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

Academic Article

Abstract

  • 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 serumimmunosuppressed 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 phosphoribosyl-transferase, 5ʹ-nucleotidase, and dihydrouracil dehydrogenase, did not differ between the two cell lines. © 1984, American Association for Cancer Research. All rights reserved.
  • Published In

  • Cancer Research  Journal
  • Author List

  • Chu MYW; Naguib FNM; Iltzsch MH; el Kouni MH; Chu SH; Cha S; Calabresi P
  • Start Page

  • 1852
  • End Page

  • 1856
  • Volume

  • 44
  • Issue

  • 5