We have made important new insights into three factors that determine tumor response to radiotherapy, intrinsic mechanisms of radiosensitivity, hypoxic modulation of radiosensitivity and p21- modulated apoptosis. When taken on concert, these data suggest novel patterns of dose and dose-rate may achieve improved radiotherapy. We have measured in detail the response of genetically-defined human colorectal tumor cells to protracted and acute irradiation. These studies identify two distinct radio-response phenotypes that segregate only with p53 status. Further these data show radioresistance can be manipulated by differing patters of dose and dose rate to achieve either resistance or sensitivity. Most important we have also shown radio- resistant tumors to be susceptible to radiosensitization by factors up to 8 fold by protracted, low dose-rate irradiation. We also have demonstrated hypoxia to the dominant modulator of radioresponse in xenograft tumors for cells of similar intrinsic radiosensitivity and developed methodology to assay hypoxia distributions in tumor cells quantitatively. Further, we have demonstrated that p21-modulated apoptosis does not alter after in vitro radiosensitivity but does alter tumor response Thus these studies provide insights and methodology for improving radiotherapy through regiments that exploit the characteristics of radioresponse of cells of particular tumors, including their modulation by tumor microenvironment and apoptosis. We now propose to determine if new protocols based on our observations will improve radiotherapy. Our approach will be novel in four ways First, we will use a new cellular radiosensitivity model, termed the alpha-omega model that has fundamental differences from current models and suggest new protocols for maximum therapeutic efficiency. Second, our studies will evaluate concomitantly the contribution of three factors that are the major determinants of tumor response: i) intrinsic radiosensitivity ii) tumor microenvironment and iii) p21-modulated apoptosis. Third we will focus on protracted irradiation with or without IUdR as a potent radiosensitizer, particularly for radio-resistant tumors. Fourth, as current methodology as limited in delivering low dose-rate irradiation in adequate duration for radio-sensitizing radio- resistant tumor cells, we will also develop methodology for delivering protracted irradiation by fluid injection of immunomicrospheres containing therapeutic levels of radionuclides. Our program is composed of three projects: Cellular Mechanisms of Radiosensitivity, Microenvironmental Modulation of Radiosensitivity; and Immunomicrospheres as Radionuclide Carriers; and two Cores: Administration and Clinical Correlates, and Dosimetry, Modeling and Experimental Xenograft Therapy.