Coordinated chemoradiation therapy with genital preservation for the treatment of primary invasive carcinoma of the male urethra.

PURPOSE: We evaluated the efficacy of a combined chemoradiation therapy protocol for the primary treatment of primary invasive carcinoma of the male urethra. MATERIALS AND METHODS: From January 1991 to December 2006, 18 patients with invasive carcinoma of the male urethra referred to our institution were treated with a chemoradiation therapy protocol, consisting of 2 cycles of 5-fluorouracil (1,000 mg/m(2)) on days 1 to 4 and days 29 to 32, and mitomycin-C (10 mg/m(2)) on days 1 and 29 with concurrent external beam radiation therapy (45 to 55 Gy in 25 fractions during 5 weeks) to the genitalia, perineum, and inguinal and external iliac lymph nodes. Kaplan-Meier curves were constructed to assess overall, disease specific and disease-free survival. RESULTS: The stage and node distribution was T2N0 in 2 patients (11%), T3N0 in 8 (44%), T4N0 in 2 (11%), TXN1 in 1(6%) and TXN2 in 5 (28%). The most prevalent histology was moderately (7 of 18 patients or 39%) or poorly (10 of 18 or 56%) differentiated squamous cell carcinoma (17 of 18 or 95%). Overall 83% (15 of 18) of the patients had a complete response to the primary chemoradiation therapy protocol, and the 5-year overall and disease specific survival rates were 60% and 83%, respectively. Five-year disease-free survival rates after chemoradiation therapy and after chemoradiation therapy with salvage surgery were 54% and 72%, respectively. The 3 nonresponders died of disease after undergoing salvage surgery and 5 of the 15 complete responders (30%) had recurrence. Complex urethral reconstruction was required in 3 of 10 patients (30%) who had prolonged disease-free survival. CONCLUSIONS: The chemoradiation therapy protocol is an alternative primary treatment modality for invasive urethral carcinoma. It enables an unprecedented potential for organ preservation.

The src-family kinase inhibitor PP2 suppresses the in vitro invasive phenotype of bladder carcinoma cells via modulation of Akt.

OBJECTIVE: To evaluate PP2 as a modulator of the cadherin/catenin complex in late-stage bladder carcinoma cells, and to assess its potential invasion-suppressor activity in this model. MATERIALS AND METHODS: A panel of five human bladder carcinoma cells, characterizing late-stage disease, was used to determine the concentration for 50% inhibition of PP2 in cell-proliferation assays. Modulation of cadherin/catenin expression by PP2 was determined in Western blot analysis, with an assessment of the activation status of mitogen-activated protein kinase and Akt signalling pathways. Altered invasive capacity linked to these variables was determined in standard in vitro invasion assays. RESULTS: PP2 elicited concentration-dependent growth inhibition in all bladder cell lines within the panel, with growth suppression recorded at 10-35 micromol/L PP2. Distinct morphological changes were recorded in cell lines exposed to PP2, accompanied by up-regulation of plakoglobin expression in a subset of lines. Exposure of cells to PP2 resulted in inactivation of Akt in all cells and a concomitant reduction in in vitro invasive capacity. CONCLUSIONS: These results show that PP2 inhibits bladder carcinoma cell growth and can modulate plakoglobin expression in a subset of cell lines. In addition, PP2 can suppress the in vitro invasive capacity of bladder carcinoma cells by modulating the activation status of Akt.

Histone deacetylase inhibitors upregulate plakoglobin expression in bladder carcinoma cells and display antineoplastic activity in vitro and in vivo.

Histone deacetylase inhibitors (HDACis) are emerging as a promising new class of anticancer agents displaying growth-inhibitory activity and low toxicity in vivo. In this study, we examined the effect of sodium butyrate (NaB) and trichostatin A (TSA) on the growth of human bladder carcinoma cell lines in culture and TSA on the growth of EJ and UM-UC-3 human bladder xenografts in nude mice. NaB and TSA suppressed the growth of bladder cell lines at millimolar (1.5-4.3 mM) and micromolar (0.03-0.33 microM) concentrations, respectively, inducing concentration-dependent cell death. Bladder carcinoma cells within the experimental panel displayed the phenotype of late-stage bladder lesions expressing N-cadherin in the absence of E-cadherin accompanied by low levels of plakoglobin expression. Exposure of these cells to HDACis resulted in upregulation of plakoglobin with no change in E-cadherin expression. A 2-hr exposure to TSA was the minimal time required to upregulate plakoglobin in cells with downregulation to baseline levels occurring within 24 hr following drug removal. In mice bearing EJ and UM-UC-3 bladder xenografts, TSA (500 microg/kg/day) caused suppression of tumor growth compared with mice receiving vehicle alone. A > 70% reduction in mean final tumor volume was recorded in both bladder xenograft models with no detectable toxicity. The results suggest that TSA inhibits bladder carcinoma cell growth and may be a useful, relatively nontoxic agent for consideration in the treatment of late-stage bladder tumors.