Cancer chemotherapy and pharmacology
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Cancer Chemother. Pharmacol. · Oct 2005
Potent reversal of multidrug resistance by ningalins and its use in drug combinations against human colon carcinoma xenograft in nude mice.
To evaluate the pharmacological properties and the possible therapeutic applications of a series of synthetic marine natural product analogs, ningalins (N1-N6), in terms of cytotoxicity, MDR-reversing activity, and enhancement of drug combinations with antitumor agents in vitro and in vivo. ⋯ The profound enhancement of antitumor cytotoxicity of vinblastine and taxol in vitro by ningalins may have multiple mechanisms including the MDR-reversing effects. The mechanisms for collateral sensitivity by ningalins against sensitive (parent) cells are not yet clear. The marked enhancement of therapeutic effect of taxol by ningalins against xenograft tumors in nude mice suggests potential applications of therapeutic use of ningalins.
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Cancer Chemother. Pharmacol. · Oct 2005
Randomized Controlled Trial Multicenter Study Clinical TrialExploratory study of drug plasma levels during bicalutamide 150 mg therapy co-administered with tamoxifen or anastrozole for prophylaxis of gynecomastia and breast pain in men with prostate cancer.
A randomized multicenter (14 centers) trial was conducted in 114 men with prostate cancer to determine whether the antiestrogen tamoxifen ('Nolvadex') 20 mg or the aromatase inhibitor anastrozole ('Arimidex') 1 mg prevent gynecomastia and breast pain during treatment with the non-steroidal antiandrogen bicalutamide ('Casodex') 150 mg, without compromising efficacy, safety, or quality of life. Plasma samples were collected in a subgroup of these patients to investigate whether trough (pre-dose) concentrations of bicalutamide 150 mg are influenced by concomitant administration of tamoxifen 20 mg or anastrozole 1 mg; the results of this pilot study are reported in this article. ⋯ The findings of this pilot study suggest that trough plasma concentrations of bicalutamide enantiomers following administration of bicalutamide 150 mg are not markedly influenced by concomitant administration of tamoxifen 20 mg or anastrozole 1 mg. However, an effect of tamoxifen on bicalutamide pharmacokinetics can not be completely excluded due to the size of this study. Further studies are needed to clarify the effect of tamoxifen on bicalutamide pharmacokinetics and prostate cancer control in bicalutamide-treated patients. 'Arimidex', 'Casodex', and 'Nolvadex' are trademarks of the AstraZeneca group of companies.
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Cancer Chemother. Pharmacol. · Oct 2005
Peroxisome proliferator activated receptor-gamma ligands induced cell growth inhibition and its influence on matrix metalloproteinase activity in human myeloid leukemia cells.
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is one of the best characterized nuclear hormone receptors (NHRs) in the superfamily of ligand-activated transcriptional factors. PPAR-gamma ligands have recently been demonstrated to affect proliferation, differentiation and apoptosis of different cell types. The present study was undertaken to investigate PPAR-gamma ligands induced cell growth inhibition and its influence on matrix metalloproteinase MMP-9 and MMP-2 activities on leukemia K562 and HL-60 cells in vitro. ⋯ The expressions of MMP-9 and MMP-2 as well as their gelatinolytic activities in both HL-60 and K562 cells were inhibited by 15d-PGJ2 and TGZ significantly. We therefore conclude that PPAR-gamma ligands 15d-PGJ2 and TGZ have significant growth inhibition effects on myeloid leukemia cells in vitro, and that PPAR-gamma ligands can inhibit K562 and HL-60 cell adhesion to and invasion through ECM as well as downregulate MMP-9 and MMP-2 expressions. The data suggest that PPAR-gamma ligands may serve as potential anti-leukemia reagents.
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Cancer Chemother. Pharmacol. · Sep 2005
P450 induction alters paclitaxel pharmacokinetics and tissue distribution with multiple dosing.
Paclitaxel (Taxol) is an effective agent against a broad range of human cancers. Studies on the metabolism and disposition of paclitaxel have shown that it is primarily eliminated via hepatic metabolism by P450 enzymes (2C8 and 3A4) to essentially inactive metabolites, and that biliary and gut transport by P-glycoprotein (PGP) as well as urinary elimination of the parent compound play relatively minor roles. Recent studies in vitro have shown that paclitaxel treatment increases the level of CYP2C8 and CYP3A4 in human hepatocytes as well as PGP in colon tumor cells. The data suggest that previous paclitaxel exposure may influence metabolism and elimination of subsequent doses. Further, since weekly paclitaxel dose schedules are becoming more common as opposed to the original every 21-day dosing, the likelihood of enzyme induction from previous doses impacting that from subsequent doses is increased. ⋯ The results of our studies showed that paclitaxel pharmacokinetics are altered by previous paclitaxel exposure up to 96 h earlier.
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Cancer Chemother. Pharmacol. · Aug 2005
Randomized Controlled Trial Clinical TrialPhase-I dose escalation and sequencing study of docetaxel and continuous infusion topotecan in patients with advanced malignancies.
Anti-tumor activity can often be enhanced with combination therapy in managing patients with metastatic cancer. However, dose sequence and schedule of delivery can alter the pharmacokinetics, toxicity, and anti-tumor response. Therefore, attention to drug-drug interactions which may be sequence or schedule-dependent are necessary. Docetaxel and topotecan are non-cross-resistance cytotoxic agents with activity in a variety of malignancies. The goal of this study was to determine the maximum tolerated dose of docetaxel and continuous infusion topotecan using two sequences of administration. ⋯ The observed toxicity was not sequence-dependent, despite the observed change in kinetics. Docetaxel and topotecan can be administered with acceptable toxicity at the recommended phase-II dose of docetaxel 60 mg m(-2) and topotecan 0.85 mg m(-2) day(-1)x3 days.