Previous studies from our laboratories have shown that (a)
Triapine() is a potent inhibitor of
ribonucleotide reductase activity and (b)
hydroxyurea-resistant
L1210 leukemia cells are fully sensitive to
Triapine. In an analogous manner,
Triapine was similarly active against the wild-type and a
hydroxyurea-resistant subline of the human KB
nasopharyngeal carcinoma.
Triapine was active in vivo against the
L1210 leukemia over a broad range of dosages and was curative for some mice. This agent also caused pronounced inhibition of the growth of the murine M109 lung
carcinoma and human A2780 ovarian
carcinoma xenografts in mice. Optimum anticancer activity required twice daily dosing due to the duration of inhibition of
DNA synthesis which lasted 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 than
hydroxyurea in inhibiting
DNA synthesis in L1210 cells in vivo, and the effects of
Triapine were more pronounced. In addition, the duration of the inhibition of
DNA synthesis in
leukemia cells from mice treated with
Triapine was considerably longer than in those from animals treated with
hydroxyurea. Combination of
Triapine with various classes of agents that damage
DNA (e.g. etoposide, cisplatin, doxorubicin, and 1-acetyl-1,2-bis(methylsulfonyl)-2-(2-chloroethyl)hydrazine) resulted in synergistic inhibition of the
L1210 leukemia, producing long-term survivors of
tumor-bearing mice treated with several dosage levels of the combinations, whereas no enhancement of survival was found when
Triapine was combined with
gemcitabine or
cytosine arabinoside. The findings demonstrate the superiority of
Triapine over
hydroxyurea as an
anticancer agent and further suggest that prevention by
Triapine of repair of DNA lesions created by agents that damage
DNA may result in efficacious
drug combinations for the treatment of
cancer.