RESISTANCE TO CYTOSINE-ARABINOSIDE IN CELLS TRANSFECTED WITH ACTIVATED HA-RAS ONCOGENE

The molecular basis for cancer cell resistance to 1-beta-D-arabinofura nosylcytosine (al a-C) is not well understood. Since aberrant expressi on and mutations of various ms oncogenes have been implicated in the p oor prognosis of human cancers and in several mechanisms of drug resis tance, 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 fibro blasts and human mammary HBL100 cells. We found that a) transfection o f cells by Ha-ras renders cells resistance to ara-C, b) resistance was not associated either with a decrease of intracellular ara-CTP format ion and retention or lack of incorporation of ara-C into DNA, c) resis tance was due to deoxycytidine kinase inactivity and decrease of mRNA expression of the gene, d) the degree of ara-C resistance correlated d irectly with the level of Ha-ras expression, e) an inverse correlation was found between ras expression and kinase expression, f) the increa sed expression of ras mRNA rather than I ns mutation influenced al a-C resistance. These findings suggest that c-Hn-l as levels may influenc e therapeutic success in some tumors and may regulate metabolic pathwa ys of drug such as al ara-C.