Imexon, a novel
pro-oxidant,
thiol-binding agent, is currently in phase I/II clinical trials in patients with advanced solid
tumors. The aim of this study was to characterize the preclinical pharmacology of
imexon in vivo. We investigated the anticancer activity of
imexon in several
cancer cell lines grown as xenografts in severe combined immunodeficient mice.
Imexon was active against both hematologic and solid
tumor types. The maximally tolerated dose, at the selected dosing schedule, was 150 mg/kg. Using the maximally tolerated dose of
imexon, we sought to identify a potential pharmacodynamic
biomarker to monitor the mechanistic effect systemically. As
imexon binds cellular
thiols in vitro,
thiol depletion by
imexon in vivo was evaluated as a potential
biomarker. Following a single 150 mg/kg dose of
imexon by
intraperitoneal injection,
glutathione levels decreased by 40% at 3 h in mouse erythrocytes. In mouse plasma,
imexon treatment led to a significant decrease in
cystine levels 2-4 h after drug administration. Notably, by this time, free
imexon plasma levels were nondetectable. By investigating the pharmacokinetics of
imexon, we also found that
imexon undergoes rapid clearance from plasma in a dose-independent fashion with a half-life of 12-15 min. In summary,
imexon is active against several
cancer types in vivo.
Imexon also decreases circulating
thiols and exhibits dose-independent pharmacokinetics in mice. Plasma
cystine levels may represent a
biomarker of
imexon activity in vivo.