EFFECT OF BCL-2 ON IONIZING-RADIATION AND 1-BETA-D-ARABINOFURANOSYLCYTOSINE-INDUCED INTERNUCLEOSOMAL DNA FRAGMENTATION AND CELL-SURVIVAL INHUMAN MYELOID-LEUKEMIA CELLS

1-beta-D-Arabinofuranosylcytosine (ara-C) is an anti-leukemic agent th at incorporates into cellular DNA leading to inhibition of DNA synthes is and loss of clonogenic survival. In contrast, ionizing radiation in duces DNA damage through the generation of reactive oxygen intermediat es. Although little is known of the specific determinants of ara-C and ionizing radiation-induced cytotoxicity, recent work has shown that b oth are capable of inducing internucleosomal DNA fragmentation in a pa ttern consistent with programmed cell death (apoptosis). In order to a ssess the importance of apoptosis in drug and ionizing radiation-induc ed cytotoxicity in the U-937 myelomonocytic cell line, we created cell lines that constitutively express a transfected bc1-2 gene. Bc1-2 was capable of inhibiting 40-50% of the ara-C and ionizing radiation-indu ced internucleosomal DNA fragmentation at all tested concentrations. H owever, cell survival following exposure to these agents was only incr eased in the bc1-2 transfectants at relatively low doses of ara-C and ionizing radiation. These data demonstrate that although bc1-2 is capa ble of inhibiting ara-C and ionizing radiation-induced DNA fragmentati on in myeloid cells, it increases cell survival only at low doses of t hese agents. This suggests that apoptosis may be a less important mech anism of cytotoxicity at higher doses of ara-C and ionizing radiation than it is at lower doses.