Metabolic effects of some tumor-inhibitory pyridine carboxaldehyde thiosemicarbazones.

SUMMARY 2-F o rmylpy rid i ne thiosemicarbazone (PT), 3-hydroxy-2-formylpyridine thiosemicarbazone (3-HP), and 5-hydroxy-2-formylpyridine thiosemicarbazone (5-HP) are potent inhibitors of the growth of Sarcoma 180 ascites cells. PT is quite toxic to the tumor-bearing host and does not markedly extend the lifespan of mice bearing Sarcoma 180; however, the therapeutic potential of 3-1-IP and 5-HP is considerably greater, and treatment with these agents results in a pronounced lengthening of the survival time of the tumor-bearing animals. Evidence that the heteroaromatic ring nitrogen atom is required for biological activity was provided by the finding that salicylaldehyde thiosemicarbazone is inactive. PT, 3-HP, and 5-HP cause pronounced inhibition of the incorporation of thymidine into DNA; these agents do not prevent the conversion of thymidine to the triphosphate level but inhibit the subsequent incorporation of CITTP into DNA. The inhibitory effects of 3-HP and 5-HP on the formation of DNA do not appear to result from extensive catabolism of DNA in drug-treated cells. The utilization of uridine for the formation of RNA is depressed by PT, 3-HP, and 5-HP, and slight but significant inhibition of leucine incorporation into residual protein is also produced. INTRODUCFION PT2 has been shown by Brockman et al. (5) to be an inhibitor of the growth of transplanted rodent neoplasms. The therapeutic potency of PT as a tumor-inhibitory agent was markedly increased by substitution of the heteroaromatic ring with a hydroxyl group in either the 3-or 5-position to form 3-HP or 5-HP, respectively (1, 8). PT and 5-HP are also significant inhibitors of DNA viruses of the herpes family (4). The biochemical mechanism of action of a related series of carcinosta tic a-(N)-he te rocyclic carboxaldehyde thiosemicarbazones of the isoquinoline type has been extensively studied by this laboratory (10, 12†" 14,18). One of 1This study was supported inpart byGrant CA-028 17from the National Cancer Institute, USPHS, and Grant T-23 from the American Cancer Society.