BCL-2 family protein expression and platinum drug resistance in ovarian carcinoma

The expression of the BCL-2 family proteins, BCL-2, BAX, BCLXL and BAK have been determined in a panel of 12 human ovarian carcinoma cell lines encomp assing a wide range in sensitivity to cisplatin. Whereas BAX, BCLXL and BAK levels did not correlate with sensitivity, there was a statistically signi ficant inverse correlation (r = -0.81; P = 0.002) between growth inhibition by cisplatin and BCL-2 levels. In sublines possessing acquired resistance to various platinum-based drugs or across a panel of human ovarian carcinom a xenografts, there was no consistent pattern of BCL-2 expression. Two rela tively sensitive lines (A2780 and CH1) have been stably transfected with bc l-2 and bcl(XL) respectively and two relatively resistant lines (A2780cisR and SKOV-3) stably transfected with bar. Overexpression of BCL-2 in A2780 c ells led to resistance to cisplatin compared to the vector control when ass ayed at 48 h post-drug incubation but a significant. increase in sensitivit y at 96 h. Relative rates of apoptosis at 48- and 96-h post-cisplatin expos ure mirrored the growth inhibition. There was no significant difference in sensitivity of the pair of lines by clonogenic assay. No significant change s in chemosensitivity to a variety of DMA-damaging or tubulin-interactive a gents were observed in the remaining transfected lines. Taken together, the se results suggest that, in human ovarian carcinoma cells, high BCL-2 level s (either naturally occurring or through gene transfection) confers: a tren d towards sensitivity not resistance to platinum drugs. (C) 2000 Cancer Res earch Campaign.