Suppression of cytokine-inducible nitric oxide synthesis during intraperitoneal meth A tumor growth

Nitric oxide (NO•) synthesis is induced within many tumors. The timecourse of NO• synthesis was evaluated during intraperitoneal Meth A fibrosarcoma progression. While increasing macrophage recruitment into ascites was noted, inducible nitric oxide synthase (iNOS) antigen and function peaked between days 3-6 after tumor implantation. The capacity of cells to respond to LPS and IFNγ stimulation was markedly depressed on day 9 and 11. Cellular proliferation correlated in an inverse fashion with levels of NO• synthesis. Electron paramagnetic resonance spectroscopy and nitrotyrosine immunostaining failed to show accumulation of characteristic target cell lesions induced by NO•. These findings lead us to conclude that NO• production was increasingly suppressed during Meth A tumor progression. Depression of NO• production did not correlate with levels of the inhibitory cytokines TGF β and IL-10, but could be partially overcome by addition of sepiapterin (a tetrahydrobiopterin prodrug). Thus, depletion of essential co-factors necessary for iNOS function may contribute to depressed NO• responses during cancer progression.