Tiazofurin: a new antitumor agent.

Tiazofurin is an interesting drug now entering Phase I trials, with marked preclinical antitumor activity against P388 and L1210 leukemias, and the Lewis lung carcinoma. Schedule dependency favoring frequent administration has been noted. The drug has a novel mechanism of action, being metabolized to an inhibitory cofactor of inosine monophosphate dehydrogenase. Tiazofurin is widely distributed after i.v. administration exhibiting a triphasic pattern of plasma decay, with a terminal half-life of 3-16 h in the three species studied. Approximately 90% of the drug was excreted unchanged in the urine within 24 h. A significant potential for the slower release of intracellularly retained drug exists. Anticipated organ toxicities based on the studies described include myelotoxicity, hepatotoxicity and nephrotoxicity. These were mild and reversible at lower doses, and were not seen at levels corresponding to the starting doses in man. A potential for hyperuricemia exists; this should be easily controllable by the use of allopurinol, without compromising the drug's antitumor effect. Phase I trials under the sponsorship of the NCI are underway in a number of institutions.