Pentamethylmelamine: review of an aqueous analog of hexamethylmelamine

The s-triazine derivatives have shown preclinical antitumor activity against several histologic types. The most widely used compound of this class in the clinic, hexamethylmelamine, has been largely restricted to oral use because of its low solubility and lack of stability in solutions suitable for parenteral administration. New analogs were sought which were soluble and stable and retained antitumor activity. Pentamethylmelamine (PMM), the monodemethylated derivative, showed these promising characteristics. Preclinical toxicology studies of PMM in mice, dogs, and monkeys showed toxic manifestations that involved the hematopoietic, lymphatic, renal, male reproductive, gastrointestinal, and nervous systems; these changes were both infusion-rate- and dose-dependent. Clinical phase I trials of PMM were performed using a variety of infusion durations and frequency schedules. The dose-limiting toxic effect common to all of these trials was protracted nausea and vomiting. In addition, some studies reported dose-limiting central nervous system manifestations in the form of agitation, drowsiness, somnolence, and even coma. Mild to moderate hematologic changes were noted. Because of the severity and frequency of the gastrointestinal and central nervous system toxic effects observed in the completed trials, no new clinical trials of PMM sponsored by the National Cancer Institute are planned. However, the interest in finding a clinically useful parenteral triazine continues.