Mechanisms of resistance to fluoropyrimidines.
The fluoropyrimidines fluorouracil (5-FU) and 5-fluoro-2'-deoxyuridine (FdUrd) have shown activity in a variety of malignancies. Nevertheless, even in initially responsive tumors, the development of resistance is a frequent problem. To understand the biochemical basis for acquired resistance, two pairs of cell lines were investigated. MCF7/Adr cells were obtained from the breast cancer cell line MCF7 by incubation with increasing concentrations of Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH). These cells are resistant to Adriamycin (200- to 600-fold) and cross-resistant to 5-FU (25-fold) and FdUrd (67-fold). The resistant cells showed significantly increased levels of thymidylate synthase, the target enzyme of the fluoropyrimidines' active metabolite, 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP). Other biochemical characteristics, including folate pools, drug uptake, metabolism, and retention, were unchanged. Fd9XR cells have been selected from a human colon cancer cell line (HCT-8) by exposure to FdUrd. These cells are resistant to FdUrd (1,000-fold) but not 5-FU. Biochemical evaluations show that the resistant cells are deficient of thymidine kinase and are thus unable to convert FdUrd to FdUMP. This understanding of the various biochemical mechanisms is essential for the design of specific modulations to overcome resistance to fluoropyrimidines.
Zhang
Z G
ZG
Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, NY 14263.
Harstrick
A
A
Rustum
Y M
YM
D002430:Cecal Neoplasms / Q000378:metabolism; D003856:Deoxyuracil Nucleotides / Q000378:metabolism; D004351:Drug Resistance; D005467:Floxuridine / Q000378:metabolism*; D005468:Fluorodeoxyuridylate / Q000378:metabolism; D005472:Fluorouracil / Q000378:metabolism*; D006801:Humans; D007078:Ileal Neoplasms / Q000378:metabolism; D002955:Leucovorin / Q000494:pharmacology*; D013763:Tetrahydrofolates / Q000378:metabolism; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014407:Tumor Cells, Cultured
D003856:Deoxyuracil Nucleotides; D013763:Tetrahydrofolates; D005467:Floxuridine; C013123:5,10-methylenetetrahydrofolic acid; C027078:deoxyuridine triphosphate; D005468:Fluorodeoxyuridylate; D013940:Thymidylate Synthase; D002955:Leucovorin; D005472:Fluorouracil