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Studies of the Antineoplastic Activity and Metabolism of -(N)-Heterocyclic Carboxaldehyde Thiosemicarbazones in Dogs and Mice¹

Departments of Medicine [W. A. C., R. L. C.] and Pharmacology [W. A.C., K. C. A., R. L. C., K. K. S., A. C. S.], Yale University School of Medicine, New Haven, Connecticut 06510

The antineoplastic effects of -(N)-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'-¹⁴C 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 CO₂ when side-chain labeled (3'-¹⁴C) but not ring labeled (1-¹⁴C) 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 hr 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.

¹ This investigation was supported in part by USPHS Grants CA-08341 and CA-02817 and by Grants T-335, ET-14F, and T-23 from the American Cancer Society.

² Present address: Department of the Army, Medical Research Laboratory, Edgewood Arsenal, Md. 21010.

Received 9/ 1/71. Accepted 12/ 3/71.

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