[Radiosensitizing effects of nitroimidazole derivative, KIN-804]

KIN-804(2-nitroimidazole-1-methylacetohydroxamate) is a new hypoxic cell radiosensitizer developed in Japan. It showed a high level of radiosensitizing effect in vitro experiments and is expected to have low neurotoxicity because of its hydrophilic side chain. In this paper, the in vivo characteristics of KIN-804 were studied. Acute toxicity, pharmacokinetics and radiosensitizing effect were studied using C3H/He mice and SCC VII carcinoma. Misonidazole was used as a standard comparison. LD50/7 was used for the evaluation of acute toxicity. The LD50/7 of KIN-804 and Misonidazole were 3200 mg/kg and 2000 mg/kg, respectively. Pharmacokinetics were studied using high performance liquid chromatography. The concentration of KIN-804 in the tumor peaked 20 min after administration and reached 62% of the maximum concentration in blood. The concentrations in brain and sciatic nerve were low. The radiosensitizing effect was evaluated using the growth delay method. The enhancement ratios of KIN-804 were 1.71, 1.50 and 1.22 at doses of 200, 100 and 50 mg/kg, respectively, compared with 1.36 for Misonidazole at a dose of 100 mg/kg. When irradiation was performed with double fractionation, the enhancement ratio of KIN-804 at a dose of 100 mg/kg decreased to 1.25. Based on these results, KIN-804 is considered a promising radiosensitizer.