Dissociation of estrogenic and cytotoxic properties of an estrogen receptor-binding platinum complex in human breast cancer cell lines

Abstract

The Pt complex [meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]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 2 human mammary tumor cell lines, MCF-7 (ER+) and MDA-MB231 (ER-), were used and the effects of estradiol, tamoxifen, and cisplatin 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). The Pt complex was able to induce ER processing and increase the level of the progesterone receptor at concns. of 1-10 nM. Growth of MCF-7 cells was inhibited at concns. of meso-6-PtSO4 > 10 micro M. MDA-MB231 cells were inhibited likewise by the Pt complex, indicating a lack of selectivity for the ER+ cells. Meso-6-PtSO4 possesses both estrogen-like and cisplatin-like properties. Since growth inhibition did not correlated with ER-mediated processes, these 2 properties are expressed independently at the cellular level. The selective growth inhibitory effect of meso-6-PtSO4 in vivo is suggested to involve endocrinol. and/or immunol. factors.