Produção de óxido nítrico e expressão da enzima sintase de óxido nítrico em tumores ovarianos císticos.

Abstract

Introduction: Nitric oxide (NO) is a biological messenger synthesized from the L-arginine amino acid by the action of the nitric oxide synthase (NOS) enzyme. The endothelial and neuronal NOS are constitutive in many cell types, while the inducible NOS (iNOS) is induced in leucocytes, endothelial cells and other cell types after stimulation by bacterial endotoxin or cytokines, with NO produced at higher concentrations. NO can present a dual role in tumor development. Evidences suggest that it is cytotoxic and cytostatic against microorganisms and malignant cells. The NO production by neoplastic cells promotes angiogenesis, essential to the growing and maintenance of the tumor, besides it can increase the metastatic behavior of the tumor. NO is a biological signaling molecule, but when produced for a long period of time, the excess of NO could lead to mutations and to cancer. Objectives: The objectives of this study were to quantify the levels of NO metabolites and the expression of iNOS enzyme in ovarian tumors; to evaluate the relationship of NOS expression and the levels of NO metabolites with the ovarian cancer staging and the grade of tumoral differentiation; to compare intracystic nitrate levels with immunohistochemical staining of the iNOS enzyme. Material and Methods: The study enrolled 63 women underwent surgery for an adnexal mass, divided in three groups: non-neoplastic tumors (n=15), benign neoplasias (n=28), and malignant neoplasias (n=20). The cystic fluid samples were collected by punction after surgical resection for determination of nitrate concentration (Griess method). Immunohistochemical study was performed in the tumoral tissue. Results: iNOS immunostaining was significantly increased in ovarian cancer compared with non-neoplastic tumors (p=0.0014) and benign neoplasias (p=0.0003). The NO metabolite levels were significantly increased in malignant tumors compared to benign neoplasias (p=0.045). In ovarian cancer, the number of cases with NO intracystic levels > 80 μM in stage I was significantly higher compared with NO intracystic levels < 80μM (p=0.0498). The expression of iNOS in well - differentiated carcinomas was significantly higher than in moderately / poorly differentiated tumors (p=0.004). There was not correlation between intracystic NO levels and intensity of immunohistochemical staining. Conclusion: Expression of iNOS enzyme in the tissue of malignant neoplasias of the ovary is higher related to the benign neoplasias and non-neoplastic tumors; production of NO metabolites is increased in ovarian malignant neoplasias; expression of iNOS is increased in well - differentiated tumors compared to moderately / poorly differentiated tumors; NO intracystic levels is increased in stage I of ovarian cancer compared to stages III / IV; and there is not a correlation between intracystic NO levels and NO produced in the tissue.