Preclinical toxicology, pharmacokinetics and formulation of N2, N4, N6-trihydroxymethyl-N2, N4, N6-trimethylmelamine (trimelamol), a water-soluble cytotoxic s-triazine which does not require metabolic activation

N2,N4,N6-Trihydroxymethyl-N2,N4,N6-trimethylmelamine (Trimelamol) is a water-soluble synthetic s-triazine which, unlike hexamethylmelamine (HMM) and pentamethylmelamine (PMM), does not require metabolic activation. The physico-chemical characteristics of Trimelamol were studied with the aim of overcoming the problems of chemical instability, low solubility and polymerisation which had hindered the development of the drug for clinical use. Trimelamol had similar activity to PMM against the murine PC6 plasmacytoma, but enhanced activity with respect to PMM against the Walker 256 carcinosarcoma in the rat, a species which metabolizes PMM less efficiently. Pharmacokinetic studies in mouse, rat and man did not show the major species differences characteristic of PMM. The drug exhibited similar toxicity to PMM against rodents, but had virtually no neurotoxicity. The potential advantages of Trimelamol over previously tested melamines are discussed.