Summary
Diethylstilbestrol (DES), diethylstilbestrol monophosphate (DES-MP) and diethylstilbestrol diphosphate (DES-DP) were tested for their estrogen receptor affinity, estrogenic potency and mammary tumor-inhibiting activity in vitro and in vivo. DES had a much higher receptor binding affinity than its mono-or diphosphate. All three compounds inhibited the growth of the hormone-dependent MCF-7 and hormone-independent MDA-MB 231 breast cancer line only at relatively high concentrations. The estrogenic potency in the immature mouse uterine weight test decreased in the order DES>DES-MP≫DES-DP. The hormone-dependent MXT mammary tumor of the mouse was inhibited by all three compounds at a dosage of 1.0 mg/kg per week. At a dose of 0.01 mg/kg, DES, DES-MP, and DES-DP stimulated the tumor growth. Thus, for the first time, a biphasic effect on tumor growth was demonstrated in intact mature animals. As the effects of all three compounds were similar in this assay, a cleavage of the phosphate groups is likely. A decrease in estrogenic potency concomitant with a retained antitumor effect of DES-MP and DES-DP compared to DES was not demonstrable in the mature mouse using the MXT assay, only in the uterotrophic test in the immature mouse.
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References
Angerer E von, Prekajac J, Berger M (1985) The inhibitory effect of 5-acetoxy-2-(4-acetoxyphenyl)-1-ethyl-3-methylindole (D 16726) on estrogen-dependent mammary tumors. Eur J Cancer Clin Oncol 21:531–537
Brandes LJ, Hermonat MW (1983) Receptor status and subsequent sensitivity of subclones of MCF-7 human breast cancer cells surviving exposure to diethylstilbestrol. Cancer Res. 43:2831–2835
Davis HL (1979) Hormonal manipulation in the treatment of cancer of the female breast. In: Rose DP (ed) Endocrinology of cancer. CRC Press, Boca Raton, Vol II, p 61
Dörner G, Knappe G (1960) Zur Frage der organspezifischen cytostatischen Wirkung von Diethylstilböstroldiphosphat auf das Prostatacarcinom. Klin Wochenschr 38:67–69
Dörner G, Stahl F, Rohde W, Schnorr D (1975) An apparently direct inhibitory effect of estrogen on the human testis. Endocrinologie 66:221–224
Druckrey H (1952) Experimentelle Grundlagen der Chemotherapie des Krebses. Dtsch Med Wochenschr 77:1534–1537
Druckrey H, Brock N (1960) Zum Wirkmechanismus von Stilböstrol-Diphosphat (Honvan) beim Prostatakarzinom. Münch Med Wochenschr 102:1626–1629
Goldenberg GJ, Froese EK (1982) Drug and hormone sensitivity of estrogen receptor-positive and-negative human breast cancer cells in vitro. Cancer Res 42:5147–5151
Goldenberg GJ, Froese EK (1985) Induction of DNA single- and double-strand breaks by diethylstilbestrol in murine L 5178 Y lymphoblasts in vitro. Biochem Pharmacol 34:771–776
Hartmann RW (1983) Tumor growth-stimulating and inhibiting effects of antiestrogens on the DMBA-induced mammary carcinoma of the ovariectomized, diethylstilbestrol-treated SD rat. Eur J Cancer Clin Oncol 19:959–964
Heuson JC, Legros N, Heuson-Stiennon JA, Leclercq G, Pasteels JL (1976) Hormone dependence of rat mammary tumors. In: Heuson JC, Mattheiem WH, Rozencweig M (eds) Breast cancer: trends in research and treatment. Raven Press, New York
Hodges CV (1979) Hormonal therapy of prostatic cancer. In: Rose DP (ed) Endocrinology of cancer. CRC Press, Boca Raton, Vol II, p 57
Kranzfelder G, Schneider M, von Angerer E, Schönenberger H (1980) Entwicklung neuer Antiöstrogene vom Typ des 3,3′-Dihydroxy-α,β-diethylstilbens und ihre Prüfung am DMBA-induzierten, hormonabhängigen Mammacarcinom der SD-Ratte. J Cancer Res Clin Oncol 97:167–186
Lippman, M (1976) Hormone-responsive human breast cancer in continuous tissue culture. In: Heuson JC, Mattheiem WH, Rozencweig M (eds) Breast cancer: trends in research and treatment. Raven Press, New York
Lippman M, Monaco ME, Bolan G (1977) Effects of estrone, estradiol and estriol on hormone-responsive human breast cancer in long-term tissue culture. Cancer Res 37:1901–1907
Ölschläger H, Rothley D, Dunzendorfer U (1984) Plasmaspiegel von Fosfestrol und seinem Monophosphat, von Diethylstilbestrol und seinem Monoglucuronid nach intravenöser Gabe bei Patienten mit metastasierendem Prostatakarzinom. Drug Res 34:1333–1336
Pollack A, Block NL, Stover BJ, Irvin III GL, Fuentes MP, Claflin AJ, Malinin TJ (1983) In vivo selection of androgen-insensitive cells in R 3327-G rat prostate tumors: diethylstilbestrol diphosphate treatment versus orchiectomy. J Natl Cancer Inst 170:907–914
Promislow C, Connolly J, Clarke A (1970) Uptake of tritiated stilbestrol diphosphate by the prostate gland. J Urol 104:146–150
Schmähl D (1954) Zytotoxische Wirkungen des Stilböstrols auf die Zellen des Walker-Carcinoms der Ratte. Arzneimittel-Forsch 4:481–484, and references cited therein
Schneider MR, Kranzfelder G, von Angerer E, 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
Schneider MR, von Angerer E, Schönenberger H, Michel RT, Fortmeyer HP (1982) 1,1,2-Triphenylbut-1-enes: Relationship between structure, estradiol receptor affinity, and mammary tumor inhibiting properties. J Med Chem 25:1070–1077
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 28:1880–1885
Scholl SM, Huff KK, Lippman ME (1983) Antiestrogenic effects of LY 117018 in MCF-7 cells. Endocrinology 113:611–617
Teller MN, Kaufman RJ, Bowie M, Stock CC (1969) Influence of estrogens and endocrine ablation on duration of remission produced by ovariectomy or androgen treatment of 7,12 dimethylbenz[a]anthracene-induced rat mammary tumors. Cancer Res 29:349–352
Watson C, Medina D, Clark JH (1977) Estrogen receptor characterization in a transplantable mouse mammary tumor. Cancer Res 37:3344–3348
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Dedicated to Professor Dietrich Schmähl on occasion of his 60th birthday
Supported by the Deutsche Forschungsgemeinschaft and by the Verband der Chemischen Industrie, Fonds der Chemischen Industrie. The authors thank Dr. Weigert, Asta-Werke AG, Degussa Pharma Gruppe, Bielefeld, FRG, for the analysis of DES-MP and DP
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Schneider, M.R., von Angerer, E., Prekajac, J. et al. Studies on the mammary tumor-inhibiting effects of diethylstilbestrol and its mono- and diphosphate. J Cancer Res Clin Oncol 111, 110–114 (1986). https://doi.org/10.1007/BF00400747
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DOI: https://doi.org/10.1007/BF00400747