Apoptotic regression of prostatic tissue induced by short-term doxazosin treatment in benign prostatic hyperplasia.

OBJECTIVES: Benign enlargement of the prostate comprises both hypertrophy and in particular hyperplasia of prostatic stromal and glandular compartments. Alpha adrenergic blockade has been shown to be effective in the management of BPH. Recent investigations have shown that this effect may in part be due to apoptosis. METHODS: A total of 29 patients who were symptomatic due to BPH were enrolled into this prospective placebo controlled, double-blind randomized study and underwent prostatectomy at the end of the 4th week. Clinical efficacy was evaluated by a set of detailed investigations. Surgical specimens were analyzed by immunohistochemistry and tissue components of stroma, smooth muscle and glandular epithelium were calculated by a software on a computer after representative areas were scanned and captured as high resolution images. Apoptosis in each tissue specimen was analyzed by Terminal Deoxynucleotidyl Transferase End Labelling (TUNEL) method utilizing Biotin-16-dUTP. RESULTS: Both groups were similar in terms of baseline evaluation in all aspects. There was a steady decline in patients' urinary complaints as evidenced by International Prostate Symptom Score System (IPSS) in the doxazosin group compared to placebo. Uroflowmetric investigations on patients revealed that maximum flow rates in the active drug group increased throughout the study. Mean PSA levels decreased by 14% at the end of the study in the doxazosin group, while it increased by 11% in the placebo group. Average stroma to epithelial ratio in the doxazosin group was 2:1 in comparison to a value of 1:1 in the placebo group. The rate of apoptosis was 2.2% and 3.2% for the epithelial and stromal compartments, respectively, in the doxazosin group, and 1.2% and 2.7% for the placebo arm. CONCLUSIONS: These data suggest apoptosis as the possible underlying molecular mechanism partly responsible for the clinical efficacy and morphological changes induced by doxazosin treatment in BPH.

Prognostic Role of in Vitro Survival Efficiency in Human Transitional-Cell Carcinoma.

The purpose of this study was to assess the correlation of in vitro growth features of transitional-cell carcinoma (TCC) specimens with the clinical behavior of the respective tumors. We also analyzed the impact of depth of tumor invasion, histologic differentiation, morphologic characteristics, and nuclear p53 accumulation of tumors on the in vitro survival efficiency of microtumor cultures and the significance of these factors in predicting recurrence and progression of bladder cancer. The tumor cell lines derived from surgical specimens were cultured at 37 degrees C in 5% CO(2) and constant humidity. Microtumor cultures were classified into three groups according to their in vitro lifespan. Our results indicate that higher survival efficiency implies a propensity for aggressive clinical behavior of the tumor in vivo. Factors that imply a poorer prognosis account for longer lifespans for microtumour cultures. These prognostic indicators are also associated with higher rates of recurrence and progression for tumors that exhibit higher survival efficiency in vitro.

Alteration of epidermal growth factor receptor expression following ischaemia of renal tissue.

This study was aimed to investigate Epidermal Growth Factor Receptor (EGF-R) expression after ischaemic injury in renal tissue and the effects of calcium channel blockers in the prevention of damage due to ischaemic insult. Simple nephrectomy was performed in a group of Sprague-Dawley rats, and kidneys were grouped according to cold ischaemia time (1, 6, 12, 24 and 48 hours, respectively) and to the type of calcium channel blockers (diltiazem and verapamil) used. EGF-R expression status was investigated in each group by immunohistochemistry on paraffin sections. Overall expression of EGF-receptor was detected in 8 (22.8%) kidneys. In terms of localization of EGF-receptor expression cortical tubular staining was detected in 8 (100%) kidneys, medullar tubular staining in (62.5%) kidneys and glomerular mesangial staining in 5 (62.5%) kidneys. There was no difference between various ischaemia times and different calcium channel blockers used. It has been concluded that hypoxia and cold ischaemia causes widespread down-regulation of EGF-receptor expression in renal tissue regardless of treatment with calcium channel blockers.

Bcl-2 and p53 overexpression as associated risk factors in transitional cell carcinoma of the bladder.

Bcl-2 and p53 genes are implicated in cell cycle regulation with roles on programmed cell death. Consequently, presence of Bcl-2 and nuclear accumulation of p53 were proposed to confer a growth advantage tumour cells. We have investigated their role as prognostic factors in fresh tumour samples from a cohort of twenty patients with transitional cell carcinoma of the bladder by immunohistochemical analysis in paired specimens. Expression of Bcl-2 was observed in 11 cases (69%) and nuclear p53 accumulation in 9 (45%). In the presence of Bcl-2 protein expression, tumours showed a slightly higher rate of recurrence (55% vs. 40%) and significantly more progression (36% vs. 0%). Recurrence and progression rates were not significantly different in tumours with and without nuclear p53 overexpression (recurrence rates 56% vs. 55% and progression rates 33% vs. 27%, respectively). Grade and stage appeared as important prognosticators since 75% of grade 3 tumours showed recurrence and 50% progressed in contrast to 44% and 13%, respectively, of grades 1 and 2 tumours. Similarly, 50% of Ta-T1 tumours recurred and 20% progressed, while these rates were 75% and 75% for T2-T3 tumours. Also, expression of Bcl-2 and nuclear accumulation of p53 correlated with grade. In grade 3 tumours, 75% showed nuclear p53 overexpression and 80% cytoplasmic Bcl-2 protein. These figures were 25% and 64% for grades 1 and 2 tumours. In conclusion, Bcl-2 protein expression in transitional cell carcinoma appears to be associated with a poorer prognosis and together with nuclear p53 overexpression they are associated with tumour de-differentiation.

The role of in vitro chemosensitivity tests to predict the clinical efficacy of antineoplastic agents in genito-urinary tumors.

OBJECTIVE: To develop an in vitro screening system to predict the response to treatment of common malignancies of the genito-urinary tract. MATERIAL AND METHODS: Flow cytometric analysis and cytotoxicity assays (trypan blue and lactic dehydrogenase colorimetric tests) were performed on hormone resistant prostate cancer cell line PC-3 and primary transitional cell carcinoma samples treated with different antineoplastic agents and their combinations. Apoptosis induced by different agents was also investigated by previously established criteria. RESULTS: There were 9 bladder tumors (47.4%) in the study group that displayed drug resistance to at least one antineoplastic agent. When the drugs were examined individually, there was resistance to cis-platinum in 3 patients (15.8%), methotrexate in 6 (31.6%), vinblastine in 7 (36.8%), epirubicin in 2 and adriamycin in 2 patients (10.5%). Stratification of patients according to the stage of the tumor revealed statistically significant difference between the superficial and invasive tumors in terms of drug resistance (p < 0.05). In prostate cancer cell line vinblastine treatment resulted in a significant increase in S phase fraction. Percent cytotoxicity by trypan blue exclusion test was 26.1% and was significantly higher than the control group (8.7%, p < 0.002). Also, an increase in apoptotic index after the treatment was observed (44.4% and 12.1%, respectively; p < 0.0001). CONCLUSION: Both toxicity assays showed a very good correlation (p < 0.005) and can be used to evaluate the effects of different antineoplastic agents on individual tumors.