Resistance to cytosine arabinoside in cells transfected with activated Ha-ras oncogene.

The molecular basis for cancer cell resistance to 1-beta-D-arabinofuranosylcytosine (ara-C) is not well understood. Since aberrant expression and mutations of various ras oncogenes have been implicated in the poor prognosis of human cancers and in several mechanisms of drug resistance, we tested this hypothesis by determining the effect of varying level of c-Ha-ras expression and the presence of ras gene mutation on resistance to 1-beta-D-arabinofuranosylcytosine in rodent Rat-1a fibroblasts and human mammary HBL100 cells. We found that a) transfection of cells by Ha-ras renders cells resistance to ara-C, b) resistance was not associated either with a decrease of intracellular ara-CTP formation and retention or lack of incorporation of ara-C into DNA, c) resistance was due to deoxycytidine kinase inactivity and decrease of mRNA expression of the gene, d) the degree of ara-C resistance correlated directly with the level of Ha-ras expression, e) an inverse correlation was found between ras expression and kinase expression, f) the increased expression of ras mRNA rather than ras mutation influenced ara-C resistance. These findings suggest that c-Ha-ras levels may influence therapeutic success in some tumors and may regulate metabolic pathways of drug such as ara-C.