Key targets of hormonal treatment of prostate cancer. Part 2: the androgen receptor and 5alpha-reductase.
OBJECTIVE
The inhibition of 5alpha-reductase (5AR) blocks the synthesis of the most powerful intracellular androgen, dihydrotestosterone (DHT). The prostate has two 5AR isoenzymes (5AR1 and 5AR2) that change in expression and cellular location during the development of prostate cancer and tumour progression. The objective of this review is to provide an understanding of the pharmacological properties and the potential clinical benefits of 5AR inhibition.


METHODS
We searched Pubmed for data obtained from pharmacological, preclinical and clinical studies.


RESULTS
5AR1 expression increases with increasing aggressiveness and extension of malignant prostatic disease. Conversely, 5AR2 expression decreases from benign prostatic tissue to localized prostate cancer. The efficacy of 5AR2 monotherapy with finasteride alone or in combination with an androgen receptor antagonist on more final outcome measures seems to be limited. Combining an androgen receptor antagonist with a 5AR inhibitor in patients with asymptomatic, locally advanced or recurrent prostate cancer might be a reasonable first therapeutic hormonal approach. As plasma testosterone levels are maintained, beneficial effects on quality of life, potency and sexual function are expected. From studies on the dual 5AR inhibitor dutasteride, the drug produces a biochemical response in some men who progressed under androgen-deprivation therapy, and is generally well tolerated.


CONCLUSIONS
Achieving more potent suppression of intracellular DHT synthesis by 5AR inhibition is expected to provide clinical benefit to patients. Previous studies have shown that 5AR inhibition, by dutasteride in particular, halts/delays the progression of disease, and might even cause regression of disease in patients with advanced prostate cancer.
Vis
André N
AN
Department of Urology, VU Medical Centre, Amsterdam, the Netherlands. a.vis@vumc.nl
Schröder
Fritz H
FH
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism; D058891:5-alpha Reductase Inhibitors; D059002:Androgen Receptor Antagonists; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001378:Azasteroids / Q000737:chemistry / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D000068538:Dutasteride; D018120:Finasteride / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology
D058891:5-alpha Reductase Inhibitors; D059002:Androgen Receptor Antagonists; D018931:Antineoplastic Agents, Hormonal; D001378:Azasteroids; D018120:Finasteride; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D000068538:Dutasteride