DOES THE BCR/ABL-MEDIATED INCREASE IN THE EFFICACY OF DNA REPAIR PLAY A ROLE IN THE DRUG RESISTANCE OF CANCER CELLS?

BCR/ABL oncogenic tyrosine kinase is responsible for the pathogenesis of Philadelphia chromosome-positive human leukemia and is generated by a specific reciprocal chromosome translocation, t(9;22)(q34-;q11+). We examined the role of DNA repair in therapeutic drug resistance to idarubicin in the murine pro-B lymphoid cell line BaF3 and its BCR/ABL-transformed clone. These cells can be used as models of human leukemias. The MTT assay revealed that BCR/ABL-transformed cells displayed resistance to idarubicin in the range 0.3-0.5μM, compared with the control BaF3 cells. Idarubicin at 0.3 and 1μM induced DNA damage in the form of strand-breaks and/or alkali labile sites in both transformed and control cells in comet assays. The BCR/ABL-transformed cells needed only 60 min to remove damage to their DNA, whereas controls took 120 min. We hypothesize that this observed increase in the efficacy of repair in BCR/ABL-positive cells is involved in their resistance to idarubicin.