Effects of reduced glutathione (GSH) on oxaliplatin pharmacokinetics (OXA pk) and on Pt-DNA adducts formation in advanced colorectal cancer patients treated by FOLFOX4 regimen

Abstract

2559 Background: Neurotoxicity is a common OXA toxicity in FOLFOX4 regimen for patients with advanced colorectal cancer. Recently, Cascinu et al. (JCO 2002; 20: 3478–3483) provided evidence that GSH reduces the OXA-induced neurotoxicity, but GSH influence on the formation of Pt-DNA adducts still remains unknown. This study evaluated the effect of GSH addition on OXA pk and on Pt-DNA adducts formation Table of Contents Methods: 28 patients were given twelve FOLFOX4 courses and randomized to receive either GSH 1,500 mg/m2 or normal saline solution (placebo) before OXA iv infusion. OXA pk and Pt-DNA adducts formation were evaluated at courses 5, 9 and 12. Total and ultrafiltered platinum were analyzed by atomic adsorption, Pt-DNA adducts in leukocytes (as model for tumour tissue) by adsorptive stripping voltammetry. Pk analysis were done by non-compartmental analysis, statistical analysis by non-parametric Mann-Whitney test. Results: Median total and ultrafiltered platinum median Cmax and AUCtot values were comparable to previously reported ones, being higher in the placebo arm, due to a moderate reduction of platinum clearance. The formation of Pt-DNA adducts was more pronounced in GSH arm (median value 20.3 Pt atoms/106 nucleotides vs. 5.7 Pt atoms/106 nucleotides), even not statistically significant. Conclusions: The addition of GSH to FOLFOX4 regimen is able to reduce the OXA-induced neurotoxicity, without affecting either the OXA pk behaviour or the formation of Pt-DNA adducts, without modifying FOLFOX4 clinical efficacy. [Table: see text] No significant financial relationships to disclose.