Triapine (3-aminopyridine-2-carboxaldehydethiosemicarbazone): A potent inhibitor of ribonucleotide reductase activity with broad spectrum antitumor activity

Previous studies from our laboratories have shown that (a) Triapine(TM) is a potent inhibitor of ribonucleotide reductase activity and (b) hydroxyurea resistant L1210 leukemia cells are fully sensitive to Triapine; In an anal ogous manner, Triapine was similarly active against the wild-type and a hyd roxyurea-resistant subline of the human KB nasopharyngeal carcinoma. Triapi ne was active in vivo against the L1210 leukemia over a broad range of dosa ges and was curative for some mice. This agent also caused pronounced inhib ition of the growth of the murine M109 lung carcinoma and human A2780 ovari an carcinoma xenografts in mice. Optimum anticancer activity required twice daily dosing due to the duration of inhibition of DNA synthesis which last ed about 10 hr in L1210 cells treated with Triapine in vivo. DNA synthesis in normal mouse tissues (i.e. duodenum and bone marrow) uniformly recovered faster than that in L1210 leukemia cells, demonstrating a pharmacological basis for the therapeutic index of this agent. Triapine was more potent tha n hydroxyurea in inhibiting DNA synthesis in L1210 cells in vivo, and the e ffects of Triapine were more pronounced. In addition, the duration of the i nhibition of DNA synthesis in leukemia cells from mice treated with Triapin e was considerably longer than in those from animals treated with hydroxyur ea. Combination of Triapine with various classes of agents that damage DNA (e.g. etoposide, cisplatin, doxorubicin, and 1-acetyl-1,2-bis(methylsulfony l)-2 (2-chloroethyl)hydrazine) resulted in synergistic inhibition of the L1 210 leukemia, producing long-term survivors of tumor-bearing mice treated w ith several dosage levels of the combinations, whereas no enhancement of su rvival was found when Triapine was combined with gemcitabine or cytosine ar abinoside. The findings demonstrate the superiority of Triapine over hydrox yurea as an anticancer agent and further suggest that prevention by Triapin e of repair of DNA Lesions created by agents that damage DNA may result in efficacious drug combinations for the treatment of cancer. (C) 2000 Elsevie r Science Inc.