SCIENCE BEHIND TOTAL ANDROGEN BLOCKADE - FROM GENE TO COMBINATION THERAPY

Probably the most important finding in the endocrine therapy of prosta te cancer is that the testicles and adrenals contribute approximately equal amounts of dihydrotestosterone (DHT), the active androgen that s timulates normal and cancerous prostatic cell growth and function. Str ucture of the cDNAs and genes encoding most of the enzymes responsible for the transformation of the adrenal precursor dehydroepiandrosteron e (DHEA) into DHT have recently been elucidated, namely 3 beta-hydroxy steroid dehydrogenase/Delta(5)-Delta(4) isomerase, 17 beta-hydroxyster oid dehydrogenase, and 5 alpha-reductase. With the action of these enz ymes, DHT is then made locally in the prostate from circulating DHEA o f adrenal origin. Given such an important role of the adrenals, it is essential to use a pure antiandrogen for maximal blockade of the inter action of DHT with the androgen receptor while the testicles are block ed by orchiectomy or treatment with a luteinizing hormone-releasing ho rmone (LHRH) super-agonist. This combination therapy was first develop ed to treat advanced prostate cancer. The multicenter clinical data re cently obtained confirm our original data and demonstrate the major im portance of the intracrine or in situ formation of androgens in the hu man prostate from the inactive adrenal steroid precursors. Combination therapy thus permits, for the first time, to prolong life in advanced prostate cancer and, most importantly, offers the possibility of a ma jor improvement in the efficacy of a curative therapy, namely, radical prostatectomy in early stage disease.