Effect of tamoxifen and 2-methoxyestradiol alone and in combination on human breast cancer cell proliferation

Endocrine therapy is widely accepted for the treatment of hormone receptor-positive breast cancer. However, in many cases eventually resistance will develop and tumor regrows. Combination therapy may be one way to resolve this problem. In the present study we investigated the effect of a combination of the widely used antiestrogen tamoxifen with the endogenous estradiol metabolite 2-methoxyestradiol (2-ME) on the proliferation of human estrogen receptor-positive and receptor-negative breast cancer cells. The receptor-positive cell line MCF-7 and the receptor-negative cell line BM were treated with 4-hydroxytamoxifen (4-OHTam) and 2-methoxyestradiol in the concentration range of 0.8-25 muM alone and equimolar combinations for 4 days. The proliferation of the cells was determined using the ATP-chemosensitivity test. 4-Hydroxytamoxifen inhibited proliferation of MCF-7 and BM cells with IC50 values of 31 and 10 muM, the corresponding figures for 2-methoxyestradiol were 52 and 8 muM. The combination showed IC50 values of 6 muM and 4 muM. These results indicate that a combination of tamoxifen with 2-methoxyestradiol showed an additive inhibitory effect concerning the proliferation of estrogen receptor-positive and receptor-negative breast cancer cell lines. Thus a combination of these substances may allow ameliorating of adverse events of tamoxifen by reducing its concentrations and probably also drug resistance and should be tested in clinical trials. (C) 2003 Elsevier Science Ltd. All rights reserved.