The pure antiandrogen RU 23908 (Anandron), a candidate of choice for the combined antihormonal treatment of prostatic cancer: a review.
The nonsteroidal antiandrogen RU 23908 ( Anandron ) weakly interacts with the prostatic cytosolic androgen receptor and shows a fast dissociation rate. When administered to immature castrated rats up to the daily dose of 100 mg/kg, it is devoid of any androgenic activity but efficiently blocks the growth-promoting activity of androgens on ventral prostate and seminal vesicle weight, thus showing the characteristics of a pure antiandrogen. In intact animals, on the other hand, the antiandrogen administered alone exerts only a partial inhibition of prostate and seminal vesicle weight. This is due to the property of the pure antiandrogen to neutralize the inhibitory feedback effect of androgens at the pituitary level on the LH responsiveness to LHRH, as illustrated in vitro in rat anterior pituitary cells in culture as well as in vivo in intact and castrated animals. In intact animals, neutralization of the inhibitory feedback action of endogenous androgens leads to an increased LH and testosterone secretion, which partly overcomes the direct action of the antiandrogen at the level of the prostate and seminal vesicles. In fact, the plasma testosterone concentration is more than doubled 6 hr after the administration of 10 mg of RU 23908 while plasma LH and testosterone levels are increased by 7- and 17-fold, respectively, after 14 days of similar daily treatment. Efficient neutralization of the androgenic action at the prostatic level in intact animals thus requires prevention of this escape phenomenon through inhibition of LH secretion. Although inhibition of LH release can be achieved by estrogen and progestins, an optimal inhibitory effect on the prostate is obtained by the combined administration of the antiandrogen with an LHRH agonist that causes a specific blockage of testicular androgen biosynthesis as well as an inhibition of the LH responsiveness to LHRH.
D000726:Androgen Antagonists / Q000494:pharmacology*; D000728:Androgens / Q000378:metabolism; D000818:Animals; D004359:Drug Therapy, Combination; D005246:Feedback; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D048289:Imidazolidines; D066298:In Vitro Techniques; D007986:Luteinizing Hormone / Q000378:metabolism; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011944:Receptors, Androgen / Q000378:metabolism
D000726:Androgen Antagonists; D000728:Androgens; D007093:Imidazoles; D048289:Imidazolidines; D011944:Receptors, Androgen; D007987:Gonadotropin-Releasing Hormone; C021277:nilutamide; D007986:Luteinizing Hormone