Oestrogen receptor status and the response of human breast cancer cell lines to a combination of methotrexate and 17-β oestradiol

We have investigated the modifying influence of 17-β oestradiol (E2), on the cytotoxicity of methotrexate (MTX) towards two cell lines derived from human breast carcinoma. E2 (10^-7M -10^-6M) significantly reduced the antimetabolic effects of the drug towards an E2 non-responsive cell line, MDAMB- 436, whilst potentiating the action of MTX in an E2 responsive line, MCF-7. Similarly, E2 (10^-6 M) partially reversed the anti-proliferative effects of MTX in the MDA-MB-436 line and potentiated growth inhibition in the E2 responsive cells. This potentiation was not observed if E2 was replaced by the less biologically active α-isomer. In both cell lines pharmacological concentrations of the E2 reduced intracellular levels of MTX achieved during a 48h treatment period. The latter finding is consistent with the ability of E2 to protect MDA-MB-436 cells from the action of MTX. Potentiation of the effects of MTX towards MCF-7 cells occurs despite reduced intra-cellular drug levels.