Cancer chemotherapy and pharmacology
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Cancer Chemother. Pharmacol. · Jun 2006
Comparative StudyModulation of the cellular pharmacology of JM118, the major metabolite of satraplatin, by copper influx and efflux transporters.
Satraplatin is an orally bioavailable platinum analog that has activity in prostate cancer. JM118 is the most abundant species found in the plasma following the oral ingestion of satraplatin and has anti-tumor activity in vitro against cell lines that are resistant to cisplatin (DDP). The goal of the current study was to determine whether the activity of JM118 in some DDP-resistant cells can be explained by differences in the cellular pharmacology of the two drugs. ⋯ Second, ATP7A and ATP7B, while they both mediate resistance, have opposite effects on the accumulation of Pt in DNA following exposure to the two drugs. ATP7A and ATP7B appear to be able to modulate the toxicity of the Pt that accumulates in DNA following exposure to JM118. These results suggest that JM118 will retain activity in cells in which DDP resistance is due to the loss of CTR1, but not in cells in which resistance is due to enhanced expression of ATP7A or ATP7B.
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Cancer Chemother. Pharmacol. · Jun 2006
Phase I dose-finding study and a pharmacokinetic/pharmacodynamic analysis of the neutropenic response of intravenous diflomotecan in patients with advanced malignant tumours.
To determine the maximum tolerated dose (MTD) of intravenous (iv) diflomotecan administered once every 3 weeks, and to characterize the relationship between pharmacokinetics and neutropenic effect, using a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. ⋯ The MTD and RD after a 20-min iv infusion of diflomotecan every 3 weeks are 4 and 5 mg/m2, respectively. Diflomotecan showed linear pharmacokinetic behaviour and the selected PK/PD model described adequately the time course of neutropenia. The mean model predicted values of nadir and time to nadir after a 20-min iv infusion of 4 mg/m2 of diflomotecan was 0.86 x 10(9) /L neutrophil cell counts and 11 days, respectively.
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Cancer Chemother. Pharmacol. · Jun 2006
Comparative StudyBiomarkers for assessment of pharmacologic activity for a vascular endothelial growth factor (VEGF) receptor inhibitor, PTK787/ZK 222584 (PTK/ZK): translation of biological activity in a mouse melanoma metastasis model to phase I studies in patients with advanced colorectal cancer with liver metastases.
PTK/ZK is a novel, oral angiogenesis inhibitor that specifically targets all 3 vascular endothelial growth factor (VEGF) receptor tyrosine kinases and is currently in phase III clinical trials. In early clinical trials, PTK/ZK demonstrated a dose-dependent reduction in tumor vascular parameters as measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and an acute increase in plasma VEGF levels. The reduction in tumor vascularity was significantly correlated with improved clinical outcome in patients with advanced colorectal cancer and liver metastases. ⋯ Furthermore, at doses of 50 mg/kg PTK/ZK and above, an increase in plasma VEGF level 10 h after drug administration was observed in mice which was consistent with findings from the clinical trials. In conclusion, the preclinical pharmacodynamics of PTK/ZK correlate well with clinical activity in phase I trials over comparable exposures to the drug. Thus, data from this preclinical model proved to be consistent with and thus predictive of the biologic effects of PTK/ZK in phase I/II clinical trials.