Mechanisms for 5-fluorouracil resistance in human colon cancer DLD-1 cells.
A 5-fluorouracil (5-FU)-resistant subline, DLD-1/5-FU, was established by repeated 5-d exposures of human colon cancer DLD-1 cells to 5-FU. DLD-1/5-FU cells were 41- and more than 75-fold resistant to 96-h and 1-h exposures to 5-FU, respectively. When exposed to 5-FU, DLD-1/5-FU cells exhibited marked resistance to in situ thymidylate synthase (TS) inhibition by 5-FU as compared to DLD-1 cells, and incorporation of 5-FU into cellular RNA in DLD-1/5-FU cells decreased to 25% of that in DLD-1 cells. As causes of resistance to DNA and RNA-directed actions of 5-FU, remarkable reduction of intracellular levels of both 5-fluorouridine 5'-triphosphate (FUTP) and 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) in DLD-1/5-FU cells was confirmed. It was found that activities of uridine kinase, orotate phosphoribosyltransferase and thymidine kinase of DLD-1/5-FU cells were significantly lower than those of the parent cells. Intracellular levels of TS were similar between the two cell lines. These results indicated that the mechanism of resistance to 5-FU in DLD-1/5-FU cells involves reduced enzymatic activation of 5-FU.
Inaba
M
M
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Naoe
Y
Y
Mitsuhashi
J
J
D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D002452:Cell Count / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D005467:Floxuridine / Q000494:pharmacology; D005472:Fluorouracil / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D010754:Phosphoribosyl Pyrophosphate / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014529:Uridine / Q000031:analogs & derivatives / Q000494:pharmacology
D000964:Antimetabolites, Antineoplastic; D012334:RNA, Neoplasm; D005467:Floxuridine; C001943:5-fluorouridine; D010754:Phosphoribosyl Pyrophosphate; D013940:Thymidylate Synthase; D005472:Fluorouracil; D014529:Uridine