A comparison of 5-fluorouracil metabolism in human colorectal cancer and colon mucosa.
The metabolism of 5-fluorouracil (5-FU) was studied in biopsy specimens of primary colorectal cancer and healthy colonic mucosa obtained from previously untreated patients immediately after surgical removal. The conversion of 5-FU to anabolites was measured under saturating substrate (5-FU) and cosubstrate concentrations. For all enzymes, the activity was about threefold higher in tumor tissue compared with healthy mucosa of the same patient. The activity of pyrimidine nucleoside phosphorylase with deoxyribose-1-phosphate (dRib-1-P) was about tenfold higher (about 130 and 1200 nmol/hr/mg protein in tumors) than with ribose-1-phosphate (Rib-1-P), both in tumor and mucosa. Synthesis of the active nucleotides (5-fluoro-uridine-5'-monophosphate [FUMP] and 5-fluoro-2'-deoxyuridine-5'-monophosphate [FdUMP]) was studied by adding physiologic concentrations of adenosine triphosphate (ATP) to the reaction mixture; the rate of FdUMP synthesis was 50% of that of FUMP (about 4 and 7 nmol/hr/mg protein in tumors). Direct synthesis of FUMP from 5-FU in the presence of 5-phosphoribosyl-1-pyrophosphate (PRPP) was about 2 nmol/hr/mg protein. With the natural substrate for this reaction, orotic acid, the activity was about 14-fold higher. To obtain insight into the recruitment of precursors for these cosubstrates, the authors also tested the enzyme activity of pyrimidine nucleoside phosphorylase with inosine and ribose-5-phosphate (Rib-5-P, as precursors for Rib-1-P) and deoxyinosine (as a precursor for dRib-1-P); enzyme activities were approximately 7%, 7%, and 3%, respectively, of that with the normal substrates, both in tumors and mucosa. However, when ATP and Rib-5-P were combined, the synthesis of FUMP was about 70% of that with PRPP, but only in tumors. In normal tissues no activity was detectable. These data suggest a preference of colon tumor over colon mucosa for the conversion of 5-FU to active nucleotides by a direct pathway; a selective antitumor effect of 5-FU may be related to this difference.
Peters
G J
GJ
Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
van Groeningen
C J
CJ
Laurensse
E J
EJ
Pinedo
H M
HM
D000255:Adenosine Triphosphate / Q000032:analysis; D000368:Aged; D000369:Aged, 80 and over; D003106:Colon / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000378:metabolism*; D005468:Fluorodeoxyuridylate / Q000378:metabolism; D005472:Fluorouracil / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D008875:Middle Aged; D009962:Orotate Phosphoribosyltransferase / Q000378:metabolism; D010430:Pentosyltransferases / Q000032:analysis; D010754:Phosphoribosyl Pyrophosphate / Q000032:analysis; D057845:Pyrimidine Phosphorylases; D012004:Rectal Neoplasms / Q000378:metabolism*; D012267:Ribosemonophosphates / Q000032:analysis; D014500:Uracil Nucleotides / Q000378:metabolism; D014544:Uridine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism
D012267:Ribosemonophosphates; D014500:Uracil Nucleotides; D005468:Fluorodeoxyuridylate; C031154:ribose 1-phosphate; C031302:2-deoxyribose 1-phosphate; C025635:5-fluorouridine 5'-triphosphate; D010754:Phosphoribosyl Pyrophosphate; D000255:Adenosine Triphosphate; C016462:5-fluorouridine 5'-phosphate; D010430:Pentosyltransferases; D057845:Pyrimidine Phosphorylases; D009962:Orotate Phosphoribosyltransferase; D005472:Fluorouracil; D014544:Uridine Triphosphate