FLUDARABINE IMPROVES THE THERAPEUTIC RATIO OF RADIOTHERAPY IN MOUSE-TUMORS AFTER SINGLE-DOSE IRRADIATION

Purpose: Fludarabine, an adenine nucleoside analogue, and an effective inhibitor of chromosome repair, was previously shown to synergistical ly enhance radiation-induced regrowth delay in three murine tumors. Th e purpose of this study was to assess whether fludarabine can increase the therapeutic ratio of radiotherapy in murine tumors, that is, to i ncrease local tumor control without significantly modifying the radiat ion-induced normal tissue response. Methods and Materials: Mice bearin g 8-mm tumors in the right thigh (SA-NH sarcoma and MCA-K mammary carc inoma) were given 800 mg/kg fludarabine IP 3 h or 24 h before single d oses of photon irradiation. Local tumor control was assessed by the TC D50 assay 100 days after treatment. Acute normal tissue toxicity was a ssessed in the skin (degree of epilation 30 days after irradiation) an d in the jejunum (crypt regeneration assay), and late normal tissue to xicity was assessed by a leg contracture assay 120 days after treatmen t. Results: In both tumors and with both drug schedules, fludarabine e nhanced radiation-induced local tumor control (dose modification facto rs (DMF) of 1.24 (95% confidence limits 1.19-1.31) and 1.26 (95% confi dence limits 1.20-1.32) for SA-NH, and 1.38 (95% confidence limits 1.2 5-1.50) and 1.35 (95% confidence limits 1.22-1.16) for MCA-K tumors). When given 3 h before radiation, fludarabine offered a slight protecti on from skin toxicity (DMF = 0.83, 95% confidence limits 0.77-0.86) bu t enhanced jejunum toxicity (DMF = 1.53). When fludarabine was given 2 4 h before irradiation, the reverse trend was observed (DMF = 1.11 (95 % confidence limits 1.07-1.16) and 0.89, respectively). No enhancement of leg contracture was observed for either fludarabine schedule. Conc lusion: The data presented here demonstrate that fludarabine can poten tiate local tumor control induced by single-dose irradiation. While je junum sensitization limited the relative effectiveness when fludarabin e was administered 3 h before irradiation, a therapeutic ratio greater than one was always achieved when fludarabine was given 24 h before i rradiation.