Potentiation by the hypoxic cytotoxin SR 4233 of cell killing produced by fractionated irradiation of mouse tumors.

The new bioreductive drug 3-amino-1,2,4-benzotriazine 1,4-dioxide (SR 4233) shows a high selective cytotoxicity for hypoxic cells, both in vitro and in tumors in vivo. In the present experiments, we have tested the hypothesis that this selective killing of hypoxic cells might be exploited by taking advantage of the fluctuating hypoxia in tumors by use of a multidose regimen of SR 4233 with multiple small doses of X-rays. We have tested four different transplantable mouse tumors using a standard fractionated protocol of 8 x 2.5 Gy in 4 days, using a well tolerated dose of SR 4233 given with each radiation dose. All of the tumors showed a substantial enhancement of cell killing by SR 4233 over that produced by radiation alone with dose-modifying factors of 1.5 to 3.0 for the different tumors. In all four tumors, the enhancement of cell killing was greater than that produced by a large dose of the hypoxic cell sensitizer SR 2508 given before each irradiation, thereby demonstrating the superiority of the approach of using a hypoxic cytotoxic agent rather than a radiosensitizer in fractionated radiation protocols. The data suggest that SR 4233 has considerable promise as an adjunct to standard radiotherapy.