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with paclitaxel and Stat3 siRNA were successfully synthesized, and their applications in cancer cells were investigated. Methods: Firstly, paclitaxel was enclosed by PLGA nanoparticles through solvent evaporation. They were then coated with cationic polyethylenimine polymer (PLGA-PEI-TAX), enabling it to carry Stat3 siRNA on its surface through electrostatic interactions (PLGA-PEI-TAX-S3SI). The size, zeta potential, deliver efficacy, and release profile of the PLGA nanocomplexes were characterized in vitro. The cellular uptake, intracellular nanoparticle trajectory, and subsequent cellular events were evaluated after treatment with various PLGA nanocomplexes in human lung cancer A549 cells and A549-derived paclitaxel-resistant A549/T12 cell lines with ?-tubulin mutation. Results: A549 and A549/T12 cells contain constitutively activated Stat3, and silencing Stat3 by siRNA made both cancer cells more sensitive to paclitaxel. Therefore, PLGA-PEI-TAX-S3SI was synthesized to test its therapeutic role in A549 and A549/T12 cells. Transmission electron microscopy showed the size of PLGA-PEI-TAX-S3SI to be around 250 nm. PLGA-PEI nanoparticles were nontoxic. PLGA-PEI-TAX was taken up by A549 and A549/T12 cells more than free paclitaxel, and they induced more condensed microtubule bundles and had higher cytotoxicity in these cancer cells. Moreover, the yellowish fluorescence observed in the cytoplasm of the cancer cells indicates that the PLGA-PEI nanoparticles were still simultaneously delivering Oregon Green paclitaxel and cyanine-5-labeled Stat3 siRNA 3 hours after treatment. Furthermore, after the cancer cells were incubated with the synthesized PLGA nanocomplexes, PLGA-PEI-TAX-S3SI suppressed Stat3 expression and induced more cellular apoptosis in A549 and A549/T12 cells compared with PLGA-PEI-TAX. Conclusion: The PLGA-PEI-TAX-S3SI complex provides a new therapeutic strategy to control cancer cell growth.

Su, Wen-Pin; Cheng, Fong-Yu; Shieh, Dar-Bin; Yeh, Chen-Sheng; Su, Wu-Chou

2012-01-01

375

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

376

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

377

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

SciTech Connect

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

Lupe, Krystine [Department of Radiation Oncology, University of Western Ontario and London Health Sciences Centre, London, Ontario (Canada); Kwon, Janice [Division of Gynecologic Oncology, University of Western Ontario and London Health Sciences Centre, London, Ontario (Canada)]. E-mail: Janice.kwon@lhsc.on.ca; D'Souza, David [Department of Radiation Oncology, University of Western Ontario and London Health Sciences Centre, London, Ontario (Canada); Gawlik, Christine [Department of Pharmacy, University of Western Ontario and London Health Sciences Centre, London, Ontario (Canada); Stitt, Larry [Department of Biostatistics and Epidemiology, University of Western Ontario and London Health Sciences Centre, London, Ontario (Canada); Whiston, Frances [Clinical Cancer Research Program, University of Western Ontario and London Health Sciences Centre, London, Ontario (Canada); Nascu, Patricia [Department of Obstetrics and Gynecology, University of Western Ontario and London Health Sciences Centre, London, Ontario (Canada); Wong, Eugene [Department of Radiation Oncology, University of Western Ontario and London Health Sciences Centre, London, Ontario (Canada); Carey, Mark S. [Division of Gynecologic Oncology, University of Western Ontario and London Health Sciences Centre, London, Ontario (Canada)

2007-01-01

378

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

379

Paclitaxel-loaded Pluronic nanoparticles formed by a temperature-induced phase transition for cancer therapy.  

PubMed

We prepared nanoparticles by a temperature-induced phase transition in a mixture of Pluronic F-68 and liquid PEG (polyethylene glycol, molecular weight: 400) containing paclitaxel (PTX) with a fast, simple, continuous and solvent-free process. The liquid PEG is used as solubilizer of PTX and the polymer for the encapsulation of PTX is composed of Pluronic F-68. At the phase transition temperature, the polymer mixture was changed to the liquid phase, and stirring the liquid 0 °C to form Pluronic nanoparticles. The morphology and size distribution of the prepared Pluronic nanoparticles were observed using FE-SEM and TEM, and a particle size analyzer and cryo-TEM were used to observe the shape of paclitaxel-loaded Pluronic nanoparticles in an aqueous state. To apply Pluronic nanoparticles as a delivery system for cancer therapy, the release pattern of PTX, a model anti-cancer drug, was observed and the tumor growth was monitored by injecting the PTX-loaded Pluronic nanoparticles into the tail veins of tumor-bearing mice. We also evaluated the time-dependent excretion profile, in vivo biodistribution, circulation time, and tumor targeting ability of PTX-loaded Pluronic nanoparticles using non-invasive live animal imaging technology. In the early stage within 7h of release, the loaded PTX was rapidly released and the sustained release was observed for up to 48 h. In vivo studies, PTX-loaded Pluronic nanoparticles were observed with higher anti-tumor efficacy compared with PTX formulated in Cremophor EL. PMID:20797418

Oh, Keun Sang; Song, Ji Yung; Cho, Sun Hang; Lee, Bum Suk; Kim, Sang Yoon; Kim, Kwangmeyung; Jeon, Hyesung; Kwon, Ick Chan; Yuk, Soon Hong

2010-08-24

380

Aptamer conjugated paclitaxel and magnetic fluid loaded fluorescently tagged PLGA nanoparticles for targeted cancer therapy  

NASA Astrophysics Data System (ADS)

Controlled and targeted drug delivery is an essential criterion in cancer therapy to reduce the side effects caused by non-specific drug release and toxicity. Targeted chemotherapy, sustained drug release and optical imaging have been achieved using a multifunctional nanocarrier constructed from poly (D, L-lactide-co-glycolide) nanoparticles (PLGA NPs), an anticancer drug paclitaxel (PTX), a fluorescent dye Nile red (NR), magnetic fluid (MF) and aptamers (Apt, AS1411, anti-nucleolin aptamer). The magnetic fluid and paclitaxel loaded fluorescently labeled PLGA NPs (MF-PTX-NR-PLGA NPs) were synthesized by a single-emulsion technique/solvent evaporation method using a chemical cross linker bis (sulfosuccinimidyl) suberate (BS3) to enable binding of aptamer on to the surface of the nanoparticles. Targeting aptamers were then introduced to the particles through the reaction with the cross linker to target the nucleolin receptors over expressed on the cancer cell surface. Specific binding and uptake of the aptamer conjugated magnetic fluid loaded fluorescently tagged PLGA NPs (Apt-MF-NR-PLGA NPs) to the target cancer cells induced by aptamers was observed using confocal microscopy. Cytotoxicity assay conducted in two cell lines (L929 and MCF-7) confirmed that targeted MCF-7 cancer cells were killed while control cells were unharmed. In addition, aptamer mediated delivery resulting in enhanced binding and uptake to the target cancer cells exhibited increased therapeutic effect of the drug. Moreover, these aptamer conjugated magnetic polymer vehicles apart from actively transporting drugs into specifically targeted tumor regions can also be used to induce hyperthermia or for facilitating magnetic guiding of particles to the tumor regions.

Aravind, Athulya; Nair, Remya; Raveendran, Sreejith; Veeranarayanan, Srivani; Nagaoka, Yutaka; Fukuda, Takahiro; Hasumura, Takahashi; Morimoto, Hisao; Yoshida, Yasuhiko; Maekawa, Toru; Sakthi Kumar, D.

2013-10-01

381

The dual PI3K/mTOR inhibitor NVP-BEZ235 enhances nab-paclitaxel antitumor response in experimental gastric cancer.  

PubMed

Gastric cancer is the second most common cause of cancer-related deaths worldwide. Taxanes have shown therapeutic effects against gastric cancer while also activating the PI3K/mTOR signaling pathway. We investigated the effects of NVP-BEZ235 (BEZ235), a novel dual PI3K/mTOR inhibitor, alone and in combination with nanoparticle albumin-bound (nab)-paclitaxel in experimental gastric cancer. Cell proliferation and protein expression were measured by WST-1 assay and immunoblotting. Tumor growth and survival studies were performed in murine xenografts. Phosphorylated mTOR and 4E-BP1 levels were elevated in gastric cancer cells and tumor tissues by nab-paclitaxel. BEZ235 effectively inhibited cell proliferation in vitro and provided additive effects in combination with nab-paclitaxel. Furthermore, BEZ235 blocked the activated PI3K/mTOR pathway either alone or in combination with nab-paclitaxel in gastric cancer cells. BEZ235 and nab-paclitaxel caused an increase in PARP-1 and caspase-3 cleavage. Net local tumor growth inhibition for the BEZ235, nab-paclitaxel and BEZ235+nab-paclitaxel groups was 45.1, 77.9 and 97% compared to controls. The effects of therapy on intratumoral proliferation and apoptosis corresponded with tumor growth inhibition data. BEZ235 also caused a decrease in phospho-mTOR and phospho-Akt in tumor tissue lysates. Median animal survival (controls, 23 days) was 26.5 days after BEZ235 (p=0.227), 90.5 days after nab-paclitaxel (p=0.001) and 97 days in the BEZ235+nab-paclitaxel combination treatment group (p=0.001). Our findings suggest that BEZ235 exerts some antitumor effects against gastric cancer and enhances effects of nab-paclitaxel through inhibition of cell proliferation and modulation of the PI3K/mTOR pathway. This approach may represent a promising combination targeted therapy for gastric cancer. PMID:24042258

Zhang, Chang-?ua; Awasthi, Niranjan; Schwarz, Margaret A; Schwarz, Roderich E

2013-09-13

382

Paclitaxel combined with ifosfamide in anthracycline- and docetaxel-pretreated metastatic breast cancer: activity independence of prior docetaxel resistance  

Microsoft Academic Search

Background  We evaluated the efficacy and tolerability of combined paclitaxel and ifosfamide in anthracycline- and docetaxel-pretreated\\u000a metastatic breast cancer (MBC).\\u000a \\u000a \\u000a \\u000a \\u000a Methods  Patients received paclitaxel (175 mg\\/m2 i.v. in a 3-h infusion) on day 1 and ifosfamide (1.5 g\\/m2 i.v. in a 15-min infusion) on days 1–3, every 3 weeks for a maximum of nine cycles. The tumor response was assessed every\\u000a two cycles.\\u000a \\u000a \\u000a \\u000a \\u000a Results  We enrolled

Yong Wha Moon; Joo Hyuk Sohn; Hye Jin Choi; Hyun Chang; Byeong-Woo Park; Seung Il Kim; Ja Seung Koo; Yong Tai Kim; Jae Kyung Roh; Hyun Cheol Chung; Joo-Hang Kim

2010-01-01

383

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

PubMed Central

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

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

2010-01-01

384

Tumor-host interaction in the optimization of paclitaxel-based combination therapies with vascular targeting compounds.  

PubMed

Targeting of the tumor stroma, including the tumor vasculature, represents a new frontier in the treatment of malignancy. Preclinical studies and clinical experiences have established that stroma-directed novel agents must be combined with conventional therapies in order to achieve relevant therapeutic efficacy. Here we review our preclinical experience on combinations of paclitaxel with a tyrosine kinase receptor inhibitor of angiogenesis (SU6668) and a vascular disrupting agent (VDA, ZD6126), and discuss the critical factors that determine the outcome of these treatments. We also analyze the relevance of the intrinsic sensitivity of the tumor to the drugs, as well as the possibility that the two combined agents synergistically affect the vasculature or independently target the host and the tumor compartments. Finally, we discuss the need to carefully optimize scheduling and sequencing, through the use of reliable end points, in order to avoid negative pharmacological interactions and to improve the antineoplastic efficacy of paclitaxel-based combination treatments. PMID:17896168

Giavazzi, Raffaella; Bani, Maria Rosa; Taraboletti, Giulia

2007-12-01

385

Effective drug delivery, in vitro and in vivo, by carbon-based nanovectors noncovalently loaded with unmodified Paclitaxel.  

PubMed

Many new drugs have low aqueous solubility and high therapeutic efficacy. Paclitaxel (PTX) is a classic example of this type of compound. Here we show that extremely small (<40 nm) hydrophilic carbon clusters (HCCs) that are PEGylated (PEG-HCCs) are effective drug delivery vehicles when simply mixed with paclitaxel. This formulation of PTX sequestered in PEG-HCCs (PTX/PEG-HCCs) is stable for at least 20 weeks. The PTX/PEG-HCCs formulation was as effective as PTX in a clinical formulation in reducing tumor volumes in an orthotopic murine model of oral squamous cell carcinoma. Preliminary toxicity and biodistribution studies suggest that the PEG-HCCs are not acutely toxic and, like many other nanomaterials, are primarily accumulated in the liver and spleen. This work demonstrates that carbon nanomaterials are effective drug delivery vehicles in vivo when noncovalently loaded with an unmodified drug. PMID:20681596

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

2010-08-24

386

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

PubMed

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

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

2013-01-01

387

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

388

Poly(vinyl alcohol)-graft-poly(lactide-co-glycolide) nanoparticles for local delivery of paclitaxel for restenosis treatment  

Microsoft Academic Search

Catheter-based local delivery of biodegradable nanoparticles (NP) with sustained release characteristics represents a therapeutic approach to reduce restenosis. Paclitaxel-loaded NP consisting of poly(vinyl alcohol)-graft-poly(lactide-co-glycolide) (PVA-g-PLGA) with varying PLGA chain length as well as poly(lactide-co-glycolide) (PLGA), were prepared by a solvent evaporation technique. NP of <180 nm in diameter characterized by photon correlation spectroscopy (PCS), scanning electron microscopy (SEM), and atomic force

Ulrich Westedt; Marc Kalinowski; Matthias Wittmar; Thomas Merdan; Florian Unger; Jutta Fuchs; Susann Schäller; Udo Bakowsky; Thomas Kissel

2007-01-01

389

Monotherapy with paclitaxel as third-line chemotherapy against anthracycline-pretreated and docetaxel-refractory metastatic breast cancer  

Microsoft Academic Search

We describe a patient with anthracycline-pretreated and docetaxel-refractory metastatic breast cancer who achieved a complete\\u000a response after third-line chemotherapy with paclitaxel. A 59-year-old woman underwent modified radical mastectomy for advanced\\u000a cancer in her left breast after local arterial neoadjuvant chemotherapy with anthracycline. Postoperatively anthracycline-containing\\u000a adjuvant therapy was administered. Pulmonary metastases occurred 15 months after surgery, which did not respond to

Jun Kinoshita; Shunsuke Haga; Tadao Shimizu; Hiroshi Imamura; Osamu Watanabe; Hiroshi Nagumo; Yoshihito Utada; Toshihiko Okabe; Kiyomi Kimura; Akira Hirano; Tetsuro Kajiwara

2002-01-01

390

Phase II Study of Carboplatin-Paclitaxel Combination Chemotherapy in Elderly Patients with Advanced Non-small Cell Lung Cancer  

Microsoft Academic Search

Background: More than 30% of cases of non-small cell lung cancer (NSCLC) arise in patients aged >70 years. The efficacy and safety of carboplatin-paclitaxel combination chemotherapy in elderly patients with advanced NSCLC were evaluated in a phase II trial. Methods: Twenty-five patients aged >70 years (median, 76; range, 70-83) with chemotherapy- naõ¨ve advanced NSCLC were enrolled between January 2001 and

Isamu Okamoto; Eiji Moriyama; Shinji Fujii; Hiroto Kishi; Masanobu Nomura; Eisuke Goto; Chikage Kiyofuji; Fumiya Imamura; Takashi Mori; Mitsuhiro Matsumoto

2005-01-01

391

Weekly docetaxel for patients with platinum\\/paclitaxel\\/irinotecan-resistant relapsed ovarian cancer: a phase I study  

Microsoft Academic Search

Background This study was designed to investigate the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended dose (RD) of weekly docetaxel treatment in patients with relapsed ovarian cancer after the administration of platinum\\/paclitaxel\\/irinotecan. Methods Patients were enrolled on the basis of inclusion and exclusion criteria. Docetaxel was administered intravenously over a 60-min period on days 1, 8, and 15.

Fumitoshi Terauchi; Takayuki Hirano; Hideki Taoka; Kazuo Masaki; Yasuhiro Yamamoto; Hisao Ogura; Harumi Kubo

2003-01-01

392

A phase I clinical and pharmacokinetic study of paclitaxel and docetaxel given in combination in patients with solid tumours  

Microsoft Academic Search

The aim of this study was to determine the safety and feasibility profile of paclitaxel (PTX) and docetaxel (DTX) in combination and the pharmacokinetic and pharmacodynamic interaction between these two drugs in two different alternated sequences of administration. The starting dose was PTX (100mg\\/m2) as a 3-h IV infusion followed by DTX (50mg\\/m2) as 1-h IV infusion or the alternative

Miguel Angel Izquierdo; Margarita García; José Luis Pontón; Marisa Martínez; Vicente Valentí; Matilde Navarro; Miguel Gil; Felipe Cardenal; Ricard Mesía; Xavier Pérez; Ramón Salazar; Josep Ramón Germà-Lluch

2006-01-01

393

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

394

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

395

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

396

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

397

Process utilized oligo-?-cyclodextrin substituted agarose gel medium for efficient purification of paclitaxel from Taxus cuspidata  

Microsoft Academic Search

An efficient and economical process utilized oligo-?-cyclodextrin substituted agarose gel medium has been developed for paclitaxel recovery and purification directly from the plant materials of Taxus cuspidata. The process is a combination of extraction, alkaline Al2O3 chromatography step, oligo-?-cyclodextrin substituted agarose gel column chromatography which employed a novel oligo-?-cyclodextrin-Sepharose HP as the packing material, and crystallization. The Al2O3 normal-phase chromatography

Li Yang; Tianwei Tan; Liqun Zhang

2009-01-01

398

Patterns of activation and deposition of platelets exposed to the polymeric surface of the paclitaxel eluting stent  

Microsoft Academic Search

The interaction of platelets with the polymeric surface of drug eluting stents has not been fully described in the literature.\\u000a Our aim was to analyze the patterns of activation and deposition of platelets exposed to two different stent platforms; (a)\\u000a the polymeric surface of the paclitaxel eluting stent (Taxus® stent, PES,) and (b) the metallic surface of a stent with

Juan F. Granada; Carlos L. Alviar; David Wallace-Bradley; Matthew Osteen; Bijal Dave; Armando Tellez; Htut K. Win; Neal S. Kleiman; Greg L. Kaluza; Eli I. Lev

2010-01-01

399

Administration sequence-dependent antitumor effects of paclitaxel and 5-fluorouracil in the human gastric cancer cell line MKN45  

Microsoft Academic Search

Background: The clinical outcome of gastric cancer patients has been improved by combination of 5-fluorouracil (5-FU) and paclitaxel\\u000a (PXL). However, the optimal schedule of this combination has not been determined. Methods: The efficacies of sequential administrations of 5-FU and PXL on the gastric cancer cell line MKN45 were investigated using\\u000a a WST-8 colorimetric assay. The cell cycle distribution of each

Yuji Toiyama; Koji Tanaka; Naomi Konishi; Yasuhiko Mohri; Hitoshi Tonouchi; Chikao Miki; Masato Kusunoki

2006-01-01

400

Phase II study of NK105, a paclitaxel-incorporating micellar nanoparticle, for previously treated advanced or recurrent gastric cancer  

Microsoft Academic Search

Summary  \\u000a Purpose NK105 is a new drug delivery system formulation for paclitaxel (PTX) whose recommended dose (RD)?is 150 mg PTX equivalent\\/m2 administered every 3 weeks, as determined in a phase I trial. This study aimed to evaluate the efficacy and safety of NK105\\u000a in patients with advanced gastric cancer after failure of first-line chemotherapy. Experimental design Eligible patients had measurable disease and

Ken Kato; Keisho Chin; Takaki Yoshikawa; Kensei Yamaguchi; Yasushi Tsuji; Taito Esaki; Kenji Sakai; Masami Kimura; Tetsuya Hamaguchi; Yasuhiro Shimada; Yasuhiro Matsumura; Ryuji Ikeda

401

Pilot neoadjuvant trial in HER2 positive breast cancer with combination of nab-paclitaxel and lapatinib.  

PubMed

Lapatinib, a dual kinase inhibitor against epidermal growth factor receptor (EGFR) and human epidermal receptor two (HER2) has shown efficacy in treating HER2 positive breast cancer. Nanoparticle albumin bound (nab) paclitaxel was developed to reduce toxicities from paclitaxel and improve its efficacy. Thirty patients with stage I-III HER2 positive breast cancer were treated in the neoadjuvant setting with lapatinib 1,000 mg/day and nab-paclitaxel 260 mg/m(2) every 3 weeks for four cycles. The primary end point of the trial was clinical response rate (cRR) with secondary end points including pathologic complete response rate (pCR), tolerability of the combination, and marker response. The cRR was 82.8% (24 patients) with six (20.7%) patients having complete clinical response, 18 (62.1%) having partial clinical response, and five (17.2%) stable disease. A pCR was observed in five of the 28 patients (17.9%). The most frequent grade 2 toxicities