Studies of the antineoplastic activity and metabolism of -(N)-heterocyclic carboxaldehyde thiosemicarbazones in dogs and mice.

SUMMARY The antineoplastic effects of a-(/V)-heterocyclic Carboxaldehyde thiosemicarbazones were studied in dogs with lymphosarcoma, and some of their metabolic features were studied in both mice and dogs. Significant regression (38 to 72%) of tumor masses occurred in dogs treated with i.v. doses of 2 to 6 mg of the sodium salt of 1-formylisoquinoline thiosemicarbazone per kg for a maximum of 5 consecutive days. These doses produced moderate anemia and leukopenia. In a chihuahua with lymphoblastic lymphosarcoma, the water-soluble sodium salt of 5-hydroxy-2-formylpyridine thiosemicarbazone, given in dosages up to 5 mg/kg twice a day for 2 days during each treatment, produced more than 80% reduction in tumor masses and circulating blasts without affecting normal blood elements. The tissue distribution of radioactivity was studied in mice after the i.p. injection of 1-formylisoquinoline thiosemicarbazone labeled with either 1-14C. 3'-14C, or 35S. The greatest activity occurred in the intestine (24 to 40%), liver (4 to 12%), and stomach (2 to 6%). Lesser amounts were present in other tissues, but about 40% was found in the residual carcass at the end of an 8-hr period. Of the label from the 3'-I4C compound, 20% was excreted in the urine and 2.8% in the feces in 16 hr. During an 8-hr period, approximately 2% of the radioactivity was present in the respiratory C02 when side-chain labeled (3'-'4C) but not ring labeled (1-I4C) agent was administered. In dogs, the half-life of radioactivity in the blood from labeled 1-formylisoquinoline thiosemicarbazone was about 4 hr. Between 28 and 46% of the label was excreted in the urine during a 48-hr period. Significant amounts of unchanged drug could not be detected in the urine. Desulfuration was extensive, affecting 75% of the total metabolites in urine collected more than 11 hi after administration of the thiosemicarbazone. Between 11 and 16% of the side chain was cleaved from the molecule both by apparent azoreductase action leading to urea and thiourea and by hydrolysis to yield semicarbazide and thiosemicarbazide. About 13% of the urinary metabolites were in the form of glucuronides, conversion to these presumably occurring after some change such as hydroxylation.