In vitro and in vivo radiosensitizing effects of 2-nitroimidazole derivatives with sugar component.

A new type of hypoxic cell sensitizer, 2-nitroimidazole substituted with an acyclic sugar analogue at the N-1 position of the imidazole ring (RK compounds) has been developed and tested on HeLa S3 and Chinese hamster V79 cells. As might be expected from their electron affinities, which are stronger than that of misonidazole, the abilities of RK compounds to sensitize hypoxic cells were correspondingly increased. One millimole of RK28 [1-(4'-hydroxy-2'-butenoxy)methyl-2-nitroimidazole] gave an enhancement ratio of 1.56 or 1.84 in comparison with 1.40 or 1.71 for the same concentration of misonidazole to HeLa S3 or V79 cells, respectively. RK28 showed slight cytotoxicity to aerobic HeLa S3 cells at a concentration of 5 mM after a three-hour exposure, whereas under hypoxic conditions, the agent was markedly cytotoxic. In vivo radiosensitization studies in ICR mice with Ehrlich ascites tumor indicated that RK28 produced an increase in DMF to hypoxic tumor cells with increased dose of the compound. Their DMF values were 1.63, 1.97 and 2.34 at 0.075, 0.15 and 0.3 mg/gbw of RK28, respectively. A dose of 0.3 mg/gbw of RK28 produced a DMF around 1.5 to two times greater than that resulting from the same dose of misonidazole. Pharmacokinetic studies of RK28 in ICR mice with Sarcoma-180 revealed a faster clearance from the serum and a slower decrease in the tumor than with misonidazole.