Synergistic effect of paclitaxel and 4-hydroxytamoxifen on estrogen receptor-negative colon cancer and lung cancer cell lines

Antiestrogen tamoxifen (Tam) is the most prescribed drug for the treatment of estrogen receptor (ER)-positive breast cancers. It is also used in long- term clinical trials with encouraging preliminary results as a chemoprevent ive agent far breast cancer. The effect of Tam an ER-negative cancers, howe ver, is unclear. Here we reported that paclitaxel and 4-hydroxytamoxifen (4 -HT) have a synergistic cytotoxic effect on the ER-negative colon cancer ce ll line HCT15, which is refractory to paclitaxel atone. Our results showed that 4-HT at submicromolar concentrations effectively enhanced the antiprol iferative effect of paclitaxel. In addition, at 1/10 of the paclitaxel conc entrations used for HCT15, 4-HT and paclitaxel also showed synergistic effe ct on NCI H460, an ER-negative lung cancer cell line. For both cell lines, the effective concentration for paclitaxel to inhibit cell growth was 1 log lower in the combination treatment than the concentration used in the sing le treatment. Cell cycle analysis showed that the combination of paclitaxel and 4-HT increased the G(2)/M population and resulted in the increase of a poptosis in both cell lines. Enhanced early release of cytochrome c from mi tochondria may be the apoptotic pathway activated in the combination treatm ent in HCT15 cells. [(C) 1999 Lippincott Williams & Wilkins.].