Continuous intravenous infusions of bromodeoxyuridine as a clinical radiosensitizer.

Abstract

Twelve patients were treated with continuous i.v. (24 h) infusions of bromodeoxyuridine (BUdR) at 650 or 1000 mg/m2 per day for up to 2 wk. Myelosuppression, especially thrombocytopenia, was the major systemic toxicity and limited the infusion period to 9-14 days. Bone marrow recovery occurred within 7-10 days, allowing for a 2nd infusion in most patients. Local toxicity (within the radiation field) was minimal, with the exception of 1 of 4 patients, who underwent abdominal irradiation. Pharmacology studies revealed a steady-state arterial plasma level of 6 .times. 10-7 mol/l and 1 .times. 10-6 mol/l during infusion of 650 and 1000 mg/m2 per day, respectively. In vivo BUdR uptake into normal bone marrow was evaluated in 2 patients by comparison of preinfusion and postinfusion in vitro radiation survival curves of marrow CFUc granulocyte-macrophage colony forming unit with enhancement ratios (D0-pre/D0-post) of 1.8 (with 650 mg/m2 per day) and 2.5 (with 1000 mg/m2 per day). In vivo BUdR incorporation into normal skin and tumor cells using an anti-BUdR monoclonal antibody and immunohistochemistry was demonstrated in biopsies from 3 patients revealing substantially less cellular incorporation into normal skin (< 10%) compared with tumor (up to 50% to 70%). Local and systemic toxicity of continuous infusion of BUdR at 1000 mg/m2 per day for approximately 2 wk is tolerable. The observed normal tissue toxicity is comparable with our previous clinical experience with intermittent (12 h every day for 2 wk) infusions of BUdR. Theoretically, a constant infusion should allow for greater incorporation of BUdR into cycling tumor cells and for further enhancement of radiosensitization.