Short alleles of both GGN and CAG repeats at the exon-1 of the androgen receptor gene are associated to increased PSA staining and a higher Gleason score in human prostatic cancer.

The exon 1 of the human androgen receptor (AR) gene contains two length polymorphisms of CAG (polyglutamine) and GGN (polyglycine). "In vitro" experiments suggest that the larger GGN repeats provide a lower AR-protein yield, whereas the larger CAG repeats decrease the AR transcriptional activity, both decreasing the AR signalling intensity. Here we have tested such possibilities in human prostatic cancer (CaP) specimens. We used 72 archival samples of radical prostatectomy. Parallel slides were used for AR protein or PSA immunohistochemistry, and for genotyping studies. Polymorphisms were genotyped by PCR, fragment length analysis and sequencing selected samples. The AR staining was positively correlated with the Gleason score (r=0.320; P=0.005), but it was not correlated to CAG or GGN repeat length or PSA staining. The number of GGN repeats was negatively correlated to the intensity of PSA staining (r=-0.243; P=0.04). Combination of short alleles of both tracts was significantly higher in: the heavier stained tertiles for PSA (P=0.03) and AR (P=0.06); and in the subgroup of samples having a Gleason score of 7 or higher (P=0.021). The results support the hypothesis that the shorter alleles of CAG and GGN repeats in the AR gene are associated to an increased AR signalling intensity in human prostate cancer, and with more aggressive forms of the disease.

Maintenance Therapy with 3-monthly Bacillus Calmette-Guérin for 3 Years is Not Superior to Standard Induction Therapy in High-risk Non-muscle-invasive Urothelial Bladder Carcinoma: Final Results of Randomised CUETO Study 98013.

BACKGROUND: Bacillus Calmette-Guérin (BCG) maintenance therapy for 3 yr following BCG induction can reduce the progression of urothelial bladder carcinoma versus BCG induction alone, but is associated with high toxicity. OBJECTIVE: To investigate whether a modified 3-yr BCG maintenance regimen following induction therapy is more effective than standard BCG induction therapy alone and exhibits a low toxicity profile. DESIGN, SETTING, AND PARTICIPANTS: Patients from the outpatient clinics of the participating centres with high-risk non-muscle-invasive bladder carcinoma (NMIBC) were randomised between October 1999 and April 2007. INTERVENTION: Participants received BCG induction once-weekly for 6 wk (no maintenance arm) or BCG induction followed by one BCG instillation every 3 mo for 3 yr (maintenance arm). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary endpoints were disease-free interval (DFI) and time to progression (TTP). Secondary endpoints included survival duration and toxicity. Differences between treatment arms were tested using Student's t test and χ(2) and log-rank tests. RESULTS AND LIMITATIONS: A total of 397 patients were randomised, 195 to the no-maintenance and 202 to the maintenance arm. A median time to recurrence was not reached in either treatment arm. DFI was similar between the arms (hazard ration [HR] 0.83; 95% CI 0.61-1.13; p=0.2) with disease relapse at 5 yr of 33.5% and 38.5%, respectively. TTP was also similar between the treatment arms (HR 0.79; 95% CI 0.50-1.26; p=0.3), with a progression rate at 5 yr of 16% and 19.5%, respectively. There were no significant differences between the treatment groups for overall survival and cancer-specific survival at 5 yr. Twenty and five patients in the maintenance and no-maintenance arms, respectively, stopped treatment because of toxicity. The most common local side effects were frequency (65% of patients), dysuria (63%), and haematuria (43%); the most frequent systemic side effects were general malaise (7.2%) and fever (34%). CONCLUSIONS: In NMIBC patients treated with maintenance therapy comprising a single BCG instillation every 3 mo for 3 yr following standard induction BCG, we did not observe a decrease in recurrence and progression rates versus induction therapy alone. PATIENT SUMMARY: Patients who undergo surgery to remove bladder cancer are usually treated with bacillus Calmette-Guérin (BCG) for 6 wk if there is a high risk of disease recurrence. Extending BCG therapy by 3 yr can further minimise disease recurrence and progression, but is associated with more side effects. We report that a modified 3-yr BCG treatment regimen showed low toxicity, but seemed to be no more effective than 6-wk treatment. TRIAL REGISTRATION: CUETO 98013.

Transition to androgen-independence in prostate cancer.

Prostate carcinoma is the most frequently diagnosed malignancy and the second leading cause of death as a result of cancer in men in the western countries. Withdrawal of androgens or the peripheral blockage of androgen action remain the critical therapeutic options for the treatment of advanced prostate cancer. However, after initial regression, most of the prostate cancers become androgen-independent and progress further, with eventual fatal outcome. Understanding the mechanisms of transition to androgen independence and tumor progression in prostate cancer is critical to finding new ways to treat aged patients that are ineligible for conventional chemotherapy. A large number of different molecular mechanisms might be responsible for the transition to androgen-independence. Many of these involve the androgen receptor (AR) and its signalling pathways, but they might also include genetic changes that affect several genes, which results in the activation of oncogenes or the inactivation of tumor suppressor genes. Here, we discuss the most recent and relevant findings on androgen resistance in prostate cancer in order provide a comprehensive interpretation of the clinical behaviour of tumors at molecular levels.

Polymorphisms of glutathione S-transferase µ and θ, MDR1 and VEGF genes as risk factors of bladder cancer: a case-control study.

OBJECTIVE: The present study was aimed at examining the local distribution of GSTM1, GSTT1, MDR1, and VEGF gene polymorphisms as possible risk factors contributing to the development of bladder cancer among the population from Canary Islands, Spain. MATERIALS AND METHODS: The genotypes were determined by PCR-based methods in a hospital-based case-control study consisting of 119 cases and 110 controls. The socio-demographic and clinicopathologic data were collected, including the smoking habits of the population covered in the study. RESULTS: The observed allelic frequencies were (%): GSTM1-GSTT1, (positive) 54 and (null) 46 in cases, and 65 and 35, respectively, in controls (P = 0.144); MDR1 C3435T, (C) 57 and (T) 43 in cases, and 54 and 46, respectively, in controls (P = 0.633); VEGF A2578C, (A) 40 and (C) 60 in cases, and 51 and 49, respectively, in controls (P = 0.221). Among Canary Islands subjects, GSTT1-null genotype appeared as a significant risk factor for bladder cancer (odds ratio (OR) 2.0; 95% confidence interval (CI), 1.0-3.7; P = 0.041), in multivariate analysis adjusted by age and smoking habits. No statistical changes in genotype distribution of GSTM1, MDR1 C3435T, and VEGF A2578C gene polymorphisms were observed between cases and controls. The distribution of the initial clinical stage, clinical grade, or recurrence status was not significantly different among the polymorphic variants in the case group (P = NS). CONCLUSIONS: Subjects with the GSTT1-null genotype might be at an increased risk of bladder cancer in Canary Islands, Spain. However, extensive studies are required for accurate confirmation of these results.