POTENTIATION OF 5-FLUORO-2'-DEOXYURIDINE ANTINEOPLASTIC ACTIVITY BY THE URIDINE PHOSPHORYLASE INHIBITORS BENZYLACYCLOURIDINE AND BENZYLOXYBENZYLACYCLOURIDINE

  • 1 January 1984
    • journal article
    • research article
    • Vol. 44  (5) , 1852-1856
Abstract
At a nontoxic dose (50 .mu.M), the 2 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 .mu.M) enhanced the cytocidal effect of FdUrd (1 .mu.M, 3 h) on DAN grown on soft agar from 75-88%. In antithymocyte serum-immunosuppressed mice bearing DAN, the mean tumor weight in animals treated with FdUrd (50 mg/kg per day for 2 days) was 11% less than that of untreated controls. When BBAU (10 mg/kg per 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 2 cell lines.

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