Intravenous ifosfamide/mesna is associated with depletion of plasma thiolswithout depletion of leukocyte glutathione

Depletion of cellular glutathione (GSH) enhances the efficacy of many antic ancer agents in preclinical systems. Limited published data showing depleti on 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 23 an d 36 h, respectively, at equal daily doses; carboplatin was given after ifo sfamide to a target plasma area under the curve of 1 mg.min.ml(-1). Plasma and peripheral WBC thiols were quantitated by high-performance liquid chrom atography. The dose of ifosfamide was escalated from 2 to 8 g/m(2); the max imum tolerated dose mas 6 g/m2. Significant depletion in plasma cysteine an d homocysteine, precursors for GSH synthesis, was observed (maximum, 95% to >99% at 8 g/m(2)), Plasma mesna and cysteine/ homocysteine levels were inv ersely correlated; nadir levels of cysteine/homocysteine were maintained fo r several hours after ifosfamide infusion had stopped and while mesna infus ion was continuing. In vitro coincubation experiments confirmed that mesna reduces these thiols from disulfides to sulfhydryls, which are readily clea red, as evidenced by the significantly increased rate of excretion of cyste ine in urine. In contrast, ifosfamide/mesna treatment caused a moderate dep letion of plasma GSH in only 60% of the patients, with a nadir at 23 h and recovery immediately after the end of ifosfamide infusion. The GSH depletio n in these patients was not dose related. The profile of GSH recovery in pl asma after ifosfamide and the fact that mesna could not reduce GSH disulfid es in vitro suggest that the observed GSH depletion in plasma in 60% of the patients may be related to direct reactions of GSH with ifosfamide metabol ites and/or mesna. Our results indicate that mesna is a modulator of GSH pr ecursors and that a prolonged infusion of mesna mag be required to achieve GSH precursor starvation and the consequent GSH depletion in cells.