Abstract
Human head and neck xenografts (HNX) tumor lines represent an unique model to study the action of anticancer drugs. 1/4 HNX lines resistant to 5-fluorouracil (5FU) was sensitive to its analog 5′deoxy-5-fluorouridine (5′dFUR). To explain these differences we studied metabolism of 5FU and 5′dFUR in 4 HNX lines (DU, KE, E, G) and for comparison also in two murine colon carcinoma lines (Colon 26 and 38). Initial conversion of 5′dFUR to 5FU catalyzed by pyrimidine nucleoside phosphorylase (PNP), was highest in Colon 26, 15-20 times lower in DU, KE and Colon 38 and intermediate in both other tumors. The Km for 5′dFUR in all tumors was 1-2 mM. PNP also catalyzes further anabolism of 5FU to flu-orouridine (FUR) or 2′-deoxyfluorouridine (FUdR); the same pattern of activity was found as with 5′dFUR as substrate. In all HNX tumors 5FU conversion to FUdR was 5-10 fold than of 5FU to FUR; in the colon tumors this was 3 fold. The conversion of 5FU to the active nucleotides FUMP and FdUMP (via FUR and FUdR, resp) was measured by addition of ATP to the PNP assay; FUMP synthesis showed the following pattern: Colon 26 » DU > G > E > KE » Colon 38, and FdUMP synthesis: Colon 26 ≥ DU = KE>E > G = Colon 38. For the direct conversion of 5FU to FUMP the following pattern was observed: Colon 26 > Colon 38 > KE > E = DU = G. Colon 26, 38 and KE were sensitive to 5′dFUR. Conclusion: the anabolism of 5′dFUR to 5FU and subsequently to nucleotides (via 5FU-> FUMP) may be related to the differential sensitivity of the tumors.
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Laurensse, E., Braakhuis, B., Pinedo, H. et al. 114 FLUOROPYRIMIDINE METABOLISM IN HUMAN HEAD AND NECK CANCER XENOGRAFTS AND MURINE COLON TUMORS. Pediatr Res 24, 130 (1988). https://doi.org/10.1203/00006450-198807000-00138
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DOI: https://doi.org/10.1203/00006450-198807000-00138