Mechanism of the antileukemic effects of 1-p-carboxamidophenyl-3,3-dimethyltriazene and its in vitro metabolites.
DM-CONH2, a dimethyltriazene active in prolonging the survival time of mice bearing TLX5 lymphoma, requires metabolic activation by liver homogenate supernatant and cofactors in order to exert in vitro cytotoxic effects on the same tumor cells, as determined by in vivo bioassay of their viability. From the examination of the metabolites produced during these in vitro experiments, it is found that in vitro cytotoxicity is attributable to the generation of MM-CONH2 by oxidative N-demethylation of DM-CONH2. Also the generation of DM-COO is observed, although this compound is not cytotoxic in vitro. The in vivo effects of DM-CONH2 and CM-COOK on TLX5 lymphoma are not caused exclusively by cytotoxic effects of the drugs, since they are evident also when no reduction in the number or viability of peritoneal tumor cells is evident, whereas these parameters are significantly reduced by MM-CONH2. The increase in survival time of mice bearing TLX5 lymphoma caused by the dimethyltriazenes used appears to be caused by the drugs without being subjected to metabolic activation, with a mechanism different from cytotoxicity for tumor cells.
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D008223:Lymphoma / Q000188:drug therapy; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D009374:Neoplasms, Experimental / Q000188:drug therapy; D013997:Time Factors; D014226:Triazenes / Q000378:metabolism / Q000494:pharmacology*
D000970:Antineoplastic Agents; D014226:Triazenes; C036576:1-(4-carboxamidophenyl)-3,3-dimethyltriazene