Testing of hypoxic cell radiosensitizers in vivo.

The sensitizing action of misonidazole in a range of animal tumors is reviewed and the conclusion is drawn that all tumor cells are capable of sensitization if they are hypoxic. There is no evidence of drug diffusion problems to distant hypoxic cells. The misonidazole sensitization at low doses enables an estimate of hypoxic fractions to be made in both mouse and human tumors; these mostly fall in the same range of 5-50%. The optimum way of using misonidazole, based on survival curve characteristics, is briefly reviewed. The potential therapeutic gain factor is based on sensitization of tumor cells more than of normal cells. The evidence for sensitization of some normal tissues in mice is reviewed. The search for better radiosensitizers, either based on the same effect for a lower dosage, or a greater effect for the same normal tissue toxicity, is illustrated with two other nitroimidazoles: Ro-03-8799 and Ro-12-5272. These have been studied in the artificially hypoxic skin clone assay and also by regrowth delay in a fibrosarcoma in mice.