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Controlled release low dose medroxyprogesterone acetate (MPA) inhibits the development of mammary tumors induced by dimethyl-benz(a) anthracene in the rat

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Summary

Medroxyprogesterone acetate (MPA) is well recognized to have beneficial effects for the treatment of advanced breast cancer which are comparable to those achieved with other forms of endocrine therapy. Using mammary tumors induced in the rat by dimethylbenz(a)anthracene (DMBA) as a model, we have studied the possibility that low dose MPA could prevent the development of these tumors. Single subcutaneous injection of Depo-Provera (crystalline suspension of MPA) or MPA encapsulated in biodegradable microspheres of 50 : 50 poly[DL-lactide-co-glycolide] was given 7 days before oral DMBA. While 63% of intact animals developed palpable mammary tumors within 85 days after DMBA administration, tumor incidence decreased to 28% and 23% in animals who had received 30 mg and 100 mg of Depo-Provera, respectively. The same amounts of MPA delivered in microspheres caused a further decrease in tumor incidence to respective values of 7% and 6%. Average tumor area, on the other hand, decreased from 4.89 cm2 in intact rats to about 0.75 (0.57–0.88) cm2 and approximately 0.20 (0.14–0.22) cm2 in the Depo-Provera and microsphere-treated groups, respectively. Using the 50 : 50 formulation of poly[DL-lactide-co-glycolide] designed to release MPA at a constant rate for a 4-month period, the serum MPA concentration at 3 months was measured at 4.99 ± 0.43 ng/ml. Such data suggest that administration of a low dose controlled-release formulation of MPA in 50 : 50 poly[DL-lactide-co-glycolide] microspheres could well be an efficient and well tolerated approach for the prevention of breast cancer in women.

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References

  1. American Cancer Society: Cancer Facts and Figures, 1992

  2. Sledge GW, McGuire WL: Steroid hormone receptors in human breast cancer. Cancer Res 38: 61–75, 1984

    Google Scholar 

  3. Witliff JL: Steroid hormone receptors in breast cancer. Cancer 53: 630–643, 1984

    Google Scholar 

  4. Poulin R, Labrie F: Stimulation of cell proliferation and estrogenic response by adrenal C19-Δ5 steroids in the ZR-75-1 human breast cancer cell line. Cancer Res 46: 4933–4937, 1986

    Google Scholar 

  5. Poulin R, Baker D, Labrie F: Androgens inhibit basal and estrogen-induced cell proliferation in the ZR-75-1 human breast cancer cell line. Breast Cancer Res Treat 12: 213–225, 1988

    Google Scholar 

  6. Poulin R, Baker D, Poirier D, Labrie F: Androgen and glucocorticoid receptor-mediated inhibition of cell proliferation by medroxyprogesterone acetate in ZR-75-1 human breast cancer cells. Breast Cancer Res Treat 13: 161–172, 1989

    Google Scholar 

  7. Poulin R, Simard J, Labrie C, Petitclerc L, Dumont M, Lagacé L, Labrie F: Down-regulation of estrogen receptors by androgens in the ZR-75-1 human breast cancer cell line. Endocrinology 125: 392–399, 1989

    Google Scholar 

  8. Simard J, Hatton AC, Labrie C, Dauvois S, Zhao H, Haagensen DE, Labrie F: Inhibitory effect of estrogens on GCDFP-15 mRNA levels and secretion in ZR-75-1 human breast cancer cells. Mol Endocrinol 31: 694–702, 1989

    Google Scholar 

  9. Dumont M, Dauvois S, Simard J, Garcia T, Schachter B, Labrie F: Antagonism between estrogens and androgens on GCDFP-15 gene expression in ZR-75-1 cells and correlation between GCDFP-15 and estrogen as well as progesterone receptor expression in human breast cancer. J Steroid Biochem 34: 397–402, 1989

    Google Scholar 

  10. Simard J, Dauvois S, Haagensen DE, Lévesque C, Mérand Y, Labrie F: Regulation of progesterone-binding breast cyst protein GCDFP-24 secretion by estrogens and androgens in human breast cancer cells: a new marker of steroid action in breast cancer. Endocrinology 126: 3223–3231, 1990

    Google Scholar 

  11. Fels E: Treatment of breast cancer with testosterone proprionate. A preliminary report. J Clin Endocrinol 4: 121–125, 1944

    Google Scholar 

  12. Segaloff A, Gordon D, Horwitt BN, Schlosser JV, Murison PJ: Hormonal therapy in cancer of the breast. 1. The effect of testosterone propionate therapy on clinical course and hormonal excretion. Cancer 4: 319–323, 1951

    Google Scholar 

  13. Cooperative Breast Cancer Group: Testosterone propionate therapy of breast cancer. J Amer Med Assoc 188: 1069–1072, 1964

    Google Scholar 

  14. Kennedy BJ: Fluoxymesterone therapy in treatment of advanced breast cancer. New Engl J Med 259: 673–675, 1958

    Google Scholar 

  15. Gordon GS: Cancer in man. In Kochakian CD (ed) Handbook of Experimental Pharmacology. Springer-Verlag, New York, 1976, p 499

    Google Scholar 

  16. Segaloff A: The use of androgens in the treatment of neoplastic disease. Pharmac Ther C2: 33–37, 1977

    Google Scholar 

  17. Wagner RK, Jungblut PW: Oestradiol and dihydrotestosterone receptors in normal and neoplastic human mammary tissue. Acta Endocrinol 82: 105–120, 1976

    Google Scholar 

  18. Trams G, Maass H: Specific binding of estradiol and dihydrotestosterone in human mammary cancer. Cancer Res 37: 258–261, 1977

    Google Scholar 

  19. Allegra JC, Lippman ME, Thompson EG, Simon R, Green L, Barlock A, Huff KK, Aitkin S, Do HMT, Warren R: Distribution of frequency and quantitative analysis of estrogen, progesterone, androgen and glucocorticoid receptors in human breast cancer. Cancer Res 39: 1447–1454, 1979

    Google Scholar 

  20. Miller WR, Telford J, Dixon JM, Hawkins RA: Androgen receptor activity in human breast cancer and its relationship with oestrogen and progesterone receptor activity. Brit J Cancer Clin Oncol 21: 539–542, 1985

    Google Scholar 

  21. Bryan RM, Mercer RJ, Bennett RC, Rennie GC, Lie TH, Morgan FJ: Androgen receptors in breast cancer. Cancer 54: 2436–2440, 1984

    Google Scholar 

  22. Mattsson W: Current status of high dose progestin treatment in advanced breast cancer. Breast Cancer Res Treat 3: 231–235, 1983

    Google Scholar 

  23. Blumenschein GR: The role of progestins in the treatment of breast cancer. Semin Oncol 10: 7–10, 1983

    Google Scholar 

  24. Hortobagyi GN, Buzdar AM, Frye D, Yap HY, Hug V, Pinnamaneni K, Fraschini G, Halvorson HC, Blumenschein GR: Oral medroxyprogesterone acetate in the treatment of metastatic breast cancer. Breast Cancer Res Treat 5: 321–326, 1985

    Google Scholar 

  25. Haller DG, Glick JH: Progestational agents in advanced breast cancer: an overview. Semin Oncol 13: 2–8, 1986

    Google Scholar 

  26. Poulin R, Baker D, Poirier D, Labrie F: Multiple actions of synthetic ‘progestins’ on the growth of ZR-75-1 human breast cancer cells: anin vitro model for the simultaneous assay of androgen, progestin, estrogen and glucocorticoid agonistic and antagonistic activities of compounds. Breast Cancer Res Treat 17: 197–210, 1990

    Google Scholar 

  27. Dauvois S, Geng CS, Lévesque C, Mérand Y, Labrie F: Additive inhibitory effects of an androgen and the antiestrogen EM-170 on estradiol-stimulated growth of human ZR-75-1 breast tumors in athymic mice. Cancer Res 51: 3131–3135, 1991

    Google Scholar 

  28. Huggins C, Briziarelli G, Sutton Jr H: Rapid induction of mammary carcinoma in the rat and the influence of hormones on the tumors. J Exp Med 109: 25–41, 1959

    Google Scholar 

  29. 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

    Google Scholar 

  30. Welsch CW: Host factors affecting the growth of carcinogen-induced rat mammary carcinomas: a review and tribute to Charles Brenton Huggins. Cancer Res 45: 3415–3443, 1985

    Google Scholar 

  31. 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

    Google Scholar 

  32. Plante M, Lapointe S, Labrie F: Stimulatory effect of synthetic progestins currently used for the treatment of prostate cancer on growth of the androgen-sensitive Shionogi tumor in mice. J Steroid Biochem 31: 61–64, 1988

    Google Scholar 

  33. Luthy IA, Bégin DJ, Labrie F: Androgenic activity of synthetic progestins and spironolactone in androgen-sensitive mouse mammary carcinoma (Shionogi) cells in culture. J Steroid Biochem 31: 845–852, 1988

    Google Scholar 

  34. Labrie C, Simard J, Zhao HF, Pelletier G, Labrie F: Synthetic progestins stimulate prostatic binding protein messenger RNAs in the rat ventral prostate. Mol Cell Endocrinol 68: 169–179, 1990

    Google Scholar 

  35. Dauvois S, Spinola PG, Labrie F: Additive inhibitory effects of bromocriptine (CB-154) and medroxyprogesterone acetate (MPA) on dimethylbenz(a)anthracene (DMBA)-induced mammary tumors in the rat. Eur J Cancer Clin Oncol 24: 891–897, 1989

    Google Scholar 

  36. Bélanger A, Picard V, Caron S: Simultaneous radioimmunoassay of progestins, androgens, and estrogens in the rat testis. J Steroid Biochem 13: 185–191, 1985

    Google Scholar 

  37. Bélanger A, Labrie F, Angeli A: Unconjugated and glucuronide steroids levels in human breast cyst fluid. In: Angeli A, Bradlow HL, Chasalow FI, Gogliotti L (eds) Biochemistry of breast cyst fluid. Correlation with breast cancer risk. Annals of the New York Academy of Sciences, vol 586, 1990, pp 93-100

  38. Kramer CY: Extension of multiple range tests to group means with unequal numbers of replications. Biometrics 12: 307–310, 1956

    Google Scholar 

  39. Jabara AG: Effects of progesterone on 9,10-dimethyl-2-benzanthracene-induced mammary tumors in Sprague-Dawley rats. Brit J Cancer 21: 418–429, 1967

    Google Scholar 

  40. Kelly PA, Asselin J, Turcot-Lemay L, Labrie F, Raynaud JP: Effects of progesterone and R2323 on the development of dimethylbenz(a)anthracene-induced mammary tumors. Eur J Cancer 15: 1243–1251, 1979

    Google Scholar 

  41. McCormick GM, Moon RC: Effect of increasing doses of estrogen and progesterone on mammary carcinogenesis in the rat. Eur J Cancer 9: 483–486, 1973

    Google Scholar 

  42. Terenius L: Effect of antiestrogens on initiation of mammary cancer in the female rat. Eur J Cancer 7: 65–70, 1971

    Google Scholar 

  43. Kledzik GS, Bradley CJ, Meites J: Reduction of carcinogen-induced mammary cancer incidence in rats by early treatments with hormones or drugs. Cancer Res 34: 2953–2956, 1974

    Google Scholar 

  44. Ferland L, Drouin J, Labrie F: Role of sex steroids on LH and FSH secretion in the rat. In: Labrie F, Meites J, Pelletier G (eds) Hypothalamus and Endocrine Functions. Plenum Press, New York, 1976, pp 191–209

    Google Scholar 

  45. Drouin J, Labrie F: Selective effect of androgens on LH and FSH release in anterior pituitary cells in culture. Endocrinology 98: 1528–1534, 1976

    Google Scholar 

  46. Labrie F, Peletier G, Raynaud JP, Ducommun P, Delgago A, MacIntosh B, Fortier C: Liaison transcortine-corticostéroïdes et interactions entre hypophyse, thyroïde, surrénales et gonades. Médecine & Hygiène 28: 266–281, 1970

    Google Scholar 

  47. Asselin J, Mélançon 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

    Google Scholar 

  48. Witliff JL: Steroid-binding proteins in normal and neoplastic mammary cells. In: Bush H (ed) Methods in Cancer Research. Academic Press, New York, vol 11, 1975, pp 298–304

    Google Scholar 

  49. Lippman M, Bolan G, Huff K: The effects of androgens and antiandrogens on hormone-responsive human breast cancer in long-term tissue culture. Cancer Res 36: 4610–4618, 1976

    Google Scholar 

  50. Horwitz KB, Zava DT, Thilagar AK, Jensen EM, McGuire WL: Steroid receptor analyses of nine human breast cancer cell lines. Cancer Res 38: 2434–2437, 1978

    Google Scholar 

  51. Nathanson IT: Endocrine aspects of human cancer. Rec Progr Horm Res 1: 261–291, 1947

    Google Scholar 

  52. Adair FE, Herrmann JB: The use of testosterone propionate in the treatment of advanced carcinoma of the breast. Ann Surg 123: 1023–1035, 1946

    Google Scholar 

  53. Adair FE: The use of male sex hormone in women with breast cancer. Surg Gynecol Obstet 84: 719–722, 1947

    Google Scholar 

  54. Adair FE, Mellors RC, Farrow JH, Woodard HQ, Escher GS, Urban JA: The use of estrogens and androgens in advanced mammary cancer. J Amer Med Assoc 15: 1193–2000, 1949

    Google Scholar 

  55. Poulin R, Labrie F: Stimulation of cell proliferation and estrogenic trogenic response by adrenal C19-Δ5-steroids in the ZR-75-1 human breast cancer cell line. Cancer Res 46: 4933–4937, 1986

    Google Scholar 

  56. Dauvois S, Li S, Martel C, Labrie F: Inhibitory effect of androgens on DMBA-induced mammary carcinoma in the rat. Breast Cancer Res Treat 14: 299–306, 1989

    Google Scholar 

  57. Horwitz KB: The structure and function of progesterone receptors in breast cancer. J Steroid Biochem 27: 447–457, 1987

    Google Scholar 

  58. Lippman ME: Antiestrogen therapy of breast cancer. Semin Oncol 10: (suppl) 11–19, 1983

    Google Scholar 

  59. Blossey HC, Wander HE, Kiebberling J, Nagel GA: Pharmacokinetic and pharmacodynamic basis for the treatment of metastatic breast cancer with high-dose medroxyprogesterone acetate. Cancer 54: 1208–1215, 1984

    Google Scholar 

  60. van Veelen H, Willemse PHB, Sleijfer DT, van der Ploeg E, Sluiter WJ, Doorenbos H: Mechanism of adrenal suppression by high-dose medroxyprogesterone acetate in breast cancer patients. Cancer Chemother Pharmacol 15: 167–170, 1985

    Google Scholar 

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Authors and Affiliations

  1. MRC Group in Molecular Endocrinology, CHUL Research Center and Laval University, 2705 Laurier Boulevard, Quebec, G1V 4G2, Québec, Canada

    Fernand Labrie, Shengmin Li, Alain Bélanger, Jean Côté, Yves Mérand & Martin Lepage

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  1. Fernand Labrie
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  2. Shengmin Li
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Labrie, F., Li, S., Bélanger, A. et al. Controlled release low dose medroxyprogesterone acetate (MPA) inhibits the development of mammary tumors induced by dimethyl-benz(a) anthracene in the rat. Breast Cancer Res Tr 26, 253–265 (1993). https://doi.org/10.1007/BF00665803

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