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Potentiation of 5-Fluoro-2'-deoxyuridine Antineoplastic Activity by the Uridine Phosphorylase Inhibitors Benzylacyclouridine and Benzyloxybenzylacyclouridine¹

Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912 [M. Y. W. C., F. N. M. N., M. H. I., M. H. e. K., S. H. C., S. C., P. C.], and the Roger Williams General Hospital, Providence, Rhode Island 02908 [M. Y. W. C., P. C.]

At a nontoxic dose (50 µM), the two potent uridine phosphorylase inhibitors, benzylacyclouridine and benzyloxybenzylacyclouridine (BBAU), potentiated 5-fluoro-2'-deoxyuridine (FdUrd) growth inhibition of human pancreatic carcinoma (DAN) and, to a lesser extent, human lung carcinoma (LX-1) cells in culture. BBAU was more effective than benzylacyclouridine. BBAU (50 µM) enhanced the cytocidal effect of FdUrd (1 µM, 3 hr) on DAN grown on soft agar from 75 to 88%. In antithymocyte serum-immunosuppressed mice bearing DAN, the mean tumor weight in animals treated with FdUrd (50 mg/kg/day for 2 days) was 11% less than that of untreated controls. When BBAU (10 mg/kg/day for 2 days) was coadministered, the mean tumor weight at Day 10 was 78% less than untreated controls, with no apparent host toxicity, clearly demonstrating the potentiation of the antitumor effects of FdUrd by BBAU. The fact that DAN responded better than LX-1 to benzylacyclouridine and BBAU could be due, in part, to the lower relative activity of thymidine phosphorylase to uridine phosphorylase in DAN compared to LX-1. The activities of other enzymes involved in FdUrd metabolism, thymidine kinase, uridine kinase, orotate phosphoribosyltransferase, 5'-nucleotidase, and dihydrouracil dehydrogenase, did not differ between the two cell lines.

¹ This investigation was supported by USPHS Grants CA 25631, CA 34228, CA 31650, CA 13943, and CA 20892 awarded by the National Cancer Institute, Department of Health and Human Services, and Grant CH 136 awarded by the American Cancer Society.

² To whom requests for reprints should be addressed, at the Roger Williams Hospital.

³ Recipient of support from the Training Program in Cancer Research, USPHS Grant CA 02904, awarded by the National Cancer Institute, Department of Health and Human Services.

Received 11/ 7/83. Accepted 2/ 2/84.

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