Springer Nature is making Coronavirus research free. View research | View latest news | Sign up for updates

Platinum(II) complexes interfering with testicular steroid biosynthesis: drugs for the therapy of advanced or recurrent prostate cancers? Preclinical studies


[Meso-1,2-bis(2,6-dihalo-3/4-hydroxyphenyl)ethylenediamine]platinum(II) complexes (meso-1-PtLL′: 2,6-F2,3-OH; meso-2-PtLL′: 2,6-F2,4-OH; meso-3-PtLL′: 2,6-Cl2,3-OH; meso-4-PtLL′: 2,6-Cl2,4-OH; L = OH2, L′ = OSO3 or L,L′ = Cl2) were designed with the aim to get drugs comprising both cytotoxic and testosterone level lowering potencies. It is assumed that such compounds are more efficient than the established endocrine therapeutic measures and can affect the development of hormone refractory prostate cancer (PC). With exception of meso-3-PtLL′ all Pt-complexes and the comparison compound cisplatin significantly reduced the testosterone level in experiments on male rats. However, in the test on the Dunning R3327 PC of the rat only cisplatin and meso-4-PtLL′ showed a significant anti-tumor activity at well-tolerated dose ranges. Meso-4-PtLL′ also significantly extended the time to disease progression in comparison with orchiectomy in this tumor model. Interestingly, the relapsed tumor, too, responded to meso-4-PtLL′ as demonstrated in a long-term study on orchiectomized rats bearing Dunning R3327 PC grafts. This effect cannot be ascribed to cytotoxic effects of meso-4-PtLL′ because of its inactivity on the human LNCaP/FGC PC cell line. Therefore, the contribution of an additional mechanism to the anti-prostate cancer activity of meso-4-PtLL′, presumably owing to its estrogenic potency, must be considered. This assumption was supported by test results with diethylstilbestrol (DES) (non-steroidal estrogen) on the Dunning R3327 PC of the rat relapsed after orchiectomy. This tumor model was strongly inhibited by DES. The possible mode of action of meso-4-PtLL′ is thoroughly discussed.

This is a preview of subscription content, log in to check access.

Chart 1
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5





Prostate cancer








Seminal vesicle


Androgen receptor


Estrogen receptor


  1. Angerer E von, Birnböck H, Kager M, Maucher A (1992) The effect of a combination of zindoxifene and cisplatin on Dunning R3327-G PC of the rat. J Cancer Res Clin Oncol 118:339–343

  2. Bektic J, Berger AP, Pfeil K, Dobler G, Bartsch G, Klocker H (2004) Androgen receptor regulation by physiological concentrations of the isoflavonoid genistein in androgen-dependent LNCaP cells is mediated by estrogen receptor ß. Eur Urol 45:245–251

  3. Bernhard G, Reile H, Birnböck H, Spruß T, Schönenberger H (1992) Standardized kinetik microassay to quantify differential chemosensitifity on the basis of proliferative activity. J Cancer Res Clin Oncol 118:35–43

  4. Burk K, Jonas D (1987) Sinn und Unsinn von Therapiekombinationen beim fortgeschrittenen Prostatakarzinom. In: Nagel R (ed) Konservative Therapie des Prostatakarzinoms. Springer, Berlin Heidelberg New York, pp 125–132

  5. Corey E, Quinn JE, Emond MJ, Buhler KR, Brown LG, Vesella RL (2002) Inhibition of androgen-independent growth of prostate cancer xenografts by 17ß-estradiol. Clin Cancer Res 8:1003–1007

  6. Dullin A, Dufrasne F, Gelbcke M, Gust R (2004) Enantiomerically pure [1,2-diamino-1-(4-fluorophenyl)butane]platinum(II) complexes: synthesis and antitumor activity against MCF-7 and MDA-MB 231 breast cancer and LNCaP/FGC prostate cancer cell lines. Arch Pharm Pharm Med Chem 337:654–667

  7. Gilligan T, Kantoff PW (2002) Chemotherapy for prostate cancer. Urology 60(Suppl 3A):94–100

  8. Gust R, Schönenberger H (1993a) Synthesis and evaluation of the anti-mammary tumor activity and of the estrogenic side effects of [1,2-bis(2,6-dihalo-3-hydroxyphenyl)ethylenediamine]platinum(II) complexes. Eur J Med Chem 28:103–115

  9. Gust R, Schönenberger H (1993b) Breast cancer-inhibiting properties of leaving group derivatives of [1,2-bis(2,6-difluoro-3-hydroxyphenyl)ethylenediamine]platinum(II). Eur J Med Chem 28:117–127

  10. Gust R, Schönenberger H (1993c) Mammary tumor-inhibiting [1,2-bis(2,6-dihalo-3-hydroxyphenyl)ethylenediamine]platinum(II) complexes. Relationship between structure, and estrogenic activity of the diamine ligands, their sulfatoplatinum(II) and diiodoplatinum(II) complexes. Arch Pharm (Weinheim) 326:405–413

  11. Hay R (1988) The seed stock concept and quality control for cell lines. Anal Biochem 171:225–237

  12. Hedlund PO, Henriksson P (2000) Parenteral estrogen versus total androgen ablation in the treatment of advanced prostate carcinoma: effects on overall survival and cardiovascular mortality. Urology 55:328–333

  13. Henriksson P, Carlström K, Pousette A, Gunnarsson PO, Johansson CJ, Eriksson B, Altersgärd-Brorsson AK, Nordle Ö, Stege R (1999) Time for revival of estrogens in the treatment of advanced prostatic carcinoma? Pharmacokinetics, and endocrine and clinical effects of a parenteral estrogen regimen. Prostate 40:76–82

  14. Heston WD, Menon M, Tananis C, Walsh PC (1978) Androgen, estrogen and progesterone receptors of the R3327-H Copenhagen rat prostatic tumor. Cancer Lett 6:45–50

  15. Ho S-M (2004) Estrogens and antiestrogens: key mediators of prostate carcinogenesis and new therapeutic candidates. J Cell Biochem 91:491–503

  16. Hodges CV (1979) Hormonal therapy of prostatic cancer. In: Rose DP (ed) Endocrinology of cancer, vol II. CRC Press Inc., Boca Raton, pp 57–68

  17. Horoszewicz JS, Leong SS, Kawinski E, Kaar JP, Rosenthal H, Chu TM, Mirand EA Murphy GP (1983) LNCaP model of human prostatic carcinoma. Cancer Res 43:1809–1818

  18. Huan SD, Stewart DJ, Aitken SE, Segal R, Yau JC (1999) Combination of epirubicin and cisplatin in hormone-refractory metastatic prostate cancer. Am J Clin Oncol 22:471–474

  19. Huben RP, Murphy GP (1987) Chemotherapy of prostatic cancer. In: Bruce AW, Trachtenberg J (eds) Adenocarcinoma of the prostate. Springer, London, pp 185–196

  20. International Prostate Health Council Study Group (2001) Estrogens and prostatic disease. Prostate 45:87–100

  21. Isaacs JT (1984) The timing of estrogen ablation therapy and/or chemotherapy in the treatment of prostatic cancer. Prostate 5:1–17

  22. Isaacs JT (1986) New principles in the management of metastatic prostatic cancer. In: Das Prostatakarzinom zwischen Hormontherapie und Zytostase, Medical Trends: Solingen, pp 5–27

  23. Isaacs JT, Heston WDW, Weissman RM, Coffey DS (1978) Animal models of the hormone-sensitive and -insensitive prostatic adenocarcinomas, Dunning R3327-H, R3327-HI, and R3327-AT. Cancer Res 38:4353–4359

  24. Joseph IBJK, Isaacs JT (1998) Macrophage role in the anti-prostate cancer response to one class of anti-angiogenic agents. J Natl Cancer Inst 90:1648–1653

  25. Kager M, Spruß T, Schneider MR, Angerer E von (1992) Dunning R3327-G prostate carcinoma of the rat: an appropriate model for drug evaluation. J Cancer Res Clin Oncol 118:334–338

  26. Keuppens F, Denis L, Smith P, Carvalho AP, Newling D, Bond A, Sylvester R, De Pauw M, Vermeylen K, Ongena P (1990) Zoladex and flutamide versus bilateral orchiectomy. A randomized phase III EORTC 30853 study. The EORTC GU Group. Cancer 66:1045–1057

  27. Kranzfelder G, Schneider MR, Angerer E von, Schönenberger H (1980) Entwicklung neuer Antiöstrogene vom Typ des 3,3′-Dihydroxy-α,ß-diäthylstilbens und ihre Prüfung am DMBA-induzierten, hormonabhängigen Mammacarcinom der SD-Ratte. J Cancer Res Clin Oncol 97:167–186

  28. Li Y, Sarkar FH (2002) Gene expression profiles of genistein-treated PC3 prostate cancer cells. J Nutr 132:3623–3631

  29. Ludwig GR (1987) Überblick über die therapeutischen Möglichkeiten des fortgeschrittenen Prostatakarzinoms. In: Nagel R (ed) Konservative Therapie des Prostatakarzinoms. Springer, Berlin Heidelberg New York, pp 39–53

  30. Maki Y, Tsushima T, Nasu Y, Kumon H, Ohmori H, Tanahashi T, Nanba K, Ohashi T, Kondo K, Saika T, Asahi T, Saegusa M, Ozaki Y, Yamashita Y, Katayama Y, Kobuke M, Uno S, Ochi J, Kobashi K, Hata K (1998) Combination chemotherapy with cis-platinum and ifosfamide for hormone-unresponsive prostate cancer. Nippon Hinyokika Gakkai Zasshi (Jpn J Urol) 89:657–664

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

  32. Murphy GP (1999) Review of phase II hormone-refractory prostate cancer trials. Urology 54(Suppl 6A):19–21

  33. Paz-Ares LG, Smith MR (2001) Genitourinary malignancies, 5. Prostate cancer. In: Giaccone G, Schilsky R, Sondel P (eds) Cancer chemotherapy and biological response modifiers, Annual 19. Elsevier Amsterdam, Chap 26, pp 586–595

  34. Raghavan D, Koczwara B, Javle M (1997) Evolving strategies of cytotoxic chemotherapy for advanced prostate cancer. Eur J Cancer 33:566–574

  35. Reile H, Birnböck H, Bernhardt G, Spruß T, Schönenberger H (1990) Computerized determination of growth kinetic curves and doubling times from cells in microculture. Anal Biochem 187:262–267

  36. Ryan CJ, Small EJ (2003) Role of secondary hormonal therapy in the management of recurrent prostate cancer. Urology 62(Suppl 6B):87–94

  37. Schertl S, Hartmann RW, Batzl-Hartmann C, Bernhardt G, Spruß T, Beckenlehner K, Koch M, Krauser R, Schlemmer R, Gust R, Schönenberger H (2004a) [1,2-Bis(2,6-difluoro-3-hydroxyphenyl)ethylenediamine]platinum(II) complexes, compounds for the endocrine therapy of breast cancer—Mode of action I: antitumor activity due to the reduction of the endogenous estrogen level. Arch Pharm Pharm Med Chem 337:335–348

  38. Schertl S, Hartmann RW, Batzl-Hartmann C, Bernhardt G, Spruß T, Beckenlehner K, Koch M, Krauser R, Schlemmer R, Gust R, Schönenberger H (2004b) [1,2-Bis(2,6-difluoro-3-hydroxyphenyl)ethylenediamine]platinum(II) complexes, compounds for the endocrine therapy of breast cancer—Mode of action II: contribution of drug inactivation, cellular drug uptake and sterical factors in the drug-target interaction to the antitumor activity. Arch Pharm Pharm Med Chem 337:349–359

  39. Schneider MR, Hartmann RW, Sinowatz F, Amselgruber W (1986) Nonsteroidal antiestrogens and partial estrogens with prostatic tumor inhibiting activity. J Cancer Res Clin Oncol 112:258–265

  40. Schneider MR, Angerer E von, Höhn W, Sinowatz F (1987) Antitumor activity of antiestrogenic phenylindoles on experimental prostate tumors. Eur J Cancer Clin Oncol 23:1005–1015

  41. 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

  42. Schneider MR, Schiller CD, Humm A, Angerer E von (1991) Effect of zindoxifene on experimental prostatic tumours of the rat. J Cancer Res Clin Oncol 117:33–36

  43. Schnurr B (2002) Platin(II)-Komplexe mit chelatgebundenen Dicarbonsäuren als Abgangsgruppe: Untersuchungen zur Stabilität, Struktur, Löslichkeit, Reaktivität und Antitumoraktivität. PhD Thesis, Freie Universität Berlin

  44. Sergejew TF, Hartmann RW (1996) Effect of a diphenylethylenediamineplatinum complex on steroidogenesis in rats. J Steroid Biochem Mol Biol 58:243–248

  45. Smith DC, Redman BG, Flaherty LE, Li L, Strawderman M, Pienta KJ (1998) A phase II trial of oral diethylstilbestrol as a second-line hormonal agent in advanced prostate cancer. Urology 52:257–260

  46. Smolev JK, Coffey DS, Scott WW (1977a) Experimental models for the study of prostatic adenocarcinoma. J Urol 118:216–220

  47. Smolev JK, Heston WDW, Scott WW, Coffey DS (1977b) Characterisation of the Dunning R3327-H prostatic adenocarcinoma: an appropriate model for prostatic cancer. Cancer Treat Rep 61:273–287

  48. Spruß T, Schertl S, Schneider MR, Gust R, Bauer K, Schönenberger H (1993) [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

  49. Steiner MS, Raghow S (2003) Antiestrogens and selective estrogen receptor modulators reduce prostate cancer risk. World J Urol 21:31–36

  50. Sternberg CN (2003) Randomized phase III trial of a new oral platinum, Satraplatin (JM-216) plus prednisone or prednisone alone in patients with hormone refractory prostate cancer. In: Annual meeting of the American Society of Clinical Oncology, Chicago (ASCD 2003), Abstract # 1586

  51. Tennant TR, Kim H, Sokoloff M, Rinker-Schaeffer CW (2000) The Dunning model. Prostate 43:295–302

  52. Van Steenbrugge GJ, Van Uffelen CJC, Bolt J, Schröder FH (1991) The human prostatic cancer cell line LNCaP and its derived sublines: an in vitro-model for the study of androgen-sensitivity. J Steroid Biochem 40:207–214

Download references


This work was supported by the “Fonds der Chemischen Industrie”. The technical assistance of O. Baumann, S. Bergemann, S. Paulus and F. Wiesenmayer is gratefully acknowledged.

Author information

Correspondence to Ronald Gust.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Schertl, S., Hartmann, R.W., Batzl-Hartmann, C. et al. Platinum(II) complexes interfering with testicular steroid biosynthesis: drugs for the therapy of advanced or recurrent prostate cancers? Preclinical studies. J Cancer Res Clin Oncol 133, 153–167 (2007).

Download citation


  • [1,2-Diphenylethylenediamine]platinum(II) complexes
  • Cisplatin
  • Diethylstilbestrol
  • Anti-prostate cancer activity
  • Mode of action