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[meso-1,2-Bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]-dichloroplatinum(II), a new drug not only parenterally but also orally active in the therapy of breast and prostate cancer

  • Original Papers
  • Experimental Oncology
  • Published:
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Abstract

The platinum complex [meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl)-ethylenediamine]dichloroplatinum(II), K, was tested for its antitumor activity on hormonesensitive tumor models under peroral administration. The resorption from the gastrointestinal tract was proved by determining the estrogenic effect of K in a dose/activity study using the immature-mouse uterine weight test. In comparison to the subcutaneous injection, a tenfold peroral dose was administered to achieve identical effects. By peroral treatment of the hormone-sensitive MXT(M3.2) mammary carcinoma of the mouse with K an almost complete inhibition of the tumor growth was obtained. This effect was superior to that of subcutaneously applied cisplatin and significantly better than that obtained by perorally administered ligand L at an equimolar dose, indicating that the antitumor effect is caused by the intact complex K and not by the liberated ligand L. The strong antitumor activity of perorally applied K was also demonstrated on the hormone-sensitive Noble Nb-R prostatic carcinoma of the rat. Histological examinations showed that the platinum complex K did not cause cisplatin-like kidney damage or irritations of gastric or intestinal mucosa when given perorally.

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Abbreviations

DMBA:

dimethylbenz[a]anthracene

ER:

estrogen receptor

K:

complex

[meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl:

(ethylenediamine]dichloroplatinum(II)

L:

ligand:meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine

LM:

1∶1 mixture (v/v) of polyethyleneglycol 400 and 1.8% NaCl

PEG:

polyethylene glycol

References

  • Bednarski PJ, Trümbach B, Kratochwil NA, Schönenberger H (1992) Diamine ligand release from the cisplatin analogue [meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl)-ethylenediamine]dichloroplatinum(II) in cell culture medium. J Med Chem 35:4479–4485

    PubMed  Google Scholar 

  • Bernges F, Holler E (1991) The reaction of pllatinum(II) complexes with DNA. Kinetics of intrastrand crosslink formation in vitro. Nucleic Acids Res 19:1483–1489

    PubMed  Google Scholar 

  • Bernges F, Holler E (1992) Ring-substituted diaqua(1,2-diphenylethylenediamine)platinum(II) sulfate reacts with DNA through a dissociable complex. Eur J Biochem 208:573–579

    PubMed  Google Scholar 

  • De Vita VT Jr, Hellman S, Rosenberg SA (1989) Cancer principles and practice of oncology, 3rd edn. Lippincott Philadelphia, p 1050

    Google Scholar 

  • Drago JR, Goldman LB, Gershwin ME (1980a) Chemotherapeutic and hormonal considerations of the Nb rat prostatic adenocarcinoma model. Prog Clin Biol Res 37:325–363

    PubMed  Google Scholar 

  • Drago JR, Goldman LB, Maurer RE (1980b) The Nb rat prostatic adenocarcinoma model system. Prog Clin Biol Res 37:265–291

    PubMed  Google Scholar 

  • Gust R, Schönenberger H, Klement U, Range KJ (1993) Aqua[1-(2,6-dichloro-4-hydroxyphenyl)-2-phenylethylenediamine]sulfatoplatinum(II) complexes with variable substituents in the 2-phenyl ring. Part II. Correlation of molecular structure and estrogenic activity of breast and prostate cancer inhibiting [erythro-1-(2,6-dichloro-4-hydroxyphenyl)-2-(2-halo-4-hydroxyphenyl)ethylenediamine]platinum(II) complexes. Arch Pharm (Weinheim) (in press)

  • Hacker MP (1991) Toxicity of platinum-based anticancer drugs. In: Powis, G, Hacker MP (eds) The toxicity of anticancer drugs. Pergamon, New York, pp 82–105

    Google Scholar 

  • Haddow AL, Watkinson JM, Patterson E, Koller E (1944) Influence of synthetic oestrogens upon advanced malignant disease. Br Med J 2:393–398

    Google Scholar 

  • Handelsman M, Goldsmith H, Broder L, Carter S, Slarik M (1976) Clinical brochure. Natl Cancer Inst Monogr 1: 10

    Google Scholar 

  • Harrap KR, Murrer BA, Giandomenico C, Morgan SE, Kelland LR, Jones M, Goddad PM, Schurig J (1991) Ammine/amine platinum IV dicarboxylates: a novel class of complexes which circumvent intrinsic cisplatin resistance. In: Howell SB (ed) Platinum and other metal coordination compounds in cancer chemotherapy. Plenum, New York, pp 391–399

    Google Scholar 

  • Hartley-Asp B, Kruse E (1986) Nuclear protein matrix as a target for estramustine induced cell death. Prostate 9: 387–395

    PubMed  Google Scholar 

  • Hartmann RW (1983) Tumor growth-stimulating and inhibiting effects of antiestrogens on the DMBA-induced mammary carcinoma of the ovariectomized, diethylstilbestrol-treated SD-rat. A study on the mechanism of action of antiestrogens. Eur J Cancer Clin Oncol 19:959–964

    PubMed  Google Scholar 

  • Hartmann RW, Kranzfelder G, Angerer E von, Schönenberger H (1980) Antiestrogens. Synthesis and evaluation of mammary tumor inhibiting activity of 1,1,2,2-tetraalkyl-1,2-diphenylethanes. J Med Chem 23:841–848

    PubMed  Google Scholar 

  • Hartmann RW, Schönenberger H, Wrobel K-H (1982) 3,4-Bis-(3-hydroxyphenyl)hexane — a new mammary tumor-inhibiting compound-studies on the mechanism of action on the DMBA-induced, hormone-dependent mammary tumor of the rat. J Cancer Res Clin Oncol 103:241–254

    PubMed  Google Scholar 

  • Hartmann RW, Sinchai T, Kranzfelder G (1985) Antiproliferative effects of 1,2-diphenylethane effects of 1,2-diphenylethane estrogens and antiestrogens on human breast cancer cells. J Cancer Res Clin Oncol 110:17–24

    PubMed  Google Scholar 

  • Hasegawa Y, Morita M, Muto N (1980) Antitumor activity of cisplatin on experimental animal system. Jpn J Cancer Chem 7:621–630

    Google Scholar 

  • Hasegawa Y, Masuguki M (1985) Antitumor effect of oral cisplatin on certain murine tumors. Chem Pharm Bull (Tokyo) 33:5511–5514

    Google Scholar 

  • Holler E, Bauer R, Bernges F (1992) Monofunctional DNA-platinum(II) adducts block frequently DNA polymerases. Nucleic Acid Res 20:2307–2312

    PubMed  Google Scholar 

  • Humm A (1988) Synthese und biologische Testung nichtsteroidaler Antiandrogene und Untersuchungen am Nb-R Prostatakarzinom der Noble-Ratte. PhD thesis, University of Regensburg

  • Janistyn H (1978) Handbuch der Kosmetika und Riechstoffe, Vol. 1. Hüthig, Heidelberg, p 731

    Google Scholar 

  • Karl JF-X (1985) Versuche zur Entwicklung Östrogenrezeptor-affiner Platinkomplexe mit einer spezifischen Wirkung am hormonabhängigen Mammacarcinom. PhD thesis, University of Regensburg

  • Karl J, Gust R, Spruß T, Schneider M, Schönenberger H, Engel J, Wrobel KH, Lux F, Trebert-Haeberlin S (1988) Ring substituted [1,2-bis(4-hydroxyphenyl)ethylenediamine]dichloroplatinum(II)-complexes: compounds with a selective effect on the hormone-dependent mammary carcinoma. J Med Chem 31:72–83

    PubMed  Google Scholar 

  • Koop R (1992) Molekulare Wirkmechanismen von Antiestrogenen und Estrogenrezeptor-affinen Platin(II)-Verbindungen. PhD thesis, University of Regensburg

  • Maron DM, Ames BN (1983) Revised methods for theSalmonella mutagenicity test. Mutat Res 113:173–215

    PubMed  Google Scholar 

  • Maucher A (1992) Pharmakologische Untersuchungen über neue Möglichkeiten zur endokrinen und cytostatischen Behandlung des Prostatakarzinoms. PhD thesis, University of Regensburg

  • Montemurro DG (1971) Inhibition of hypothalamic obesity in the mouse with diethylstilbestrol. Can J Physiol Pharmacol 49:554–558

    PubMed  Google Scholar 

  • Otto AM, Faderl M, Schönenberger H (1991) Dissociation of estrogenic and cytotoxic properties of an estrogen receptor-binding platinum complex in human breast cancer cell lines. Cancer Res 51:3217–3223

    PubMed  Google Scholar 

  • Otto AM, Bednarski PJ, Eggers H, Trümbach B, Schönenberger H (1992) [meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl)-ethylenediamine]dichloroplatinum(II), an estrogenic Pt(II)-complex for the therapy of breast cancer: relationship between stability and effect. Pharm Pharmacol Lett 1:103–106

    Google Scholar 

  • Prestayko AW, Crooke ST, Carter SK (1980) Cisplatin current status and new developments. Academic Press, NY

    Google Scholar 

  • Reile H, Bernhardt G, Koch M, Schönenberger H, Hollstein M, Lux F (1992) Chemosensitivity of human MCF7 breast cancer cells to diastereomeric diaqua(1,2-diphenylethylenediamine)platinum (II) sulfates and specific platinum accumulation. Cancer Chemother Pharmacol 30:113–122

    PubMed  Google Scholar 

  • Rubin BL, Dorfman AS, Black L, Dorfman RJ (1951) Bioassay of estrogens using the mouse uterine response. Endocrinology 49:429

    PubMed  Google Scholar 

  • Schiller CD (1988) Synthese und biologische Testung nichtsteroidaler Antiandrogene und Untersuchungen zum Wirkungsmechanismus neuer Prostatakarzinom Therapeutika an R 3327 Tumormodellen. PhD thesis, University of Regensburg

  • Schneider MR, Kranzfelder G, Angerer E von, Schönenberger H, Metzler M, Michel RT, Fortmeyer HP, Ruckdeschel G (1981) The tumor inhibiting effect of diethylstilbestrol-3,4-oxide. J Cancer Res Clin Oncol 100:247–254

    PubMed  Google Scholar 

  • Schneider MR, Ball H, Schönenberger H (1985) Acetoxy-substituted 1,1,2-triphenylbut-1-enes with antiestrogenic and mammary tumor inhibiting properties. J Med Chem 28:1880–1985

    PubMed  Google Scholar 

  • Schneider MR, Angerer E von, Prekajac J, Brade WP (1986) Studies on the mammary tumor-inhibiting effects of diethylstilbestrol and its mono- and diphosphate. J Cancer Res Clin Oncol 111:110–114

    PubMed  Google Scholar 

  • Schneider MR, Spruß T, Schiller CD, Humm A, Schönenberger H (1988). Selective prostatic tumor inhibiting effect of an endocrine active platinum complex. In: Bresciani F, King RJB, Lippman ME, Raynaud JP (eds) Progress in cancer research and therapy, vol 35. Hormones and cancer. Raven Press, New York, p 509

    Google Scholar 

  • Schneider MR, Schiller CD, Humm A, Spruß T, Schönenberger H, Amselgruber W, Sinowatz F (1989) [1,2-Bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]-dichloroplatinum(II): an endocrine-active platinum complex with a specific prostatic tumor-inhibiting activity. Prostate 15:135–148

    PubMed  Google Scholar 

  • Schneider MR, Humm A, Graf AH (1990) The tumor-inhibiting effect of diethylstilbestrol and its diphosphate on the Nb-H and Nb-R prostatic carcinomas of the rat. J Cancer Res Clin Oncol 116:159–167

    PubMed  Google Scholar 

  • Seeger R, Neumann HG (1986) DAZ-Giftlexikon: platin. Dtsch Apoth Ztg 126:157–160

    Google Scholar 

  • Siddik ZH, Newell DR, Boxall FE, Jones M, McGhee KG, Harrap KR (1984) Biliary excretion, renal handling and red cell uptake of cisplatin and CBDCA in animals. In: Hacker MP, Douple EB, Krakoff IH (eds) Platinum coordination complexes in Cancer chemotherapy. Martinus Nijhoff, Boston

    Google Scholar 

  • Smyth HF Jr, Carpenter CP, Shaffer BC (1945) The subacute toxicity and irritation of polyethylene glycols of approximate molecular weights of 200, 300 and 400. J Am Pharm Assoc Sci Ed 34:172–174

    Google Scholar 

  • Smyth HF Jr, Carpenter CP, Weil CS (1950) The toxicology of polyethylene glycols. J Am Pharm Assoc Sci Ed 39:349–354

    Google Scholar 

  • Spruß T (1988) Modelle zur Untersuchung von Platinkomplexen mit hormoneller und zytotoxischer Aktivität. PhD thesis, University of Regensburg

  • Spruß T, Gust R, Müller R, Engel J, Schönenberger H (1990) Mammary tumor inhibiting properties of the (S,S)-configurated [1,2-bis(4-hydroxyphenyl)ethylenediamine]dichloroplatinum(II) complex. Arch Pharm (Weinheim) 232:99–102

    Google Scholar 

  • Spruß T, Bernhardt G, Schlemmer R, Schönenberger H (1992) Differing responses of hormone-dependent rodent tumors grown in immunodeficient and immunocompetent hosts to hormone-like therapy. Contrib Oncol 42:397–407

    Google Scholar 

  • Wolpert-De Filippes MK (1979) Antitumor activity ofcis-dichlorodiammineplatinum(II). Cancer Treat Rep 63:1453–1458

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Institut für Pharmazie, Lehrstuhl Pharmazeutische Chemie II, Universität Regensburg, Universitätsstrasse 31, W-8400, Regensburg, Germany

    Thilo Spruß, Martin R. Schneider, Ronald Gust & Helmut Schönenberger

  2. Institut für Pharmazie, Albert-Ludwigs-Universität, Hermann-Herder-Strasse 7, W-7800, Freiburg, Germany

    Sabine Schertl & Kurt Bauer

Authors
  1. Thilo Spruß
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  2. Sabine Schertl
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  3. Martin R. Schneider
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  4. Ronald Gust
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  5. Kurt Bauer
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  6. Helmut Schönenberger
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Spruß, T., Schertl, S., Schneider, M.R. et al. [meso-1,2-Bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]-dichloroplatinum(II), a new drug not only parenterally but also orally active in the therapy of breast and prostate cancer. J Cancer Res Clin Oncol 119, 707–716 (1993). https://doi.org/10.1007/BF01195341

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  • DOI: https://doi.org/10.1007/BF01195341

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