5α还原酶抑制剂与前列腺癌预防

5α还原酶抑制剂通过抑制5α还原酶降低双氢睾酮水平。应用5α还原酶抑制剂进行的前列腺癌预防研究显示,5α还原酶抑制剂可以降低前列腺癌发病率,但同时也出现高级别前列腺癌病例增加的现象,引起广泛关注。有研究和分析显示,5α还原酶抑制剂使前列腺体积缩小,同时也缩小Gleason评分为3分患者的前列腺癌体积,使得再次穿刺更容易发现Gleason评分为4分以上的前列腺癌。另外5α还原酶抑制剂显著提高前列腺穿刺诊断前列腺癌和高级别前列腺癌敏感度。笔者认为5α还原酶抑制剂不但不增加高级别前列腺癌的发生率,反而会帮助我们更早发现高级别前列腺癌。     

Key targets of hormonal treatment of prostate cancer. Part 2: the androgen receptor and 5α‐reductase

OBJECTIVE

The inhibition of 5α‐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.     

Decreased gene expression of steroid 5 alpha-reductase 2 in human prostate cancer: implications for finasteride therapy of prostate carcinoma

BACKGROUND: Steroid 5alpha-reductase 2 (SRD5A2) catalyzes the conversion of testosterone to the more potent androgen, DHT, in the prostate. The therapeutic influence of SRD5A2 inhibitor finasteride on prostate cancer is currently unknown. The direction and extent of changes in SRD5A2 expression in disease tissues is a relevant issue in this regard. METHODS: The expression differences of SRD5A2 in tissues representative of normal, benign, and malignant growth in the human prostate were examined in parallel by comparative analysis of relevant microarray gene expression data. Semiquantitative RT-PCR was used to further verify the gene expression differences of SRD5A2. RESULTS: Consistently decreased expression of SRD5A2 was observed in 25 prostate cancer samples when compared to 25 matched normal samples and nine BPH samples. Expression differences among these samples for six other genes were presented in parallel as indicators of the direction and extent of expression changes. These additional genes include SRD5A1, Hepsin (overexpressed in prostate cancer), AMACR (overexpressed in prostate cancer), Keratin 8 (epithelial marker), smooth muscle actin (stromal marker), Nell2 (overexpressed in BPH). Semiquantitative RT-PCR verified the expression differences for SRD5A2 in six normal, six BPH, and six prostate cancer samples. CONCLUSIONS: Results from this study, combined with those from previous studies, indicate an association of prostate cancer with reduced 5alpha-reductase enzymatic activity as a result of remarkably decreased expression of the SRD5A2 gene. The implications of this study for finasteride therapy of prostate cancer are discussed.     

Can dutasteride delay or prevent the progression of prostate cancer in patients with biochemical failure after radical therapy? Rationale and design of the Avodart after Radical Therapy for Prostate Cancer Study

OBJECTIVE

To describe the Avodart after Radical Therapy for prostate cancer Study (ARTS), investigating the use of dutasteride (a dual 5α‐reductase inhibitor that suppresses intraprostatic dihydrotestosterone, reduces tumour volume and improves other markers of tumour regression in prostate cancer) to prevent or delay disease progression in patients with biochemical recurrence after therapy with curative intent.

PATIENTS AND METHODS

An increasing serum prostate‐specific antigen (PSA) level after radical prostatectomy (RP) or radiotherapy (RT) is indicative of recurrent prostate cancer and typically pre‐dates clinically detectable metastatic disease by several years. ARTS is an ongoing European multicentre trial in which patients are stratified by previous therapy (RP with or without salvage RT vs primary RT) and randomized to double‐blind treatment with dutasteride 0.5 mg or placebo once daily for 2 years. Eligible patients will have a PSA doubling time (DT) of 3–24 months. Biochemical recurrence is defined as three increases in PSA level from the nadir, with each increase ≥4 weeks apart and each PSA level ≥0.2 ng/mL, and a final PSA level of ≥0.4 ng/mL (after RP) or ≥2 ng/mL (after primary RT). Study endpoints include time to PSA doubling, time to disease progression, treatment response (PSA decrease or an increase of ≤15% from baseline), changes in PSA and PSADT, and changes in anxiety (Memorial Anxiety Scale for Prostate Cancer).

CONCLUSIONS

ARTS will be the first study to evaluate the effects of dutasteride on PSADT, disease progression and treatment response in patients with biochemical failure after RP or RT, and should help to elucidate the potential role of dual 5α‐reductase inhibition in prostate cancer.     

5-α-Reductase inhibitors for prostate cancer chemoprevention: an updated Cochrane systematic review

OBJECTIVE

• ? To estimate the benefits and harms of 5‐α‐reductase inhibitors (5‐α‐RIs) in preventing prostate cancer.

MATERIALS AND METHODS

• ? We searched MEDLINE and the Cochrane Collaboration Library through June 2010 to identify randomized trials.
• ? We included articles if they examined 5‐α‐RI vs control, were ≥1 year in duration and provided clinical outcomes.
• ? Our primary outcome was prostate cancer period‐prevalence ‘for‐cause’.

RESULTS

• ? Eight studies met inclusion criteria but only the Prostate Cancer Prevention Trial and the Reduction by Dutasteride of Prostate Cancer Events were designed to assess the impact of 5‐α‐RIs on prostate cancer period‐prevalence. The mean age of enrolees was 64 years, 92% were White, and mean PSA level was 3.1 ng/mL. For‐cause prostate cancers comprised 54% of all cancers detected in placebo‐controlled studies.
• ? Compared with placebo, 5‐α‐RI resulted in a 25% relative risk (RR) reduction in prostate cancers detected for‐cause [RR 0.75, 95% confidence interval (CI) 0.67–0.83; 1.4% absolute risk reduction (3.5% vs 4.9%)]. One BPH trial reported that the risk of prostate cancers detected for‐cause was significantly reduced with dutasteride and combined dutasteride plus tamsulosin compared with tamsulosin monotherapy.
• ? Six trials vs placebo assessed prostate cancers detected overall. There was a 26% RR reduction favouring 5‐α‐RI [RR 0.74, 95% CI 0.55–1.00; 2.9% absolute risk reduction (6.3% vs 9.2%)]. There were reductions across categories of age, race and family history of prostate cancer.
• ? One placebo‐controlled trial of men that investigators considered at greater risk for prostate cancer (based on age, elevated PSA level and having a previous suspicion of prostate cancer leading to a prostate biopsy) reported that dutasteride did not reduce prostate cancers detected for‐cause based on needle‐biopsy but did reduce risk of overall incident prostate cancer detected by biopsy by 23%[RR 0.77, 95% CI 0.70–0.85; absolute reduction 16.1% vs 20.8%]. There were reductions across age, family history of prostate cancer, PSA level, and prostate volume subgroups.
• ? Incidences of erectile dysfunction, ejaculate volume, decreased libido, and gynaecomastia were greater with 5‐α‐RI vs placebo.

CONCLUSIONS

• ? 5‐α‐RIs reduce the risk of being diagnosed with prostate cancer among men who are screened regularly for prostate cancer.
• ? Information is inadequate to assess the effect of 5‐α‐RIs on prostate cancer or all‐cause mortality.
• ? 5‐α‐RIs increase sexual and erectile dysfunction.

     

Comparison of dutasteride and finasteride for treating benign prostatic hyperplasia: the Enlarged Prostate International Comparator Study (EPICS)

Study Type – Therapy (RCT) Level of Evidence 1b What’s known on the subject? and What does the study add? Both dutasteride and finasteride inhibit type 2 5α‐reductase, the dominant form of 5α‐reductase in benign prostatic tissue, making these effective treatments for BPH. In comparison with finasteride, dutasteride has a longer half‐life and leads to a greater and more consistent suppression of serum and intraprostatic DHT. EPICS is currently the only prospective, randomized, double‐blind study of finasteride vs dutasteride for BPH endpoints conducted for longer than a few months. Over a one‐year period, treatment with dutasteride and finasteride led to similar reductions in prostate volume, and improvements in peak urine flow and urinary symptoms associated with BPH in men with an enlarged prostate. Men treated with finasteride and dutasteride also experienced similar rates of adverse events over the course of one year, which suggests that inhibition of both type 1 and type 2 5α‐reductase, resulting in greater DHT suppression than type 2 inhibition alone, does not confer an increase in adverse events. Given the long‐term, progressive nature of BPH, the one‐year duration of EPICS may limit the potential to observe major differences between dutasteride and finasteride treatment.

OBJECTIVE

• ? To assess the efficacy and safety of dutasteride compared with finasteride in treating men with symptomatic benign prostatic hyperplasia (BPH) for 12 months.

PATIENTS AND METHODS

• ? The Enlarged Prostate International Comparator Study was a multicentre, randomized, double‐blind, 12‐month, parallel‐group study.
• ? Men aged ≥50 years with a clinical diagnosis of BPH received once‐daily treatment with dutasteride 0.5 mg (n= 813) or finasteride 5 mg (n= 817). After a 4‐week placebo run‐in period, patients were randomized to receive dutasteride or finasteride for 48 weeks, followed by an optional 24‐month, open‐label phase, during which patients received dutasteride 0.5 mg once daily.
• ? The primary endpoint was change in prostate volume, and the secondary endpoints included improvement in American Urological Association Symptom Index (AUA‐SI) scores, improvement in maximum urinary flow rate (Q_max) and long‐term safety in the 24‐month open‐label phase.

RESULTS

• ? Both dutasteride and finasteride were effective at reducing prostate volume with no significant difference between the two treatments during the study.
• ? Similar reductions in mean AUA‐SI scores and Q_max were also observed for men in both treatment groups.
• ? A similar percentage of adverse events was experienced by patients of both treatment groups, and no new adverse events were reported in the open‐label phase.

CONCLUSION

• ? Dutasteride and finasteride, when administered for 12 months, were similarly effective in reducing prostate volume and improving Q_max and urinary symptoms associated with BPH in men with an enlarged prostate.

     

Dutasteride, the dual 5alpha-reductase inhibitor, inhibits androgen action and promotes cell death in the LNCaP prostate cancer cell line

BACKGROUND: Reduction of T to DHT by 5alphaR in the prostate enhances androgenic activity for most targets. Inhibition of 5alphaR activity with finasteride attenuates androgen action in men and animal models. The objective of this study was to compare and contrast the effects of a potent new 5alphaR inhibitor, dutasteride, with finasteride in the LNCaP prostate cancer cell line. METHODS: LNCaP cells were incubated for varying times with T or DHT in steroid-free medium in the absence or presence of increasing doses of dutasteride or finasteride and the effects on 5alphaR activity, PSA accumulation in the medium, and on cell proliferation were determined. Drug effects on apoptosis were investigated using Annexin V staining and a cell death ELISA assay. Effects of the drugs on AR ligand-binding activity and on AR protein levels were determined. RESULTS: Dutasteride inhibited (3)H-T conversion to (3)H-DHT and, as anticipated, inhibited T-induced secretion of PSA and proliferation. However the drug also inhibited DHT-induced PSA secretion and cell proliferation (IC(50) approximately 1 microM). Finasteride also inhibited DHT action but was less potent than dutasteride. Dutasteride competed for binding the LNCaP cell AR with an IC(50) approximately 1.5 microM. High concentrations of dutasteride (10-50 microM), but not finasteride, in steroid-free medium, resulted in enhanced cell death, possibly by apoptosis. This was accompanied by loss of AR protein and decreased AR ligand-binding activity. Occupation of AR by R1881 partly protected against cell death and loss of AR protein. PC-3 prostate cancer cells, which do not contain AR, also were killed by high concentrations of dutasteride, as well as by 50 microM finasteride. CONCLUSIONS: Dutasteride exhibited some inhibitory actions in LNCaP cells possibly related to 5alphaR inhibition but also had antiandrogenic effects at relatively low concentrations and cell death-promoting effects at higher concentrations. Finasteride also was antiandrogenic, but less than dutasteride. The antiandrogenic effects may be mediated by the mutant LNCaP cell AR. Promotion of cell death by dutasteride can be blocked, but only in part, by androgens.     

Prostate cancer antigen-1 as a potential novel marker for prostate cancer

Aim： To examine the expression of prostate cancer antigen-1 （PCA-1） in prostate cancer （PCa） and to validate it as a potential marker for diagnosis of PCa. Methods： In situ hybridization analysis of PCA-1 mRNA expression was performed on 40 benign prostate hyperplasia （BPH）, 16 high-grade prostatic intraepithelial neoplasm （HG-PIN）, 74 PCa and 34 other malignant carcinoma specimens. The level of PCA- 1 expression was semiquanfitatively scored by assessing both the percentage and intensity of PCA- 1 positive staining cells in the specimens. We then compared the PCA-1 expression between BPH, HG-PIN and PCa and evaluated the correlation of PCA-1 expression level with clinical parameters of PCa. Results： PCA-1 mRNA was expressed in the majority of both PCa and HG-PIN specimens but not in BPH and other malignant carcinoma. The expression level of PCA-1 increased along with a high Gleason score （P 〈 0.05）, and was unrelated to other clinical parameters of PCa （all P 〉 0.05）. Conclusion： The data suggest that PCA-1 might be a novel diagnostic marker for PCa, and that increased PCA-1 expression might denote more aggressive variants of PCa.     

Prostate cancer and genetic susceptibility: a genome scan incorporating disease aggressiveness

BACKGROUND: Prostate cancer is a heterogeneous disease, both genetically and phenotypically. Linkage studies attempting to map genes for hereditary prostate cancer (HPC) have proved challenging, and one potential problem contributing to this challenge is the variability in disease phenotypes. METHODS: We collected clinical data on 784 affected men with prostate cancer from 248 HPC families for whom a genomic screen was performed. Disease characteristics (i.e., Gleason score, stage, prostate-specific antigen (PSA)) were used to classify affected men into categories of clinically insignificant, moderate, or aggressive prostate cancer. To potentially enrich for a genetic etiology, we restricted linkage analyses to only men with aggressive disease, although we used genotype information from all family members; linkage analyses used both dominant and recessive models. In addition, subset analyses considered age at diagnosis, number of affected men per family and other stratifications to try to increase genetic homogeneity. RESULTS: Several regions of interest (heterogeneity LOD score, HLOD>1.0) were identified in families (n=123) with >or=2 affecteds with aggressive prostate cancer. "Suggestive" linkage was observed at chromosome 22q11.1 (Dominant model HLOD=2.18) and the result was stronger (Dominant HLOD=2.75) in families with evidence of male-to-male transmission. A second region at 22q12.3-q13.1 was also highlighted (Recessive model HLOD=1.90) among men with aggressive disease, as was a region on chromosome 18. CONCLUSIONS: These analyses suggest that using clinically defined phenotypes may be a useful approach for simplifying the locus heterogeneity problems that confound the search for prostate cancer susceptibility genes.