Pharmacology of antiandrogens and value of combining androgen suppression with antiandrogen therapy.

Antiandrogens are compounds able to block the effect of androgens directly on their target cells by inhibiting their binding to the androgen receptor (AR). Two chemical classes of antiandrogens are presently on the market or in clinical trials: steroids (cyproterone, megestrol acetates), and nonsteroids (flutamide, nilutamide). Steroid antiandrogens interact not only with AR but also with progestin and glucocorticoid receptors and thus give rise to progestin and glucocorticoid effects. By contrast, nonsteroid antiandrogens interact only with AR and are thus devoid of other hormonal or antihormonal activities. Nilutamide does not need to be transformed into an active metabolite, unlike flutamide, and interacts with dog, rat, and human prostate AR in vitro. Its kinetics lead to a prolonged interaction with AR in vivo after administration to rats. In prostate cancer treatment, it is necessary to combine an antiandrogen to surgical or chemical (estrogens, LH-RH agonists) castration to obtain a complete suppression of androgens. The antiandrogen will block specifically, at the target site, the trophic effect of adrenal androgens left intact by castration, and the secretion of which can only be suppressed by treatments (adrenalectomy, aminoglutethimide, ketoconazole) that also suppress corticoid synthesis. We have shown that nilutamide counteracts the trophic effect, on the prostate of castrated rats, of adrenal androgens administered continuously (minipumps) at circulating levels similar to those recorded in castrated men. Nilutamide will also impede the flare-up effect of the testosterone increase induced by LH-RH agonists at the beginning of treatment. We have shown in the rat treated with buserelin that the increase in prostate weight observed during the initial days of treatment by the LH-RH agonist can be inhibited by a combined treatment with nilutamide. This combined treatment "nilutamide plus castration" has been tested in an experimental androgen-dependent cancer model, the Shionogi tumor. The administration of nilutamide to mice, castrated twenty-four hours before the inoculation of tumor cells, delayed the appearance of tumors and reduced their number. Finally, the absence of androgen effect and the antiandrogen activity of the product were also demonstrated in human tumor cells in culture (T-47 D cells) transfected with the MMTV androgen-dependent promoter coupled with the CAT reporter gene.