The ability of oestrogen to modulate the effects of cytotoxic drugs in human breast cancer cells: influence of oestrogen receptor status and choice of drug

We have previously demonstrated that pharmacological concentrations of 17j-oestradiol (E2) increase the cytotoxicity of methotrexate towards hormone responsive MCF-7 human breast cancer cells (Clarke et al., 1985), and this compares with the ability of E2 to potentiate the cytotoxic effects of cytosine arabinoside in these cells (Weichselbaum et al., 1978). However, E2 reduces both the antimetabolic and the antiproliferative effects of methotrexate towards E2-unresponsive MDA-MB-436 cells (Clarke et al., 1983). We have subsequently investigated the ability of M-E2 to modulate the effects of clinically achievable concentrations of vincristine (VCR), melphalan (MEL) and adriamycin (ADR) in both MCF-7 and MDA-MB-436 cells. MDA-MB-436 and MCF-7 cells were maintained as previously described (Clarke et al., 1983, 1985). Cells were seeded into 24 place multiwell dishes at lo4 cells per well and allowed to attach for 24 h. The growth medium was then replaced with medium containing M E ~ where relevant for a further 24 h. The cells were then exposed to the drug for 24h in the presence or absence of 10-6~-E2 for 24h. Cell number was estimated on removal of the drug (day 0) and 6 days later (day 6). Cell proliferation is expressed as cell number on day 6 as a percentage of cell number on day 0. In MCF-7 cells, E2 produces a variable stimulation of cell proliferation (Fig. la) (Page et al., 1983; Jakesz et al., 1984; Katzenellenbogen et al.. 1984) but does not influence proliferation of MDA-MB-436 cells (Fig. lb) (Clarke et al., 1983). The inhibitory effects of both VCR and MEL are consistently potentiated in MCF-7 cells (Fig. la) but not in MDA-MB-436 cells (Fig. 16). Thus, the potentiation of the effects of VCR and MEL in the hormone-responsive MCF-7 cells may be the result of the mitogenic potential of E2. However, perturbation of other biochemical pathways not currently identified cannot be precluded. Whilst the cytotoxic effects of ADR are increased in MCF-7 cells treated in medium containing lo-’ M-E2, epidermal growth factor, insulin and hydrocortisone (Hug et al., 1986), E2 alone fails to potentiate the cytotoxic effects of ADR (Fig. la). The additional mitogens in the medium described by Hug et al. may compensate for any reduction in ADR cytotoxicity induced by E2, for example, by inducing a greater perturbation in cell cycle kinetics. E2 reduces the fluidity of the cellular membranes of both MCF-7 and MDA-MB-436 cells (Clarke et al., 1987). Since ADR may act on the plasma membrane (Tritton & Yee, 1982; Salazar & Cohen, 1984) alterations in membrane fluidity may obscure any increased cytotoxicity resulting from the mitogenic effects of E2 in MCF-7 cells. The inability of E2 to influence ADR-induced cytotoxicity in MDA-MB-436 cells