It was previously reported that tumor cells in vivo are far more heat sensitive than are the cells cultured in vitro. Interestingly enough, the heat sensitivity of in vivo tumor cells gradually becomes similar to that of the cells cultured in vitro when the in vivo cells are kept in complete medium with neutral pH in vitro, indicating that the difference in the heat sensitivity between tumor cells in vivo and in vitro may be due to the variance in the environment. The fact that cell death progresses, even after heating when the tumors are left in situ following heating, could be attributed to the heat-induced vascular damage and ensuing acidic, hypoxic and nutritionally deprived intratumor environment. The role of intratumor environment in the thermal response of tumor cells has not yet been clarified, even though it is important for determining the heat sensitivity of tumors. This study proposes to determine the relative importance of environmental factors, such as pH, pO2 and glucose supply, for the thermal response of tumor cells in vivo with the use of SCK and RIF-1 tumors of mice. Since the microenvironment of tumor cells cannot be precisely controlled in vivo, the tumors will be dispersed to single cells or tumor pieces and the cells or pieces will be subjected to various environments in vitro. Three specific experiments are planned: (1) In order to elucidate the role of environment DURING HEATING in the heat-induced cell killing, the dispersed cells or pieces from the two types of tumors will be immediately heated in vitro under various environmental conditions. The survival of the tumor cells will be determined by in vitro cloning method. (2) The implication of PRE-HEATING environment on the thermal response of tumor cells will be investigated. The dispersed cells or pieces from the two types of tumors will be heated after exposure to different environments for varying lengths of time. 3) The importance of POST-HEATING environment for the thermal response of tumors in vivo will be delineated. The tumors will be heated in situ, and immediately dispersed to single cells or tumor pieces. The dispersed cells or pieces will then be kept under various environments, and the change in cell survival as a function of time will be determined. This study may provide important information pertinent to the thermosensitization of tumors in clinical hyperthermia.
