INDUCTION OF RESISTANCE TO FLUORODEOXYURIDINE CYTOTOXICITY AND DNA-DAMAGE IN HUMAN TUMOR-CELLS BY EXPRESSION OF ESCHERICHIA-COLI DEOXYURIDINETRIPHOSPHATASE

Recent studies from our laboratory suggested that, in some human color ectal tumor cell lines, sensitivity to fluorodeoxyuridine may depend u pon the extent of dUTP accumulation that occurs following drug treatme nt and that elevation of dUTPase activity might be the basis for some instances of resistance to fluoropyrimidines. To test this model, we e xpressed Escherichia coli dUTPase in an established human tumor cell l ine (HT29) and measured the effect of this manipulation on response to fluorodeoxyuridine. As predicted, HT29 derivatives containing dUTPase activity 4-5-fold higher than controls were protected from fluorodeox yuridine-induced loss of clonogenicity and from formation of DNA doubl e strand breaks. These data provide the first direct evidence that alt eration in a component of the uracil misincorporation/misrepair pathwa y can confer resistance to fluoropyrimidines in human tumor cells.