Sequence specificity on the growth suppression and induction of apoptosis of chronic myeloid leukemia cells by BCR-ABL anti-sense oligodeoxynucleoside phosphorothioates.

Sequence specificity of inhibitory effects of various BCR-ABL anti-sense oligodeoxynucleoside phosphorothioates (AS PS-ODN) on the proliferation of the chronic myeloid-leukemia cell line BV173 was examined. We confirmed that 26, 18, and 16mer B2A2 AS PS-ODN had strong inhibitory effects on the proliferation of BV173 cells with B2A2 mRNA expression, and that B3A2 AS PS-ODN were equally inhibitory when cultures were initiated at lower cell concentrations. However, at higher cell concentrations, the inhibitory effects by B3A2 AS PS-ODN were reduced and B2A2 AS PS-ODNs could suppress the proliferation of BV173 cells with much more relative sequence specificity. The 26mer B2A2 AS PS-ODN induced apoptosis of BV173 cells following reduction of BCR-ABL mRNA expression and p210 protein synthesis. Various sense (S), reverse order, and random sequences had no inhibitory effects except 16mer B2A2 S and B3A2 S that revealed significant suppressive effects. Furthermore, 26mer B3A2 AS also reduced B2A2 mRNA expression and p210 protein synthesis, while 16mer S sequences did not. These results suggest that B2A2 AS may be cross-reactive with B3A2 AS on the growth suppression of CML cells under certain culture conditions, possibly due to their partial hybridization to the ABL portion of the target mRNA, although other non-sequence-specific mechanisms are also possible.