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 mu M and 5.0 mu M dideoxycytidine (ddC) resulted in isolation of ddC-resistant H9-ddC0.5w and H9-ddC5.0w cell lines. In addition, these cell lines were also resistan t to azidothymidine and had reduced deoxycytidine kinase and thymidine kina se activities, We now show that these cell lines are 4-fold and 2000-fold c ollaterally 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. (C) 1999 Acad emic Press.