Abstract
Initial FU metabolism is catalyzed by either pyrimidine phosphorylase (PNP) or orotate phosphoribosyltransferase (OPRT). The human colon carcinoma cell line WiDr is 3 times more sensitive to FU and 5 times more sensitive to 5'deoxy-5-fluorouridine than the intestinal cell line Intestine 407. However, in both cell lines PNP activity with either ribose-1-P (Rib-1-P) or deoxyRib-1-P (dRib-1-P) is comparable with OPRT activity (1-2 nmol/hr per 106 cells). Modulation of the availability of co-substrates with purine nucleosides might elucidate the mechanism of action of FU. PNP activity with inosine as co-substrate was 30 and 86% in WiDr and Intestine 407, and with deoxyinosine 7 and 19%, respectively, of the activity with Rib-1-P and dRib-1-P. Inosine increased the Rib-1-P levels 2-4-fold, while deoxyinosine enhanced dRib-1-P levels several fold. Inosine did not show a synergism with FU in growth-inhibition. Deoxyinosine at 0.1-1 mM showed synergism with FU at non-toxic concentrations (0.1-0.5 uM). Deoxyinosine itself was not toxic. The synergism was greater with Intestine 407 cells than with WiDr. Examination of the medium at 24 hr showed that in both cell lines deoxyinosine was rapidly broken down to hypoxanthine (at 0.1 mM for 80% in Intestine 407 and 50% in WiDr). Growth inhibition could be reversed by 2-10 uM thymidine in Intestine 407, but only partly in WiDr cells. The results show that low non-toxic concentrations of FU can be made toxic by supplementary dRib-1-P. The effect of thymidine shows that inhibition of thymidylate synthase differs in the cell lines.
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Peters, G., Laurensse, E., Leyya, A. et al. MODULATION OF CYTOTOXICITY AND METABOLISM OF 5-FLUOROURACIL (FU) IN TWO INTESTINE CELL LINES: 156. Pediatr Res 19, 769 (1985). https://doi.org/10.1203/00006450-198507000-00176
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DOI: https://doi.org/10.1203/00006450-198507000-00176