The application in radiation therapy of substances which modify cellular radiation response

Compounds to be considered as potential adjuvants in radiotherapy should indicate a strong mechanistic rationale for a differential response between tumor and normal tissues. Drugs which selectively radiosensitize hypoxic cells might be exploited in radiotherapy to increase the sterilization of resistant hypoxic areas of solid tumors which have outgrown their vascular supply. Several compounds have been shown to selectively radiosensitize hypoxic mammalian cells in vitro but their application in clinical studies in presently limited by their toxicity at the high drug dosages required to effect the sensitization. Phase I and Phase II clinical studies have now been completed with the sensitizer, metronidazole. This drug was tolerated by patients at dosages of 6 g/m2 three times a week for 3 weeks with a minimum of side effects, and survival of patients with glioblastoma multiforme treated with fractionated radiotherapy was significantly increased when the sensitizer was used in combination with the radiation. Drugs which selectively radioprotect oxygenated cells might also be exploited in therapy be permitting the use of higher radiation doses and thereby incurring more damage to the resistant hypoxic cells in tumours. Again, drug toxicity appears to be a limiting factor with this approach. If toxicities are not additive, combinations of radiosensitizers and radioprotectors might prove more effective than either individual approach.