On the role of nitric oxide in bladder cancer and renal cell carcinoma

Sammanfattning: The role of nitric oxide (NO) in tumour biology is unclear. There are conflicting reports in the literature whether NO will promote or inhibit tumour growth. The aim of the present thesis was to investigate the role of NO in bladder cancer and renal cell carcinoma. Furthermore, the possible involvement of NO in the anti-tumour effect of bacillus Calmette-Guérin (BCG) in the treatment of superficial bladder cancer was investigated. Calcium-dependent and calcium-independent NO synthase (NOS) activity was found in bladder cancer cells and modulation of the L-argininc/NO pathway may have a dual effect on tumour cell growth. Thus, 0Uj- data suggest that low concentrations ofNO stimulates cell growth whereas high concentrations inhibit cell growth and induce bladder cancer cells to undergo apoptosis. Furthermore, our data suggest that cytokine treatment may inhibit cell growth and induce bladder cancer cells to undergo apoptosis via the L-argininc/NO pathway. BCG treatment induced calcium-dependent and calcium-independent NOS activity in the urinary bladder. A 30-fold increase in urinary bladder luminal NO concentration was seen in patients with superficial bladder cancer following BCG treatment. Furthermore, induction of high levels of NO, measured as urinary nitrite, was associated with a better treatment response. Thus, these findings suggest that an increased NO formation in the urinary bladder may be involved in the anti-tumour effect of BCG in the treatment of superficial bladder cancer. Calcium-dependent NOS activity was found in renal tumours and there was an inverse correlation between NOS activity and tumour grade. Cytokine treatment induced calcium-independent NOS activity in renal cell lines and exogenous NO exerted cytostatic effects on renal cell carcinoma cells. These findings suggest that NO may be associated to tumour progression in renal cell carcinoma. A new minimal invasive technique for direct measurements of urinary bladder NO formation is presented. By using this technique we demonstrate increased luminal NO levels in patients with urinary bladder inflammation. This technique may be clinically used to monitor urinary bladder inflammation and may predict treatment response in patients with superficial bladder cancer treated with BCG.