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

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