[meso-1,2-Bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]sulfato-platinum(II) — Pharmacokinetic Studies

Bernhardt, Günther; Koch, Marion; Spruß, Thilo; Gust, Ronald; Krauser, Rudolf; Schlemmer, Richard; Hollstein, Michael; Lux, F.; Schönenberger, Helmut

doi:10.1002/(sici)1521-4184(19996)332:6<195::aid-ardp195>3.3.co;2-8

Cited by 6 publications

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“…In recent publications (Schlemmer et al 1999a;Bernhardt et al 1999) we have shown that the ER-anic [meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]platinum(II) complexes, meso-1-PtLL¢; L,L¢ Cl 2 and H 2 O, SO 4 caused strong activity on hormonesensitive (i.e., ER + ), rodent breast cancers, mainly due to their estrogenic side eects. An ER-mediated drug accumulation in the nucleus of the tumor cell followed by an increased formation of DNA-intrastrand crosslinks is unlikely as cause of action (mechanism A).…”

Section: Introductionmentioning

confidence: 69%

“…An ER-mediated drug accumulation in the nucleus of the tumor cell followed by an increased formation of DNA-intrastrand crosslinks is unlikely as cause of action (mechanism A). Such an interference in the metabolism of the tumor cell was formerly postulated by us for meso-1-PtLL¢ (Schlemmer et al 1999a;Bernhardt et al 1999;Karl et al 1988). …”

Section: Introductionmentioning

confidence: 72%

“…In contrast to cDDP, meso-1-PtLL¢, even in the very high 10 lM concentration, at best causes marginal inhibitory eects on breast cancer cells (Schlemmer et al 1999a). We assume that in vivo an interference with the DNA function of the tumor cell contributes nothing or only little to the strong activity of meso-1-PtLL¢ on hormone-sensitive, rodent breast cancers, since we could not achieve such a high level of this drug in mice in pharmacokinetic experiments (Bernhardt et al 1999). To ®nd out whether a cDDP-like mode of action can also be excluded in the case of aqua[1-(2,6-dichloro-4hydroxyphenyl)-2-phenylethylenediamine]sulfatoplatinum(II) complexes, we tested these compounds on the hormone-insensitive, human MDA-MB-231 breast cancer cell line (Table 2).…”

Section: Discussionmentioning

confidence: 99%

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[Aqua-1-(2,6-dichloro-4-hydroxyphenyl)-2-phenylethylenediamine] sulfatoplatinum(II) complexes with variable substituents in the 2-phenyl ring

Gust¹,

Faderl²,

Schönenberger³

2000

Journal of Cancer Research and Clinical Oncology

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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.

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Section: Introductionmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

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[Aqua-1-(2,6-dichloro-4-hydroxyphenyl)-2-phenylethylenediamine] sulfatoplatinum(II) complexes with variable substituents in the 2-phenyl ring

Gust¹,

Faderl²,

Schönenberger³

2000

Journal of Cancer Research and Clinical Oncology

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“…The corrected cell number of a leukocyte subpopulation was calculated according to the equation --- 2) Up to now experiments on breast cancer bearing animals to detect a TAM number reducing potency of phytoestrogens have not been performed. 3) In preceding publications of this series [8,9] we have shown that the anti-breast cancer activity of meso-1-PtCl2 is caused by its estrogenic potency and that a cDDP-like mode of action does not substantially contribute to the inhibition of the tumor. Studies with 1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethane, the hormonally active pharmacophor of meso-1-PtCl2, which, despite the absence of the cytotoxic PtCl2-group, also inhibits the growth of the murine MXT-M-3,2 breast cancer, confirm the discussed mode of action [15,16] .…”

Section: Experimental Schedulementioning

confidence: 99%

“…Like steroidal and non-steroidal estrogens [7][8][9] or selective estrogen receptor modulators (SERMs) [10,11] , phytoestrogens are thought to be also useful as drugs in the therapy and prevention of breast cancer [12][13][14] .…”

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confidence: 99%

Does [meso-1,2-bis(2,6-dichloro-4-hydroxy-phenyl) ethylenediamine]dichloroplatinum(II) act as an immune response modifier? IV. Inhibition of the proliferation-increasing effect of progressively growing MXT-M-3,2 breast cancer on phagocytes by the title compound

Schlemmer

Spruß

Bernhardt

et al. 2001

Arch. Pharm. Pharm. Med. Chem.

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In female B6D2F1 mice bearing an MXT‐M‐3,2 breast cancer graft the level of the phagocytic cells (e.g. of granulocytes and macrophages in the spleen and of granulocytes and monocytes in the blood) is significantly elevated. The positive correlation between the number of the phagocytic cells and the weight of the tumor indicates that the MXT‐M‐3,2 breast cancer promotes myelopoiesis, presumably by secretion of hematopoietic growth factors like GM‐CSF. This process can be described for each phagocyte type by a regression equation. Due to its hormonal potency [meso‐1,2‐bis(2,6‐dichloro‐ 4‐hydroxyphenyl)ethylenediamine]dichloroplatinum(II) (meso‐1‐PtCl2) can reduce the excessive numbers of the granulocytes and macrophages, which seem to be responsible for the progressive growth of the MXT‐M‐3,2 breast cancer. This process leads to an interruption of the vicious circle of mutual growth stimulation of breast cancer cells and these phagocytes. The target of meso‐1‐PtCl2 is the estrogen receptor (ER) of the breast cancer cell. The interaction between meso‐1‐PtCl2 and the ER presumably results in a diminished secretion of hematopoietic growth factors and hence in a decline of the number of phagocytic cells. Meso‐1‐PtCl2 does not inhibit the proliferation of tumor cells by direct interaction with their DNA, as is described for platinum complexes like cDDP. In its mode of action the equipotent, breast cancer inhibiting drug cDDP differs from meso‐1‐PtCl2. This is obvious from the fact that in cDDP‐ but not in meso‐1‐PtCl2‐treated, tumor bearing mice the number of granulocytes and macrophages does not markedly deviate from that in untreated control mice with tumors of the same weight. The drug cDDP probably does not interfere with the mechanism of the secretion of hematopoietic growth factors. The reduction of the number of tumor cells by cDDP leads to a decline of the number of phagocytic cells in accordance with the respective regression equations. In contrast to meso‐1‐PtCl2 and cDDP, ovariectomy causes elevated phagocyte numbers, probably due to the strongly reduced estrogen level. The studies described in this publication indicate that the anti‐breast cancer activity of meso‐1‐PtCl2 is caused by a decimation of phagocytes and with this by an abolition of the tumor promoting effect. Furthermore, a restoration of the natural immunosurveillance seems to be of importance.

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1-(2,6-Dichloro-4-hydroxyphenyl)-2-phenylethanes — New Biological Response Modifiers for the Therapy of Breast Cancer. Synthesis and Evaluation of Estrogenic/Antiestrogenic Properties

Schertl

Hartmann

Batzl‐Hartmann

et al. 2001

Arch. Pharm. Pharm. Med. Chem.

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[meso-1,2-Bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]sulfato-platinum(II) — Pharmacokinetic Studies

Cited by 6 publications

References 0 publications

[Aqua-1-(2,6-dichloro-4-hydroxyphenyl)-2-phenylethylenediamine] sulfatoplatinum(II) complexes with variable substituents in the 2-phenyl ring

[Aqua-1-(2,6-dichloro-4-hydroxyphenyl)-2-phenylethylenediamine] sulfatoplatinum(II) complexes with variable substituents in the 2-phenyl ring

Does [meso-1,2-bis(2,6-dichloro-4-hydroxy-phenyl) ethylenediamine]dichloroplatinum(II) act as an immune response modifier? IV. Inhibition of the proliferation-increasing effect of progressively growing MXT-M-3,2 breast cancer on phagocytes by the title compound

1-(2,6-Dichloro-4-hydroxyphenyl)-2-phenylethanes — New Biological Response Modifiers for the Therapy of Breast Cancer. Synthesis and Evaluation of Estrogenic/Antiestrogenic Properties

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