Selective Radiosensitization of the Hypoxic Cells of Mouse Tumors with the Nitroimidazoles Metronidazole and Ro 7-0582

BROWN, J. M. Selective Radiosensitization of the Hypoxic Cells of Mouse Tumors with the Nitroimidazoles Metronidazole and Ro 7-0582. Radiat. Res. 64, 633-647 (1975). A study was made of the effect of two nitroimidazoles, metronidazole and the Roche product Ro 7-0582, on the radiosensitivity of the EMT6 mouse tumor. Both drugs at the high concentration of 1.0 and 1.2 mg/g (metronidazole and Ro 7-0582, respectively) reduced the slope of the resistant portion of the tumor cell survival curve. The radiosensitization was maximum at 30 min after intraperitoneal injection, and was gradually lost during the next 6 hr. Experiments performed to determine the degree of radiosensitization as a function of amount of Ro 7-0582 injected showed near-maximum radiosensitization of the hypoxic cells (as judged by the slope change of the resistant portion of the cell survival curve) at concentrations above 0.1 mg/g. At these concentrations dose modification factors for the hypoxic tumor cells (DMF's) of approximately 2.5 were obtained. A tumor control study with the MDAH/MCa4 mammary carcinoma confirmed both the high DMF (=2.3) at high Ro 7-0582 concentration, and the lack of a large reduction in the DMF (> 1.8) when the concentration was reduced to 0.3 mg/g. There was some cytotoxicity at the high drug doses. Concentrations of Ro 7-0582 of both 0.3 and 1.0 mg/g radiosensitized the normal skin at doses of 3000 rad and above, presumably due to lack of full oxygenation of this tissue.