Radiosensitizing effect of the nitroimidazole derivatives RK28 and DNIE on murine tumors

Acute toxicity, radiosensitizing effects, and pharmacokinetics of two nitroimidazole derivatives, 1-(4'-hydroxy-2'-butenoxy)-methyl-2-nitroimidazole (RK28) and 2,4-dinitroimidazole-1-ethanol (DNIE) were examined in male C3H/He mice and rabbits. Misonidazole (MISO) served as a control. Tumor cells were transplanted into the footpad of the mice and a single irradiation was given without anesthesia. Enhancement ratio (ER) of the compounds was defined as the ratio of a single irradiation necessary for tumor growth delay in the absence of radiosensitizer to that in the presence of radiosensitizer. Lethal doses 50 percent (LD50) of RK28 and DNIE given by intraperitoneal injection were 830 mg/kg and 300 mg/kg, respectively. The ERs of RK28 were 1.74 and 1.37 with 1/2 and 1/4 of the LD50, respectively. For DNIE, they were 1.52, 1.18, and 1.00 with 5/6, 1/2, and 1/4 of the LD50, respectively. MISO showed 1.41 for the ER with 1/2 of the LD50. RK28 was excreted more rapidly and retained in a smaller amount in the plasma and brain than MISO when injected into the peritoneal cavity. However, DNIE was rapidly metabolized. The results suggest the feasibility of using RK28 in the clinical settings in view of its less neurotoxicity and higher ER than MISO. (Namekawa, K.)