Collateral resistance of a dideoxycytidine-resistant cell line to 5-fluoro-2'-deoxyuridine.
Exposure of a human lymphocytic cell line, H9 cells, to 0.5 microM and 5.0 microM dideoxycytidine (ddC) resulted in isolation of ddC-resistant H9-ddC0.5w and H9-ddC5.0w cell lines. In addition, these cell lines were also resistant to azidothymidine and had reduced deoxycytidine kinase and thymidine kinase activities. We now show that these cell lines are 4-fold and 2000-fold collaterally resistant to 5-fluoro-2'-deoxyuridine (FdUR), respectively, but not to 5-fluorouracil (FU). Biochemical evaluations show that, compared to the parental cells, the FdUR phosphorylation was reduced to 36.3% and 9.2% and the FdUMP levels were decreased to 48.1% and 1.2% in these cell lines. Taken together, the data suggest that ddC, an antiviral agent, is capable of inducing resistance to FdUR-a drug that is not its analog and which has a different metabolism, target site, and mechanism of action.
Agarwal
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RP
Department of Medicine (M-862), University of Miami School of Medicine, Miami, Florida, 33101, USA. ragarwal@mednet.med.miami.edu
Han
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T
Fernandez
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M
D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005467:Floxuridine / Q000493:pharmacokinetics / Q000633:toxicity*; D006801:Humans; D007700:Kinetics; D010766:Phosphorylation; D013937:Thymidine Kinase / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016047:Zalcitabine / Q000633:toxicity*
D000964:Antimetabolites, Antineoplastic; D005467:Floxuridine; D016047:Zalcitabine; D013937:Thymidine Kinase