Moderate hyperthermia is used clinically as an adjuvant to radiation therapy, however, the mechanism of radiosensitization remains unknown. Experiments are proposed to test the hypothesis that premature entry into mitosis occurs following irradiation, resulting in spontaneous premature chromosome condensation and a catastrophic mitosis. It is suggested that MH enhances this process and that this process is dependent on alterations in cyclin B levels or activity affecting the G2/M checkpoint. Model systems using characterized normal fibroblasts and altered derivatives with characterized G2/M checkpoint abnormalities will be used for the proposed experiments. Manipulations of levels of cyclin B and/or related molecules will be done to investigate cause and effect relationships in cellular outcome after irradiation and MH. Successful completion of the proposed studies may lead to identification of a molecular basis for MH-induced radiosensitization.
