Tumor hypoxia can be exploited to preferentially sensitize tumors to fractionated irradiation.

The present study describes a new way in which tumors may be made more sensitive to fractionated irradiation without affecting the sensitivity of surrounding normal tissues. It involves exploiting the cycling or intermittent hypoxia that occurs in at least some solid tumors, but not in normal tissues, using a new drug SR 4233, a benzotriazine di-N-oxide, which is rapidly metabolized in hypoxic cells to a product that kills these cells. Using this approach with a rodent tumor in a fractionated x-ray treatment regimen similar to that used in human radiotherapy, the addition of SR 4233 produced a large enhancement of the radiation response of the tumor with no change in the sensitivity of normal mouse skin. Under identical circumstances, there was no effect of the hypoxic cell radiosensitizer SR 2508, showing that SR 4233 with intermittent hypoxia was superior to a protocol which sensitized the hypoxic cells to doses of 2.5 Gy per fraction.