Abstract
The nonsteroidal antiandrogen casodex has been described as a peripherally selective drug for the treatment of prostatic cancer. In this study we determined its activity in various models of hormone-dependent malignancies including those of the prostate and the breast. Analysis of endocrine effects in rats after 15 days of treatment revealed a strong reduction of the weights of prostates and seminal vesicles and a significant rise of testosterone serum levels as a result of the interference with central feedback mechanisms. The growth of androgen-sensitive human LNCaP/FGC prostate cancer cells was strongly inhibited by casodex. Unlike hydroxyflutamide, casodex was also active in hormone-depleted medium. The inhibitory effect was overcome by addition of testosterone propionate, which indicates an androgen-receptor-mediated mode of action. In rats bearing Dunning R3327-G prostate carcinomas casodex exerted a strong antitumour effect at the beginning of therapy. However, after 4 weeks of treatment tumours resumed growth whereas diethylstilboestrol-treated tumours remained static. In MXT-M3.2 mouse mammary tumours with significant quantities of androgen receptors casodex was also effective in inhibiting tumour growth. After 6 weeks of treatment, tumour weights were reduced by 69% whereas uterine weights were significantly increased, possibly because of a progestin-like activity of the drug. Casodex is very active in various models of hormone-dependent carcinomas. However, the limited duration of action in prostatic tumours and the incomplete growth inhibition in mammary tumours suggest that it should be used only combination with other endocrine therapies.
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Abbreviations
- DDC:
-
dextran-coated charcoal
- FCS:
-
fetal calf serum
References
Ayub M, Levell MJ (1989) The effect of ketoconazol related imidazol drugs and antiandrogens on [3H]R1881 binding to prostatic androgen receptor and [3H)5α-dihydrotestosterone and [3H]cortisol binding to plasma proteins. J Steroid Biochem 33:251–255
Birnböck H (1988) Untersuchungen zur Pharmakokinetik des Zindoxifens und zur Wirkung von Inhibitoren der Steroidsulfatase an hormonabhängigen Tumoren. Dissertation, Universität Regensburg
Chandolia RK, Weinbauer GF, Behre HM, Nieschlag E (1991) Evaluation of a peripherally selective antiandrogen (casodex) as a tool for studying the relationship between testosterone and spermatogenesis in the rat. J Steroid Biochem 38:367–375
Furr BJA, Curry VB, Woodburn JR, Chesterson G, Tucker H (1987) ICI 176334: a novel nonsteroidal peripherally selective antiandrogen. J Endocrinol 113:R7-R9
Hall RE, Tilley WD, McPhaul MJ, Sutherland RL (1992) Regulation of androgen receptor gene expression by steroids and retinoic acid in human breast-cancer cells. Int J Cancer 52:778–784
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
Isaacs JT (1984) The timing of androgen ablation therapy and/or chemotherapy in the treatment of prostatic cancer. Prostate 5:1–17
Isaacs JT, Wake N, Coffey DS, Sandberg AA (1982) Genetic instability coupled to clonal selection as a mechanism for tumor progression in the Dunning R-3327 rat prostatic adenocarcinoma system. Cancer Res 42:2353–2361
Kager M, Spruß T, Schneider MR, von Angerer E (1992) Dunning R3327-G prostate carcinoma of the rat: an appropriate model for drug evaluation. J Cancer Res Clin Oncol 118:334–338
Maass H, Jonat W (1980) Endocrine treatment of advanced breast cancer. In: Henningsen B, Linder F, Steichele C (eds) Endocrine treatment of breast cancer. Springer, Berlin Heidelberg New York, pp 102–111
Maucher A, Kager M, von Angerer E (1993) Evaluation of the antitumour activity of coumarin in prostate cancer models. J Cancer Res Clin Oncol 119:150–154
Millward MJ, Cantwell BMJ, Dowsett M, Carmichael J, Harris AL (1991) Phase II clinical and endocrine study of Anandron (RU-23908) in advanced post-menopausal breast cancer. Br J Cancer 63:763–764
Morris JJ, Hughes LR, Glen AT, Taylor PJ (1991) Non-steroidal antiandrogens. Design of novel compounds based on an infrared study of the dominant conformation and hydrogen-bonding properties of a series of anilide antiandrogens. J Med Chem 34:447–455
Ormandy CJ, Clarke CL, Kelly PA, Sutherland RL (1992) Androgen regulation of prolactin-receptor gene expression in MCF-7 and MDA-MB-453 human breast cancer cells. Int J Cancer 50:777–782
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
Schneider MR, von Angerer E, Höhn W, Sinowatz F (1987) Antitumor activity of antiestrogenic phenylindoles on experimental prostate tumors. Eur J Cancer Clin Oncol 23:1005–1015
Schneider MR, Schiller C-D, Humm A, Spruß, T, Schönenberger H, Amselgruber W, Sinowatz F (1989) [1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylendiamine]dichloroplatinum(II) complex with a specific prostatic tumor-inhibiting activity Prostate 15:135–148
Schneider MR, Schiller CD, Humm A, von Angerer E (1991) Effect of zindoxifene on experimental prostatic tumours of the rat. J Cancer Res Clin Oncol 117:33–36
Sciarra F, Toscano V, Concolino G, Di Silverio F (1990) Antiandrogens: clinical applications. J Steroid Biochem Mol Biol 37:349–362
Shain SA, Huot RI (1988) Antiandrogen effects in models of androgen responsive cancer. J Steroid Biochem 31:711–718
Sonnenschein C, Olea N, Pasanen ME, Soto AM (1989) Negative controls of cell proliferation: human prostate cancer cells and androgens. Cancer Res 49:3474–3481
Tucker H, Crook JW, Chesterson GJ (1988) Nonsteroidal antiandrogens. Synthesis and structure-activity relationships of 3-substituted derivatives of 2-hydroxypropionanilides. J Med Chem 31:954–959
Van Steenbrugge GJ, Van Uffelen CJC, Bolt J, Schröder FH (1991) The human prostatic cancer cell line LNCaP and its derived sublines: anin vitro model for the study of androgen sensitivity. J Steroid Biochem 40: 207–214
Veldscholte J, Ris-Stalpers C, Kuiper GGJM, Jenster G, Berrevoets C, Claassen E, Van Rooij HCJ, Trapman J, Brinkmann AO, Mulder E (1990) A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androgens. Biochem Biophys Res Commun 173:534–540
Veldscholte J, Berrevoets CA, Ris-Stalpers C, Kuiper GGJM, Jenster G, Trapman J, Brinkmann AO, Mulder E (1992) The androgen receptor in LNCaP cells contains a mutation in the ligand binding domain which affects steroid binding characteristics and response to antiandrogens. J Steroid Biochem 41:665–669
von Angerer E, Birnböck H, Knebel N (1989) Platinum complexes with a selective action on estrogen receptor positive mammary tumors. Anti-Cancer Drug Design 4:21–25
von Angerer E, Birnböck H, Kager M, Maucher A (1992) The effect of a combination of zindoxifene and cisplatin on Dunning R3327-G prostatic carcinomas of the rat. J Cancer Res Clin Oncol 118:339–343
Wolf DA, Schulz P, Fittler F (1991) Synthetic androgens suppress the transformed phenotype in the human prostate carcinoma cell line LNCaP. Br J Cancer 64:47–53
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Maucher, A., von Angerer, E. Antiproliferative activity of casodex (ICI 176.334) in hormone-dependent tumours. J Cancer Res Clin Oncol 119, 669–674 (1993). https://doi.org/10.1007/BF01215986
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DOI: https://doi.org/10.1007/BF01215986