Hudak et al prostate cancer diagnosis. Other analyses from the PCPT regarding the effect of ﬁnasteride on tumor grade and the interaction of the reduction in gland volume with detection of cancer and high grade cancer are expected in the near future. Expression of type 1 5AR is greater in some cell lines of neoplastic prostate tissue (Iehle et al 1999; Andriole et al 2004). As discussed previously, dutasteride inhibits both type-1 and type-2 5AR. Secondary analysis of a large scale clinical trial evaluating the efﬁcacy of dutasteride for BPH noted a 1.1% rate of prostate cancer diagnosis in the treatment group compared with 1.9% in the placebo group (Roehrborn et al 2002). A clinical trial is underway to prospectively evaluate the role of dutasteride in the prevention of prostate cancer. The REDUCE trial is a multicenter, randomized, international, placebo-controlled, double blind clinical trial initiated in 2003 which is designed to evaluate the ability of dutasteride to decrease the risk of biopsy detectable prostate cancer in men with moderately elevated PSA levels (Andriole et al 2004).The relative efﬁcacy of ﬁnasteride versus dutasteride for prevention must await the conclusion of this trial but the substantially different characteristics of subjects in the two studies will probably make such conclusions challenging regardless of the study’s outcomes. Treatment of prostate cancer with 5-alpha reductase inhibitors The heterogeneous behavior of prostate cancer as well as multiple factors limiting patient accrual are some of the inherent challenges in the development and completion of clinical trials comparing various therapeutic modalities (active surveillance, surgical extirpation, surgical ablation, radiation therapy, hormonal therapy, and chemotherapy). As a result, studies are typically small, poorly controlled, and fraught with a number of biases (Cookson 2006). However, the search for the optimal method of prostate cancer management (greatest cancer control rate with lowest risk of complications and side effects) continues. In spite of these limitations, a number of studies have addressed the potential role of 5AR inhibitors in the management of prostate cancer. Murine prostatic carcinoma has been used for the investigation of various hormonal therapy regimens. Various cell lines of murine prostate cancer (Dunning R3327, Fisher 344) share several important characteristics with human prostate cancer, including basic histology, slow rate of growth, hormonal sensitivity, and expression of 5AR 428 (Zaccheo et al 1997). Murine models have demonstrated the ability of various 5AR inhibitors to inhibit macroscopic rat prostate carcinogenesis (Tsukamoto et al 1998) and decrease the rate of rat prostate cancer growth (Zaccheo et al 1997, 1998). However, when compared with medical and surgical castration, 5AR inhibitors produce a lesser reduction in rat prostate cancer growth. In summary, results from animal model studies do not support the use of 5AR inhibitors as monotherapy for the treatment of prostate cancer. While surgical extirpation or radiation therapy are commonly recommended for the treatment of localized prostate cancer, hormonal therapy is most frequently used for locally advanced disease, biochemical recurrence after localized therapy, and metastatic disease. Medical or surgical castration is the most effective form of hormonal therapy. However, it is poorly tolerated, with a high percentage of patients experiencing erectile dysfunction, loss of libido, “hot ﬂashes”, osteoporosis, fatigue, and muscle wasting. While monotherapy with 5AR inhibitors has a minimal impact on prostate cancer (Presti et al 1992), there is much interest with combining the well tolerated hormonal effects of 5AR inhibitors with other therapeutic modalities. To demonstrate the effect of 5AR inhibitors prior to localized therapy, Andriole and colleagues (2004) randomized 46 men with clinically localized prostate cancer to either dutasteride or placebo for 6 to 10 weeks prior to radical prostatectomy (Andriole et al 2004). While this double blind, prospective, randomized clinical trial was not powered for speciﬁc clinical end points, important effects of 5AR inhibition were observed. Serum and intraprostatic DHT was decreased by over 95% in the dutasteride group, versus no change in the placebo group. Cellular apoptosis indices were increased in the dutasteride group while measurements of vascular density were decreased. Finally, tumor volume and prostatic intraepithelial neoplasia (PIN) volume were lower in the dutasteride group. There were no clinical differences between the two groups (ie, pathologic grade/stage or rate of positive surgical margins) (Andriole et al 2004). The clinical signiﬁcance of the observed effects of dutasteride is unknown. The morbidity associated with medical and surgical castration make them less attractive regimens for routine use in the prevention of recurrent disease or disease progression following localized therapy for prostate cancer (radical prostatectomy or radiation). Given its excellent tolerability, investigators have evaluated the role of ﬁnasteride as a potential agent for the prevention of Clinical Interventions in Aging 2006:1(4)