SR 4233: a tumor specific radiosensitizer active in fractionated radiation regimes

The benzotriazine SR 4233, in addition to preferential killing of hypoxic cells both in vitro and in vivo, also radiosensitizes aerobic cells in vitro if the cells are exposed to the drug under hypoxic conditions, either before or after irradiation. We have attempted to exploit this aerobic radiosensitization in vivo, by giving SR 4233 with the hypoxia inducing agent, hydralazine, after each radiation dose in a 8 x 2.5 Gy fractionated regime. The results show greater than additive cytotoxicity using both cell survival and regrowth delay as the endpoints of radiation response, but no radiosensitization in parallel groups treated with the hypoxic cell radiosensitizer SR 2508. The data are, therefore, consistent with radiosensitization of the tumor aerobic cells by the SR 4233 treatments. Significantly, the effect occurred with equal magnitude with or without hydralazine. Further, there was no radiosensitization to radiation induced leg contraction in the thighs of mice, a late responding normal tissue endpoint. The results, therefore, demonstrate a selective radiosensitization of tumors to a multifraction regime and suggest that SR 4233, or a close analog, may be useful in radiation therapy.