Differential alterations in 5α‐reductase type 1 and type 2 levels during development and progression of prostate cancer

Thomas, Lynn N.; Lazier, Catherine B.; Gupta, R.; Norman, Richard W.; Troyer, Dean A.; O’Brien, Shane; Rittmaster, Roger S.

doi:10.1002/pros.20188

Cited by 170 publications

(103 citation statements)

References 29 publications

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“…Thomas et al 8 suggested that 5a-R1 is of greater importance in promoting and maintaining prostate cancer as compared to 5a-R2. In an extension of this work, Thomas et al 9 found that 5a-R1 moderate plus high intensity immunostaining was augmented from 4.8% of total epithelial area in BPH to 17% in primary over 38% in recurrent, and 55.8% in metastases of prostate cancer, whereas 5a-R2 showed varying responses. Using semiquantitative reverse transcriptase-PCR it was demonstrated, that 5a-R2 is consistently underexpressed in prostate cancer versus normal or hyperplastic prostates.…”

Section: Methodssupporting

confidence: 51%

5α-Reductase inhibitor treatment of prostatic diseases: background and practical implications

Dörsam¹,

Altwein

2008

Prostate Cancer Prostatic Dis

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This literature review discusses the theoretical background of 5a-reductase inhibitor (5ARI) treatment and the resulting clinical implications. A Medline-based search for peer-reviewed articles addressing 5ARIs, benign prostatic hyperplasia and prostate cancer was performed. The 5ARIs Finasteride and Dutasteride, which specifically inhibit the production of dihydrotestosterone by acting as competitive inhibitors of 5a-reductase, are clinically well tolerated and represent an effective treatment option for benign prostatic obstruction. Finasteride is the first compound which has a proven efficacy in chemoprevention of prostate cancer. The aim of this review was to elucidate, if there are sufficient data available to point out clinically relevant differences between the drugs. Both compounds achieve a significant reduction of prostate volume, an improvement of symptoms and a lower risk of acute urinary retention. Whether the different pharmacokinetic and pharmacodynamic properties of Finasteride and Dutasteride are of clinical importance cannot be judged at this time.

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Section: Methodssupporting

confidence: 51%

5α-Reductase inhibitor treatment of prostatic diseases: background and practical implications

Dörsam¹,

Altwein

2008

Prostate Cancer Prostatic Dis

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“…3). 21 In contrast, type 2 expression is lower in PIN and primary cancer compared with that in BPH and no different from that in BPH in recurrent and metastatic prostate cancer. Another study has also shown higher type 1 than type 2 expression in recurrent prostate cancer, androgen stimulated benign prostate and androgen stimulated prostate cancer, 22 and a 2.1-fold increase in type 1 expression in metastatic vs primary cancer.…”

Section: Expression Of 5αr In Health and Diseasementioning

confidence: 96%

The Rationale for Inhibiting 5α-Reductase Isoenzymes in the Prevention and Treatment of Prostate Cancer

2008

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Purpose-Androgens are essential for prostatic growth and development but they also have a significant role in prostate disease pathogenesis. Dihydrotestosterone, the primary prostatic androgen, is transformed from testosterone by types 1 and 2 5α-reductase and, thus, a potential therapeutic benefit could be achieved through the inhibition of 5α-reductase.Materials and Methods-A literature review was performed using PubMed®/MEDLINE® and congress abstracts to examine evidence supporting the potential of 5α-reductase inhibitors in the primary prevention of prostate cancer and in limiting the progression of diagnosed disease.Results-Prostate disease development is associated with increased expression of each 5α-reductase isoenzyme with over expression of type 1 of particular importance in prostate cancer development and progression. The 2 5α-reductase inhibitors currently clinically available are finasteride, a type 2 5α-reductase inhibitor, and dutasteride, a dual 5α-reductase inhibitor. Dual inhibition by dutasteride has been shown to translate into a greater degree and consistency of dihydrotestosterone suppression compared with finasteride. The Prostate Cancer Prevention Trial showed that finasteride significantly decreased the 7-year risk of prostate cancer in men with prostate specific antigen 3.0 ng/ml or less, while the ongoing Reduction by Dutasteride of Prostate Cancer Events study is assessing whether dutasteride decreases the risk of biopsy detectable prostate cancer in men with prostate specific antigen 2.5 to 10 ng/ml and a previous negative biopsy. Small-scale studies have demonstrated potential effects of 5α-reductase inhibition in prostate cancer treatment that warrant further investigation, while dutasteride use in men undergoing expectant treatment is also being examined.Conclusions-The inhibition of 5α-reductase represents a valid target for prostate cancer risk reduction and treatment strategies. The greater suppression of dihydrotestosterone observed with agents that inhibit each 5α-reductase isoenzyme may translate into enhanced outcomes and studies are under way to test this hypothesis. Keywordsprostate; prostatic neoplasms; cholestenone 5 alpha-reductase; androgens; dihydrotestosterone Prostate cancer is the most common cancer and a leading cause of cancer death in men. Decreasing the risk of cancer (primary prevention) could offer substantive benefits, while slowing or preventing disease progression (secondary prevention) or delaying progression in those in whom curative therapy (tertiary prevention) fails could decrease prostate cancer related

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“…HSD17B3 mRNA was increased over 30 fold in PCa biopsies and the enzyme has been shown to be upregulated 8-fold in LuCaP-23 and LuCAP-35 PCa cell lines, obtained from metastatic tissues of a patient resistant to castration therapy [15,22] SRD5 A1 During PCa development its expression increases. A 2-4 fold increase of SRD5A1 expression, induced by activation of AR, has been observed in three androgen-responsive PCa cell lines [88,89,[178][179][180][181] A2 Predominant isoform expressed in the normal prostate. During PCa development, its expression decreases.…”

Section: Cyp17a1mentioning

confidence: 93%

Androgen-AR axis in primary and metastatic prostate cancer: chasing steroidogenic enzymes for therapeutic intervention

Pippione¹,

Boschi²,

Pors³

et al. 2017

JCMT

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Androgens play an important role in prostate cancer (PCa) development and progression. Although androgen deprivation therapy remains the front-line treatment for advanced prostate cancer, patients eventually relapse with the lethal form of the disease. The prostate tumor microenvironment is characterised by elevated tissue androgens that are capable of activating the androgen receptor (AR). Inhibiting the steroidogenic enzymes that play vital roles in the biosynthesis of testosterone (T) and dihydrotestosterone (DHT) seems to be an attractive strategy for PCa therapies. Emerging data suggest a role for the enzymes mediating pre-receptor control of T and DHT biosynthesis by alternative pathways in controlling intratumoral androgen levels, and thereby influencing PCa progression. This supports the idea for the development of multi-targeting strategies, involving both dual and multiple inhibitors of androgen-metabolising enzymes that are able to affect androgen synthesis and signalling at different points in the biosynthesis. In this review, we will focus on CYP17A1, AKR1C3, HSD17B3 and SRD5A, as these enzymes play essential roles in all the three androgenic pathways. We will review also the AR as an additional target for the design of bifunctional drugs. Targeting intracrine androgens and AKR1C3 have potential to overcome enzalutamide and abiraterone resistance and improve survival of advanced prostate cancer patients.

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Differential alterations in 5α‐reductase type 1 and type 2 levels during development and progression of prostate cancer

Cited by 170 publications

References 29 publications

5α-Reductase inhibitor treatment of prostatic diseases: background and practical implications

5α-Reductase inhibitor treatment of prostatic diseases: background and practical implications

The Rationale for Inhibiting 5α-Reductase Isoenzymes in the Prevention and Treatment of Prostate Cancer

Androgen-AR axis in primary and metastatic prostate cancer: chasing steroidogenic enzymes for therapeutic intervention

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