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). Plasma and peripheral WBC thiols were quantitated by high-performance liquid chromatography. The dose of ifosfamide was escalated from 2 to 8 g/m2; the maximum tolerated dose was 6 g/m2. Significant depletion in plasma cysteine and homocysteine, precursors for GSH synthesis, was observed (maximum, 95% to >99% at 8 g/m2). Plasma mesna and cysteine/ homocysteine levels were inversely correlated; nadir levels of cysteine/homocysteine were maintained for several hours after ifosfamide infusion had stopped and while mesna infusion was continuing. In vitro coincubation experiments confirmed that mesna reduces these thiols from disulfides to sulfhydryls, which are readily cleared, as evidenced by the significantly increased rate of excretion of cysteine in urine. In contrast, ifosfamide/mesna treatment caused a moderate depletion of plasma GSH in only 60% of the patients, with a nadir at 24 h and recovery immediately after the end of ifosfamide infusion. The GSH depletion in these patients was not dose related. The profile of GSH recovery in plasma after ifosfamide and the fact that mesna could not reduce GSH disulfides 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 metabolites and/or mesna. Our results indicate that mesna is a modulator of GSH precursors and that a prolonged infusion of mesna may be required to achieve GSH precursor starvation and the consequent GSH depletion in cells.
Pendyala
L
L
Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. lakshmi.pendyala@roswellpark.org
Creaven
P J
PJ
Schwartz
G
G
Meropol
N J
NJ
Bolanowska-Higdon
W
W
Zdanowicz
J
J
Murphy
M
M
Perez
R
R
D000079:Acetaldehyde / Q000031:analogs & derivatives / Q000097:blood; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003545:Cysteine / Q000097:blood / Q000187:drug effects / Q000652:urine; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000097:blood / Q000187:drug effects*; D006710:Homocysteine / Q000097:blood / Q000187:drug effects; D006801:Humans; D007069:Ifosfamide / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism; D015080:Mesna / Q000097:blood / Q000494:pharmacology*; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy; D010084:Oxidation-Reduction; D020011:Protective Agents / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000097:blood*
D018906:Antineoplastic Agents, Alkylating; D020011:Protective Agents; D013438:Sulfhydryl Compounds; D006710:Homocysteine; C004656:chloroacetaldehyde; D005978:Glutathione; D000079:Acetaldehyde; D003545:Cysteine; D015080:Mesna; D007069:Ifosfamide