Studies of the mode of action of antitumour triazenes and triazines-III. Metabolism studies on hexamethylmelamine

There is good evidence that the antitumour agent hexamethylmelamine (HMM) undergoes oxidative metabolic activation which might occur in the liver and/or extrahepatically. The hepatic microsomal N-methylmelamine metabolizing enzymes were investigated in mice and exhibited different affinities for different melamine derivatives. The apparent K_m values are 0.09 mM for HMM, 0.23 mM for pentamethylmelamine, 0.91 mM for 2,2,4,6-tetramethylmelamine and 1.7 mM for trimethylmela-mine. HMM inhibited its own metabolism in vitro at substrate concentrations > 0.5 mM. Its hepatic microsomal N-demethylation rate was reduced when the mice were pretreated with the hepatic gluta-thione depleting agent methyliodide. Injection of hexaethylmelamine, a derivative of HMM without antineoplastic properties against the M5076 sarcoma in mice, lead to plasma concentrations of drug and metabolite pentaethylmelainine which were only a fraction of the drug and metabolite levels achieved after a similar dose of HMM.