Administration of reduced glutathione in FOLFOX4 adjuvant treatment for colorectal cancer: effect on oxaliplatin pharmacokinetics, Pt-DNA adduct formation, and neurotoxicity

Abstract

Oxaliplatin is a promising drug for cancer therapy and the oxaliplatin/5-fluorouracil/leucovorin (FOLFOX) regimen has become the standard adjuvant treatment for colorectal cancer. However, the oxaliplatin-induced neurotoxicity still represents a clinical problem leading to a discontinuation of the therapy. Many strategies have been proposed in order to manage the neurotoxicity, but their effect on antitumoral efficacy is still unclear. In this study, we investigated the effect of reduced glutathione administration on neurotoxicity, oxaliplatin pharmacokinetics, and platinum-DNA (Pt-DNA) adduct formation in patients affected by colorectal cancer treated with FOLFOX4 adjuvant regimen. Twenty-seven patients were randomized to receive GSH 1500 mg/m or saline solution before oxaliplatin infusion. Evaluation of neurotoxicity, pharmacokinetics of plasmatic total and ultrafiltered Pt, and determination of Pt-DNA adduct formation on white blood cells was performed during the 5th, 9th, and 12th cycles. At the end of all cycles of therapy, the patients in the GSH arm showed a statistically significant reduction of neurotoxicity (P=0.0037) compared with the placebo arm. There were no significant differences in the main pharmacokinetic parameters between the two arms except a lower area under the plasma concentration-time curve and a smaller apparent steady-state volume of distribution (Vss) when GSH was coadministered. This difference can be explained by the natural function of GSH in the detoxification of oxaliplatin and by its ability to remove the Pt bound to plasma proteins. The determination of Pt-DNA adduct formation shows no statistically significant differences between the two arms. In conclusion, this study indicates that coadministration of GSH is an effective strategy to reduce the oxaliplatin-induced neurotoxicity without impairing neither the pharmacokinetics of oxaliplatin, nor the Pt-DNA adduct formation.

A phase III randomized, placebo-controlled study of topical amitriptyline and ketamine for chemotherapy-induced peripheral neuropathy (CIPN): a University of Rochester CCOP study of 462 cancer survivors

“…Calcium and magnesium infusions were shown to decrease the incidence of oxaliplatin-induced neuropathy in a retrospective cohort study[21] and a smaller randomized placebo-controlled study[22], but these results have yet to be confirmed in a phase III study. Multiple clinical trials suggest that glutathione may decrease the severity of CIPN[23–25], but again, these results have not been confirmed in a large trial. Small studies have identified other possible treatments for CIPN including the selective serotonin norepinephrine reuptake inhibitor, venlafaxine[26,27], the anti-epileptic drug, pregabalin[28], α-lipoic acid[29,30], and acetyl L-carnitine[31].…”

Research design considerations for chronic pain prevention clinical trials

“…Whether the treatment would likely be best given throughout the full duration of the prescribed chemotherapy or only proximal to each chemotherapy infusion depends on the proposed mechanism and mode of administration of the investigational drug. For example, a bolus intravenous dose of an anti-inflammatory or other agent hypothesized to prevent nerve damage may be best administered directly before or after each chemotherapy infusion as was performed in multiple studies [102,104,113,141,155]. In fact, daily infusions of an investigational prophylactic CIPN treatment throughout the full course of chemotherapy are not likely to be feasible.…”

Effects of Oral Glutathione Supplementation on Systemic Oxidative Stress Biomarkers in Human Volunteers

“…Witschi et al administered a single oral dose of up to 3 g of GSH to seven healthy subjects and did not observe an increase in blood GSH levels, concluding ''it is not feasible to increase circulating GSH to a clinically beneficial extent by the oral administration of 3 g of GSH.'' 22 Yet three studies have evaluated the impact of reduced GSH supplementation combined with oxidative chemotherapeutic agents in patients with various cancers [23][24][25] ; all three trials demonstrated reduced adverse effects of the chemotherapy without negative effects on the effectiveness of the regimen, suggesting some physiologic effect from oral dosing. Unfortunately GSH status was not measured in any of these trials.…”