Elucidation of pathways of 5-fluorouracil metabolism in xenografts of human colorectal adenocarcinoma.
Hypoxanthine (Hx) and allopurinol (HPP) have been shown experimentally to reduce the conversion of 5-fluorouracil (FUra) to FUMP by orotate phosphoribosyltransferase (OPRTase). This study was designed to elucidate the major pathway by which FU ra was metabolized to ribonucleotides by human colorectal tumors. Consequently, the effect of Hx and HPP on the metabolism of [6-3H]-FUra was examined in 5 human colorectal adenocarcinomas maintained as xenografts in immune-deprived mice. In 2 tumors the formation of ribonucleotides from FUra was depressed by Hx and HPP in combination during the first hour after treatment, while in 3 other lines ribonucleotide concentrations were not reduced. The data suggested that these 5 xenograft lines may be divided into 2 groups: (1) group 1 tumors formed relatively high levels of FUrd and low levels of fluorinated ribonucleotides after the injection of FUra, with no decrease in ribonucleotide concentrations after the administration of Hx and HPP. These tumors possessed high ratios of uridine (Urd) phosphorylase/orotate phosphoribosyltransferase (OPRTase: 7-24) and ribose-1-phosphate (R-1-P)/5-phosphoribosyl-1-pyrophosphate (PRPP;5), and thus appeared to metabolize FUra by the U rd phosphorylase and U rd kinase pathway; (2) group 2 tumors formed low levels of FU rd, higher concentrations of fluorinated ribonucleotides and a reduction in levels of these nucleotides after administration of the purine combination. Group 2 tumors demonstrated a lower enzyme ratio (1-2), higher endogenous levels of PRPP, a lower R-1-P/PRPP ratio (1) and appeared to metabolize FUra predominantly by the activity of OPRTase. Hypoxanthine and HPP, alone or in combination, caused a rapid depletion of PRPP in each tumor line examined. In group 2 tumors this may be responsible for the decreased formation of FUra ribonucleotides observed.
D000230:Adenocarcinoma / Q000378:metabolism*; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D003110:Colonic Neoplasms / Q000378:metabolism*; D005260:Female; D005472:Fluorouracil / Q000378:metabolism*; D006801:Humans; D007042:Hypoxanthines / Q000494:pharmacology; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000378:metabolism; D009962:Orotate Phosphoribosyltransferase / Q000378:metabolism; D009963:Orotic Acid / Q000378:metabolism; D010754:Phosphoribosyl Pyrophosphate / Q000378:metabolism; D012004:Rectal Neoplasms / Q000378:metabolism*; D012267:Ribosemonophosphates / Q000378:metabolism; D014183:Transplantation, Heterologous; D014543:Uridine Phosphorylase / Q000378:metabolism
D007042:Hypoxanthines; D012267:Ribosemonophosphates; C031154:ribose 1-phosphate; D009963:Orotic Acid; D000493:Allopurinol; D010754:Phosphoribosyl Pyrophosphate; D009962:Orotate Phosphoribosyltransferase; D014543:Uridine Phosphorylase; D005472:Fluorouracil