Summary
Using dimethylbenz(a)anthracene (DMBA)-induced mammary tumors in the rat as model, comparison was made of the effect of treatment for 20 days with the aromatase inhibitor 4-hydroxyandrostenedione (4-OH-A) (7.5 mg, twice daily) or the antiandragen flutamide (5 mg, twice daily) on tumor growth as well as on plasma and tumor content of estrogens, androgens, and their precursors and metabolites. Tumor number and size were markedly decreased following treatment with either drug, the effect of treatment being more important on size than number, and on new tumors which developed during treatment than on tumors already present at start of treatment. Treatment with the aromatase inhibitor 4-OH-A caused a parallel decrease in plasma and tumor levels of pregnenolone (Preg), progesterone (P), and 17-OH P, while there was a marked increase in dehydroepiandrosterone (DHEA), androst-5-ene-3β,17β-diol (Δ5-diol), androstenedione (Δ4-dione), testosterone (T), androstane-3α, 17β-diol (3α-diol), and androstane-3β, 17β-diol (3β-diol), with no significant change in dihydrotestosterone (DHT) and 17β-estradiol levels. The marked increase in tissue T content coupled to a decrease in P levels could well contribute to the inhibition of tumor growth induced by 4-OH-A. Flutamide, on the other hand, caused a marked fall in plasma and tissue levels of Preg, 17-OH Preg, P, and 17-OH P, with no significant change in the concentration of the other steroids, thus suggesting a possible role of the fall in tissue P levels in the inhibition of tumor growth. Since both drugs are potent inhibitors of DMBA-induced tumor growth in intact animals, better knowledge of their mechanism of action should add to our understanding of the multiple endocrine factors controlling the growth of these tumors.
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Huggins C, Briziarelli G, Sutton Jr H: Rapid induction of mammary carcinoma in the rat and the influence of hormones on the tumors. J Expl Med 109: 25–41, 1959
Welsch CW: Host factors affecting the growth of carcinogen-induced rat mammary carcinomas: A review and tribute to Charles Brenton Huggins. Cancer Res 45: 2315–3443, 1985
Asselin J, Kelly PA, Caron MG, Labrie F: Control of hormone receptor levels and growth of 7,12-dimethylbenz (a)anthracene-induced mammary tumors by estrogens, progesterone, and prolactin. Endocrinology 101: 666–671, 1977
Leung BS, Sasaki GH, Leung JS: Estrogen-prolactin dependency in 7,12-dimethylbenz(a)anthracene-induced tumors. Cancer Res 35: 621–627, 1975
Garcia M, Rochefort H: Androgen effects mediated by estrogen receptor in 7,12-dimethylbenz(a)anthracene-induced rat mammary tumors. Cancer Res 38: 3922–3929, 1978
Teller MN, Stock CC, Bowie M: Effects of 17α-thioestradiol, two estradiol analogs, and two androgens on 7,12-dimethylbenz(a)anthracene-induced rat mammary tumors. Cancer Res 26: 2329–2331, 1966
Asselin J, Mélaçon R, Moachon G, Bélanger A: Characteristics of binding to estrogen, androgen, progestin, and glucocorticoid receptors in 7,12-dimethylbenz(a)anthracene-induced mammary tumors and their hormonal control. Cancer Res 40: 1612–1622, 1980
Asselin J, Labrie F: Effects of estradiol and prolactin on steroid receptor levels in 7,12-dimethylbenz(a)anthraceneinduced mammary tumors and uterus in the rat. J Steroid Biochem 9: 1079–1082, 1978
Bryan RM, Mercer RJ, Bennett RC, Rennie GC, Lie TH, Morgan FJ: Androgen receptors in breast cancer. Cancer 54: 2436–2440, 1984
Trams G, Maass H: Specific binding of estradiol and dihydrotestosterone in human mammary cancers. Cancer Res 37: 258–261, 1977
Matsumoto K, Sato B, Kitamura Y: Roles of androgen and its receptors in mouse mammary tumor. In: Leung S (ed) Hormonal Regulation of Mammary Tumors, Vol. 1B. Eden Press, Montreal, 1982, pp 216–244
Labrie F, Kelly PA, Asselin J, Raynaud JP: Potent inhibitory activity of a new antiestrogen, RU 16117, on the development and growth of DMBA-induced rat mammary adenocarcinoma. In: St-Arneault G, Band P, Israel L (eds) Recent Results in Cancer Research, Chapter 10, Vol 57. Springer-Verlag, Berlin/Heidelberg, 1976, pp 109–120
Cassell E, Meites J, Welsch CW: Effects of ergocornine and ergocryptine on growth of 7,12-dimethylbenzanthraceneinduced mammary tumors in rats. Cancer Res 31: 1051–1053, 1971
Heuson JC, Waelbroeck C, Legros N, Gallez G, Robyn C, L'Hermite M: Inhibition of DMBA-induced mammary carcinogenesis in the rat by 2-Br-ergocryptine (CB-154), an inhibitor of prolactin secretion, and by nafoxidine (U-11,000A) an estrogen antagonist. Gynec Invest 2: 130–137, 1971
Quadri SK, Kledzik GS, Meites J: Enhanced regression of DMBA-induced mammary cancer in rats by a combination of ergocornine with ovariectomy or high doses of estrogen. Cancer Res 34: 499–501, 1974
Brodie AMH, Schwarzel WC, Shaikh AA, Brodie HJ: The effect of an aromatase inhibitor, 4-hydroxy-4-androstene-3,17-dione, on estrogen-dependent processes in reproduction and breast cancer. Endocrinology 100: 1684–1695, 1977
Brodie AMH, Brodie HJ, Romanoff L, Williams JG, Williams KIH, Wu JT: Inhibition of estrogen biosynthesis and regression of mammary tumors by aromatase inhibitors. Adv Exp Med Biol 138: 179–190, 1982
Wing L, Garrett NM, Brodie AMH: Effects of aromatase inhibitors, aminoglutethimide and 4-hydroxyandrostenedione, on cyclic rats and rats with 7,12-dimethylbenz(a) anthracene-induced mammary tumors. Cancer Res 45: 2425–2428, 1985
Meites J: Relation of prolactin and estrogen to mammary tumor genesis in the rat. J Natl Cancer Inst 48: 1217–1224, 1972
Spinola PG, Marchetti B, Labrie F: Adrenal steroids stimulate growth and progesterone receptor levels in rat uterus and dimethylbenz(a)anthracene (DMBA)-induced mammary tumors. Breast Cancer Res Treat 8: 241–248, 1986
Spinola PG, Marchetti B, Labrie F: The pure antiandrogen Flutamide inhibits the growth of dimethylbenz(a)anthracene-induced mammary tumors in the rat (Abstract). Anticancer Res 6: ©3, Part A, 1986
Brodie AMH, Schwarzel WC, Shaikh AA, Brodie HJ: The effect of an aromatase inhibitor, 4-hydroxy-4-androstene-3, 17-dione, on estrogen-dependent processes in reproduction and breast cancer. Endocrinology 100: 1684–1695, 1977
Bélanger A, Picard V, Caron S: Simultaneous radioimmunoassay of progestins, androgens, and estrogens in the rat testis. J Steroid Biochem 13: 185–190, 1980
Rodbard D, Lewald JE: Computer analysis of radiohgand assay and radioimmunoassay data. In: Diczfalusy E (ed) 2nd Karolinska Symposium in Research Methods in Reproductive Endocrinology. Bogtrykleriet Forum, Copenhagen, 1970 p 79–103
Kramer CY: Extension of multiple range tests to group means with unequal numbers of replication. Biometrics 12: 307–310, 1956
Brodie AMH, Marsh DA, Wu JT, Brodie HJ: Aromatase inhibitors and their use in controlling oestrogen-dependent processes. J Steroid Biochem 11: 107–112, 1979
Brodie AMH, Longcope C: Inhibition of peripheral aromatization by aromatase inhibitors 4-hydroxy and 4-acetoxy androstenedione. Endocrinology 106: 19–21, 1980
Brodie AMH, Wing LY, Goss P, Dowsett M, Coombes RC: Aromatase inhibitors and their potential clinical significance. J Steroid Biochem 25: 859–965, 1986
Proulx L, Drouin J, Labrie F: Role of sex steroids on LH and FSH secretion in the rat. In: Labrie F, Meites J, Pelletier F (eds) Hypothalamus and Endocrine Functions. Plenum, New York, 1976, pp 192–209
Giguère V, Lefebvre FA, Labrie F: Androgens decrease LHRH binding sites in rat anterior pituitary cells in culture. Endocrinology 108: 350–352, 1981
Wing L, Tsai-Morris C, Brodie A: The effect of aromatase inhibitor 4-hydroxyandrostenedione on sex steroid target tissues (Abstract). Proc. of the 7th Int. Congress of Endocrinology, Quebec, 1984, p. 1528, #2535
Robinson SP, Jordan VC: Reversal of the antitumor effects of tamoxifen by progesterone in the 7,12-dimethylbenz(a) anthracene-induced rat mammary carcinoma model. Cancer Res 47: 5386–5390, 1987
Neri R, Florance K, Koziol P, Van Cleave S: A biological profile of a non steroidal antiandrogen, Sch 13521, 4′-nitro-3′-trifluoromethylisobutyranilide. Endocrinology 91: 427–437, 1972
Poyet P, Labrie F: Comparison of the antiandrogenic/androgenic activities of flutamide, cyproterone acetate, and megestrol acetate. Mol Cell Endocrinol 32: 283–288, 1985
Simard J, Luthy I, Guay J, Bélanger A, Labrie F: Characteristics of interaction of the antiandrogen flutamide with the androgen receptor in various target tissues. Mol Cell Endocrinol 44: 261–270, 1986
Labrie C, Cusan L, Plante M, Lapointe S, Labrie F: Analysis of the androgenic activity of synthetic ‘progestins’ currently used for the treatment of prostate cancer. J Steroid Biochem 28: 379–384, 1987
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Spinola, P.G., Marchetti, B., Mérand, Y. et al. Effects of the aromatase inhibitor 4-hydroxyandrostenedione and the antiandrogen flutamide on growth and steroid levels in DMBA-induced rat mammary tumors. Breast Cancer Res Tr 12, 287–296 (1988). https://doi.org/10.1007/BF01811241
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DOI: https://doi.org/10.1007/BF01811241