Aqua[meso-1, 2-bis(2, 6-difluoro-3-hydroxyphenyl)ethylenediamine]sulfatoplatinum(II) (meso-3-PtSO(4)) and its racemate (rac-3-PtSO(4)) are highly active on the hormone-sensitive MXT-M-3, 2 breast cancer of the mouse. In vitro, on the MXT(+) cell culture derived from this tumor, however, they are inactive (meso-3-PtSO(4)) or moderately active (rac-3-PtSO(4)) in concentrations corresponding to levels of these drugs in animal experiments. The in vivo effect is mainly caused by a reduction of the endogenous estrogen level in the host animals due to an interference with the ovarian steroid biosynthesis as demonstrated for meso-3-PtSO(4). Therefore, a reversal of the breast cancer inhibiting effect of meso-3-PtSO(4) can be achieved by simultaneous estrone administration. Histological results on ovaries, uterus, and tumor of meso-3-PtSO(4)-treated mice also favor such a mode of action. However, especially for rac-3-PtSO(4) cytotoxic effects contributing to the anti-breast cancer activity cannot be excluded. Considerations on the mode of action of Pt-complexes which inhibit breast cancer by interference with estrogen receptor mediated processes of growth control and with DNA replication are presented.

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The marked activity of [meso-1, 2-bis(2, 6-difluoro-3-hydroxyphenyl)ethylenediamine]platinum(II) (meso-3-PtLL', L, L' = Cl(2) or L = OH(2), L' = OSO(3)) on the hormone-sensitive MXT-M-3, 2 breast cancer implanted in mice is most probably due to a mechanism based on the reduction of the endogenous estrogen level. Cytotoxic effects which are poorly pronounced in experiments on several breast cancer cell lines (e.g. MCF-7), do not significantly contribute to the anti-breast cancer activity of this compound. In contrast to this, the standard cisplatin and the structurally related comparison compound [meso-1, 2-bis(4-fluorophenyl)ethylenediamine]platinum(II) (meso-4-PtLL', L, L' = Cl(2) or L = OH(2), L' = OSO(3)) are strongly active in vivo as well as in vitro. Both effects entail programmed cell death, which is responsible for the inhibition of the tumor growth. The minor cytotoxicity of meso-3-PtLL' in breast cancer cell cultures is caused neither by an inappropriate rate of reaction with bionucleophiles (e.g. by a too fast inactivation by plasma proteins) nor solely by the observed poor absorption by the tumor cells resulting in an insufficient drug concentration at the DNA. Additionally, an impeded reaction with biologically important, guanine-rich sequences of DNA (owing to the 2, 6-standing F atoms which hinder the drug-target inter action) must be assumed as cause of its marginal cytotoxicity.

The maximally attainable level of the non‐plasma protein bound fraction of a single 10.0 μmol/kg i.p. dose of [meso‐1,2‐bis(2,6‐di‐chloro‐4‐hydroxyphenyl)ethylenediamine]sulfatoplatinum(II), a drug active on the murine, hormone‐sensitive MXT‐M‐3.2 breast cancer, lies markedly below the concentration causing a significant cytotoxic effect on a cell line derived from this tumor. This result confirms our opinion that the strong in vivo activity of this drug on hormone‐sensitive breast cancers is mediated by its estrogenic potency by analogy with high dosed steroidal and non‐steroidal estrogens. A specific cytotoxic effect utilizing the estrogen receptor as carrier, as formerly postulated, is unlikely.

The establishment of two new breast cancer cell lines, MXT+ and MXT−, derived from the murine breast cancer models MXT‐M‐3, 2 MC (hormone‐sensitive) and MXT‐M‐3, 2 (ovex) MC (hormone‐insensitive), is described. Characterization of the cell lines was performed by investigation of morphology, steroid hormone receptor state, growth kinetics, and drug response as well as by cytogenetic analysis. MXT+ contains estrogen receptors (ER; 6.9 fmol/mg protein) as well as progesterone receptors (PgR; 9.2 fmol/mg protein) and therefore is inhibited by tamoxifen (Tam). MXT− proved to be ER− but PgR+ (23.4 fmol/mg protein) and, as expected, resistant against Tam.The sensitivity of MXT+ and MXT− against a pattern of therapeutically established anti‐breast cancer drugs (cDDP, cisplatin; JM‐8, carboplatin; DX, adriamycin; 5‐FU, 5‐fluorouracil; MTX, methotrexate; VLB vinblastine) was studied by use of a computerized, kinetic chemosensitivity assay based on quantification of biomass by staining cells with crystal violet. For each compound the inhibition profile reflecting cytostatic, transient cytotoxic, or cytocidal drug effects as well as development of resistance was evaluated. The following order of activity was found: MTX >, VLB ≥ DX > cDDP ≥ 5‐FU > JM‐8. The test data of 5‐FU, VLB, cDDP, and Tam on MXT+ as well as on MXT− were compared with those from studies on ER+ and ER− human breast cancer cell lines (MCF‐7, ZR‐75‐1, T‐47‐D, and MDA‐MB‐231, respectively). They revealed comparable inhibition profiles and sensitivities of human and murine breast cancer cell lines, an indication that the results achieved in combined in vitro‐/in vivo tests by use of the murine test models MXT+, MXT−, MXT‐M‐3, 2 MC, and MXT‐M‐3, 2(ovex) MC are relevant for therapy in humans.