Summary
Nitric oxide (NO) is a free radical that is involved in the inflammatory process and carcinogenesis. There are four nitric oxide synthase enzymes involved in NO production: induced nitric oxide synthase (iNOS), endothelial NO synthase (eNOS), neural NO synthase (nNOS), and mitochondrial NOS. iNOS is an inducible and key enzyme in the inflamed tissue. Recent literatures indicate that NO as well as iNOS and eNOS can modulate cancer-related events including nitro-oxidative stress, apoptosis, cell cycle, angio-genesis, invasion, and metastasis. This chapter focuses on linking NO/iNOS/eNOS to inflammation and carcinogenesis from experimental evidence to potential targets on cancer prevention and treatment.
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References
Li, C.Q. and Wogan, G.N. (2005) Nitric oxide as a modulator of apoptosis. Cancer Lett 226, 1–15.
Stamler, J.S. (1994) Redox signaling: nitrosylation and related target interactions of nitric oxide. Cell 78, 931–936.
Butler, A.R., Flitney, F.W., and Williams, D.L. (1995) NO, nitrosonium ions, nitroxide ions, nitrosothiols and iron-nitrosyls in biology: a chemist's perspective. Trends Pharmacol Sci 16, 18–22.
Wink, D.A., Hanbauer, I., Grisham, M.B., Laval, F., Nims, R.W., Laval, J., Cook, J., Pacelli, R, Liebmann, J., Krishna, M., Ford, P.C., and Mitchell, J.B. (1996) Chemical biology of nitric oxide: regulation and protective and toxic mechanisms. Curr Top Cell Regul 34, 159–187.
Nathan, C. (2004) The moving frontier in nitric oxide-dependent signaling. Sci STKE 2004, pe52.
Goyal, R.K. and He, X.D. (1998) Evidence for NO• redox form of nitric oxide as nitrergic inhibitory neurotransmitter in gut. Am J Physiol 275, G1185–G1192.
Moncada, S., Palmer, R.M., and Higgs, E.A. (1991) Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 43, 109–142.
Lincoln, J., Hoyle, H., and Burnstock, G. (1997) Nitric Oxide in Health and Disease, Cambridge University Press, Cambridge
Stuehr, D.J. and Marletta, M.A. (1985) Mammalian nitrate biosynthesis: mouse macrophages produce nitrite and nitrate in response to Escherichia coli lipopoly-saccharide. Proc Natl Acad Sci U S A 82,7738–7742.
Stuehr, D.J. and Marletta, MA. (1987) Induction of nitrite/nitrate synthesis in murine macrophages by BCG infection, lym-phokines, or interferon–gamma. J Immunol 139, 518–525.
Thomassen, M.J. and Kavuru, M.S. (2001) Human alveolar macrophages and monocytes as a source and target for nitric oxide. Int Immunopharmacol 1, 1479–1490.
van der Veen, RC. (2001) Nitric oxide and T helper cell immunity. Int Immunopharmacol 1, 1491–1500.
Cifone, M.G., Ulisse, S., and Santoni, A. (2001) Natural killer cells and nitric oxide. Int Immunopharmacol 1, 1513–1524.
Iijima, H., Duguet, A., Eum, S.Y., Hamid, Q., and Eidelman, D.H. (2001) Nitric oxide and protein nitration are eosinophil dependent in allergen-challenged mice. Am J Respir Crit Care Med 163, 1233–1240.
Bidri, M., Feger, F., Varadaradjalou, S., Ben Hamouda, N., Guillosson, J.J., and Arock, M. (2001) Mast cells as a source and target for nitric oxide. Int Immunopharmacol 1, 1543–1558.
Forsythe, P., Gilchrist, M., Kulka, M., and Befus, A.D. (2001) Mast cells and nitric oxide: control of production, mechanisms of response. Int Immunopharmacol 1, 1525–1541.
Bogdan, C., Rollinghoff, M., and Diefen-bach, A. (2000) Reactive oxygen and reactive nitrogen intermediates in innate and specific immunity. Curr Opin Immunol 12, 64–76.
Langrehr, J.M., Hoffman, R.A., Lancaster, J.R., Jr., and Simmons, R.L. (1993) Nitric oxide – a new endogenous immunomodula-tor. Transplantation 55, 1205–1212.
Barnes, P.J. and Liew, F.Y. (1995) Nitric oxide and asthmatic inflammation. Immunol Today 16, 128–130.
Taylor-Robinson, A.W., Liew, F.Y., Severn, A., Xu, D., McSorley, S.J., Garside, P., Padron, J., and Phillips, R.S. (1994) Regulation of the immune response by nitric oxide differentially produced by T helper type 1 and T helper type 2 cells. Eur J Immunol 24, 980–984.
Thuring, H., Stenger, S., Gmehling, D., Rollinghoff, M., and Bogdan, C. (1995) Lack of inducible nitric oxide synthase activity in T cell clones and T lymphocytes from naive and Leishmania major–infected mice. Eur J Immunol 25, 3229–3234.
Wei, X.Q., Charles, I.G., Smith, A., Ure, J., Feng, G.J., Huang, F.P., Xu, D., Muller, W., Moncada, S., and Liew, F.Y. (1995) Altered immune responses in mice lacking inducible nitric oxide synthase. Nature 375, 408–411.
Armstrong, R. (2001) The physiological role and pharmacological potential of nitric oxide in neutrophil activation. Int Immu-nopharmacol 1, 1501–1512.
Bentz, B.G., Simmons, R.L., Haines, G.K., III, and Radosevich, J.A. (2000) The yin and yang of nitric oxide: reflections on the physiology and pathophysiology of NO. Head Neck 22, 71–83.
Stark, M.E. and Szurszewski, J.H. (1992) Role of nitric oxide in gastrointestinal and hepatic function and disease. Gastroenterology 103, 1928–1949.
Coleman, J.W. (2001) Nitric oxide in immunity and inflammation. Int Immunopharmacol 1, 1397–1406.
Fang, F.C. (1997) Perspectives series: host/ pathogen interactions. Mechanisms of nitric oxide–related antimicrobial activity. J Clin Invest 99, 2818–2825.
Alam, M.S., Akaike, T., Okamoto, S., Kubota, T., Yoshitake, J., Sawa, T., Miyamoto, Y., Tamura, F., and Maeda, H. (2002) Role of nitric oxide in host defense in murine salmonellosis as a function of its antibacterial and antiapoptotic activities. Infect Immun 70, 3130–3142.
Granger, D.L., Hibbs, J.B., Jr., Perfect, J.R., and Durack, D.T. (1988) Specific amino acid (L–arginine) requirement for the micro-biostatic activity of murine macrophages. J Clin Invest 81, 1129–1136.
James, S.L. (1995) Role of nitric oxide in parasitic infections. Microbiol Rev 59, 533–547.
Mannick, J.B., Asano, K., Izumi, K., Kieff, E., and Stamler, J.S. (1994) Nitric oxide produced by human B lymphocytes inhibits apoptosis and Epstein-Barr virus reactivation. Cell 79, 1137–1146.
Nathan, C. and Shiloh, M.U. (2000) Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens. Proc Natl Acad Sci U S A 97, 8841–8848.
Wink, D.A., Hanbauer, I., Krishna, M.C., DeGraff, W., Gamson, J., and Mitchell, J.B. (1993) Nitric oxide protects against cellular damage and cytotoxiCity from reactive oxygen species. Proc Natl Acad Sci U S A 90, 9813–9817.
Berendji-Grun, D., Kolb-Bachofen, V., and Kroncke, K.D. (2001) Nitric oxide inhibits endothelial IL-1[beta]-induced ICAM-1 gene expression at the transcriptional level decreasing Sp1 and AP-1 activity. Mol Med 7, 748–754.
Clancy, R., Varenika, B., Huang, W., Ballou, L., Attur, M., Amin, A.R., and Abramson, S.B. (2000) Nitric oxide synthase/COX cross-talk: nitric oxide activates COX-1 but inhibits COX-2-derived prostaglandin production. J Immunol 165, 1582–1587.
De Caterina, R., Libby, P., Peng, H.B., Thannickal, V.J., Rajavashisth, T.B., Gim-brone, M.A., Jr., Shin, W.S., and Liao, J.K. (1995) Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest 96, 60–68.
Gurjar, M.V., DeLeon, J., Sharma, R.V., and Bhalla, R.C. (2001) Mechanism of inhibition of matrix metalloproteinase-9 induction by NO in vascular smooth muscle cells. J Appl Physiol 91, 1380–1386.
Peng, H.B., Rajavashisth, T.B., Libby, P., and Liao, J.K. (1995) Nitric oxide inhibits macrophage-colony stimulating factor gene transcription in vascular endothelial cells. J Biol Chem 270, 17050–17055.
Stadler, J., Harbrecht, B.G., Di Silvio, M., Curran, R.D., Jordan, M.L., Simmons, R.L., and Billiar, T.R. (1993) Endogenous nitric oxide inhibits the synthesis of cycloox-ygenase products and interleukin-6 by rat Kupffer cells. J Leukoc Biol 53, 165–172.
Friebe, A. and Koesling, D. (2003) Regulation of nitric oxide-sensitive guanylyl cyclase. Circ Res 93, 96–105.
Nathan, C. and Xie, Q.W. (1994) Nitric oxide synthases: roles, tolls, and controls. Cell 78, 915–918.
Forstermann, U., Pollock, J.S., Tracey, W.R., and Nakane, M. (1994) Isoforms of nitric-oxide synthase: purification and regulation. Methods Enzymol 233, 258–264.
Geller, D.A. and Billiar, T.R. (1998) Molecular biology of nitric oxide synthases. Cancer Metastasis Rev 17, 7–23.
Laubach, V.E., Shesely, E.G., Smithies, O., and Sherman, P.A. (1995) Mice lacking induc-ible nitric oxide synthase are not resistant to lipopolysaccharide-induced death. Proc Natl Acad Sci U S A 92, 10688–10692.
MacMicking, J.D., Nathan, C., Hom, G., Chartrain, N., Fletcher, D.S., Trum-bauer, M., Stevens, K., Xie, Q.W., Sokol, K., Hutchinson, N., et al. (1995) Altered responses to bacterial infection and endo-toxic shock in mice lacking inducible nitric oxide synthase. Cell 81, 641–650.
Gregg, A.R., Schauer, A., Shi, O., Liu, Z., Lee, C.G., and O'Brien, W.E. (1998) Limb reduction defects in endothelial nitric oxide synthase-deficient mice. Am J Physiol 275, H2319–H2324.
Huang, P.L., Huang, Z., Mashimo, H., Bloch, K.D., Moskowitz, M.A., Bevan, J.A., and Fishman, M.C. (1995) Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 377, 239–242.
Huang, P.L., Dawson, T.M., Bredt, D.S., Snyder, S.H., and Fishman, M.C. (1993) Targeted disruption of the neuronal nitric oxide synthase gene. Cell 75, 1273–1286.
Nathan, C.F. and Hibbs, J.B., Jr. (1991) Role of nitric oxide synthesis in macrophage antimicrobial activity. Curr Opin Immunol 3, 65–70.
Hofseth, L.J., Hussain, S.P., Wogan, G.N., Harris, C.C. (2003) Nitric oxide in cancer and chemoprevention. Free Radic Biol Med 34, 955–968.
Hussain, S.P., Amstad, P., Raja, K., Ambs, S., Nagashima, M., Bennett, W.P., Shields, P.G., Ham, A.J., Swenberg, J.A., Marrogi, A.J., and Harris, C.C. (2000) Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis: a cancer-prone chronic inflammatory disease. Cancer Res 60, 3333–3337.
Jaiswal, M., LaRusso, N.F., Burgart, L.J., and Gores, G.J. (2000) Inflammatory cytokines induce DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxide-dependent mechanism. Cancer Res 60, 184–190.
Lirk, P., Hoffmann, G., and Rieder, J. (2002) Inducible nitric oxide synthase – time for reappraisal. Curr Drug Targets Inflamm Allergy 1, 89–108.
Marletta, M.A. (1994) Nitric oxide synthase: aspects concerning structure and catalysis. Cell 78, 927–930.
Michel, T. and Feron, O. (1997) Nitric oxide synthases: which, where, how, and why? J Clin Invest 100, 2146–2152.
Berkman, N., Robichaud, A., Robbins, R.A., Roesems, G., Haddad, E.B., Barnes, P.J., and Chung, K.F. (1996) Inhibition of induc-ible nitric oxide synthase expression by inter-leukin-4 and interleukin-13 in human lung epithelial cells. Immunology 89, 363–367.
Nussler, A.K. and Billiar, T.R. (1993) Inflammation, immunoregulation, and inducible nitric oxide synthase. J Leukoc Biol 54, 171–178.
Tozer, G.M. and Everett, S.A. (1997) Nitric oxide in tumor biology and cancer therapy. Part 2: therapeutic implications. Clin Oncol (R Coll Radiol) 9, 357–364.
Hibbs, J.B., Jr., Vavrin, Z., and Taintor, R.R. (1987) L-Arginine is required for expression of the activated macrophage effector mechanism causing selective metabolic inhibition in target cells. J Immunol 138, 550–565.
Karupiah, G., Xie, Q.W., Buller, R.M., Nathan, C., Duarte, C., and MacMicking, J.D. (1993) Inhibition of viral replication by interferon–gamma–induced nitric oxide syn– thase. Science 261, 1445–1448.
Green, S.J., Nacy, C.A., and Meltzer, M.S. (1991) Cytokine-induced synthesis of nitrogen oxides in macrophages: a protective hostresponse to Leishmania and other intracel-lular pathogens. J Leukoc Biol 50, 93–103.
Davies, M.G., Fulton, G.J., and Hagen, P.O. (1995) Clinical biology of nitric oxide. Br J Surg 82, 1598–1610.
Geller, D.A., Nussler, A.K., Di Silvio, M., Lowenstein, C.J., Shapiro, R.A., Wang, S.C., Simmons, R.L., and Billiar, T.R. (1993) Cytokines, endotoxin, and glucocorticoids regulate the expression of inducible nitric oxide synthase in hepatocytes. Proc Natl Acad Sci U S A 90, 522–526.
Jaiswal, M., LaRusso, N., and Gores, G. (2000) Cholangiocarcinoma and pro-inflammatory cytokines. Cancer Alert 1, 141–144.
Nathan, C. and Xie, Q.W. (1994) Regulation of biosynthesis of nitric oxide. J Biol Chem 269, 13725–13728.
Darnell, J.E., Jr., Kerr, I.M., and Stark, G.R. (1994) Jak–STAT pathways and transcrip– tional activation in response to IFNs and other extracellular signaling proteins. Science 264, 1415–1421.
Xie, Q.W., Kashiwabara, Y., and Nathan, C. (1994) Role of transcription factor NF–kappa B/Rel in induction of nitric oxide synthase. J Biol Chem 269, 4705–4708.
Stark, G.R., Kerr, I.M., Williams, B.R., Silverman, R.H., and Schreiber, R.D. (1998) How cells respond to interferons. Annu Rev Biochem 67, 227–264.
Geller, D.A., Di Silvio, M., Nussler, A.K., Wang, S.C., Shapiro, R.A., Simmons, R.L., and Billiar, T.R. (1993) Nitric oxide syn-thase expression is induced in hepatocytes in vivo during hepatic inflammation. J Surg Res 55, 427–432.
Nussler, A.K., Geller, D.A., Sweetland, M.A., Di Silvio, M., Billiar, T.R., Madariaga, J.B., Simmons, R.L., and Lancaster, J.R., Jr. (1993) Induction of nitric oxide synthesis and its reactions in cultured human and rat hepatocytes stimulated with cytokines plus LPS. Biochem Biophys Res Commun 194, 826–835.
Kamijo, R., Harada, H., Matsuyama, T., Bosland, M., Gerecitano, J., Shapiro, D., Le, J., Koh, S.I., Kimura, T., Green, S.J., et al. (1994) Requirement for transcription factor IRF-1 in NO synthase induction in macrophages. Science 263, 1612–1615.
Saura, M., Zaragoza, C., Bao, C., McMillan, A., and Lowenstein, C.J. (1999) Interaction of interferon regulatory factor-1 and nuclear factor kappaB during activation of inducible nitric oxide synthase transcription. J Mol Biol 289, 459–471.
Perrella, M.A., Pellacani, A., Wiesel, P., Chin, M.T., Foster, L.C., Ibanez, M., Hsieh, C.M., Reeves, R., Yet, S.F., and Lee, M.E. (1999) High mobility group-I(Y) protein facilitates nuclear factor-kappaB binding and transactivation of the inducible nitric–oxide synthase promoter/enhancer. J Biol Chem 274, 9045–9052.
Rodriguez-Pascual, F., Hausding, M., Ihrig-Biedert, I., Furneaux, H., Levy, A.P., Forstermann, U., and Kleinert, H. (2000) Complex contribution of the 3′-untranslated region to the expressional regulation of the human inducible nitric-oxide synthase gene. Involvement of the RNA-binding protein HuR. J Biol Chem 275, 26040–26049.
Ratovitski, E.A., Bao, C., Quick, R.A., McMillan, A., Kozlovsky, C., and Lowen- stein, C.J. (1999) An inducible nitric-oxide synthase (NOS)-associated protein inhibits NOS dimerization and activity. J Biol Chem 274, 30250–30257.
Vodovotz, Y., Bogdan, C., Paik, J., Xie, Q.W., and Nathan, C. (1993) Mechanisms of suppression of macrophage nitric oxide release by transforming growth factor beta. J Exp Med 178, 605–613.
Taylor, B.S., Alarcon, L.H., and Billiar, T.R. (1998) Inducible nitric oxide synthase in the liver: regulation and function. Biochemistry (Mosc) 63, 766–781.
Sessa, W.C. (2004) eNOS at a glance. J Cell Sci 117, 2427–2429.
Grumbach, I.M., Chen, W., Mertens, S.A., and Harrison, D.G. (2005) A negative feedback mechanism involving nitric oxide and nuclear factor kappa-B modulates endothe-lial nitric oxide synthase transcription. J Mol Cell Cardiol 39, 595–603.
Blais, V. and Rivest, S. (2001) Inhibitory action of nitric oxide on circulating tumor necrosis factor-induced NF-kappaB activity and COX-2 transcription in the endothe-lium of the brain capillaries. J Neuropathol Exp Neurol 60, 893–905.
Connelly, L., Jacobs, A.T., Palacios-Cal-lender, M., Moncada, S., and Hobbs, A.J. (2003) Macrophage endothelial nitric-oxide synthase autoregulates cellular activation and pro-inflammatory protein expression. J Biol Chem 278, 26480–26487.
Furchgott, R.F. and Zawadzki, J.V. (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288, 373–376.
Ignarro, L.J., Cirino, G., Casini, A., and Napoli, C. (1999) Nitric oxide as a signaling molecule in the vascular system: an overview. J Cardiovasc Pharmacol 34, 879–886.
Ohashi, Y., Kawashima, S., Hirata, K., Yamashita, T., Ishida, T., Inoue, N., Sakoda, T., Kurihara, H., Yazaki, Y., and Yokoyama, M. (1998) Hypotension and reduced nitric oxide-elicited vasorelaxation in transgenic mice overexpressing endothelial nitric oxide synthase. J Clin Invest 102, 2061–2071.
Beck, P.L., Xavier, R., Wong, J., Ezedi, I., Mashimo, H., Mizoguchi, A., Mizoguchi, E., Bhan, A.K., Podolsky, D.K. (2004) Paradoxical roles of different nitric oxide syn-thase isoforms in colonic injury. Am J Physiol Gastrointest Liver Physiol 286, G137–G147.
Sasaki, M., Bharwani, S., Jordan, P., Elrod, J.W., Grisham, M.B., Jackson, T.H., Lefer, D.J., and Alexander, J.S. (2003) Increased disease activity in eNOS-deficient mice in experimental colitis. Free Radic Biol Med 35, 1679–1687.
Vallance, B.A., Dijkstra, G., Qiu, B., van der Waaij, L.A., van Goor, H., Jansen, P.L., Mashimo, H., and Collins, S.M. (2004) Relative contributions of NOS isoforms during experimental colitis: endothelial-derived NOS maintains mucosal integrity. Am J Physiol Gastrointest Liver Physiol 287, G865–G874.
DiMagno, M.J., Williams, J.A., Hao, Y., Ernst, S.A., and Owyang, C. (2004) Endothe-lial nitric oxide synthase is protective in the initiation of caerulein-induced acute pancreatitis in mice. Am J Physiol Gastrointest Liver Physiol 287, G80–G87.
Qiu, B.S., Mashimo, H., Vallance, B.A., Blennerrhassett, P.A., and Collins, S.M. (1998) Susceptibility of mice with specific NOSgene deletions to experimental colitis. Gastroenterology 114, A1065
Sato, J., Nair, K., Hiddinga, J., Eberhardt, N.L., Fitzpatrick, L.A., Katusic, Z.S., and O'Brien, T. (2000) eNOS gene transfer to vascular smooth muscle cells inhibits cell proliferation via upregulation of p27 and p21 and not apoptosis. Cardiovasc Res 47, 697–706.
Stamler, J.S., Lamas, S., and Fang, F.C. (2001) Nitrosylation. the prototypic redox–based signaling mechanism. Cell 106, 675–683.
Kroncke, K.D., Fehsel, K., Suschek, C., and Kolb-Bachofen, V. (2001) Inducible nitric oxide synthase–derived nitric oxide in gene regulation, cell death and cell survival. Int Immunopharmacol 1, 1407–1420.
Ohshima, H., Tatemichi, M., and Sawa, T. (2003) Chemical basis of inflammation-induced carcinogenesis. Arch Biochem Biophys 417, 3–11.
Yoshie, Y. and Ohshima, H. (1997) Nitric oxide synergistically enhances DNA strand breakage induced by polyhydroxyaromatic compounds, but inhibits that induced by the Fenton reaction. Arch Biochem Biophys 342, 13–21.
Wink, D.A., Grisham, M.B., Mitchell, J.B., and Ford, P.C. (1996) Direct and indirect effects of nitric oxide in chemical reactions relevant to biology. Methods Enzymol 268, 12–31.
Beckman, J.S. (1991) The double-edged role of nitric oxide in brain function and superoxide-mediated injury. J Dev Physiol 15, 53–59.
Beckman, J.S. and Koppenol, W.H. (1996) Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol 271, C1424–C1437.
Pryor, W.A. and Squadrito, G.L. (1995) The chemistry of peroxynitrite: a product from the reaction of nitric oxide with super-oxide. Am J Physiol 268, L699–L722.
King, P.A., Anderson, V.E., Edwards, J.O., Gustafson, G., Plumb, R.C., and Suggs, J.W. (1992) A stable solid that generates hydroxyl radical upon dissolution in aqueous solution: reactions with proteins and nucleic acids. J Am Chem Soc 114, 5430–5432
Salgo, M.G., Stone, K., Squadrito, G.L., Battista, J.R., and Pryor, W.A. (1995) Per-oxynitrite causes DNA nicks in plasmid pBR322. Biochem Biophys Res Commun 210, 1025–1030.
Fukuto, J.M., Switzer, C.H., Miranda, K.M., and Wink, D.A. (2005) Nitroxyl (HNO): chemistry, biochemistry, and pharmacology. Annu Rev Pharmacol Toxicol45, 335–355.
Ohshima, H., Friesen, M., Brouet, I., and Bartsch, H. (1990) Nitrotyrosine as a new marker for endogenous nitrosation and nitration of proteins. Food Chem Toxicol28, 647–652.
Ischiropoulos, H. (1998) Biological tyro-sine nitration: a pathophysiological function of nitric oxide and reactive oxygen species. Arch Biochem Biophys356, 1–11.
Rohn, T.T. and Quinn, M.T. (1998) Inhibition of peroxynitrite-mediated tyrosine nitration by a novel pyrrolopyrimidine anti-oxidant. Eur J Pharmacol353, 329–336.
Singer, I.I., Kawka, D.W., Scott, S., Wei-dner, J.R., Mumford, R.A., Riehl, T.E., and Stenson, W.F. (1996) Expression of induc-ible nitric oxide synthase and nitrotyrosine in colonic epithelium in inflammatory bowel disease. Gastroenterology111, 871–885.
Iacopini, F., Consolazio, A., Bosco, D., Marcheggiano, A., Bella, A., Pica, R., Paoluzi, O.A., Crispino, P., Rivera, M., Mot-tolese, M., Nardi, F., and Paoluzi, P. (2003) Oxidative damage of the gastric mucosa in Helicobacter pyloripositive chronic atrophic and nonatrophic gastritis, before and after eradication. Helicobacter8, 503–512.
Kimura, H., Hokari, R., Miura, S., Shige-matsu, T., Hirokawa, M., Akiba, Y., Kurose, I.,Higuchi, H., Fujimori, H., Tsuzuki, Y., Serizawa, H., and Ishii, H. (1998) Increased expression of an inducible isoform of nitric oxide synthase and the formation of peroxynitrite in colonic mucosa of patients with active ulcerative colitis. Gut42, 180–187.
Kruidenier, L., Kuiper, I., Lamers, C.B., and Verspaget, H.W. (2003) Intestinal oxida-tive damage in inflammatory bowel disease: semi-quantification, localization, and association with mucosal antioxidants. J Pathol201, 28–36.
Mannick, E.E., Bravo, L.E., Zarama, G., Realpe, J.L., Zhang, X.J., Ruiz, B., Fontham, E.T., Mera, R., Miller, M.J., and Correa, P. (1996) Inducible nitric oxide synthase, nitro-tyrosine, and apoptosis in Helicobacter pylorigastritis: effect of antibiotics and antioxidants. Cancer Res56, 3238–3243.
Pignatelli, B., Bancel, B., Plummer, M., Toyokuni, S., Patricot, L.M., and Ohshima, H. (2001) Helicobacter pylorieradication attenuates oxidative stress in human gastric mucosa. Am J Gastroenterol96, 1758–1766.
Kato, H., Miyazaki, T., Yoshikawa, M., Naka-jima, M., Fukai, Y., Tajima, K., Masuda, N., Tsutsumi, S., Tsukada, K., Nakajima, T., and Kuwano, H. (2000) Nitrotyrosine in esopha-geal squamous cell carcinoma and relevance to p53 expression. Cancer Lett153, 121–127.
Jaiswal, M., LaRusso, N.F., Shapiro, R.A., Billiar, T.R., and Gores, G.J. (2001) Nitric oxide-mediated inhibition of DNA repair potentiates oxidative DNA damage in cholan-giocytes. Gastroenterology120, 190–199.
Vickers, S.M., MacMillan-Crow, L.A., Green, M., Ellis, C., and Thompson, J.A. (1999) Association of increased immunostaining for inducible nitric oxide synthase and nitrotyrosine with fibroblast growth factor transformation in pancreatic cancer. Arch Surg134, 245–251.
Seril, D.N., Liao, J., Ho, K.L., Warsi, A., Yang, C.S., and Yang, G.Y. (2002) Dietary iron sup plementation enhances DSS-induced colitis and associated colorectal carcinoma development in mice. Dig Dis Sci47, 1266–1278.
Lala, P.K. and Chakraborty, C. (2001) Role of nitric oxide in carcinogenesis and tumour progression. Lancet Oncol2, 149–156.
Wink, D.A., Vodovotz, Y., Cook, J.A., Krishna, M.C., Kim, S., Coffin, D., DeGraff, W., Deluca, A.M., Liebmann, J., and Mitchell, J.B. (1998) The role of nitric oxide chemistry in cancer treatment. Biochemistry (Mosc)63, 802–809.
Szabo, C. and Ohshima, H. (1997) DNA damage induced by peroxynitrite: subsequent biological effects. Nitric Oxide1, 373–385.
Ohshima, H., Yermilov, V., Yoshie, Y., and Rubio, J. (1999) DNA damage induced by reactive oxygen species. In Advances in DNA Damage and Repair(Dizdaroglu, M. and Karakaya, A., eds), pp. 329–339, Plenum, New York
Burney, S., Caulfield, J.L., Niles, J.C., Wish-nok, J.S., and Tannenbaum, S.R. (1999) The chemistry of DNA damage from nitric oxide and peroxynitrite. Mutat Res424, 37–49.
Dedon, P.C. and Tannenbaum, S.R. (2004) Reactive nitrogen species in the chemical biology of inflammation. Arch Biochem Bio-phys423, 12–22.
Rubbo, H., Darley-Usmar, V., and Freeman, B.A. (1996) Nitric oxide regulation of tissue free radical injury. Chem Res Toxicol9, 809–820.
Stamler, J.S., Singel, D.J., and Loscalzo, J. (1992) Biochemistry of nitric oxide and its redox-activated forms. Science258, 1898–1902.
Shimkin, M. (1977) Contrary to Nature. DHEW Publication No. (NIH) 76–720, Department of Health and Human Services, Washington, DC
Triolo, V.A. (1965) Nineteenth century foundations of cancer research advances in tumor pathology, nomenclature, and theories of oncogenesis. Cancer Res25, 75–106.
Gardner, A.W. (1959) Trauma and squa-mous skin cancer. Lancet1, 760–761.
Lawrence, E. (1952) Carcinoma arising in the scars of thermal burns. Surg Gynecol Obstet95, 579–580
Menkin, V. (1960) Role of inflammation in carcinogenesis. Br Med J5186, 1585–1594
Cruickshank, A.H., McConnell, E.M., and Miller, D.G. (1963) Malignancy in scars, chronic ulcers, and sinuses. J Clin Pathol16, 573–580.
DaCosta, J. (1903) Carcinomatous changes in an area of chronic ulceration of Marjolin's ulcer. Ann Surg37, 496–502
Lovell, W. (1957) Carcinoma of skin, sinuses and bone following chronic osteomyelitis. South Med J50, 266–271
Curry, S.S., Gaither, D.H., and King, L.E., Jr. (1981) Squamous cell carcinoma arising in dissecting perifolliculitis of the scalp. A case report and review of secondary squa-mous cell carcinomas. J Am Acad Dermatol4, 673–678.
Kapadia, C.R. (1997) Oxides, onions, and other matters gastrointestinal – 1996 – a perspective. J Clin Gastroenterol24, 133–139.
Kroncke, K.D., Fehsel, K., and Kolb-Ba-chofen, V. (1998) Inducible nitric oxide synthase in human diseases. Clin Exp Immunol113, 147–156.
Ohshima, H. and Bartsch, H. (1994) Chronic infections and inflammatory processes as cancer risk factors: possible role of nitric oxide in carcinogenesis. Mutat Res305, 253–264.
Balkwill, F. and Mantovani, A. (2001) Inflammation and cancer: back to Virchow? Lancet357, 539–545.
Coussens, L.M. and Werb, Z. (2002) Inflammation and cancer. Nature420, 860–867.
Ferguson, A. (1911) Associated bilharziosis and primary malignant disease of the urinary bladder, with observations on a series of forty cases. J Pathol Bacteriol16, 76–94
Kantor, A.F., Hartge, P., Hoover, R.N., and Fraumeni, J.F., Jr. (1988) Epidemiological characteristics of squamous cell carcinoma and adenocarcinoma of the bladder. Cancer Res48, 3853–3855.
Locke, J.R., Hill, D.E., and Walzer, Y. (1985) Incidence of squamous cell carcinoma in patients with long-term catheter drainage. J Urol133, 1034–1035.
Cameron, A.J., Ott, B.J., and Payne, W.S. (1985) The incidence of adenocarcinoma in columnar-lined (Barrett's) esophagus. N Engl J Med313, 857–859.
Dahms, B.B. and Rothstein, F.C. (1984) Barrett's esophagus in children: a consequence of chronic gastroesophageal reflux. Gastroenterology86, 318–323.
Correa, P. (1988) A human model of gastric carcinogenesis. Cancer Res48, 3554–3560.
Diehl, A.K. (1983) Gallstone size and the risk of gallbladder cancer. JAMA 250, 2323–2326.
Farges, O., Malassagne, B., Sebagh, M., and Bismuth, H. (1995) Primary sclerosing cholangitis: liver transplantation or biliary surgery. Surgery117, 146–155.
Collins, R.H., Jr., Feldman, M., and Fordtran, J.S. (1987) Colon cancer, dyspla-sia, and surveillance in patients with ulcera-tive colitis. A critical review. N Engl J Med316, 1654–1658.
Korelitz, B.I. (1983) Carcinoma of the intestinal tract in Crohn's disease: results of a survey conducted by the National Foundation for Ileitis and colitis. Am J Gastroenterol78, 44–46.
O'Byrne, K.J. and Dalgleish, A.G. (2001) Chronic immune activation and inflammation as the cause of malignancy. Br J Cancer85, 473–483.
Christen, S, et al. (1999) Chronic Inflammation, Mutation, and Cancer, Oxford University Press, New York
Adler, V., Yin, Z., Tew, K.D., and Ronai, Z. (1999) Role of redox potential and reactive oxygen species in stress signaling. Oncogene18, 6104–6111.
Shackelford, R.E., Kaufmann, W.K., and Paules, R.S. (2000) Oxidative stress and cell cycle checkpoint function. Free Radic Biol Med28, 1387–1404.
Kyriakis, J.M. and Avruch, J. (2001) Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev81, 807–869.
Cerutti, P.A. and Trump, B.F. (1991) Inflammation and oxidative stress in car-cinogenesis. Cancer Cells3, 1–7.
Shalon, D., Smith, S.J., and Brown, P.O. (1996) A DNA microarray system for analyzing complex DNA samples using two-color fluorescent probe hybridization. Genome Res6, 639–645.
Cerutti, P.A. (1985) Prooxidant states and tumor promotion. Science227, 375–381.
Wilson, K.T., Fu, S., Ramanujam, K.S., and Meltzer, S.J. (1998) Increased expression of inducible nitric oxide synthase and cycloox-ygenase-2 in Barrett's esophagus and associated adenocarcinomas. Cancer Res58, 2929–2934.
Majano, P.L., Garcia-Monzon, C., Lopez-Cabrera, M., Lara-Pezzi, E., Fernandez-Ruiz, E., Garcia-Iglesias, C., Borque, M.J., and Moreno-Otero, R. (1998) Inducible nitric oxide synthase expression in chronic viral hepatitis. Evidence for a virus-induced gene upregulation. J Clin Invest101, 1343–1352.
Tsuji, S., Tsujii, M., Sun, W.H., Gunawan, E.S., Murata, H., Kawano, S., and Hori, M. (1997) Helicobacter pyloriand gastric car-cinogenesis. J Clin Gastroenterol25 Suppl 1, S186–S197.
Rachmilewitz, D., Karmeli, F., Eliakim, R., Stalnikowicz, R., Ackerman, Z., Amir, G., and Stamler, J.S. (1994) Enhanced gastric nitric oxide synthase activity in duodenal ulcer patients. Gut35, 1394–1397.
Streitz, J.M., Jr. (1994) Barrett's esophagus and esophageal cancer. Chest Surg Clin N Am4, 227–240.
Crowell, J.A., Steele, V.E., Sigman, C.C., and Fay, J.R. (2003) Is inducible nitric oxide synthase a target for chemoprevention? Mol Cancer Ther2, 815–823.
Thomsen, L.L. and Miles, D.W. (1998) Role of nitric oxide in tumour progression: lessons from human tumours. Cancer Metastasis Rev17, 107–118.
Seril, D.N., Liao, J., and Yang, G.Y. (2007) Colorectal carcinoma development in induc-ible nitric oxide synthase-deficient mice with dextran sulfate sodium-induced ulcerative colitis. Mol Carcinog46, 341–353.
Ahn, B., Han, B.S., Kim, D.J., and Ohshima, H. (1999) Immunohistochemical localization of inducible nitric oxide synthase and 3-nitrotyrosine in rat liver tumors induced by N-nitrosodiethylamine. Carcinogenesis20, 1337–1344.
Gal, A., Tamir, S., Tannenbaum, S.R., and Wogan, G.N. (1996) Nitric oxide production in SJL mice bearing the RcsX lym-phoma: a model for in vivo toxicological evaluation of NO. Proc Natl Acad Sci U S A93, 11499–11503.
Nair, J., Gal, A., Tamir, S., Tannenbaum, S.R., Wogan, G.N., and Bartsch, H. (1998) Etheno adducts in spleen DNA of SJL mice stimulated to overproduce nitric oxide. Car-cinogenesis19, 2081–2084.
Goldstein, S.R., Yang, G.Y., Chen, X., Curtis, S.K., and Yang, C.S. (1998) Studies of iron deposits, inducible nitric oxide synthase and nitrotyrosine in a rat model for esophageal adenocarcinoma. Carcinogenesis19, 1445–1449.
Gal, A. and Wogan, G.N. (1996) Mutagen-esis associated with nitric oxide production in transgenic SJL mice. Proc Natl Acad Sci U S A93, 15102–15107.
Tamir, S., deRojas-Walker, T., Gal, A., Weller, A.H., Li, X., Fox, J.G., Wogan, G.N., and Tannenbaum, S.R. (1995) Nitric oxide production in relation to spontaneous B-cell lymphoma and myositis in SJL mice. Cancer Res55, 4391–4397.
Roediger, W.E., Lawson, M.J., and Rad-cliffe, B.C. (1990) Nitrite from inflammatory cells – a cancer risk factor in ulcerative colitis? Dis Colon Rectum33, 1034–1036.
Rosen, C.B., Nagorney, D.M., Wiesner, R.H., Coffey, R.J., Jr., and LaRusso, N.F. (1991) Cholangiocarcinoma complicating primary sclerosing cholangitis. Ann Surg213, 21–25.
Watanapa, P. (1996) Cholangiocarcinoma in patients with opisthorchiasis. Br J Surg83, 1062–1064.
Taylor, B.S., de Vera, M.E., Ganster, R.W., Wang, Q., Shapiro, R.A., Morris, S.M., Jr., Billiar, T.R., and Geller, D.A. (1998) Multiple NF-kappaB enhancer elements regulate cytokine induction of the human inducible nitric oxide synthase gene. J Biol Chem273, 15148–15156.
Mirvish, S.S. (1995) Role of N-nitroso compounds (NOC) and N-nitrosation in etiology of gastric, esophageal, nasopharyn-geal and bladder cancer and contribution to cancer of known exposures to NOC. Cancer Lett93, 17–48.
Haswell-Elkins, M.R., Satarug, S., Tsuda, M., Mairiang, E., Esumi, H., Sithithaworn, P., Mairiang, P., Saitoh, M., Yongvanit, P., and Elkins, D.B. (1994) Liver fluke infection and cholangiocarcinoma: model of endogenous nitric oxide and extragastric nitrosa-tion in human carcinogenesis. Mutat Res305, 241–252.
Mordan, L.J., Burnett, T.S., Zhang, L.X., Tom, J., and Cooney, R.V. (1993) Inhibitors of endogenous nitrogen oxide formation block the promotion of neoplastic transformation in C3H 10T1/2 fibroblasts. Carcinogenesis14, 1555–1559.
Ahn, B. and Ohshima, H. (2001) Suppression of intestinal polyposis in Apc(Min/+) mice by inhibiting nitric oxide production. Cancer Res61, 8357–8360.
Ellies, L.G., Fishman, M., Hardison, J., Kleeman, J., Maglione, J.E., Manner, C.K., Cardiff, R.D., and MacLeod, C.L. (2003) Mammary tumor latency is increased in mice lacking the inducible nitric oxide syn-thase. Int J Cancer106, 1–7.
Kisley, L.R., Barrett, B.S., Bauer, A.K., Dwyer-Nield, L.D., Barthel, B., Meyer, A.M., Thompson, D.C., and Malkinson, A.M. (2002) Genetic ablation of inducible nitric oxide synthase decreases mouse lung tum-origenesis. Cancer Res62, 6850–6856.
Nam, K.T., Oh, S.Y., Ahn, B., Kim, Y.B., Jang, D.D., Yang, K.H., Hahm, K.B., and Kim, D.Y. (2004) Decreased Helicobacter pyloriassociated gastric carcinogenesis in mice lacking inducible nitric oxide synthase. Gut53, 1250–1255.
Scott, D.J., Hull, M.A., Cartwright, E.J., Lam, W.K., Tisbury, A., Poulsom, R., Markham, A.F., Bonifer, C., and Coletta, P.L. (2001) Lack of inducible nitric oxide syn-thase promotes intestinal tumorigenesis in the Apc(Min/+) mouse. Gastroenterology121, 889–899.
Hussain, S.P., Trivers, G.E., Hofseth, L.J., He, P., Shaikh, I., Mechanic, L.E., Doja, S., Jiang, W., Subleski, J., Shorts, L., Haines, D., Laubach, V.E., Wiltrout, R.H., Djurickovic, D., and Harris, C.C. (2004) Nitric oxide, a mediator of inflammation, suppresses tum-origenesis. Cancer Res64, 6849–6853.
Wink, D.A., Kasprzak, K.S., Maragos, C.M., Elespuru, R.K., Misra, M., Dunams, T.M., Cebula, T.A., Koch, W.H., Andrews, A.W., Allen, J.S., et al. (1991) DNA deaminating ability and genotoxiCity of nitric oxide and its progenitors. Science254, 1001–1003.
Jenkins, D.C., Charles, I.G., Thomsen, L.L., Moss, D.W., Holmes, L.S., Baylis, S.A., Rhodes, P., Westmore, K., Emson, P.C., and Moncada, S. (1995) Roles of nitric oxide in tumor growth. Proc Natl Acad Sci U S A92, 4392–4396.
Ambs, S., Ogunfusika, M.O., Merriam, W.G., Bennett, W.P., Billiar, T.R., and Harris, C.C. (1998) Up-regulation of inducible nitric oxide synthase expression in cancer-prone p53 knockout mice. Proc Natl Acad Sci U S A95, 8823–8828.
Li, J., Billiar, T.R., Talanian, R.V., and Kim, Y.M. (1997) Nitric oxide reversibly inhibits seven members of the caspase family via S-nitrosylation. Biochem Biophys Res Com-mun240, 419–424.
Fukumura, D., Kashiwagi, S., and Jain, R.K. (2006) The role of nitric oxide in tumour progression. Nat Rev Cancer6, 521–534.
Lancaster, J.R., Jr. and Xie, K. (2006) Tumors face NO problems? Cancer Res66, 6459–6462.
Xie, K. and Fidler, I.J. (1998) Therapy of cancer metastasis by activation of the induc-ible nitric oxide synthase. Cancer Metastasis Rev17, 55–75.
Wang, B., Xiong, Q., Shi, Q., Le, X., Abbruzzese, J.L., and Xie, K. (2001) Intact nitric oxide synthase II gene is required for interferon-beta-mediated suppression of growth and metastasis of pancreatic adeno-carcinoma. Cancer Res61, 71–75.
Wang, B., Xiong, Q., Shi, Q., Tan, D., Le, X., and Xie, K. (2001) Genetic disruption of host nitric oxide synthase II gene impairs melanoma-induced angiogenesis and suppresses pleural effusion. Int J Cancer91, 607–611.
Juang, S.H., Xie, K., Xu, L., Shi, Q., Wang, Y., Yoneda, J., and Fidler, I.J. (1998) Suppression of tumorigeniCity and metastasis of human renal carcinoma cells by infection with retroviral vectors harboring the murine inducible nitric oxide synthase gene. Hum Gene Ther9, 845–854.
Shi, Q., Huang, S., Jiang, W., Kutach, L.S., Ananthaswamy, H.N., and Xie, K. (1999) Direct correlation between nitric oxide syn-thase II inducibility and metastatic ability of UV-2237 murine fibrosarcoma cells carrying mutant p53. Cancer Res59, 2072–2075.
Shi, Q., Xiong, Q., Wang, B., Le, X., Khan, N.A., and Xie, K. (2000) Influence of nitric oxide synthase II gene disruption on tumor growth and metastasis. Cancer Res60, 2579–2583.
Xie, K., Huang, S., Dong, Z., Gutman, M., and Fidler, I.J. (1995) Direct correlation between expression of endogenous induc-ible nitric oxide synthase and regression of M5076 reticulum cell sarcoma hepatic metastases in mice treated with liposomes containing lipopeptide CGP 31362. Cancer Res55, 3123–3131.
Xie, K., Dong, Z., and Fidler, I.J. (1996) Activation of nitric oxide synthase gene for inhibition of cancer metastasis. J Leukoc Biol59, 797–803.
Dong, Z., Staroselsky, A.H., Qi, X., Xie, K., and Fidler, I.J. (1994) Inverse correlation between expression of inducible nitric oxide synthase activity and production of metastasis in K-1735 murine melanoma cells. Cancer Res54, 789–793.
Xie, K., Huang, S., Dong, Z., Juang, S.H., Gutman, M., Xie, Q.W., Nathan, C., and Fidler, I.J. (1995) Transfection with the inducible nitric oxide synthase gene suppresses tumorigeniCity and abrogates metastasis by K-1735 murine melanoma cells. J Exp Med181, 1333–1343.
Xie, K., Huang, S., Dong, Z., Juang, S.H., Wang, Y., and Fidler, I.J. (1997) Destruction of bystander cells by tumor cells transfected with inducible nitric oxide (NO) synthase gene. J Natl Cancer Inst89, 421–427.
Ambs, S., Merriam, W.G., Ogunfusika, M.O., Bennett, W.P., Ishibe, N., Hussain, S.P., Tzeng, E.E., Geller, D.A., Billiar, T.R., and Harris, C.C. (1998) p53 and vascular endothelial growth factor regulate tumor growth of NOS2-expressing human carcinoma cells. Nat Med4, 1371–1376.
Ho, Y.S., Wang, Y.J., and Lin, J.K. (1996) Induction of p53 and p21/WAF1/CIP1 expression by nitric oxide and their association with apoptosis in human cancer cells. Mol Carcinog16, 20–31.
Wink, D.A. and Mitchell, J.B. (1998) Chemical biology of nitric oxide: Insights into regulatory, cytotoxic, and cytoprotec-tive mechanisms of nitric oxide. Free Radic Biol Med 25, 434–456.
Xu, W., Liu, L., Smith, G.C., and Charles, G. (2000) Nitric oxide upregulates expression of DNA-PKcs to protect cells from DNA-damaging anti-tumour agents. Nat Cell Biol 2, 339–345.
Hussain, S.P. and Harris, C.C. (1999) p53 mutation spectrum and load: the generation of hypotheses linking the exposure of endogenous or exogenous carcinogens to human cancer. Mutat Res 428, 23–32.
Olivier, M., Eeles, R., Hollstein, M., Khan, M.A., Harris, C.C., and Hainaut, P. (2002) The IARC TP53 database: new online mutation analysis and recommendations to users. Hum Mutat 19, 607–614.
Ekmekcioglu, S., Tang, C.H., and Grimm, E.A. (2005) NO news is not necessarily good news in cancer. Curr Cancer Drug Targets 5, 103–115.
Cooper, H.S., Everley, L., Chang, W.C., Pfeiffer, G., Lee, B., Murthy, S., and Clapper, M.L. (2001) The role of mutant Apc in the development of dysplasia and cancer in the mouse model of dextran sulfate sodium-induced colitis. Gastroenterology 121, 1407–1416.
Mabley, J.G., Pacher, P. , Bai, P. , Wallace, R., Goonesekera, S., Virag, L., Southan, G.J., and Szabo, C. (2004) Suppression of intestinal polyposis in ApcMin/+ mice by targeting the nitric oxide or poly(ADP-ribose) pathways. Mutat Res 548, 107–116.
Tamir, S., Burney, S., and Tannenbaum, S.R. (1996) DNA damage by nitric oxide. Chem Res Toxicol 9, 821–827.
Felley-Bosco, E., Mirkovitch, J., Ambs, S., Mace, K., Pfeifer, A., Keefer, L.K., and Harris, C.C. (1995) Nitric oxide and ethylni-trosourea: relative mutageniCity in the p53 tumor suppressor and hypoxanthine-phos-phoribosyltransferase genes. Carcinogenesis 16, 2069–2074.
Juedes, M.J. and Wogan, G.N. (1996) Peroxynitrite-induced mutation spectra of pSP189 following replication in bacteria and in human cells. Mutat Res 349, 51–61.
Li, C.Q., Trudel, L.J., and Wogan, G.N. (2002) GenotoxiCity, mitochondrial damage, and apoptosis in human lymphoblastoid cells exposed to peroxynitrite generated from SIN-1. Chem Res Toxicol 15, 527–535.
Tannenbaum, S.R., Tamir, S., Rojas-Walker, T.D., and Wishnok, J.S. (1994) DNA damage and cytotoxiCity of nitric oxide. In Nitrosamines and Related Nitroso-Compound Chemistry and Biochemistry (Loepsky, R.N. and Michejda, C.J., eds), pp. 120–135, American Chemical Society, Washington, DC.
Nguyen, T., Brunson, D., Crespi, C.L., Penman, B.W., Wishnok, J.S., and Tan-nenbaum, S.R. (1992) DNA damage and mutation in human cells exposed to nitric oxide in vitro. Proc Natl Acad Sci U S A 89, 3030–3034.
Cheng, K.C., Cahill, D.S., Kasai, H., Nishimura, S., and Loeb, L.A. (1992) 8-Hydroxyguanine, an abundant form of oxidative DNA damage, causes G→T and A→C substitutions. J Biol Chem 267, 166–172.
Routledge, M.N., Wink, D.A., Keefer, L.K., and Dipple, A. (1993) Mutations induced by saturated aqueous nitric oxide in the pSP189 supF gene in human Ad293 and E. coli MBM7070 cells. Carcinogenesis 14, 1251–1254.
Routledge, M.N., Wink, D.A., Keefer, L.K., and Dipple, A. (1994) DNA sequence changes induced by two nitric oxide donor drugs in the supF assay. Chem Res Toxicol 7, 628–632.
Ambs, S.B., Bennett, W.P., Merriam, W.G., Ogunfusika, M.O., Oser, S.M., Harrington, A.M., Shields, P.G., Felley-Bosco, E., Hus-sain, S.P., Harris, C.C. (1999) Relationship between p53 mutations and inducible nitric oxide synthase expression in human colorec-tal cancer. J Natl Cancer Inst 91, 86–88.
Greenblatt, M.S., Bennett, W.P., Hollstein, M., and Harris, C.C. (1994) Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 54, 4855–4878.
Harris, C.C. and Hollstein, M. (1993) Clinical implications of the p53 tumor-suppressor gene. N Engl J Med 329, 1318–1327.
Souici, A.C., Mirkovitch, J., Hausel, P., Keefer, L.K., and Felley-Bosco, E. (2000) Transition mutation in codon 248 of the p53 tumor suppressor gene induced by reactive oxygen species and a nitric oxide-releasing compound. Carcinogenesis 21, 281–287.
Yermilov, V., Rubio, J., Becchi, M., Friesen, M.D., Pignatelli, B., and Ohshima, H. (1995) Formation of 8-nitroguanine by the reaction of guanine with peroxynitrite in vitro. Carcinogenesis 16, 2045–2050.
Yermilov, V., Rubio, J., and Ohshima, H. (1995) Formation of 8-nitroguanine in DNA treated with peroxynitrite in vitro and its rapid removal from DNA by depurina-tion. FEBS Lett 376, 207–210.
Niles, J.C., Wishnok, J.S., and Tannenbaum, S.R. (2001) A novel nitroimidazole compound formed during the reaction of perox-ynitrite with 2′,3′,5′-tri-O-acetyl-guanosine. J Am Chem Soc 123, 12147–12151.
Byun, J., Henderson, J.P., Mueller, D.M., and Heinecke, J.W. (1999) 8-Nitro-2′-deoxyguanosine, a specific marker of oxidation by reactive nitrogen species, is generated by the myeloperoxidase-hydrogen peroxide-nitrite system of activated human phagocytes. Biochemistry 38, 2590–2600.
Joffe, A., Mock, S., Yun, B.H., Kolbanovskiy, A., Geacintov, N.E., and Shafirovich, V. (2003) Oxidative generation of guanine radicals by carbonate radicals and their reactions with nitrogen dioxide to form site specific 5-guanidino-4-nitroimidazole lesions in oligodeoxynucleotides. Chem Res Toxicol 16, 966–973.
Neeley, W.L., Delaney, J.C., Henderson, P.T., and Essigmann, J.M. (2004) In vivo bypass efficiencies and mutational signatures of the guanine oxidation products 2-aminoimida-zolone and 5-guanidino-4-nitroimidazole. J Biol Chem 279, 43568–43573.
Yermilov, V., Yoshie, Y., Rubio, J., and Ohshima, H. (1996) Effects of carbon dioxide/bicarbonate on induction of DNA single-strand breaks and formation of 8-ni-troguanine, 8-oxoguanine and base-prope-nal mediated by peroxynitrite. FEBS Lett 399, 67–70.
Suzuki, N., Yasui, M., Geacintov, N.E., Shafirovich, V., and Shibutani, S. (2005) Miscoding events during DNA synthesis past the nitration-damaged base 8-nitrogua-nine. Biochemistry 44, 9238–9245.
Masuda, M., Nishino, H., and Ohshima, H. (2002) Formation of 8-nitroguanosine in cellular RNA as a biomarker of exposure to reactive nitrogen species. Chem Biol Interact 139, 187–197.
Witherell, H.L., Hiatt, R.A., Replogle, M., and Parsonnet, J. (1998) Helicobacter pylori infection and urinary excretion of 8-hy-droxy-2-deoxyguanosine, an oxidative DNA adduct. Cancer Epidemiol Biomarkers Prev 7, 91–96.
Kiziltepe, T., Yan, A., Dong, M., Jonnala-gadda, V.S., Dedon, P.C., and Engelward, B.P. (2005) Delineation of the chemical pathways underlying nitric oxide-induced homologous recombination in mammalian cells. Chem Biol 12, 357–369.
Uppu, R.M., Cueto, R., Squadrito, G.L., Salgo, M.G., and Pryor, W.A. (1996) Competitive reactions of peroxynitrite with 2′-deoxyguanosine and 7,8-dihydro-8-oxo-2′-deoxyguanosine (8-oxodG): relevance to the formation of 8-oxodG in DNA exposed to peroxynitrite. Free Radic Biol Med 21, 407–411.
Niles, J.C., Wishnok, J.S., and Tannen-baum, S.R. (2004) Spiroiminodihydantoin and guanidinohydantoin are the dominant products of 8-oxoguanosine oxidation at low fluxes of peroxynitrite: mechanistic studies with 180. Chem Res Toxicol 17, 1510–1519.
Henderson, P.T., Delaney, J.C., Muller, J.G., Neeley, W.L., Tannenbaum, S.R., Burrows, C.J., and Essigmann, J.M. (2003) The hydantoin lesions formed from oxidation of 7,8-dihydro-8-oxoguanine are potent sources of replication errors in vivo. Biochemistry 42, 9257–9262.
Ohshima, H. and Bartsch, H. (1999) Quantitative estimation of endogenous N-nitrosation in humans by monitoring N-nitrosoproline in urine. Methods Enzymol 301, 40–49.
Yoshie, Y. and Ohshima, H. (1997) Syn-ergistic induction of DNA strand breakage caused by nitric oxide together with catecho-lamine: implications for neurodegenerative disease. Chem Res Toxicol 10, 1015–1022.
Yoshie, Y. and Ohshima, H. (1997) Syner-gistic induction of DNA strand breakage by cigarette tar and nitric oxide. Carcinogenesis 18, 1359–1363.
Yoshie, Y. and Ohshima, H. (1998) Syner-gistic induction of DNA strand breakage by catechol-estrogen and nitric oxide: implications for hormonal carcinogenesis. Free Radic Biol Med 24, 341–348.
Inoue, S. and Kawanishi, S. (1995) Oxida-tive DNA damage induced by simultaneous generation of nitric oxide and superoxide. FEBS Lett 371, 86–88.
Epe, B., Ballmaier, D., Roussyn, I., Briviba, K., and Sies, H. (1996) DNA damage by per-oxynitrite characterized with DNA repair enzymes. Nucleic Acids Res 24, 4105–4110.
Hogg, N., Darley-Usmar, V.M., Wilson, M.T., and Moncada, S. (1992) Production of hydroxyl radicals from the simultaneous generation of superoxide and nitric oxide. Biochem J 281 (Pt 2), 419–424.
Ohshima, H., Gilibert, I., and Bianchini, F. (1999) Induction of DNA strand breakage and base oxidation by nitroxyl anion through hydroxyl radical production. Free Radic Biol Med 26, 1305–1313.
Chazotte-Aubert, L., Oikawa, S., Gilibert, I., Bianchini, F., Kawanishi, S., and Ohshima, H. (1999) CytotoxiCity and site-specific DNA damage induced by nitroxyl anion (NO(−)) in the presence of hydrogen peroxide. Implications for various pathophysiological conditions. J Biol Chem 274, 20909–20915.
Ohshima, H., Yoshie, Y., Auriol, S., and Gilibert, I. (1998) Antioxidant and pro-ox-idant actions of flavonoids: effects on DNA damage induced by nitric oxide, peroxyni-trite and nitroxyl anion. Free Radic Biol Med 25, 1057–1065.
Kowalczykowski, S.C. (2000) Initiation of genetic recombination and recombination-dependent replication. Trends Biochem Sci 25, 156–165.
Wink, D.A., Feelisch, M., Fukuto, J., Chisto-doulou, D., Jourd'heuil, D., Grisham, M.B., Vodovotz, Y., Cook, J.A., Krishna, M., DeGraff, W.G., Kim, S., Gamson, J., and Mitchell, J.B. (1998) The cytotoxiCity of nitroxyl: possible implications for the patho-physiological role of NO. Arch Biochem Bio-phys 351, 66–74.
Bishop, A.J. and Schiestl, R.H. (2002) Homologous recombination and its role in carcinogenesis. J Biomed Biotechnol 2, 75–85.
Khanna, K.K. and Jackson, S.P. (2001) DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet 27, 247–254.
Darley-Usmar, V.M., Hogg, N., O'Leary, V.J., Wilson, M.T., and Moncada, S. (1992) The simultaneous generation of superoxide and nitric oxide can initiate lipid peroxidation in human low density lipoprotein. Free Radic Res Commun 17, 9–20.
Padgett, C.M. and Whorton, A.R. (1998) Cellular responses to nitric oxide: role of protein S-thiolation/dethiolation. Arch Bio-chem Biophys 358, 232–242.
Sawa, T., Akaike, T., and Maeda, H. (2000) Tyrosine nitration by peroxynitrite formed from nitric oxide and superoxide generated by xanthine oxidase. J Biol Chem 275, 32467–32474.
Suzuki, T., Mower, H.F., Friesen, M.D., Gilibert, I., Sawa, T., and Ohshima, H. (2004) Nitration and nitrosation of N-acetyl-L-tryptophan and tryptophan residues in proteins by various reactive nitrogen species. Free Radic Biol Med 37, 671–681.
Radi, R., Rodriguez, M., Castro, L., and Telleri, R. (1994) Inhibition of mitochon-drial electron transport by peroxynitrite. Arch Biochem Biophys 308, 89–95.
Weiss, G., Goossen, B., Doppler, W., Fuchs, D., Pantopoulos, K., Werner-Felmayer, G., Wachter, H., and Hentze, M.W. (1993) Translational regulation via iron-responsive elements by the nitric oxide/NO-synthase pathway. EMBO J 12, 3651–3657.
Lepoivre, M., Flaman, J.M., Bobe, P., Lemaire, G., and Henry, Y. (1994) Quenching of the tyrosyl free radical of ribonucle-otide reductase by nitric oxide. Relationship to cytostasis induced in tumor cells by cytotoxic macrophages. J Biol Chem 269, 21891–21897.
Chien, Y.H., Bau, D.T., and Jan, K.Y. (2004) Nitric oxide inhibits DNA-adduct excision in nucleotide excision repair. Free Radic Biol Med 36, 1011–1017.
Friedberg, E.C. (1996) Relationships between DNA repair and transcription. Annu Rev Biochem 65, 15–42.
Sancar, A. (1996) DNA excision repair. Annu Rev Biochem 65, 43–81.
Wood, R.D. (1996) DNA repair in eukaryo-tes. Annu Rev Biochem 65, 135–167.
Jaiswal, M., Lipinski, L.J., Bohr, V.A., and Mazur, S.J. (1998) Efficient in vitro repair of 7-hydro-8-oxodeoxyguanosine by human cell extracts: involvement of multiple pathways. Nucleic Acids Res 26, 2184–2191.
Laval, J., Jurado, J., Saparbaev, M., and Sidorkina, O. (1998) Antimutagenic role of base-excision repair enzymes upon free radical-induced DNA damage. Mutat Res 402, 93–102.
Laval, F., Wink, D.A., and Laval, J. (1997) A discussion of mechanisms of NO genotoxic-ity: implication of inhibition of DNA repair proteins. Rev Physiol Biochem Pharmacol 131, 175–191.
Graziewicz, M., Wink, D.A., and Laval, F. (1996) Nitric oxide inhibits DNA ligase activity: potential mechanisms for NO-mediated DNA damage. Carcinogenesis 17, 2501–2505.
Jaiswal, M., LaRusso, N.F., Nishioka, N., Nakabeppu, Y., and Gores, G.J. (2001) Human Ogg1, a protein involved in the repair of 8-oxoguanine, is inhibited by nitric oxide. Cancer Res 61, 6388–6393.
Laval, F. and Wink, D.A. (1994) Inhibition by nitric oxide of the repair protein, O6-methylguanine-DNA-methyltransferase. Carcinogenesis 15, 443–447.
Liu, L., Xu-Welliver, M., Kanugula, S., and Pegg, A.E. (2002) Inactivation and degradation of O(6)-alkylguanine-DNA alkyl-transferase after reaction with nitric oxide. Cancer Res 62, 3037–3043.
Wink, D.A. and Laval, J. (1994) The Fpg protein, a DNA repair enzyme, is inhibited by the biomediator nitric oxide in vitro and in vivo. Carcinogenesis 15, 2125–2129.
Wink, D.A., Vodovotz, Y., Laval, J., Laval, F., Dewhirst, M.W., and Mitchell, J.B. (1998) The multifaceted roles of nitric oxide in cancer. Carcinogenesis 19, 711–721.
Starke, D.W., Chen, Y., Bapna, C.P., Les-nefsky, E.J., and Mieyal, J.J. (1997) Sensitivity of protein sulfhydryl repair enzymes to oxidative stress. Free Radic Biol Med 23, 373–384.
Morita, E.H., Ohkubo, T., Kuraoka, I., Shirakawa, M., Tanaka, K., and Morikawa, K. (1996) Implications of the zinc-finger motif found in the DNA-binding domain of the human XPA protein. Genes Cells 1, 437–442.
Lindahl, T. and Barnes, D.E. (1992) Mammalian DNA ligases. Annu Rev Biochem 61, 251–281.
Roldan-Arjona, T., Wei, Y.F., Carter, K.C., Klungland, A., Anselmino, C., Wang, R.P., Augustus, M., and Lindahl, T. (1997) Molecular cloning and functional expression of a human cDNA encoding the anti-mutator enzyme 8-hydroxyguanine-DNA glycosylase. Proc Natl Acad Sci U S A 94, 8016–8020.
Tani, M., Shinmura, K., Kohno, T., Shiroi-shi, T., Wakana, S., Kim, S.R., Nohmi, T., Kasai, H., Takenoshita, S., Nagamachi, Y., and Yokota, J. (1998) Genomic structure and chromosomal localization of the mouse Ogg1 gene that is involved in the repair of 8-hydroxyguanine in DNA damage. Mamm Genome 9, 32–37.
Klungland, A., Rosewell, I., Hollenbach, S., Larsen, E., Daly, G., Epe, B., Seeberg, E., Lindahl, T., and Barnes, D.E. (1999) Accumulation of premutagenic DNA lesions in mice defective in removal of oxidative base damage. Proc Natl Acad Sci U S A 96, 13300–13305.
Rosenquist, T.A., Zharkov, D.O., and Groll-man, A.P. (1997) Cloning and characterization of a mammalian 8-oxoguanine DNA glycosylase. Proc Natl Acad Sci U S A 94, 7429–7434.
Yamamoto, F., Kasai, H., Bessho, T., Chung, M.H., Inoue, H., Ohtsuka, E., Hori, T., and Nishimura, S. (1992) Ubiquitous presence in mammalian cells of enzymatic activity specifically cleaving 8-hydroxyguanine-contain-ing DNA. Jpn J Cancer Res 83, 351–357.
Yamaguchi, S., Bell, H.S., Shinoda, J., Holmes, M.C., Wharton, S.B., and Whittle, I.R. (2002) Glioma tumourgeniCity is decreased by iNOS knockout: experimental studies using the C6 striatal implantation glioma model. Br J Neurosurg 16, 567–572.
Barreiro Arcos, M.L., Gorelik, G., Klecha, A., Goren, N., Cerquetti, C., and Cremaschi, G.A. (2003) Inducible nitric oxide synthase-me-diated proliferation of a T lymphoma cell line. Nitric Oxide 8, 111–118.
Shang, Z.J., Li, Z.B., and Li, J.R. (2006) In vitro effects of nitric oxide synthase inhibitor L-NAME on oral squamous cell carcinoma: a preliminary study. Int J Oral Maxillofac Surg 35, 539–543.
Stallmeyer, B., Anhold, M., Wetzler, C., Kahl-ina, K., Pfeilschifter, J., and Frank, S. (2002) Regulation of eNOS in normal and diabetes-impaired skin repair: implications for tissue regeneration. Nitric Oxide 6, 168–177.
Tong, X. and Li, H. (2004) eNOS protects prostate cancer cells from TRAIL-induced apoptosis. Cancer Lett 210, 63–71.
Wartenberg, M., Schallenberg, M., Hescheler, J., and Sauer, H. (2003) Reactive oxygen species-mediated regulation of eNOS and iNOS expression in multicellular prostate tumor spheroids. Int J Cancer 104, 274–282.
Murphy, P.R., Limoges, M., Dodd, F., Boudreau, R.T., and Too, C.K. (2001) Fibroblast growth factor-2 stimulates endothelial nitric oxide synthase expression and inhibits apoptosis by a nitric oxide-dependent pathway in Nb2 lymphoma cells. Endocrinology 142, 81–88.
Weller, R., Schwentker, A., Billiar, T.R., and Vodovotz, Y. (2003) Autologous nitric oxide protects mouse and human keratino-cytes from ultraviolet B radiation-induced apoptosis. Am J Physiol Cell Physiol 284, C1140–C1148.
Dodd, F., Limoges, M., Boudreau, R.T., Rowden, G., Murphy, P.R., and Too, C.K. (2000) L-Arginine inhibits apoptosis via a NO-dependent mechanism in Nb2 lym-phoma cells. J Cell Biochem 77, 624–634.
Mortensen, K., Skouv, J., Hougaard, D.M., and Larsson, L.I. (1999) Endogenous endothelial cell nitric-oxide synthase modulates apoptosis in cultured breast cancer cells and is transcriptionally regulated by p53. J Biol Chem 274, 37679–37684.
Hengartner, M.O. (2000) The biochemistry of apoptosis. Nature 407, 770–776.
Suzuki, H. and Ishii, H. (2000) Role of apoptosis in Helicobacter pylori- associated gastric mucosal injury. J Gastroenterol Hepa-tol 15 Suppl, D46–D54.
Le, X., Wei, D., Huang, S., Lancaster, J.R., Jr., and Xie, K. (2005) Nitric oxide synthase II suppresses the growth and metastasis of human cancer regardless of its up-regulation of protumor factors. Proc Natl Acad Sci U S A 102, 8758–8763.
Xie, K. and Huang, S. (2003) Contribution of nitric oxide-mediated apoptosis to cancer metastasis inefficiency. Free Radic Biol Med 34, 969–986.
Kim, Y.M., Bombeck, C.A., and Billiar, T.R. (1999) Nitric oxide as a bifunctional regulator of apoptosis. Circ Res 84, 253–256.
Kim, Y.M., Kim, T.H., Chung, H.T., Talanian, R.V., Yin, X.M., and Billiar, T.R. (2000) Nitric oxide prevents tumor necrosis factor alpha-induced rat hepatocyte apop-tosis by the interruption of mitochondrial apoptotic signaling through S-nitrosylation of caspase-8. Hepatology 32, 770–778.
Ceneviva, G.D., Tzeng, E., Hoyt, D.G., Yee, E., Gallagher, A., Engelhardt, J.F., Kim, Y.M., Billiar, T.R., Watkins, S.A., and Pitt, B.R. (1998) Nitric oxide inhibits lipopolysaccha-ride-induced apoptosis in pulmonary artery endothelial cells. Am J Physiol 275, L717–L728.
Kim, Y.M., de Vera, M.E., Watkins, S.C., and Billiar, T.R. (1997) Nitric oxide protects cultured rat hepatocytes from tumor necrosis factor-alpha-induced apoptosis by inducing heat shock protein 70 expression. J Biol Chem 272, 1402–1411.
Brune, B., von Knethen, A., and Sandau, K.B. (1999) Nitric oxide (NO): an effector of apoptosis. Cell Death Differ 6, 969–975.
Madesh, M., Ramachandran, A., and Balas-ubramanian, K.A. (1999) Nitric oxide prevents anoxia-induced apoptosis in colonic HT29 cells. Arch Biochem Biophys 366, 240–248.
Calmels, S., Hainaut, P., and Ohshima, H. (1997) Nitric oxide induces conformational and functional modifications of wild-type p53 tumor suppressor protein. Cancer Res 57, 3365–3369.
Chazotte-Aubert, L., Hainaut, P., and Ohshima, H. (2000) Nitric oxide nitrates tyrosine residues of tumor-suppressor p53 protein in MCF-7 cells. Biochem Biophys Res Commun 267, 609–613.
Cobbs, C.S., Whisenhunt, T.R., Wese-mann, D.R., Harkins, L.E., Van Meir, E.G., and Samanta, M. (2003) Inactivation of wild-type p53 protein function by reactive oxygen and nitrogen species in malignant glioma cells. Cancer Res 63, 8670–8673.
Fukunaga-Takenaka, R., Fukunaga, K., Tatemichi, M., and Ohshima, H. (2003) Nitric oxide prevents UV-induced phospho-rylation of the p53 tumor-suppressor protein at serine 46: a possible role in inhibition of apoptosis. Biochem Biophys Res Commun 308, 966–974.
Forrester, K., Ambs, S., Lupold, S.E., Kapust, R.B., Spillare, E.A., Weinberg, W.C., Felley-Bosco, E., Wang, X.W., Geller, D.A., Tzeng, E., Billiar, T.R., and Harris, C.C. (1996) Nitric oxide-induced p53 accumulation and regulation of inducible nitric oxide synthase expression by wild-type p53. Proc Natl Acad Sci U S A 93, 2442–2447.
Folkman, J. (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1, 27–31.
Gallo, O., Masini, E., Morbidelli, L., Franchi, A., Fini-Storchi, I., Vergari, W.A., and Ziche, M. (1998) Role of nitric oxide in angiogenesis and tumor progression in head and neck cancer. J Natl Cancer Inst 90, 587–596.
Ziche, M., Morbidelli, L., Masini, E., Amerini, S., Granger, H.J., Maggi, C.A., Geppetti, P., and Ledda, F. (1994) Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P. J Clin Invest 94, 2036–2044.
Gratton, J.P., Lin, M.I., Yu, J., Weiss, E.D., Jiang, Z.L., Fairchild, T.A., Iwakiri, Y., Groszmann, R., Claffey, K.P., Cheng, Y.C., and Sessa, W.C. (2003) Selective inhibition of tumor microvascular permeability by cavtratin blocks tumor progression in mice. Cancer Cell 4, 31–39.
Jadeski, L.C. and Lala, P.K. (1999) Nitric oxide synthase inhibition by N(G)-nitro-L-arginine methyl ester inhibits tumor-induced angiogenesis in mammary tumors. Am J Pathol155, 1381–1390.
Kashiwagi, S., Izumi, Y., Gohongi, T., Demou, Z.N., Xu, L., Huang, P.L., Buerk, D.G., Munn, L.L., Jain, R.K., and Fukumura, D. (2005) NO mediates mural cell recruitment and vessel morphogenesis in murine melanomas and tissue-engineered blood vessels. J Clin Invest115, 1816–1827.
Fukumura, D. and Jain, R.K. (1998) Role of nitric oxide in angiogenesis and microcirculation in tumors. Cancer Metastasis Rev17, 77–89.
Papapetropoulos, A., Garcia-Cardena, G., Madri, J.A., and Sessa, W.C. (1997) Nitric oxide production contributes to the ang-iogenic properties of vascular endothelial growth factor in human endothelial cells. J Clin Invest100, 3131–3139.
Chin, K., Kurashima, Y., Ogura, T., Tajiri, H., Yoshida, S., and Esumi, H. (1997) Induction of vascular endothelial growth factor by nitric oxide in human glioblastoma and hepatocellular carcinoma cells. Oncogene15, 437–442.
Morbidelli, L., Chang, C.H., Douglas, J.G., Granger, H.J., Ledda, F., and Ziche, M. (1996) Nitric oxide mediates mitogenic effect of VEGF on coronary venular endothe-lium. Am J Physiol270, H411–H415.
Ziche, M., Morbidelli, L., Choudhuri, R., Zhang, H.T., Donnini, S., Granger, H.J., and Bicknell, R. (1997) Nitric oxide synthase lies downstream from vascular endothelial growth factor-induced but not basic fibroblast growth factor-induced angiogenesis. J Clin Invest99, 2625–2634.
Kasuno, K., Takabuchi, S., Fukuda, K., Kizaka-Kondoh, S., Yodoi, J., Adachi, T., Semenza, G.L., and Hirota, K. (2004) Nitric oxide induces hypoxia-inducible factor 1 activation that is dependent on MAPK and phosphatidylinositol 3-kinase signaling. J Biol Chem279, 2550–2558.
Kimura, H., Weisz, A., Kurashima, Y., Hashimoto, K., Ogura, T., D'Acquisto, F., Addeo, R., Makuuchi, M., and Esumi, H. (2000) Hypoxia response element of the human vascular endothelial growth factor gene mediates transcriptional regulation by nitric oxide: control of hypoxia-inducible factor-1 activity by nitric oxide. Blood95, 189–197.
Sandau, K.B., Zhou, J., Kietzmann, T., and Brune, B. (2001) Regulation of the hypoxia-inducible factor 1alpha by the inflammatory mediators nitric oxide and tumor necrosis factor-alpha in contrast to desferroxamine and phenylarsine oxide. J Biol Chem276, 39805–39811.
Metzen, E., Zhou, J., Jelkmann, W., Fan-drey, J., and Brune, B. (2003) Nitric oxide impairs normoxic degradation of HIF-1al-pha by inhibition of prolyl hydroxylases. Mol Biol Cell14, 3470–3481.
Genius, J. and Fandrey, J. (2000) Nitric oxide affects the production of reactive oxygen species in hepatoma cells: implications for the process of oxygen sensing. Free Radic Biol Med29, 515–521.
Thomas, D.D., Espey, M.G., Ridnour, L.A., Hofseth, L.J., Mancardi, D., Harris, C.C., and Wink, D.A. (2004) Hypoxic inducible factor 1alpha, extracellular signal-regulated kinase, and p53 are regulated by distinct threshold concentrations of nitric oxide. Proc Natl Acad Sci U S A101, 8894–8899.
Huang, L.E., Willmore, W.G., Gu, J., Goldberg, M.A., and Bunn, H.F. (1999) Inhibition of hypoxia-inducible factor 1 activation by carbon monoxide and nitric oxide. Implications for oxygen sensing and signaling. J Biol Chem274, 9038–9044.
Liu, Y., Christou, H., Morita, T., Laughner, E., Semenza, G.L., and Kourembanas, S. (1998) Carbon monoxide and nitric oxide suppress the hypoxic induction of vascular endothe-lial growth factor gene via the 5′ enhancer. J Biol Chem273, 15257–15262.
Sogawa, K., Numayama-Tsuruta, K., Ema, M., Abe, M., Abe, H., and Fujii-Kuriyama, Y. (1998) Inhibition of hypoxia-inducible factor 1 activity by nitric oxide donors in hypoxia. Proc Natl Acad Sci U S A95, 7368–7373.
Quintero, M., Brennan, P.A., Thomas, G.J., and Moncada, S. (2006) Nitric oxide is a factor in the stabilization of hypoxia-inducible factor-1alpha in cancer: role of free radical formation. Cancer Res66, 770–774.
Pae, H.O., Oh, G.S., Choi, B.M., Kim, Y.M., and Chung, H.T. (2005) A molecular cascade showing nitric oxide-heme oxygen-ase-1-vascular endothelial growth factor-in-terleukin-8 sequence in human endothelial cells. Endocrinology146, 2229–2238.
Ziche, M., Parenti, A., Ledda, F., Dell'Era, P., Granger, H.J., Maggi, C.A., and Presta, M. (1997) Nitric oxide promotes proliferation and plasminogen activator production by coronary venular endothelium through endogenous bFGF. Circ Res80, 845–852.
Sawaoka, H., Tsuji, S., Tsujii, M., Guna-wan, E.S., Nakama, A., Takei, Y., Nagano, K., Matsui, H., Kawano, S., and Hori, M. (1997) Expression of the cyclooxygenase-2 gene in gastric epithelium. J Clin Gastroen-terol25 Suppl 1, S105–S110.
Tsujii, M. and DuBois, R.N. (1995) Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell83, 493–501.
Namkoong, S., Lee, S.J., Kim, C.K., Kim, Y.M., Chung, H.T., Lee, H., Han, J.A., Ha, K.S., Kwon, Y.G., and Kim, Y.M. (2005) Prostag-landin E2 stimulates angiogenesis by activating the nitric oxide/cGMP pathway in human umbilical vein endothelial cells. Exp Mol Med37, 588–600.
Ridnour, L.A., Isenberg, J.S., Espey, M.G., Thomas, D.D., Roberts, D.D., and Wink, D.A. (2005) Nitric oxide regulates angiogen-esis through a functional switch involving thrombospondin-1. Proc Natl Acad Sci U S A102, 13147–13152.
Matsunaga, T., Weihrauch, D.W., Moniz, M.C., Tessmer, J., Warltier, D.C., and Chilian, W.M. (2002) Angiostatin inhibits coronary angiogenesis during impaired production of nitric oxide. Circulation105, 2185–2191.
Babaei, S., Teichert-Kuliszewska, K., Zhang, Q., Jones, N., Dumont, D.J., and Stewart, D.J. (2003) Angiogenic actions of angiopoi-etin-1 require endothelium-derived nitric oxide. Am J Pathol162, 1927–1936.
Fukumura, D., Gohongi, T., Kadambi, A., Izumi, Y., Ang, J., Yun, C.O., Buerk, D.G., Huang, P.L., and Jain, R.K. (2001) Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability. Proc Natl Acad Sci U S A98, 2604–2609.
Duda, D.G., Fukumura, D., and Jain, R.K. (2004) Role of eNOS in neovascularization: NO for endothelial progenitor cells. Trends Mol Med10, 143–145.
Sonveaux, P., Brouet, A., Havaux, X., Gre-goire, V., Dessy, C., Balligand, J.L., and Feron, O. (2003) Irradiation-induced angiogenesis through the up-regulation of thenitric oxide pathway: implications for tumor radiotherapy. Cancer Res63, 1012–1019.
Seril, D.N., Liao, J., Yang, C.S., and Yang, G.Y. (2005) Systemic iron supplementation replenishes iron stores without enhancing colon carcinogenesis in murine models of ulcerative colitis: comparison with iron-en riched diet. Dig Dis Sci50, 696–707.
Urbich, C., Reissner, A., Chavakis, E., Dern-bach, E., Haendeler, J., Fleming, I., Zei-her, A.M., Kaszkin, M., and Dimmeler, S. (2002) Dephosphorylation of endothelial nitric oxide synthase contributes to the anti-angiogenic effects of endostatin. FASEB J16, 706–708.
Aicher, A., Heeschen, C., Mildner-Rihm, C., Urbich, C., Ihling, C., Technau-Ihling, K., Zeiher, A.M., and Dimmeler, S. (2003) Essential role of endothelial nitric oxide syn-thase for mobilization of stem and progenitor cells. Nat Med9, 1370–1376.
De Palma, M., Venneri, M.A., Galli, R., Sergi Sergi, L., Politi, L.S., Sampaolesi, M., and Naldini, L. (2005) Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of peri-cyte progenitors. Cancer Cell8, 211–226.
Duda, D.G., Cohen, K.S., Kozin, S.V., Per-entes, J.Y., Fukumura, D., Scadden, D.T., and Jain, R.K. (2006) Evidence for incorporation of bone marrow-derived endothelial cells into perfused blood vessels in tumors. Blood107, 2774–2776.
Gu, Z., Kaul, M., Yan, B., Kridel, S.J., Cui, J., Strongin, A., Smith, J.W., Liddington, R.C., and Lipton, S.A. (2002) S-Nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science297, 1186–1190.
Marcet-Palacios, M., Graham, K., Cass, C., Befus, A.D., Mayers, I., and Radomski, M.W. (2003) Nitric oxide and cyclic GMP increase the expression of matrix metallo-proteinase-9 in vascular smooth muscle. J Pharmacol Exp Ther307, 429–436.
Peters, B.A., Diaz, L.A., Polyak, K., Meszler, L., Romans, K., Guinan, E.C., Antin, J.H., Myerson, D., Hamilton, S.R., Vogelstein, B., Kinzler, K.W., and Lengauer, C. (2005) Contribution of bone marrow-derived endothelial cells to human tumor vascula-ture. Nat Med11, 261–262.
Rafii, S., Lyden, D., Benezra, R., Hattori, K., and Heissig, B. (2002) Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy? Nat Rev Cancer2, 826–835.
Yu, J., deMuinck, E.D., Zhuang, Z., Drinane, M., Kauser, K., Rubanyi, G.M., Qian, H.S., Murata, T., Escalante, B., and Sessa, W.C. (2005) Endothelial nitric oxide synthase is critical for ischemic remodeling, mural cell recruitment, and blood flow reserve. Proc Natl Acad Sci U S A102, 10999–11004.
Koike, N., Fukumura, D., Gralla, O., Au, P., Schechner, J.S., and Jain, R.K. (2004) Tissue engineering: creation of long-lasting blood vessels. Nature428, 138–139.
Jain, R.K. (2003) Molecular regulation of vessel maturation. Nat Med9, 685–693.
Jain, R.K. (2005) Normalization of tumor vasculature: an emerging concept in antian-giogenic therapy. Science307, 58–62.
Andrade, S.P., Hart, I.R., and Piper, P.J. (1992) Inhibitors of nitric oxide synthase selectively reduce flow in tumor-associated neovas-culature. Br J Pharmacol107, 1092–1095.
Fukumura, D., Yuan, F., Endo, M., and Jain, R.K. (1997) Role of nitric oxide in tumor microcirculation. Blood flow, vascular permeability, and leukocyte-endothelial interactions. Am J Pathol150, 713–725.
Swaroop, G.R., Malcolm, G.P., Kelly, P.A., Ritchie, I., and Whittle, I.R. (1998) Effects of nitric oxide modulation on tumour blood flow and microvascular permeability in C6 glioma. Neuroreport9, 2577–2581.
Tozer, G.M., Prise, V.E., and Chaplin, D.J. (1997) Inhibition of nitric oxide synthase induces a selective reduction in tumor blood flow that is reversible with L-arginine. Cancer Res57, 948–955.
Kubes, P. (1995) Nitric oxide affects microvas-cular permeability in the intact and inflamed vasculature. Microcirculation2, 235–244.
Aramoto, H., Breslin, J.W., Pappas, P.J., Hobson, R.W., II, and Duran, W.N. (2004) Vascular endothelial growth factor stimulates differential signaling pathways in in vivo microcirculation. Am J Physiol Heart Circ Physiol287, H1590–H1598.
Mayhan, W.G. (1999) VEGF increases permeability of the blood–brain barrier via a nitric oxide synthase/cGMP-dependent pathway. Am J Physiol276, C1148–C1153.
Bucci, M., Gratton, J.P., Rudic, R.D., Acevedo, L., Roviezzo, F., Cirino, G., and Sessa, W.C. (2000) In vivo delivery of the caveolin-1 scaffolding domain inhibits nitric oxide synthesis and reduces inflammation. Nat Med6, 1362–1367.
Maeda, H., Noguchi, Y., Sato, K., and Akaike, T. (1994) Enhanced vascular permeability in solid tumor is mediated by nitric oxide and inhibited by both new nitric oxide scavenger and nitric oxide synthase inhibitor. Jpn J Cancer Res85, 331–334.
Boughton-Smith, N.K., Evans, S.M., Las-zlo, F., Whittle, B.J., and Moncada, S. (1993) The induction of nitric oxide syn-thase and intestinal vascular permeability by endotoxin in the rat. Br J Pharmacol110, 1189–1195.
Fujii, E., Irie, K., Uchida, Y., Tsukahara, F., and Muraki, T. (1994) Possible role of nitric oxide in 5-hydroxytryptamine-induced increase in vascular permeability in mouse skin. Naunyn Schmiedebergs Arch Pharmacol350, 361–364.
Nakano, S., Matsukado, K., and Black, K.L. (1996) Increased brain tumor microvessel permeability after intracarotid bradykinin infusion is mediated by nitric oxide. Cancer Res56, 4027–4031.
Orucevic, A. and Lala, P.K. (1996) NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthesis, ameliorates interleukin 2-induced capillary leakage and reduces 349. tumour growth in adenocarcinoma-bearing mice. Br J Cancer73, 189–196.
Ramirez, M.M., Quardt, S.M., Kim, D., Oshiro, H., Minnicozzi, M., and Duran, W.N. (1995) Platelet activating factor modulates microvascular permeability through nitric oxide synthesis. Microvasc Res50, 223–234.
Zhang, X.M. and Xu, Q. (2001) Metastatic melanoma cells escape from immunosur-veillance through the novel mechanism of releasing nitric oxide to induce dysfunction of immunocytes. Melanoma Res11, 559–567.
Edwards, P., Cendan, J.C., Topping, D.B., Moldawer, L.L., MacKay, S., Copeland, E., and Lind, D.S. (1996) Tumor cell nitric oxide inhibits cell growth in vitro, but stimulates tumorigenesis and experimental lung metastasis in vivo. J Surg Res63, 49–52.
Iwasaki, T., Higashiyama, M., Kuriyama, K., Sasaki, A., Mukai, M., Shinkai, K., Horai, T., Matsuda, H., and Akedo, H. (1997) NG-nitro-L-arginine methyl ester inhibits bone metastasis after modified intracardiac injection of human breast cancer cells in a nude mouse model. Jpn J Cancer Res88, 861–866.
Jadeski, L.C., Chakraborty, C., and Lala, P.K. (2003) Nitric oxide-mediated promotion of mammary tumour cell migration requires sequential activation of nitric oxide synthase, guanylate cyclase and mitogen-activated protein kinase. Int J Cancer106, 496–504.
Orucevic, A., Bechberger, J., Green, A.M., Shapiro, R.A., Billiar, T.R., and Lala, P.K. (1999) Nitric-oxide production by murine mammary adenocarcinoma cells promotes tumor-cell invasiveness. Int J Cancer81, 889–896.
Siegert, A., Rosenberg, C., Schmitt, W.D., Denkert, C., and Hauptmann, S. (2002) Nitric oxide of human colorectal adenocar-cinoma cell lines promotes tumour cell invasion. Br J Cancer86, 1310–1315.
Gauthier, N., Lohm, S., Touzery, C., Chantome, A., Perette, B., Reveneau, S., Brunotte, F., Juillerat-Jeanneret, L., and Jeannin, J.F. (2004) Tumour-derived and host-derived nitric oxide differentially regulate breast carcinoma metastasis to the lungs. Carcinogenesis25, 1559–1565.
Wang, B., Wei, D., Crum, V.E., Richardson, E.L., Xiong, H.H., Luo, Y., Huang, S., Abbruzzese, J.L., and Xie, K. (2003) A novel model system for studying the double-edged roles of nitric oxide production in pancreatic cancer growth and metastasis. Oncogene22, 1771–1782.
Wang, L., Shi, G.G., Yao, J.C., Gong, W., Wei, D., Wu, T.T., Ajani, J.A., Huang, S., and Xie, K. (2005) Expression of endothe-lial nitric oxide synthase correlates with the angiogenic phenotype of and predicts poor prognosis in human gastric cancer. Gastric Cancer8, 18–28.
Ariel, I., Hochberg, A., and Shochina, M. (1998) Endothelial nitric oxide synthase immunoreactivity in early gestation and in trophoblastic disease. J Clin Pathol51, 427–431.
Jadeski, L.C., Hum, K.O., Chakraborty, C., and Lala, P.K. (2000) Nitric oxide promotes murine mammary tumour growth and metastasis by stimulating tumour cell migration, invasiveness and angiogenesis. Int J Cancer86, 30–39.
Fukumura, D., Yonei, Y., Kurose, I., Saito, H., Ohishi, T., Higuchi, H., Miura, S., Kato, S., Kimura, H., Ebinuma, H., and Ishi, H. (1996) Role in nitric oxide in Kupffer cell-mediated hepatoma cell cytotoxiCity in vitro and ex vivo. Hepatology24, 141–149.
Qiu, H., Orr, F.W., Jensen, D., Wang, H.H., McIntosh, A.R., Hasinoff, B.B., Nance, D.M., Pylypas, S., Qi, K., Song, C., Muschel, R.J., and Al-Mehdi, A.B. (2003) Arrest of B16 melanoma cells in the mouse pulmonary microcirculation induces endothelial nitric oxide synthase-dependent nitric oxide release that is cytotoxic to the tumor cells. Am J Pathol162, 403–412.
Wang, H.H., McIntosh, A.R., Hasinoff, B.B., Rector, E.S., Ahmed, N., Nance, D.M., and Orr, F.W. (2000) B16 melanoma cell arrest in the mouse liver induces nitric oxide release and sinusoidal cytotoxiCity: a natural hepatic defense against metastasis. Cancer Res60, 5862–5869.
Yamamoto, T., Terada, N., Seiyama, A., Nishizawa, Y., Akedo, H., and Kosaka, H. (1998) Increase in experimental pulmonary metastasis in mice by L-arginine under inhibition of nitric oxide production by NG-ni-tro-L-arginine methyl ester. Int J Cancer75, 140–144.
Wei, D., Richardson, E.L., Zhu, K., Wang, L., Le, X., He, Y., Huang, S., and Xie, K. (2003) Direct demonstration of negative regulation of tumor growth and metastasis by host-inducible nitric oxide synthase. Cancer Res63, 3855–3859.
Gasic, G.J., Gasic, T.B., and Stewart, C.C. (1968) Antimetastatic effects associated with platelet reduction. Proc Natl Acad Sci U S A61, 46–52.369.
Kisucka, J., Butterfield, C.E., Duda, D.G., Eichenberger, S.C., Saffaripour, S., Ware, J., Ruggeri, Z.M., Jain, R.K., Folkman, J., and Wagner, D.D. (2006) Platelets and platelet adhesion support angiogenesis while preventing excessive hemorrhage. Proc Natl Acad Sci U S A103, 855–860.
Im, J.H., Fu, W., Wang, H., Bhatia, S.K., Hammer, D.A., Kowalska, M.A., and Muschel, R.J. (2004) Coagulation facilitates tumor cell spreading in the pulmonary vas-culature during early metastatic colony formation. Cancer Res64, 8613–8619.
Mehta, P. (1984) Potential role of platelets in the pathogenesis of tumor metastasis. Blood63, 55–63.
Radomski, M.W., Jenkins, D.C., Holmes, L., and Moncada, S. (1991) Human colorec-tal adenocarcinoma cells: differential nitric oxide synthesis determines their ability to aggregate platelets. Cancer Res51, 6073–6078.
Radomski, M.W., Palmer, R.M., and Mon-cada, S. (1990) An L-arginine/nitric oxide pathway present in human platelets regulates aggregation. Proc Natl Acad Sci U S A87, 5193–5197.
Fukumura, D., Salehi, H.A., Witwer, B., Tuma, R.F., Melder, R.J., and Jain, R.K. (1995) Tumor necrosis factor alpha-induced leukocyte adhesion in normal and tumor vessels: effect of tumor type, transplantation site, and host strain. Cancer Res55, 4824–4829.
Davenpeck, K.L., Gauthier, T.W., and Lefer, A.M. (1994) Inhibition of endothe-lial-derived nitric oxide promotes P-selectin expression and actions in the rat microcircu-lation. Gastroenterology107, 1050–1058.
Kubes, P., Suzuki, M., and Granger, D.N. (1991) Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A88, 4651–4655.
Lefer, D.J., Jones, S.P., Girod, W.G., Baines, A., Grisham, M.B., Cockrell, A.S., Huang, P.L., and Scalia, R. (1999) Leukocyte-endothelial cell interactions in nitric oxide synthase-deficient mice. Am J Physiol276, H1943–H1950.
Tozer, G.M., Prise, V.E., Motterlini, R., Poole, B.A., Wilson, J., and Chaplin, D.J. (1998) The comparative effects of the NOS inhibitor, N-nitro-L-arginine, and the haemoxygenase inhibitor, zinc protoporphy-rin IX, on tumour blood flow. Int J Radiat Oncol Biol Phys42, 849–853.
Schleiffer, R., Duranton, B., Gosse, F., Berg-mann, C., and Raul, F. (2000) Nitric oxide synthase inhibition promotes carcinogen-induced preneoplastic changes in the colon of rats. Nitric Oxide4, 583–589.
Garvey, E.P., Oplinger, J.A., Tanoury, G.J., Sherman, P.A., Fowler, M., Marshall, S., Harmon, M.F., Paith, J.E., and Furfine, E.S. (1994) Potent and selective inhibition of human nitric oxide synthases. Inhibition by non-amino acid isothioureas. J Biol Chem269, 26669–26676.
Garvey, E.P., Oplinger, J.A., Furfine, E.S., Kiff, R.J., Laszlo, F., Whittle, B.J., and Knowles, R.G. (1997) 1400W is a slow, tight binding, and highly selective inhibitor of inducible nitric-oxide synthase in vitro and in vivo. J Biol Chem272, 4959–4963.
Alderton, W.K., Cooper, C.E., and Know-les, R.G. (2001) Nitric oxide synthases: structure, function and inhibition. Biochem J357, 593–615.
Rao, C.V., Indranie, C., Simi, B., Manning, P.T., Connor, J.R., and Reddy, B.S. (2002) Che-mopreventive properties of a selective induc-ible nitric oxide synthase inhibitor in colon carcinogenesis, administered alone or in combination with celecoxib, a selective cyclooxy-genase-2 inhibitor. Cancer Res62, 165–170.
Szabo, C., Ferrer-Sueta, G., Zingarelli, B., Southan, G.J., Salzman, A.L., and Radi, R. (1997) Mercaptoethylguanidine and guani-dine inhibitors of nitric-oxide synthase react with peroxynitrite and protect against per-oxynitrite-induced oxidative damage. J Biol Chem272, 9030–9036.
Florio, T., Morini, M., Villa, V., Arena, S., Corsaro, A., Thellung, S., Culler, M.D., Pfeffer, U., Noonan, D.M., Schettini, G., and Albini, A. (2003) Somatostatin inhibits tumor angiogenesis and growth via soma-tostatin receptor-3-mediated regulation of endothelial nitric oxide synthase and mitogen-activated protein kinase activities. Endocrinology144, 1574–1584.
Jaiswal, M., LaRusso, N.F., and Gores, G.J. (2001) Nitric oxide in gastrointestinal epithelial cell carcinogenesis: linking inflammation to oncogenesis. Am J Physiol Gastrointest Liver Physiol281, G626–G634.
Hobbs, A.J., Higgs, A., and Moncada, S. (1999) Inhibition of nitric oxide synthase as a potential therapeutic target. Annu Rev Pharmacol Toxicol39, 191–220.
Muscara, M.N. and Wallace, J.L. (1999) Nitric Oxide. V. therapeutic potential of nitric oxide donors and inhibitors. Am J Physiol276, G1313–G1316.
Matthews, N.E., Adams, M.A., Maxwell, L.R., Gofton, T.E., and Graham, C.H. (2001) Nitric oxide-mediated regulation of chemo-sensitivity in cancer cells. J Natl Cancer Inst93, 1879–1885.
Soler, M.N., Bobe, P., Benihoud, K., Lemaire, G., Roos, B.A., and Lausson, S. (2000) Gene therapy of rat medullary thyroid cancer by naked nitric oxide synthase II DNA injection. J Gene Med2, 344–352.
Cook, T., Wang, Z., Alber, S., Liu, K., Watkins, S.C., Vodovotz, Y., Billiar, T.R., and Blumberg, D. (2004) Nitric oxide and ionizing radiation synergistically promote apoptosis and growth inhibition of cancer by activating p53. Cancer Res64, 8015–8021.
Mitchell, J.B., Wink, D.A., DeGraff, W., Gamson, J., Keefer, L.K., and Krishna, M.C. (1993) Hypoxic mammalian cell radiosen-sitization by nitric oxide. Cancer Res53, 5845–5848.
Kundu, N., Dorsey, R., Jackson, M.J., Gui-terrez, P., Wilson, K., Fu, S., Ramanujam, K., Thomas, E., and Fulton, A.M. (1998) Interleukin-10 gene transfer inhibits murine mammary tumors and elevates nitric oxide. Int J Cancer76, 713–719.
Ying, L. and Hofseth, L.J. (2007) An emerging role for endothelial nitric oxide synthase in chronic inflammation and cancer. Cancer Res67, 1407–1410.
Acknowledgments
This study was partially supported by NIH 1R01CA104741 grant, Crohn's & Colitis Foundation of America Senior Award, and the Sam Zell Scholar Fund.
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Yang, GY., Taboada, S., Liao, J. (2009). Induced Nitric Oxide Synthase as a Major Player in the Oncogenic Transformation of Inflamed Tissue. In: Kozlov, S.V. (eds) Inflammation and Cancer. Methods in Molecular Biology™, vol 512. Humana Press. https://doi.org/10.1007/978-1-60327-530-9_8
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