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Type 1 and type 2 5alpha-reductase expression in the development and progression of prostate cancer.

Thomas LN, Douglas RC, Lazier CB, Too CK, Rittmaster RS, Tindall DJ

Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada. lynn.thohmas@dal.ca

OBJECTIVES: Both normal and pathological growth of the prostate is dependent on dihydrotestosterone (DHT) synthesis, which is catalysed by two 5alpha-reductase (5alphaR) isoenzymes, 5alphaR1 and 5alphaR2, of which only 5alphaR2 has traditionally been viewed as important in the prostate. The objective of this study was to evaluate the role of both isoenzymes during development/progression of prostate cancer. METHODS: A thorough literature search was performed with the MEDLINE database to identify studies that have assessed expression of 5alphaR1/2 in prostate tissue. RESULTS: DHT suppression data for the 5alphaR2-specific inhibitor, finasteride, and the dual 5alphaR1/2 inhibitor, dutasteride, show that both isoenzymes are active in benign prostate. Furthermore, immunostaining studies have shown that 5alphaR1 expression increases and 5alphaR2 expression decreases in prostatic intraepithelial neoplasia (PIN) and prostate cancer, compared with nonmalignant prostate tissue. Both isoenzymes appear increased in high-grade compared with low-grade localised cancer. Dual inhibition of both isoenzymes with dutasteride may, therefore, be effective in preventing or delaying the growth of prostate cancer. The 4-yr REduction by DUtasteride of prostate Cancer Events (REDUCE) trial is underway to test this hypothesis. Androgen-withdrawal therapy can reverse prostate tumour growth by reducing circulating testosterone. However, 5alphaR-catalysed DHT synthesis within the prostate can continue and most tumours eventually develop resistance to androgen-deprivation therapy. Full assessment of the role of a 5alphaR inhibitor in this scenario is warranted. CONCLUSIONS: The consensus of evidence to date shows that 5alphaR1 is present in the prostate, and that levels are higher in malignant compared with benign prostate hyperplasia tissue.

Published 24 December 2007 in Eur Urol, 53(2): 244-52.
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