Sensitization of radiolabeled monoclonal antibody therapy using bromodeoxyuridine

Abstract

Although treatment with radiolabeled monoclonal antibodies (MoAb) against tumor-associated antigens offers the potential for targeted therapy, the efficacy of this approach is limited by the low dose-rate delivered. This could be overcome by increasing tumor sensitivity through the use of radiation sensitizers. In vitro studies using LS174T human colon cancer cells showed that exposure to 1 microM bromodeoxyuridine (BrdUrd), a thymidine-analog radiation sensitizer, at a plasma concentration easily achievable through systemic administration in both animals and patients, increased the cytotoxicity of continuous low dose-rate irradiation delivered by a cesium-137 irradiator (at 12 cGy/h which resembles the dose-rate delivered by radiolabeled MoAb therapy). It was found that 1 microM BrdUrd produced marked radiosensitization (enhancement ratio of 1.42 +/- 0.03) but did not affect cell cycle distribution. Systemic administration of BrdUrd in athymic nude mice bearing LS174T xenografts was performed using osmotic pumps. Animals tolerated infusions of 200 mg/kg/day BrdUrd for 4 days, which resulted in 8.4 +/- 0.8% of thymidine replacement by BrdUrd in tumors. However, bone marrow incorporation was 15.8 +/- 1.1% under these conditions. To improve the ratio of incorporation in the tumor compared to that in the bone marrow, animals were given an infusion of BrdUrd and the pumps were removed. Incorporation of BrdUrd in the bone marrow and intestine decreased rapidly after the infusion was completed. In contrast, there was relatively little change in the incorporation into the tumor after an initial decrease. Based on these data, experiments were performed comparing the effects of 500 microCi iodine-131-labeled 17-1A MoAb alone to the same dose of iodine-131-labeled 17-1A administered 1 day after discontinuation of the infusion of BrdUrd (200 mg/kg/day for 4 days). BrdUrd tended to increase the delay in tumor growth produced by iodine-131-labeled 17-1A administration. Radiosensitization by BrdUrd in vitro appears to be caused not by cell cycle effects but by increased radiation sensitivity. The in vivo data suggests that BrdUrd improved the efficacy (tumor growth inhibition) of radiolabeled MoAb.