Potentiation of 5-fluoro-2'-deoxyuridine antineoplastic activity by the uridine phosphorylase inhibitors benzylacyclouridine and benzyloxybenzylacyclouridine.
At a nontoxic dose (50 microM), 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 microM) enhanced the cytocidal effect of FdUrd (1 microM, 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.
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005260:Female; D005467:Floxuridine / Q000633:toxicity*; D006801:Humans; D007700:Kinetics; D008175:Lung Neoplasms / Q000503:physiopathology*; D051379:Mice; D008815:Mice, Inbred Strains; D010190:Pancreatic Neoplasms / Q000503:physiopathology*; D010430:Pentosyltransferases / Q000037:antagonists & inhibitors*; D014498:Uracil / Q000031:analogs & derivatives* / Q000633:toxicity; D014543:Uridine Phosphorylase / Q000037:antagonists & inhibitors*
D005467:Floxuridine; C034753:5-benzylacyclouridine; D014498:Uracil; C034754:5-benzyloxybenzylacyclouridine; D010430:Pentosyltransferases; D014543:Uridine Phosphorylase