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[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
Author(s) -
Schlemmer Richard,
Spruß Thilo,
Bernhardt Günther,
Schönenberger Helmut
Publication year - 1999
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/(sici)1521-4184(19993)332:2<59::aid-ardp59>3.0.co;2-b
Subject(s) - diethylstilbestrol , ethylenediamine , mode of action , chemistry , hormone , mechanism of action , biological activity , stereochemistry , medicine , endocrinology , medicinal chemistry , in vitro , biology , biochemistry , organic chemistry
[meso‐1,2‐Bis(2,6‐dichloro‐4‐hydroxyphenyl)ethylenediamine]‐dichloroplatinum(II) (meso‐1‐PtCl 2 ), 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‐PtCl 2 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‐PtCl 2 (meso‐1), responsible for the hormonal effect of meso‐1‐PtCl 2 , and the cytotoxic drug cisplatin (cDDP) were used as comparative substances. Meso‐1‐PtCl 2 , 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‐PtCl 2 , 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 PtCl 2 moiety of meso‐1‐PtCl 2 to the anti‐breast cancer activity in vivo. On the ER + MXT‐M‐3.2 MC transplanted into ovariectomized mice meso‐1‐PtCl 2 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‐PtCl 2 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.