The effect of intravesical Bacillus Calmette-Guerin instillations on the expression of inducible nitric oxide synthase in humans

Abstract

The activation of the inducible isoform of nitric oxide synthase (NOS) is associated with the production of large quantities of nitric oxide in response to cytokine stimulation. Bacillus Calmette-Guerin (BCG) mode of action against bladder carcinoma remains unclear, although a plethora of local and systemic events may follow its intravesical instillation. The present study was designed to investigate the expression of inducible NOS in normal and neoplastic urothelium and its alteration following tumor resection and subsequent intravesical immunotherapy. Bladder carcinoma and autologous normal bladder tissue specimens were procured from 36 patients undergoing transurethral resection. Tissue specimens were obtained from the same patients at first cystoscopy following six weekly intravesical instillations. Inducible NOS protein expression was assessed by immunohistochemistry in all tissue specimens. Immunostaining of normal urothelium for iNOS before treatment was negative in all but four cases. BCG treatment induced iNOS expression in tumor-free bladder tissue in 24 cases (66.6%). There were only four early tumor recurrences; interestingly, they corresponded to the cases with tumor cells expressing iNOS before BCG treatment, while novel tumors were also iNOS immunoreactive. BCG upregulated iNOS expression in normal human urothelial cells in vivo suggesting a role for nitric oxide in BCG mediated antitumor activity. Inducible NOS was detected in certain tumor specimens before and after BCG treatment implying a possible involvement in pro-tumor action.