POTENTIATION OF RADIATION-INDUCED REGROWTH DELAY IN MURINE TUMORS BY FLUDARABINE

Fludarabine rabinofuranosyl-2-fluoroadenine-5'-monophosphate), an aden ine nucleoside analogue, has previously been shown to inhibit the repa ir of radiation-induced chromosome damage. Thus fludarabine may have t herapeutic utility in combination with photon irradiation. The purpose of this study was to determine whether fludarabine could enhance radi ation-induced murine tumor regrowth delay and to determine the most ef fective dose and schedule of the combination. A significant (P < 0.05) absolute regrowth delay enhancement was observed in three murine tumo r models (SA-NH, a sarcoma; and MCA-K and MCA-4, mammary carcinomas) w hen fludarabine (800 mg/kg) was given 1 h prior to 25 Gy gamma-irradia tion. While fludarabine enhanced radiation-induced tumor regrowth dela y when given between -36 h and +6 h of radiation (SA-NH tumor), the gr eatest enhancement was observed when fludarabine was given at -24 h pr ior to irradiation (radiation dose modification factor of 1.82 at -24 h compared to 1.57 at -3 h prior to radiation). The degree of fludarab ine enhancement (at -3 or -24 h) was dose dependent at doses above 200 mg/kg. When fludarabine and radiation were administered on a fraction ated schedule (fludarabine given 3 h prior to radiation each day for 4 days), the dose modification factor increased to 2.14 (1.63 if the ef fect of fludarabine alone is subtracted). These results suggest that f ludarabine enhances radiation-induced tumor regrowth delay in a more t han additive fashion after both single and fractionated treatments, an d the degree of enhancement is dependent on the sequence and timing of administration, the fludarabine dose, and the tumor type. Thus, fluda rabine may have clinical potential as a radiation enhancer in the trea tment of solid tumors.