Cancer chemotherapy and pharmacology
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Cancer Chemother. Pharmacol. · Jun 2001
Sensitivity to topoisomerase I inhibitors and cisplatin is associated with epidermal growth factor receptor expression in human cervical squamous carcinoma ME180 sublines.
The relationship between expression and function of the epidermal growth factor (EGF) family of receptors and chemosensitivity remains controversial. We studied the chemosensitivity to various anticancer agents of human cervical squamous carcinoma ME180 cells, and two resistant subclones, ME180/TNF and ME180/Pt, which also differ in their EGF receptor (EGFR) expression. Compared with ME180 cells, EGFR is overexpressed sixfold in ME180/TNF cells and is barely detectable in ME 180/Pt cells. ⋯ As a result, the resistance index of low EGFR-expressing ME180/Pt cells compared with intermediate EGFR-expressing ME180 cells was reduced only from five- to fourfold for cisplatin and from seven- to fourfold for CPT when ME180 cells were exposed to CP358774. CP358774 did not affect the sensitivity to either agent in low EGFR-expressing ME180/Pt cells. These results provide evidence that changes in EGFR expression or function may play a role in determining chemosensitivity to platinum and topoisomerase I poisons in some human tumor systems, and that the EGFR-related changes in chemosensitivity may vary depending on the level of EGFR expression and/or function.
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Cancer Chemother. Pharmacol. · Apr 2001
Clinical TrialPharmacokinetic modeling of paclitaxel encapsulation in Cremophor EL micelles.
Nonlinear disposition of paclitaxel (Taxol) in cancer patients has been described in several studies, but the underlying mechanism is still a matter of speculation. Previously, we have shown in vitro that the paclitaxel formulation vehicle, Cremophor EL (CrEL), alters the blood distribution of paclitaxel as a result of entrapment of the compound in circulating CrEL micelles, thereby reducing the free drug fraction available for cellular partitioning. Based on these findings, we prospectively re-evaluated the linearity of paclitaxel disposition in patients using whole blood and plasma analysis, and sought to define a new pharmacokinetic model to describe the data. ⋯ This was shown to be caused by a CrEL concentration-dependent decrease in paclitaxel uptake in blood cells, as reflected by the blood:plasma concentration ratios which altered significantly from 0.83 +/- 0.11 (at 135 mg/m2) to 0.68 +/- 0.07 (at 225 mg/m2). It is concluded that the nonlinear disposition of paclitaxel is related to paclitaxel dose-related levels of the formulation vehicle CrEL, leading to a disproportionate drug accumulation in the plasma fraction. The pharmacokinetic model developed accurately described the data, and will help guide future development and refinement of clinical protocols, especially in defining the exposure measure best linked to paclitaxel effects and toxicities.
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Cancer Chemother. Pharmacol. · Mar 2001
Comparative StudyComparative study of a novel nucleoside analogue (Troxatyl, troxacitabine, BCH-4556) and AraC against leukemic human tumor xenografts expressing high or low cytidine deaminase activity.
Troxacitabine (beta-L-dioxolane cytidine, BCH-4556; Troxatyl, BioChem Pharma Inc.) is a novel nucleoside analogue, which in experiments demonstrated potent antitumor activity against both leukemias and solid tumors. Since troxacitabine is a cytidine nucleoside analogue like AraC (1-beta-D-arabinofuranosylcytosine), which is currently used in the treatment of acute myelogenous leukemia, we compared the in vivo antileukemic activity of troxacitabine with that of AraC in human leukemia xenograft models. ⋯ Our findings indicate that troxacitabine is likely to be effective not only against solid tumors with high CDA activity but also in leukemias which have developed resistance to AraC due to increased CDA levels; this suggests that troxacitabine is a promising agent for the treatment of cancer. Indeed, significant antileukemic activity has been observed with troxacitabine in a phase I clinical trial in patients with primary refractory or relapsed acute myeloid leukemias (AML).
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Cancer Chemother. Pharmacol. · Jan 2000
Clinical TrialPhase I study of docetaxel and topotecan in patients with solid tumors.
Both docetaxel (DOC), a promoter and stabilizer of microtubule assembly, and topotecan (TOPO), a topoisomerase I inhibitor, have shown antitumor activity in a variety of solid tumor malignancies. This phase I trial was conducted to determine the overall and dose-limiting toxicities (DLT), the maximum tolerated dose (MTD) and the pharmacokinetics of the combination of DOC and TOPO in patients with advanced solid tumor malignancies. ⋯ DOC 80 mg/m2 given first as a 1-h infusion on day 1 with TOPO 0.75 mg/m2 given as a 0.5-h infusion on days 1, 2, 3 and 4 with G-CSF was considered the MTD. The recommended phase II dose for DOC given on day 1 is 70 mg/m2 with TOPO 0.75 mg/m2 given on days 1, 2, 3 and 4 every 21 days with G-CSF 300 micrograms s.c. on days 5-14. The alternative schedule with DOC given on day 4 and TOPO on days 1-4 is not recommended.
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Cancer Chemother. Pharmacol. · Jan 2000
Multicenter Study Clinical TrialCarzelesin phase II study in advanced breast, ovarian, colorectal, gastric, head and neck cancer, non-Hodgkin's lymphoma and malignant melanoma: a study of the EORTC early clinical studies group (ECSG).
In a phase II trial, the activity of carzelesin, a cyclopropylpyrroloindole prodrug analog, was assessed. ⋯ At this dose and schedule carzelesin did not yield activity in the types of tumors studied.