Biochemical characteristics of a 5-fluorouracil-resistant subline of P388 leukemia.
A 5-fluorouracil (5-FU)-resistant cell line of P388 mouse leukemia was established by intraperitoneal treatment with the drug. The activities of enzymes responsible for the formation of 5-fluoro-2'-deoxyuridine 5'-monophosphate and 5-fluorouridine 5'-monophosphate from 5-FU, the quantities of 5-FU metabolites, and the permeability to 5-FU were determined in both the 5-FU-sensitive and the resistant cell lines. It was found that the activities of uridine kinase and uracil phosphoribosyltransferase, the initial uptake of 5-FU, and the intracellular levels of 5-FU-nucleotides were all decreased in the resistant cells. However, the initial uptake of 5-FU into cells preincubated with KCN was the same in the sensitive and the resistant cells. These results support the view that the ineffectiveness of 5-FU against the resistant cell line of P388 leukemia can be attributed to decreases in the activities of enzymes responsible for the formation of 5-FU-nucleotides and probably also decreased transport of 5-FU in the resistant cells.
D000818:Animals; D001711:Biotransformation; D002460:Cell Line; D002463:Cell Membrane Permeability; D004351:Drug Resistance; D005472:Fluorouracil / Q000378:metabolism* / Q000494:pharmacology; D007941:Leukemia P388 / Q000188:drug therapy / Q000378:metabolism*; D007942:Leukemia, Experimental / Q000378:metabolism*; D008297:Male; D051379:Mice; D009962:Orotate Phosphoribosyltransferase / Q000378:metabolism; D010430:Pentosyltransferases / Q000378:metabolism; D013937:Thymidine Kinase / Q000378:metabolism; D014541:Uridine Kinase / Q000378:metabolism; D014543:Uridine Phosphorylase / Q000378:metabolism
D010430:Pentosyltransferases; D009962:Orotate Phosphoribosyltransferase; D014543:Uridine Phosphorylase; C035146:deoxyuridine phosphorylase; C023269:uracil phosphoribosyltransferase; D013937:Thymidine Kinase; D014541:Uridine Kinase; D005472:Fluorouracil