title: 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.
authors.affiliation: Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
authors.forename: G J
authors.initials: GJ
authors.lastname: Peters
authors.forename: B J
authors.initials: BJ
authors.lastname: Braakhuis
authors.forename: E A
authors.initials: EA
authors.lastname: de Bruijn
authors.forename: E J
authors.initials: EJ
authors.lastname: Laurensse
authors.forename: M
authors.initials: M
authors.lastname: van Walsum
authors.forename: H M
authors.initials: HM
authors.lastname: Pinedo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002277:Carcinoma / Q000188:drug therapy / Q000201:enzymology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology; D004351:Drug Resistance; D005260:Female; D005467:Floxuridine / Q000627:therapeutic use*; D005472:Fluorouracil / Q000378:metabolism* / Q000627:therapeutic use; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D007536:Isomerism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010430:Pentosyltransferases / Q000378:metabolism*; D057845:Pyrimidine Phosphorylases
chemical_list: D000970:Antineoplastic Agents; D005467:Floxuridine; D010430:Pentosyltransferases; D057845:Pyrimidine Phosphorylases; D005472:Fluorouracil; C025034:doxifluridine