In the search for new anti-breast cancer compounds a series of diastereomeric aqua[1-(2,6-dichloro-4-hydroxyphenyl)-2-phenylethylenediamine]sulfato platinum(II) complexes was tested on the hormone-sensitive MXT-M-3.2 breast cancer of the mouse. By simultaneous determination of tumor and uterine weights at the end of the experiment we obtained an insight into the mode of action. Changes in the uterine weights indicate whether the anti-breast cancer effect of the test substance is caused either by its capability to reduce the endogenous estrogen level via inhibition of estrogen biosynthesis (mechanism B), or by its estrogenic side effects which enhance the immune defense in the host animals (mechanism C). Studies on the [3H]thymidine incorporation into DNA of MDAMB-231 breast cancer cells showed that all test compounds inhibit deoxyribonucleic acid synthesis, like cisplatin (mechanism A). However, in comparison to the standard cisplatin, their activities were low. The three most effective test compounds threo-2-PtSO4 (2-phenyl-residue), threo-5-PtSO4 (2-(4-hydroxyphenyl)-residue), and threo-8-PtSO4 (2-(2-fluoro-4-hydroxyphenyl)-residue) seem to exert their anti-breast cancer effect by mechanism B. Moreover, threo-5-PtSO4 was moderately active on the hormone- insensitive MXT-M-3.2 (Ovex) breast cancer of the mouse. Aqua[erythro-1-(2,6-dichloro-4-hydroxyphenyl)-2-(2-chloro-4-hydroxypheny l) ethylenediamine]sulfato-platinum(II) (erythro-9-PtSO4) was the only breast cancer inhibiting compound of the series acting mainly according to mechanism C. A minor contribution of mechanism A, impairment of the DNA function in the tumor cell, to the anti-breast cancer activity of these aqua[1-(2,6-dichloro-4-hydroxyphenyl)-2-phenylethylenediamine]sulfato platinum(II) complexes cannot be excluded, since such effects are apparent in the MDA-MB-231 as well as in the MCF-7 breast cancer cell line at higher drug concentrations. In this test series which was performed with the crystal violet chemosensitivity assay, the MCF-7 cells proved to be somewhat more sensitive.

[1,2-Bis(4-methoxy/4-hydroxyphenyl)ethylenediamine]dichloroplatinum-(II) complexes with Cl-, CH3-, or OCH3-substituents in the ortho-positions of the aromatic rings (meso-1-PtCl2, D,L-1-PtCl2, meso-2-PtCl2, D,L-2-PtCl2, meso-3-PtCl2, meso-4-PtCl2, meso-5-PtCl2) were tested on the MDA-MB 231 breast cancer cell line, the lymphocytic leukemia P388, and the estrogen receptor-positive and -negative MXT mammary carcinoma of the mouse (MXT,ER(+)-MC, MXT,ER(-)-MC). The comparison of the effects of methoxy-substituted complexes (meso-1-PtCl2, D,L-1-PtCl2, meso-3-PtCl2) with those of the respective hydroxy-substituted ones (meso-2-PtCl2, D,L-2-PtCl2, meso-4-PtCl2) shows that a reduction of estrogenic effects as well as a total loss of the mammary tumor-inhibiting activity takes place on methylation of the 4-OH group. The exchange of the 2,6-standing chlorine atoms by methyl groups in meso-2-PtCl2 led to the non-estrogenic, but on the MXT,ER(+)-MC highly effective derivative meso-4-PtCl2 which proved to be also cytotoxic on ER(-)-tumors such as MXT,ER(-)-MC, and the P388 leukemia.