title: [meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl) ethylenediamine]dichloroplatinum(II), a compound with a specific activity on hormone-sensitive breast cancers--evidence for a diethylstilbestrol-like mode of action.
abstract: [meso-1,2-Bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]- dichloroplatinum(II) (meso-1-PtCl2), an estrogenic and cytotoxic platinum complex, shows activity against ER+ but not against ER- breast cancers in vivo (ER: estrogen receptor; ER+ and ER- indicate the presence or absence of the ER). To clarify whether its estrogenic or its cytotoxic potency or both properties are the cause of this specific inhibitory effect, we tested meso-1-PtCl2 comparatively in vivo on an ER+ and an ER- murine breast cancer (MXT-M-3.2 MC and MXT-M-3.2(ovex) MC, respectively), and in vitro on two cell lines derived from the former in vivo models (MXT+ and MXT-, respectively). The estrogens diethylstilbestrol (DES) and the ligand of meso-1-PtCl2 (meso-1), responsible for the hormonal effect of meso-1-PtCl2, and the cytotoxic drug cisplatin (cDDP) were used as comparative substances. Meso-1-PtCl2. DES and cDDP showed a strong and comparable activity on the ER+ MXT-M-3.2 MC in vivo, meso-1 being somewhat less inhibitory. In experiments on the murine, ER- MXT-M-3.2(ovex) MC only cDDP caused a marked inhibitory effect. The other compounds were inactive or only marginally active. In accordance with the in vivo results cDDP was also very active on the MXT+ and MXT- breast cancer cell line. In contrast to this meso-1-PtCl2, meso-1, and DES proved to be only weakly active or inactive on both cell lines. From these results it can be concluded that there is only little if any contribution of the cytotoxic PtCl2 moiety of meso-1-PtCl2 to the anti-breast cancer activity in vivo. On the ER+ MXT-M-3.2 MC transplanted into ovariectomized mice meso-1-PtCl2 yielded a biphasic dose activity curve, i.e. an increase of the tumor growth at low doses followed by a decrease at high doses, identical with those of the estrogens DES and meso-1. These results indicate that meso-1-PtCl2 inhibits ER+ breast cancers by its estrogenicity in the same manner as meso-1 and DES. The complex mechanism of anti-breast cancer active estrogens involves presumably the endocrine and/or the immune system. Its investigation is the subject of further studies.
authors: Lehrstuhl für Pharmazeutische Chemie II, Institut für Pharmazie, Universität Regensburg, Germany.
authors: R
authors: R
authors: Schlemmer
authors: T
authors: T
authors: Spruss
authors: G
authors: G
authors: Bernhardt
authors: H
authors: H
authors: Schönenberger
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D004054:Diethylstilbestrol / Q000494:pharmacology; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000648:ultrastructure; D051379:Mice; D008815:Mice, Inbred Strains; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000648:ultrastructure; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D010052:Ovariectomy; D011960:Receptors, Estrogen / Q000502:physiology
chemical_list: D018931:Antineoplastic Agents, Hormonal; D009944:Organoplatinum Compounds; D011960:Receptors, Estrogen; D004054:Diethylstilbestrol; C042922:dichloro(1,2-bis(4-hydroxyphenyl)ethylenediamine)platinum II