Inhibition of bacillus Calmette-Guérin-induced nitric oxide in bladder tumor cells may improve BCG treatment.
Bacillus Calmette-Guérin (BCG) is considered to be one of the most effective treatments for superficial and in situ bladder cancer. However, either failure to respond initially or relapse within the first 5 years of treatment has been observed in some patients. As nitric oxide (NO) has been detected in the bladder of BCG-treated patients, we analyzed the role of endogenous NO generated after BCG treatments on human (T24) and murine (MB49 and MBT2) bladder tumor cells in the viability of tumor and immune cells, both in vitro and in vivo. In vitro inhibition of cancer cells after BCG treatment was evaluated by cell titer assay. NO production was determined as nitrite by Griess reagent. The death of immunocytes was evaluated by 51Cr release. Tumor histology with hematoxylin and eosin and Masson's trichrome staining was performed. BCG induced a direct inhibition of tumor cell growth in vitro, independently of NO levels. Besides, BCG-mediated NO production by tumor cells induced the death of spleen and peritoneal cells in syngeneic mice. The in vivo inhibition of NO synthase (NOS) activity by NG-nitro-L-arginine methyl ester in combination with BCG, improved tumor regression by generating a healing tissue. The increase of NO generated after BCG administration may induce the death of immunocytes. The in vivo inhibition of NO ameliorated immunotherapy with BCG by additional tumor growth inhibition. Our results suggested the possibility that the final outcome of patients with bladder tumors may improve by modulating NOS activity concomitantly with BCG therapy.
Alvarez
Valeria
V
Research Area from the Institute of Oncology Angel H. Roffo, University of Buenos Aires, Av. San Martín 5481, CP 1417 DTB Buenos Aires, Argentina.
Lodillinsky
Catalina
C
Umerez
Sol
S
Sandes
Eduardo
E
Eiján
Ana María
AM
D000818:Animals; D001500:BCG Vaccine / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D015552:Injections, Intralesional; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology* / Q000627:therapeutic use; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000378:metabolism / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013997:Time Factors; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
D001500:BCG Vaccine; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester