Strategies to improve the efficacy of radioimmunotherapy: Radiobiologic aspects

The purpose of this study was to investigate methods of improving the therapeutic index (dose to tumor/dose to normal organs) and, hence, the efficacy of radioimmunotherapy (RIT). One method investigated was to increase the biologic response for a given radiation dose to tumor. To enhance the biologic efficacy of the dose, initial studies focused on first understanding the radiobiology of RIT irradiation and determining what role factors, such as radiation repair, repopulation, and redistribution, play in determining RIT response. In vitro studies using 4 colon carcinoma cell lines have compared the radiobiologic efficacy of low dose-rate irradiation delivered by Yttrium-90 (Y-90) with conventional high dose-rate external beam irradiation (XRT). Results suggested that one factor which determined a cell's sensitivity to Y-90 irradiation was its ability to repair radiation sublethal damage. In vivo studies demonstrated that those cell lines which were more sensitive to Y-90 irradiation in vitro were also more sensitive to RIT in vivo. For a more radioresistant line, WiDr, RIT was approximately two-fold less effective than an equivalent dose of single fraction XRT, while for a more radiosensitive line, LS174T, RIT was approximately as effective as an equivalent dose of single fraction XRT. Therefore, a tumor's response to RIT in vivo appeared to be, in part, dependent on the tumor cell's ability to repair radiation damage. Finally, studies investigated strategies at enhancing the biologic efficacy of RIT irradiation by combining RIT with chemotherapy agents that can potentially inhibit radiation repair. Agents, such as 5-fluorouracil, appeared to be synergistic with RIT irradiation n vitro and may therefore prove promising in improving the therapeutic index of RIT