Enhanced therapeutic efficacy of 5'deoxy-5-fluorouridine in 5-fluorouracil resistant head and neck tumours in relation to 5-fluorouracil metabolising enzymes

Abstract

Four human head and neck xenograft (HNX) tumour lines grown in nude mice and two murine colon carcinomas (Colon 26 and 38) were tested for their sensitivity to 5-fluorouracil (5-FU) and its prodrug 5'deoxy-5-fluorouridine (Doxifluridine, 5'd-FUR). 5-FU sensitivity at the maximum tolerated dose (MTD) showed the following pattern; HNX-DU less than HNX-KE = HNX-E = HNX-G less than Colon 26 much less than Colon 38. The sensitivity pattern to 5'd-FUR was: HNX-DU less than HNX-G less than HNX-E less than HNX-KE less than Colon 38 less than Colon 26. For HNX-KE, HNX-E and Colon 26 an increase in therapeutic efficacy was observed with 5'd-FUR as compared to 5-FU; Colon 38 was as sensitive to 5'd-FUR as to 5-FU. Plasma pharmacokinetics of 5'd-FUR and 5-FU were comparable in normal and nude mice. Metabolism of 5-FU and 5'd-FUR was studied in the tumours. Conversion of 5'd-FUR to 5-FU was highest in Colon 26 and 15-20 times lower in HNX-DU, HNX-KE and Colon 38. The Km for 5'd-FUR in all tumours was 1-2 mM. Further anabolism of 5-FU to fluorouridine (FUR) was 5-10 times higher than that of 5-FU to FUR in HNX tumours and 3 times in the colon tumours. 5-FU conversion to FUMP via FUR had the following pattern: Colon 26 much greater than HNX-DU greater than HNX-G greater than HNX-E greater than HNX-KE much greater than Colon 38; of 5-FU to FdUMP via FUdR: Colon 26 greater than HNX-DU = HNX-KE greater than HNX-E greater than HNX-G = Colon 38; and that of 5-FU to FUMP catalysed by orotate phosphoribosyl transferase (OPRT); Colon 26 greater than or equal to Colon 38 greater than HNX-KE greater than HNX-E = HNX-DU = HNX-G. Only those tumours with a relatively high activity of OPRT were sensitive to 5'd-FUR. Colon 26, which has a very high rate of pyrimidine nucleoside phosphorylase, showed a relatively high increase in the therapeutic efficacy. It is concluded that a low rate of pyrimidine nucleoside phosphorylase is enough to convert 5'd-FUR to 5-FU; further anabolism of 5-FU catalysed by OPRT may be limiting and explain the differential sensitivity.