Action of free radical in podophyllic acid piperindyl hydrazone nitroxide radical on its antitumor activity and toxicity

AIM: To study the action of free radical in the spin-labeled podophyllotoxi n derivative, podophyllic acid piperindyl hydrazone nitroxide radical (GP-1 ) on its antitumor activity and toxicity, by comparison with those of its f ree radical reduced product, podophylIic acid piperindyl hydrazone (GP-I-H) . METHODS: After treatment with GP-1 and GP-1-H, the inhibitory effects on the growth of mouse transplantable tumors were determined; MTT formazan for mation, [H-3]deoxythymidine ([H-3]TdR) incorporation, cell cycle progressio n, and mitotic index of SGC-7901 or L1210 cells were measured; the acute to xicity and immune function of mice were assayed. RESULTS: At doses of 1/6 a nd 1/12 LD50, the inhibitory rates against Lewis lung carcinoma were 60.3 % and 42.1 % (GP-1), 38.9 % and 10.3 % (GP-1-H), respectively; more effectiv e antitumor activity of GP-1 against P388, HePS, and S-180 than that of GP- 1-H were found. In vitro, GP-1 exhibited more powerful inhibitory effects o n the proliferation and DNA synthesis of SGC-7901 and L1210 cells than GP-1 -H. GP-1 and GP-1-H arrested the L1210 cells at G(2)/M phase with a corresp onding decrease of the cells in G(1) phase, and increased the mitotic index of the cells; but the effects of GP-1-H were weaker than those of GP-I. Af ter treatment with doses of 1/4 and 1/8 LD50 for 5 d, no significant differ ence on immune function of mice between GP-1 and GP-1-H was found. CONCLUSI ON: GP-1 had more powerful antitumor activities than GP-1-H. The free radic al in the spin-labeled podophyllotoxin derivative, GP-1, played an importan t role in its antitumor activity.