In vitro studies on the mechanisms of oxaliplatin resistance.

Purpose: We have previously reported that elevation of glutathione mediated by gamma-glutamyl transpeptidase is one mechanism of oxaliplatin resistance. This study explored other potential oxaliplatin resistance mechanisms with two aims: (1) to identify the differences between cisplatin and oxaliplatin in terms of drug accumulation, DNA-Pt adduct formation and repair, and (2) to determine whether defects in drug accumulation and enhanced repair of the DNA-Pt adduct contribute to oxaliplatin resistance.

Methods: The human ovarian carcinoma cell line A2780, an oxaliplatin-resistant variant A2780/C25 and a cisplatin-resistant variant A2780/CP along with an inherently cisplatin-resistant HT-29 colon carcinoma cell line were used in the study.

Phase I/pharmacodynamic study of N-acetylcysteine/oltipraz in smokers: early termination due to excessive toxicity.

An N-acetylcysteine (NAC)/oltipraz (OLZ) combination was studied in healthy volunteer smokers who received daily NAC (1200 mg/day) and were randomized to weekly placebo (Arm A), OLZ 200 mg (Arm B), or 400 mg (Arm C). Treatment was for 12 weeks with follow-up at 16 weeks. The objective was to study toxicity and the modulation of pharmacodynamic end points.

Intravenous ifosfamide/mesna is associated with depletion of plasma thiols without depletion of leukocyte glutathione.

Depletion of cellular glutathione (GSH) enhances the efficacy of many anticancer agents in preclinical systems. Limited published data showing depletion of GSH in vitro and in patients by ifosfamide and/or mesna provided the rationale for a Phase I trial. Ifosfamide and mesna were infused over 24 and 36 h, respectively, at equal daily doses; carboplatin was given after ifosfamide to a target plasma area under the curve of 4 mg x min x ml(-1).