Antiandrogens in combination with LH-RH agonists in prostate cancer.
The rationale of the combination of a nonsteroid antiandrogen with an LH-RH analogue (LH-RH-A) in the treatment of prostate cancer is discussed. Whereas the LH-RH-A depresses testosterone (T) levels via an action on the hypothalamus-pituitary-gonad axis, the antiandrogen counters the effect of any residual T, from the testes or adrenals, on the target organ, the prostate. Although bilateral orchiectomy and administration of estrogen or LH-RH-A give equivalent low T levels over long-term treatment, the manner and rate at which T suppression is achieved vary and each treatment presents characteristic disadvantages. Orchiectomy is irreversible, and it is known that approximately 20% of patients will not benefit from such endocrine manipulation, estrogen use is associated with cardiovascular disease, and LH-RH analogues produce an early surge in T. None of these treatments has any significant effect on adrenal androgen levels, which may contribute toward the progression of disease. Nonsteroid antiandrogens such as anandron and flutamide inhibit the uptake of androgen by the prostate by an action that probably involves the androgen receptor. They do not possess the progestational and glucocorticoid component of steroid antiandrogens or their pituitary inhibitory activity but do exert some inhibition of the 17 alpha-hydroxylase and 17,20-lyase enzyme systems. Unlike steroids, the nonsteroid antiandrogens potentiate the activity of LH-RH-A at the central level in the rat. The inhibitory action of the combined treatment of "anandron + buserelin" on the prostate is greater than that of each compound alone. Clinical pharmacology studies have demonstrated that both steroid and nonsteroid antiandrogens can help to control the effect of increased T levels (disease flare) that occur on initiating LH-RH-A administration. Prostatic acid phosphatase (PAP) levels decrease immediately in spite of the increase in T. The decrease appears faster when nonsteroid antiandrogens are used. Nonsteroid antiandrogens sensitize the pituitary to stimulation by LH-RH in eugonadal volunteers. The results of randomized clinical studies with the combination of "nonsteroid antiandrogen + LH-RH-A" have established a definite trend toward greater efficacy of the combined treatment over monotherapy. Further data are needed to confirm this trend. In particular, further dose-ranging studies are warranted since the need for LH-RH-A doses that reduce T down to castration levels may not be justified in the presence of a potent antiandrogen.(ABSTRACT TRUNCATED AT 400 WORDS)
Raynaud
J P
JP
Direction Innovation et Prospective, Roussel-Uclaf, Paris, France.
D000726:Androgen Antagonists / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives*; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy; D011467:Prostate / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy*
D000726:Androgen Antagonists; D007987:Gonadotropin-Releasing Hormone