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    • br Materials and methods br

    2023-01-28


    Materials and methods
    Results
    Discussion Prostate cancer represents an ideal candidate for chemoprevention because of its high incidence and long latency to clinically significant disease [17]. The precancerous lesion PIN may also be a suitable target for ablation in chemoprevention strategies [18]. While androgen ablation therapy is known to be effective in the reduction of PIN and treatment of PCa [19], there are significant side effects, including impotence, fatigue, decrease in bone and muscle mass, gynecomastia, and hot flashes [20]. Nakamura et al. suggest that androgen-producing Tryptone are co-expressed in human prostate cancer, and involved in the local production of DHT [21]. The role of DHT in the initiation and maintenance of the abnormal growth of prostate epithelium and the central role of 5 α-R enzymes provide a strong biological rationale for the examination of a dual 5 α-R inhibitor [22]. It has been reported that 5 α-R2 was expressed in prostate cancer, and was very important in the process of in situ production of DHT [23]. In addition, it has been hypothesized that 5 α-R2 may play a role in the pathogenesis and/or development of prostate cancer [23]. Nakamura et al. demonstrated that 5 α-R1 was frequently expressed in human prostate cancer, and a significant positive correlation between 5 α-R1 and 5 α-R2 immunoreactivity. It has been suggested that individuals with high levels of 5 α-R have an increased risk of developing prostate cancer [21]. Furthermore, previous reports have demonstrated that 5 α-R1 mRNA and activity were much greater in prostate cancer than in BPH [24]. The inhibition of 5 α-R, which may be considered as androgen attenuation therapy, has minimal side effects [25]. Dutasteride treatment, which inhibits both 5 α-R1 and 5 α-R2, has recently been reported to result in almost complete suppression of intraprostatic DHT, and increased regression of prostate cancer [26]. The most extensively studied 5 α-R inhibitor is finasteride. Presti et al. reported that finasteride treatment in patients diagnosed with metastatic prostate cancer resulted in only minor effects on this cancer, and decreased serum PSA levels by only 7% in men with advanced adenocarcinoma of the prostate [27]. In humans, finasteride was ineffective in the chemoprevention of PCa in high-risk men diagnosed with PIN [28]. However, the PCPT trial, showed that finasteride treatment caused a 25% reduction in the rate of PCa detection over 7 y, providing evidence that 5 α-R2 may be involved in the initiation and/or maintenance of prostatic carcinoma [29]. Individual 5 α-R1 and 5 α-R2 activities have been shown in specimens of benign hyperplasia [30], prostate cancer [8] and recurrent prostate cancer [2]. Results from these studies suggest that 5 α-R1, as well as 5 α-R2, are associated with the growth of prostate cancer. In this work, we assessed 5 α-R2 activity in small tissue samples. This biochemical parameter has been validated in relation to the histopathology of the prostate. The present methodology is based on 5 α-R2 activity in small core biopsies of 2.0–4.0 mg each compared to 50 mg of tissue suggested by Bjelfman et al. [1]. These results confirm the similarity to other studies on human 5 α-reductase enzymes [1], [8]. The determination of 5 α-R activity using ≤100 μg of prostate protein is a rare opportunity to study the development of PCa and BPH. Besides 5 α-R2 mRNA determination by RT-PCR, the assessment of 5 α-R2 activity in core needle prostate biopsies may be useful in evaluating the impact on prostate 5 α-R2 of different endocrine intervention therapies, as well as, other therapies used for treatment of prostate cancer. It is essential to clarify the relative changes that occur in 5 α-R2 activity during the growth of PCa, in order to improve the development of prevention and treatment options. We believe that Gleason Score might provide some additional information regarding relative changes in 5 α-R2 isoenzyme activity during the growth of PCa, but in this study we use a small number of cases.