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

Abstract

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 Km 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. © 1982.