Preferential Radiosensitization of Mouse Sarcoma Relative to Normal Skin by Chronic Intra-Arterial Infusion of Halogenated Pyrimidine Analogs

Summary

Chronic intra-arterial infusion of the halogenated pyrimidine analog 5-bromo-2′-deoxycytidine (BCdR) into tumor-bearing mice was used to study the potential of this radiosensitizing drug for clinical radiotherapy. Dose-response curves were obtained for a multifraction regimen of 10 daily doses of 250 kv X rays delivered locally to KHT sarcoma implanted in thighs of syngeneic C3H mice. Comparisons were made of the radiation response of noninfused tumors and tumors chronically infused intra-arterially with either saline, BCdR, 2′-deoxy-5-fluorouridine (FUdR), or BCdR + FUdR. The tumor response used was delay in regrowth produced by irradiation. Parallel with the comparisons of tumor response, the skin reactions of the hind feet, which were included in the irradiation field, were observed. Infusion of BCdR continuously during the fractionated regimen sensitized the tumors to × irradiation by a dose modification factor (DMF) of 1.30 ± 0.01, whereas sensitization of normal tissue (skin) was insignificant (DMF = 1.03 ± 0.02). Addition of FUdR to the infused BCdR did not significantly alter the sensitization of the tumors (DMF = 1.32 ± 0.01), though it increased the degree of replacement of thymidine by 5-bromo-2′-deoxyuridine (as judged by cesium chloride gradient studies) from 5–17%. Therapeutic gain factors (= DMF for tumor/DMF for skin) of 1.26 ± 0.03 and 1.28 ± 0.03 were calculated for the BCdR and the BCdR + FUdR infusions, respectively. The action of intra-arterial infused BCdR in preferentially radiosensitizing the tumor cells relative to the normal cells is postulated to be a result of the difference in the generation times of the two predominant cell types. The potential applicability of these studies to the treatment of cancer by radiotherapy is discussed.