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Potentiation of Radiation-induced Regrowth Delay in Murine Tumors by Fludarabine¹

Department of Clinical Investigation [V. G., W. P, W. N. H.] and Experimental Radiotherapy [N. H., L. M., W. A. B.], University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

³ To whom requests for reprints should be addressed.

Fludarabine (9-β-D-arabinofuranosyl-2-fluoroadenine-5'-monophosphate), an adenine nucleoside analogue, has previously been shown to inhibit the repair of radiation-induced chromosome damage. Thus fludarabine may have therapeutic utility in combination with photon irradiation. The purpose of this study was to determine whether fludarabine could enhance radiation-induced murine tumor regrowth delay and to determine the most effective dose and schedule of the combination. A significant (P < 0.05) absolute regrowth delay enhancement was observed in three murine tumor models (SA-NH, a sarcoma; and MCA-K and MCA-4, mammary carcinomas) when fludarabine (800 mg/kg) was given 1 h prior to 25 Gy -irradiation. While fludarabine enhanced radiation-induced tumor regrowth delay when given between –36 h and +6 h of radiation (SA-NH tumor), the greatest enhancement was observed when fludarabine was given at 24 h prior 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 fludarabine enhancement (at –3 or –24 h) was dose dependent at doses above 200 mg/kg. When fludarabine and radiation were administered on a fractionated 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 effect of fludarabine alone is subtracted). These results suggest that fludarabine enhances radiation-induced tumor regrowth delay in a more than additive fashion after both single and fractionated treatments, and the degree of enhancement is dependent on the sequence and timing of administration, the fludarabine dose, and the tumor type. Thus, fludarabine may have clinical potential as a radiation enhancer in the treatment of solid tumors.

¹ Supported by grants CA-06294, CA-27931, and CA-28596 awarded by the National Cancer Institute. Vincent Grégoire benefited from a grant of the Fond de la Recherche Scientifique Medicale from Belgium and from a research fellowship awarded by NATO. Animals used in this study were maintained in facilities approved by the American Association for Accreditation of Laboratory Animal Care in accordance with current regulations and standards of the United States Department of Agriculture and Department of Health and Human Services, NIH.

² Present address: St-Luc University Hospital, Radiation Oncology Department, 10 avenue Hippocrate, 1200 Brussels, Belgium.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 7/26/93. Accepted 11/15/93.

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