Resistance of human leukemic cell lines to 1-beta-D-arabinofuranosylcytosine: characterization of an experimental model

1-beta -D-arabinofuranosylcytosine (ara-C) is an antimetabolite used for th e treatment of acute myelogenous leukemia. The ability of ara-C to kill neo plastic cells has been correlated to the induction of apoptosis. The clinic al use of ara-C is limited by the development of drug resistance. Alteratio ns in drug-induced apoptosis play a critical role in ara-C resistance. In p articular, the proto-oncogene bcl-2 has been implicated in this phenomenon. To better understand the molecular basis of the role of bcl-2 in ara-C res istance, we investigated the relationship between the cytotoxic effect of a ra-C, the expression levels and the subcellular localization of bcl-2 in th ree human leukemic cell lines (HL-60, KG1, J111). We have also evaluated th e effects of ara-C on the J111 leukemic cell line (showing the lowest level s of Bcl-2 and the highest sensitivity to ara-C) overexpressing the bcl-2 o ncogene. The model we developed here will allow further studies on the role of post-translational events involving bcl-2 (such as translocation and/or phosphorylation) in the cellular response to ara-C treatment.