Since the late 1980s, early detection and monitoring of men for prostate cancer by serum prostate-specific antigen (PSA) measurement has resulted in an increase in the number of men presenting with a potentially curable disease. During the same time, in an attempt to provide a definitive cure, radical prostatectomy has been performed increasingly and now is regarded as the management option of choice for many patients with clinically localized prostate cancer. Radical prostatectomy involves the removal of all of the prostate tissue resulting in the serum PSA level to steadily decline to an undetectable level within 4 to 6 weeks after surgery. Despite improvements in surgical technique and a marked downward stage shift brought about by serum PSA testing, approximately 25% of men ultimately will experience a subsequent increase in serum PSA to a detectable level indicating disease recurrence after radical prostatectomy within 15 years. In this brief review, the factors associated with a high risk for disease recurrence after radical prostatectomy are discussed. Factors indicating whether the increasing serum PSA is caused by local recurrence or metastatic disease and the management options available to address serum PSA recurrence also are discussed.
[Show abstract][Hide abstract] ABSTRACT: Abstract: Prostate cancer is one of the most common cancers and remains the second leading cause of death from cancer in men. Metastatic prostate tumors express the androgen receptor (AR) regardless of their sensitivity to hormonal therapy. This offers a cellular target for receptor-mediated imaging or treatment of prostate cancer. We first identified a series of novel agents that can be used to image and treat advanced prostate cancer via high affinity interaction with the AR. One of the most promising compounds, S-26, demonstrated a favorable receptor specificity profile, pharmacokinetic properties, and nonsteroidal structure, making it amenable to further optimization for AR mediated imaging. In vivo biodistribution studies showed that radiolabeled S-26 does not accumulate in AR-rich tissues. In vivo metabolism studies were performed to further understand the factors governing disposition of this ligand. The extensive plasma clearance of S-26 and unstable iodine substituent in the A ring likely contributed to its lack of AR tissue selectivity in vivo. During studies to elaborate new pharmacophores for the human AR, we discovered a series of bis-indole analogs that do not bind the AR, but exhibit potent cytotoxic activity in a variety of human tumor cell lines. One lead compound, bis-indole I-13, inhibited the growth of a number of human cancer cell lines, including the high P-glycoprotein expressing cell line, with IC50 in the range of 0.034 to 0.162 uM. Studies of in vivo pharmacokinetics, toxicity, antitumor activity in PC-3 xenograft, and metabolism demonstrated that bis-indole analogs represent a novel class of anticancer drugs for prostate cancer and offer hope for achievable pharmacologic activity in the clinic. Thesis (Ph. D.)--Ohio State University, 2005. System requirements: World Wide Web browser.
[Show abstract][Hide abstract] ABSTRACT: The use of luteinising hormone releasing hormone (LHRH) agonists has increasingly evolved during the past 10 years. This review paper aims to discuss the role of LHRH agonists in patients with prostate cancer, a leading cause of cancer death in men.To retrieve the most relevant randomised clinical trials (RCTs), a Medline search was performed in the last quarter of 2004. Only fully published studies in English language with at least 25 patients per treatment arm and those frequently cited in review articles were included in the current review. This review does not claim to have included every single study with the selected treatment options, but aimed at including the most important trials performed and fully published with these treatments. The retrieved studies are discussed and put into perspective of the EAU guidelines.Initially, LHRH agonists were part of the treatment strategy for patients with advanced or metastatic disease. Currently, LHRH agonists are increasingly used as a treatment option in a neoadjuvant and/or adjuvant setting for patients with early or localised disease. LHRH analogues are used as adjuvant hormonal therapy after radical prostatectomy, and as neoadjuvant and adjuvant treatment to radiotherapy. Patients with early or localised disease and a low Gleason score may experience clinical benefit from the neoadjuvant addition of LHRH agonists to radiotherapy. In patients with a high Gleason score and positive lymph nodes, adjuvant LHRH agonist treatment is considered standard therapy.In patients with rising prostate specific antigen (PSA) after radical treatment, hormonal therapy is often applied in an intermittent way, but results remain inconclusive.Maximum androgen blockade (MAB), a combination of a LHRH agonist and an antiandrogen, has been applied in advanced prostate cancer. However, due to the increased incidence of side effects and very modest survival benefits, there are few arguments to offer this treatment strategy to patients with prostate cancer.In summary, LHRH agonist therapy is important in the treatment of both early and advanced prostate cancer. Additional studies are needed to further define the optimal use of LHRH agonists within various patient risk groups.
European Urology Supplements 07/2005; 4(5):4-13. DOI:10.1016/j.eursup.2005.04.003 · 3.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Prostate cancer is the most common cancer among men in the United States, and aberrant DNA methylation is known to be an early molecular event in its development. Here, we have used expression profiling to identify novel hypermethylated genes whose expression is induced by treatment of prostate cancer cell lines with the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (5-aza-dC). Of the 271 genes that were induced by 5-aza-dC treatment, 25 also displayed reduced expression in primary prostate tumors compared with normal prostate tissue, and the decreased expression of only one gene, aldehyde dehydrogenase 1 family, member A2 (ALDH1a2), was also associated with shorter recurrence-free survival. ALDH1a2 encodes an enzyme responsible for synthesis of retinoic acid (RA), a compound with prodifferentiation properties. By immunohistochemistry, we observed that ALDH1a2 was expressed in epithelia from normal prostate but not prostate cancer. Using bisulfite sequencing, we determined that the ALDH1a2 promoter region was significantly hypermethylated in primary prostate tumors compared with normal prostate specimens (P = 0.01). Finally, transfection-mediated reexpression of wild-type ALDH1a2 (but not a presumptive catalytically dead mutant) in the prostate cancer cell line DU145 resulted in decreased colony growth (P < 0.0001), comparable with treatment with either 5-aza-dC or RA. Taken together, our findings implicate ALDH1a2 as a candidate tumor suppressor gene in prostate cancer and further support a role of retinoids in the prevention or treatment of prostate cancer.
Cancer Research 10/2005; 65(18):8118-24. DOI:10.1158/0008-5472.CAN-04-4562 · 9.33 Impact Factor
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