Androgenic activity of synthetic progestins and spironolactone in androgen-sensitive mouse mammary carcinoma (Shionogi) cells in culture

Abstract

A series of compounds designed to block the action of androgens in target tissues, and called antiandrogens, have been developed for the treatment of androgen-sensitive diseases, especially prostate cancer, hirsutism, precocious puberty and deviant sexual behavior. In order to further assess the androgenic activity of these compounds, we have studied their effect on the growth of an androgen-sensitive clone of the mouse mammary carcinoma Shionogi SC-115 cells in culture. Hydroxyflutamide did not affect the doubling time (7.40 ± 0.09 vs 7.20 ± 0.12 days) characteristic of these cells. However, all of the other compounds tested stimulated cell growth. Thus, in the presence of cyproterone acetate, cells had an accelerated growth rate and shorter generation time of 6.28 ± 0.06 days (P < 0.01). In the presence of 1 μM spironolactone, the generation time was 4.96 ± 0.04 days (P < 0.01). With chlormadinone acetate, the doubling time was reduced to 3.79 ± 0.08 days while for megestrol acetate, the doubling time was 3.63 ± 0.04 days (P < 0.01). The synthetic progestin Medroxyprogesterone acetate had the most potent androgenic effect reducing the doubling time to 1.85 ± 0.05 days (P < 0.01). For comparison, dihydrotestosterone gave a doubling time of 1.76 ± 0.07 days. When hydroxy-flutamide (5 μM) was added simultaneously with each “progestin”, the ED₅₀ value of action of all the compounds was increased in a competitive manner, thus indicating that the mitogenic effect on cell growth of all compounds is mediated by the androgen receptor. Of all the compounds used, only hydroxy-Flutamide was devoid of any androgenic activity and thus meets the criteria of a pure antiandrogen.