A
2-nitroimidazole nucleoside, 1-(2',3'-dideoxy-alpha-D-erythro-hex-2'-enopyranosyl)-2-nitroimida zole (RA-263), has been investigated for its radiosensitization, pharmacokinetics, and toxicity properties. The in vitro radiosensitization tests against hypoxic Chinese hamster (V-79) cells demonstrated that
RA-263 was a more potent radiosensitizer than
misonidazole and at 2 mM concentration approached the oxic curve. Significant in vitro radiosensitization activity was also observed in EMT6 mammary
tumor cells. The in vitro cytotoxicity data suggested that
RA-263 is considerably more toxic to hypoxic cells than
misonidazole. The increased cytotoxicity may be related to its higher depletion of nonprotein
thiols (NPSH) than
misonidazole. The combined effects of radiosensitization and hypoxic cell toxicity were measured by preincubation of the V-79 cells for 4 h under hypoxic conditions before irradiation. The results demonstrated a synergistic response by causing a significant decrease in the extrapolation number with loss of shoulder of the radiation survival curves. The in vivo radiosensitization experiments conducted by the in vivo-in vitro cloning assay with the EMT6 mammary
tumor indicate that
RA-263 is an effective sensitizer. Pharmacokinetic data suggested that
RA-263 was eliminated from plasma by a rapid alpha phase and a slower beta phase with T 1/2 of 36 and 72 min, respectively. The concentration in the brain was approximately one-sixth of
tumor concentration, suggesting that
RA-263 is excluded from the CNS. Moreover,
RA-263 was two times less toxic than
misonidazole on equimolar basis by acute LD50 tests. This agent was also significantly less mutagenic than
misonidazole in a strain of Escherichia coli.