Radioimmunotherapy (RIT) is a promising new therapeutic modality. In some animal models RIT with continuous exponentially decreasing low dose rate irradiation is more effective than the same total dose given as fractionated high dose rate (HDR) external beam irradiation, for reasons that are unclear. Furthermore, clinical responses have been observed in some patients treated with RIT with tumor doses considerably lower than would be required in order to achieve similar responses with conventionally fractionated high dose rate radiation therapy. The overall objective of the proposed research is to study the radiobiology of low dose rate (LDR) irradiation associated with RIT. The efficacy of LDR irradiation will be compared with fractionated external beam irradiation using tumor cell lines with a spectrum of radiation sensitivities and growth rates in an attempt to determine the radiobiological and/or kinetic parameters that may be of predictive value for identifying tumors that may preferentially benefit from RIT compared with conventional radiation therapy. Groups of mice with tumors that vary with regard to shoulder (n, D0), alpha/beta ratio and tumor volume doubling time (VDT) in vivo will be treated for 10 days with dose- equivalent a) fractionated HDR irradiation, b) RIT, or c) continuous exponentially decreasing LDR irradiation. In vivo toxicity, tumor regrowth delay, tumor control and clonogenic tumor cell survival for the different modes of irradiation will be correlated with radiobiological parameters of tumor cell survival curves (n, D0, alpha/beta ratio) and VDT of the different tumors studied. This analysis will allow the hypothesis to be tested that the dose rate effect is minimized in tumors with survival curves characterized by small shoulders and high alpha/beta ratios, and that the dose rate effect is further modified by the tumor proliferative rate. In order to test the hypothesis that arrest of cells in G2 can contribute in part to the inverse dose rate effect observed in vivo, cell cycle distribution will be analyzed in tumors irradiated in vivo (with dose-equivalent high and LDR) that demonstrate an inverse dose rate effect. The hypoxic fraction of tumors similarly irradiated will be measured in order to ascertain whether or not measurable reoxygenation occurs during protracted exposure, which would increase the radiosensitivity of reoxygenated tumor cells. the relationship between dose rate and induction of DNA damage will be studied using fluorescence in situ hybridization (with whole chromosome probes) to measure stable reciprocal translocations. Elucidation of the role of actors such as G2 arrest, reoxygenation and induction of DNA damage as determinants of the efficacy of RIT is important for the prediction of outcome and ultimately for the optimization of treatment regimes. Lastly, in an attempt to increase the efficacy of RIT, which will probably be limited by hypoxia, the effect of combining the radiosensitizer SR 2508 and the bioreductive hypoxic cytotoxic agent SR 4233 with RIT will be studied.
