Radiosensitizing effects of nitroimidazole nucleoside analogues on cultured mammalian cells at low radiation doses

Radiosensitizing effects of nitroimidazole nucleoside analogues (RK-27, RK-28 and RK-29) were studied using cultured mouse leukemic L5178Y (L5178Y) cells and Chinese hamster V79 (CH V79) cells. There was no significant difference in sensitizer enhancement ratio among the three RK-compounds. The ratios were 1.7 for L5178Y cells and 1.6 for CH V79 cells at 1 mM concentration and were comparable to that of misonidazole. Sensitizer enhancement ratios of RK-28 for L5178Y cells irradiated with 1 to 4 Gy X-rays were, respectively, 1.5 to 1.6 at 0.5 mM concentration, which were nearly the same as those obtained at high doses. RK-28 was as effective for fractionated X-irradiation as for single X-irradiation, assuming complete repair of sublethal damage during incubation at 37degC between sessions of fractionated X-irradiation. The sensitizing effects of RK-28 were additive in combination with neocarzinostatin, an antitumor drug, which has different pharmacological and physiological properties, and enhances the radioresponse of cells. RK-28 is known to be rapidly metabolized and excreted in vivo and is thus expected to be less toxic than misonidazole. It was effective at low radiation doses routinely used in radiotherapy practice and for fractionated X-irradiation, suggesting its clinical utility. (author)