Effect of hyperthermia and misonidazole on the radiosensitivity of a transplantable murine tumor: influence of factors modifying the fraction of hypoxic cells.

Hypoxia has been demonstrated to play an important role in the effect of hyperthermia on tumors. We have studied the influence of different factors modifying the oxygenation status of a transplantable murine mammary adenocarcinoma (tumor volume and pentobarbital sodium anesthesia). The effect of hyperthermia alone on the tumor is not significantly influenced by the change in oxygenation status during the growth of the tumor. Also, the large increase of the acutely hypoxic cell fraction, as a result of anesthesia, does not change the effect of hyperthermia alone. In the combined irradiation-heat treatment there is a clear influence of the chronically hypoxic cell fraction on the response to hyperthermia: an increase in tumor size, resulting in a larger hypoxic cell fraction, leads to an increase in thermal enhancement ratio. However, the increased acutely hypoxic cell fraction, resulting from anesthesia, did not lead to an increase in thermal enhancement ratio; in fact the enhancement ratio apparently decreased. In spite of the fact that hyperthermia was applied immediately after irradiation no potentiation of radiation effects was found. The thermal enhancement of the radiation response was never larger than the enhancement as a result of misonidazole. All thermal enhancement could be explained by effects of heat on the chronically hypoxic cell fraction. Misonidazole had no effect on the response of tumors to heat alone, but greatly enhanced the effect of heat combined with irradiation. Anesthesia of the animals did not influence these effects of misonidazole.