This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Creasey, W. A. Articles by Sartorelli, A. C. Search for Related Content PubMed PubMed Citation Articles by Creasey, W. A. Articles by Sartorelli, A. C.

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.

This article has been cited by other articles:

				D. S. Kalinowski and D. R. Richardson The Evolution of Iron Chelators for the Treatment of Iron Overload Disease and Cancer Pharmacol. Rev., December 1, 2005; 57(4): 547 - 583. [Abstract] [Full Text] [PDF]

				T. B. Chaston, D. B. Lovejoy, R. N. Watts, and D. R. Richardson Examination of the Antiproliferative Activity of Iron Chelators: Multiple Cellular Targets and the Different Mechanism of Action of Triapine Compared with Desferrioxamine and the Potent Pyridoxal Isonicotinoyl Hydrazone Analogue 311 Clin. Cancer Res., January 1, 2003; 9(1): 402 - 414. [Abstract] [Full Text] [PDF]