Suppression of cytokine-inducible nitric oxide synthesis during intraperitoneal Meth A tumor growth.
Nitric oxide (NO*) synthesis is induced within many tumors. The time course of NO* synthesis was evaluated during intra-peritoneal 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 IFNgamma 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 TGFbeta 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.
Kwon
Oh-Deog
OD
University of Utah Cancer Immunotherapy Program, Department of Internal Medicine of the University of Utah School of Medicine, Salt Lake City, 84132, USA.
Yim
Chang-Yeol
CY
Jeong
Kyu-Shik
KS
Park
Seung-Chun
SC
Jung
Kyu-Yong
KY
McGregor
John R
JR
Bastian
Neil R
NR
Samlowski
Wolfram E
WE
D000818:Animals; D001201:Ascites / Q000378:metabolism*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D004578:Electron Spin Resonance Spectroscopy; D004794:Enzyme Repression / Q000187:drug effects; D005354:Fibrosarcoma / Q000378:metabolism*; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D010586:Phagocytes / Q000378:metabolism*; D011622:Pterins / Q000494:pharmacology; D013997:Time Factors
D016207:Cytokines; D008070:Lipopolysaccharides; D009573:Nitrites; D011622:Pterins; D009569:Nitric Oxide; C016727:sepiapterin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse