Dissociation of Estrogenic and Cytotoxic Properties of an Estrogen Receptor-binding Platinum Complex in Human Breast Cancer Cell Lines¹

The Pt complex [meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl)-ethyienediamine]diaqua-Pt(II) sulfate (meso-6-PtSO₄) was designed with the concept of combining the cytotoxic cisplatin with an estrogen receptor (ER)-binding ligand for targeting to ER⁺ mammary tumor cells. This Pt complex selectively inhibits growth of ER⁺ mammary tumors in rodents. To study the cellular mechanisms of action, cultures of two human mammary tumor cell lines, MCF-7 (ER⁺) and MDA-MB₂₃₁ (ER^-), were used and the effects of estradiol, tamoxifen, and cis-Pt compared with those of meso-6-PtSO₄. The relative binding affinity of the meso-6-PtSO₄ to the ER in MCF-7 cells was 0.35 compared to estradiol (relative binding affinity, 100). Nevertheless, the Pt complex was able to induce ER processing and increase the level of the progesterone receptor at concentrations of 1–10 nm. Growth of MCF-7 cells was inhibited at concentrations of meso-6-PtSO₄ >10 µm. MDA-MB₂₃₁ cells were inhibited like-wise by the Pt complex, indicating a lack of selectivity for the ER⁺ cells.

The results show that meso-6-PtSO₄ possesses both estrogen-like and cis-Pt-like properties. Since growth inhibition did not correlate with ER-mediated processes, these two properties are expressed independently at the cellular level. The selective growth inhibitory effect of meso-6-PtSO₄ in vivo is suggested to involve endocrinological and/or immunological factors.