Release of methyl isocyanate from the antitumor agent caracemide (NSC-253272).
In recent phase 1 clinical trials, caracemide [N-acetyl-N-(methylcarbamoyloxy)-N-methylurea; NSC-253272] has demonstrated a marked potential to produce severe central nervous system (CNS) toxicity. Recent in vitro studies of this antitumor agent have presented indirect evidence indicating that methyl isocyanate is a likely metabolite which results from incubation of caracemide with either phosphate buffer or human plasma. This report presents evidence that methyl isocyanate is formed from caracemide in a concentration- and time-dependent manner. These data implicate the caracemide-mediated formation of methyl isocyanate as at least a plausible explanation for the CNS toxicity exhibited by this drug.
Newman
R A
RA
Department of Medical Oncology, U.T.M.D. Anderson Hospital and Tumor Institute, Houston 77030.
Farquhar
D
D
D000970:Antineoplastic Agents / Q000378:metabolism*; D001921:Brain / Q000187:drug effects; D003485:Cyanates / Q000378:metabolism*; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D017953:Isocyanates
D000970:Antineoplastic Agents; D003485:Cyanates; D017953:Isocyanates; C008461:methyl isocyanate; C044466:caracemide; D006918:Hydroxyurea