Toxicity and antitumor activity of hexamethylmelamine and its N-demethylated metabolites in mice with transplantable tumors.
N-Demethylated metabolites of the antineoplastic agent hexamethylmelamine were synthesized, and their toxicities and antitumor activities were determined in vivo. Determinations of the lethal dose for 10% of the male C57BL X DBA/2 F1 (hereafter called BD2F1) mice showed hexamethylmelamine toxicity to be decreased by N-demethylation; the metabolites showed a direct relationship between potency (mmoles/kg/day) and number of methyl groups present. In BD2F1 mice bearing Sarcoma 180 or Lewis lung carcinoma, the antitumor activities of the methylmelamines decreased with a reduction in number of methyl groups, but were similar at equitoxic levels. Results were similar in L1210 leukemic mice treated with lethal dose levels of the metabolites for 10% of the mice when mean survival times were measured. The therapeutic equality produced with equitoxic levels, together with the ineffectiveness of melamine, suggested that the presence of a methyl group, rather than the number, was the determining factor in the antitumor activity of the methylmelamines.
D006585:Altretamine / Q000378:metabolism / Q000627:therapeutic use* / Q000633:toxicity*; D000818:Animals; D007928:Lethal Dose 50; D007939:Leukemia L1210 / Q000188:drug therapy; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000401:mortality; D012510:Sarcoma 180 / Q000188:drug therapy; D013329:Structure-Activity Relationship; D014227:Triazines / Q000627:therapeutic use* / Q000633:toxicity*
D014227:Triazines; D006585:Altretamine