Skip to main content

Therapy of cancer metastasis by activation of the inducible nitric oxide synthase

Abstract

The process of cancer metastasis consists of multiple sequential and highly selective steps. The vast majority of tumor cells that enter the circulation die rapidly; only a few survive to produce metastases. This survival is not random. Metastases are clonal in origin and are produced by specialized subpopulations of cells that preexist in a heterogeneous primary tumor. Experimental studies concluded that metastatic cells survive in the circulation whereas nonmetastatic cells do not. In part, this difference is due to an inverse correlation between expression of endogenous inducible nitric oxide synthase (iNOS) and production of nitric oxide (NO) and metastatic potential. Direct evidence for the role of iNOS in metastasis has been provided by our data on transfection of highly metastatic murine K-1735 clone 4 (C4.P) cells which express low levels of iNOS, with a functional iNOS (C4.L8), inactive mutated iNOS (C4.S2), or neomycin resistance (C4.Neo) genes in medium containing 3 mM of the specific iNOS inhibitor NG-L-methyl arginine (NMA). C4.P, C4.Neo, and C4.S2 cells were highly metastatic, whereas C4.L8 cells were not. Moreover, C4.L8 cells produced slow-growing subcutaneous tumors in nude mice, whereas the other 3 cell lines produced fast-growing tumors. In vitro studies indicated that the expression of iNOS in C4.L8.5 cells was associated with either cytostasis or cytolysis via apoptosis, depending upon NO output. The tumor cells producing high levels of NO underwent autocytolysis and produced cytolysis of bystander cells under both in vitro and in vivo conditions. Multiple i.v. injections of liposomes containing a synthetic lipopeptide upregulated iNOS expression in murine M5076 reticulum sarcoma cells growing as hepatic metastases. The induction of iNOS was associated with the complete regression of the lesions. Transfection of interferon-β suppressed tumor formation and eradicated metastases, which was apparently linked to iNOS expression and NO production in host cells such as macrophage. Besides mediating cell death, NO produced tumor suppression by regulating expression of genes related to metastasis, e.g., survival, invasion, and angiogenesis. Suppression of metastasis can be achieved through use of immunomodulators that induce iNOS expression in tumor lesions or by the direct delivery of the iNOS gene to tumor cells or host cells through liposome and/or viral vectors.

This is a preview of subscription content, access via your institution.

References

  1. 1.

    Fidler IJ: Critical factors in the biology of human cancer metastasis: Twenty-eighth G.H.A. Clowes Memorial Award Lecture. Cancer Res 50: 6130-6138, 1990

    PubMed  Google Scholar 

  2. 2.

    Willis RA: The Spread of Tumors in the Human Body. Butterworth, London, 1972

    Google Scholar 

  3. 3.

    Sugarbaker EV: Cancer metastasis: a product of tumor-host interactions. Curr Probl Cancer 3: 1-59, 1979

    Google Scholar 

  4. 4.

    Weiss L: Principles of Metastasis. Academic Press, Orlando, 1985

    Google Scholar 

  5. 5.

    Fidler IJ, Balch CM: The biology of cancer metastasis and implications for therapy. Curr Probl Surg 24: 137-209, 1987

    Article  Google Scholar 

  6. 6.

    Jain RK: Barriers to drug delivery in solid tumors. Scientific American 271: 58-65, 1994

    Google Scholar 

  7. 7.

    Fidler IJ: Modulation of the organ microenvironment for the treatment of cancer metastasis (Editorial). J Natl Cancer Inst 84: 1588-1592, 1995

    Google Scholar 

  8. 8.

    Price JE, Aukerman SL, Fidler IJ: Evidence that the process of murine melanoma metastasis is sequential and selective and contains stochastic elements. Cancer Res 46: 5172-5178, 1986

    PubMed  Google Scholar 

  9. 9.

    Aukerman SL, Price JE, Fidler IJ: Different deficiencies in the prevention of tumorigenic-low metastatic murine K-1735 melanoma cells from producing metastases. J Natl Cancer Inst 77: 915-924, 1986

    PubMed  Google Scholar 

  10. 10.

    Folkman J: Endothelial cells and angiogenic growth factors in cancer growth and metastasis (Introduction). Cancer Metastasis Rev 9: 171-174, 1990

    PubMed  Google Scholar 

  11. 11.

    Folkman J, Taylor K: Tumor angiogenesis: Its possible role in metastasis and invasion. In: Day SB, Myers WPL, Stansly P, Gerattini S, Lewis MG (eds) Cancer Invasion and Metastasis: Biologic Mechanisms and Therapy. Raven Press, New York, 1977, pp 95-103

    Google Scholar 

  12. 12.

    Fidler IJ, Ellis LM: The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell 79: 185-188, 1994

    Article  PubMed  Google Scholar 

  13. 13.

    Leek RD, Harris AL, Lewis CE: Cytokine networks in solid human tumors: regulation of angiogenesis. J Leukocyte Biol 56: 423-435, 1994

    PubMed  Google Scholar 

  14. 14.

    Liotta LA, Kleinerman J, Saidel GM: Quantitative relationships of intravascular tumor cells, tumor vessels, and pulmonary metastases following tumor implantation. Cancer Res 34: 997-1004, 1974

    PubMed  Google Scholar 

  15. 15.

    Liotta LA, Stetler-Stevenson WG: Tumor invasion and metastasis: an imbalance of positive and negative regulation. Cancer Res 51: 5054s-5059s, 1991

    PubMed  Google Scholar 

  16. 16.

    Gasic GJ: Role of plasma, platelets and endothelial cells in tumor metastasis. Cancer Metastasis Rev 3: 99-105, 1984

    PubMed  Google Scholar 

  17. 17.

    Fidler IJ, Bucana C: Mechanism of tumor cell resistance to lysis by syngeneic lymphocytes. Cancer Res 37: 3945-3956, 1977

    PubMed  Google Scholar 

  18. 18.

    Weiss L: Biomechanical interactions of cancer cells with the microvasculature during hematogenous metastasis. Cancer Metastasis Rev 11: 227-235, 1992

    PubMed  Google Scholar 

  19. 19.

    Nicolson GL: Cancer metastasis: tumor cell and host organ properties important in metastasis to specific secondary sites. Biochim Biophys Acta 948: 175-208, 1988

    Article  PubMed  Google Scholar 

  20. 20.

    Zetter BR: The cellular basis of site-specific tumor metastasis. N Engl J Med 322: 605-612, 1990

    PubMed  Google Scholar 

  21. 21.

    Hart IR, Saini A: Biology of tumor metastasis. Lancet 339: 1437-1453, 1992

    Google Scholar 

  22. 22.

    Radinsky R: Paracrine growth regulation of human colon carcinoma organ-specific metastasis. Cancer Metastasis Rev 12: 345-361, 1993

    PubMed  Google Scholar 

  23. 23.

    O'Reilly MS, Homgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sago EH, Folkman J: Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79: 315-328, 1994

    Google Scholar 

  24. 24.

    Fidler IJ, Gersten DM, Hart IR: The biology of cancer invasion and metastasis. Adv Cancer Res 28: 149-250, 1978

    PubMed  Google Scholar 

  25. 25.

    Fidler IJ: Metastasis: quantitative analysis of distribution and fate of tumor emboli labeled with 125I-5-iodo-2'-deoxyuridine. J Natl Cancer Inst 45: 773-782, 1970

    PubMed  Google Scholar 

  26. 26.

    Glaves D: Intravascular death of disseminated cancer cells mediated by superoxide anion. Invasion Metastasis 6: 101-111, 1986

    PubMed  Google Scholar 

  27. 27.

    Fidler IJ, Kripke ML: Metastasis results from preexisting variant cells within a malignant tumor. Science 197: 893-895, 1977

    PubMed  Google Scholar 

  28. 28.

    Talmadge JE, Fidler IJ: Enhanced metastatic potential of tumor cells harvested from spontaneous metastases of heterogeneous murine tumors. J Natl Cancer Inst 69: 975-980, 1982

    PubMed  Google Scholar 

  29. 29.

    Fidler IJ, Talmadge JE: Evidence that intravenously derived murine pulmonary melanoma metastases can originate from the expansion of a single tumor cell. Cancer Res 46: 5167-5171, 1986

    PubMed  Google Scholar 

  30. 30.

    Sato H, Suzuki M: Deformability and viability of tumor cells by transcapillary passage with reference to organ affinity in metastasis in cancer. In: Weiss L (ed) Fundamental Aspects of Metastasis. North-Holland, Amsterdam, 1976, pp 311-317

    Google Scholar 

  31. 31.

    Fidler IJ: The relationship of embolic homogeneity, number, size and viability to the incidence of experimental metastasis. Eur J Cancer 9: 223-227, 1973

    PubMed  Google Scholar 

  32. 32.

    Liotta LA, Kleinerman J, Seidel GM: The significance of hematogenous tumor cell clumps in the metastatic process. Cancer Res 36: 889-894, 1976

    PubMed  Google Scholar 

  33. 33.

    Hofmann M, Rudy W, Zoller M, Tolg C, Ponta H, Jerrlich P, Gunthert U: CD44 splice variants confer metastatic behavior in rats: Homologous sequences are expressed in human tumor cell lines. Cancer Res 51: 5292-5297, 1991

    PubMed  Google Scholar 

  34. 34.

    Frixen UH, Behrens J, Sachs M, Eberle G, Voss B, Warda A, Lochner D, Birchmeier V: E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells. J Cell Biol 13: 173-185, 1991

    Google Scholar 

  35. 35.

    Karpatkin S, Pearlstein E: Role of platelets in tumor cell metastasis. Ann Intern Med 95: 636-674, 1981

    PubMed  Google Scholar 

  36. 36.

    Wiltrout RH, Frost P, Morrison MK, Kerbel RS: Immune-mediated arrest and reversal of established visceral metastasis in athymic mice. Cancer Res 39: 4034-4039, 1979

    PubMed  Google Scholar 

  37. 37.

    Hanna N, Fidler IJ: The role of natural killer cells in the destruction of circulating tumor emboli. J Natl Cancer Inst 65: 801-809, 1980

    PubMed  Google Scholar 

  38. 38.

    Herberman RB: Natural killer cells. Prog Clin Biol Res 288: 161-167, 1989

    PubMed  Google Scholar 

  39. 39.

    Fidler IJ: Macrophages and metastasis - a biological approach to cancer therapy: Presidential address. Cancer Res 45: 4714-4721, 1985

    PubMed  Google Scholar 

  40. 40.

    Li L, Nicolson GL, Fidler IJ: Direct in vitrolysis of metastatic tumor cells by cytokine-activated murine vascular endothelial cells. Cancer Res 51: 245-254, 1991

    PubMed  Google Scholar 

  41. 41.

    Li L, Kilbourn RG, Adams J, Fidler IJ: Role of nitric oxide in lysis of tumor cells by cytokine-activated endothelial cells. Cancer Res 51: 2531-2535, 1991

    PubMed  Google Scholar 

  42. 42.

    Dong Z, O'Brian CA, Fidler IJ: Activation of tumoricidal properties in macrophages by lipopolysaccharide requires protein-tyrosine kinase activity. J Leukocyte Biol 53: 53-60, 1993

    PubMed  Google Scholar 

  43. 43.

    Poste G, Fidler IJ: The pathogenesis of cancer metastasis. Nature 283: 139-146, 1979

    Google Scholar 

  44. 44.

    Fidler IJ, Gruys E, Cifone MA, Barnes Z, Bucana CD: Demonstration of multiple phenotypic diversity in a murine melanoma of recent origin. J Natl Cancer Inst 67: 947-956, 1981

    PubMed  Google Scholar 

  45. 45.

    Xie K, Dong Z, Fidler IJ: Activation of nitric oxide synthase gene for inhibition of cancer metastasis (Review). J Leukocyte Biol 59: 797-803, 1996

    PubMed  Google Scholar 

  46. 46.

    Radomski MK, Jenkins DC, Jolmes L, Moncada S: Human colorectal adenocarcinoma cells: differential nitric oxide synthesis determines their ability to aggregate platelets. Cancer Res 51: 6073-6077, 1991

    PubMed  Google Scholar 

  47. 47.

    Palmer RMJ, Ferrige AG, Moncada S: Nitric oxide release accounts for the biological activity of endothelial-derived relaxing factor. Nature 327: 524-526, 1987

    Article  PubMed  Google Scholar 

  48. 48.

    Hibbs JR JB, Taintor RR, Vavrin Z: Macrophage cytotoxicity: role for L-arginine deiminase activity and amino nitrogen to nitrate. Science 235: 473-476, 1987

    PubMed  Google Scholar 

  49. 49.

    Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G: Endothelial-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA 84: 9265-9269, 1987

    PubMed  Google Scholar 

  50. 50.

    Nathan C: Nitric oxide as a secretory product of mammalian cells. FASEB J 6: 3051-3064, 1992

    PubMed  Google Scholar 

  51. 51.

    Nathan C, Xie Q-W: Nitric oxide synthases: roles, tolls, and controls. Cell 78: 915-919, 1994

    Article  PubMed  Google Scholar 

  52. 52.

    Jaffrey SR, Snyder SH: Nitric oxide: a neural messenger. Annu Rev Cell Dev Biol 11: 417-440, 1995

    Article  PubMed  Google Scholar 

  53. 53.

    Marletta MA: Nitric oxide synthase structure and mechanism. J Biol Chem 268: 12231-12234, 1993

    PubMed  Google Scholar 

  54. 54.

    Kilbourn RG, Jubran A, Gross SS, Griffith OW, Levi R, Adams J, Lodato RF: Reversal of endotoxin-mediated shock by NG-methyl-L-arginine, an inhibitor of nitric oxide synthesis. Biochem Biophys Res Commun 172: 1132-1138, 1991

    Google Scholar 

  55. 55.

    Kamijo R, Harada H, Matsuyama T, Bosland M, Gerecitano J, Shapiro D, Le J, Koh SI, Kimura T, Green SJ et al.: All authors required: Requirement for transcription factor IRF-1 in NO synthase induction in macrophages. Science 263: 1612-1615, 1994

    PubMed  Google Scholar 

  56. 56.

    Martin E, Nathan C, Xie QW: Role of interferon regulatory factor 1 in induction of nitric oxide synthase. J Exp Med 180: 977-984, 1994

    Article  PubMed  Google Scholar 

  57. 57.

    Xie QW, Kashiwabara Y, Nathan C: Role of transcription factor NF-kappa B/Rel in induction of nitric oxide synthase. J Biol Chem 269: 4705-4708, 1994

    PubMed  Google Scholar 

  58. 58.

    Adcock IM, Brown CR, Kwon O, Barnes PJ: Oxidative stress induces NF kappa B DNA binding and inducible NOS mRNA in human epithelial cells. Biochem Biophys Res Commun 199: 1518-1524, 1994

    Article  PubMed  Google Scholar 

  59. 59.

    Vodovotz Y, Bogdan C, Paik J, Xie QW, Nathan C: Mechanisms of suppression of macrophage nitric oxide release by transforming growth factor beta. J Exp Med 178: 605-613, 1993

    Article  PubMed  Google Scholar 

  60. 60.

    Kolyada AY, Savikovsky N, Madias NE: Transcriptional regulation of the human iNOS gene in vascular-smooth-muscle cells and macrophages: evidence for tissue specificity. Biochem Biophys Res Commun 220: 600-605, 1996

    Article  PubMed  Google Scholar 

  61. 61.

    Albina JE: On the expression of nitric oxide synthase by human macrophages. Why no NO? J Leukocyte Biol 58: 643-649, 1995

    PubMed  Google Scholar 

  62. 62.

    Lee SC, Dickson DW, Brosnan CF, Casadevall A: Human astrocytes inhibit Cryptococcus neoformansgrowth by a nitric oxide-mediated mechanism. J Exp Med 180: 3695-3699, 1994

    Article  Google Scholar 

  63. 63.

    Kasai K, Hattari Y, Nakanishi N, Manaka K, Banba N, Motohashi S, Shimoda S: Regulation of inducible nitric oxide production by cytokines in human thymocytes in culture. Endocrinology 136: 4261-4270, 1995

    Article  PubMed  Google Scholar 

  64. 64.

    Nussler AK, Di Silvio M, Billiar TR, Hoffman RA, Geller DA, Selby R, Madariaga J, Simmons RL: Stimulation of the nitric oxide synthase pathway in human hepatocytes by cytokines and endotoxin. J Exp Med 176: 261-264, 1992

    Article  PubMed  Google Scholar 

  65. 65.

    Nicholson S, Bonecini-Almeida M, da G Lapa e Silva JR, Nathan C, Xie QW, Mumford R, Weidner JR, Calaycay J, Geng J, Boechat N, Linhares C, Rom W, Ho JL: Inducible nitric oxide synthase in pulmonary alveolar macrophages from patients with tuberculosis. J Exp Med 183: 2293-2302, 1996

    Article  PubMed  Google Scholar 

  66. 66.

    Evans TJ, Buttery LD, Carpenter A, Springall DR, Polak JM, Cohen J: Cytokine-treated human neutrophils contain inducible nitric oxide synthase that produces nitration of ingested bacteria. Proc Natl Acad Sci USA 93: 9553-9558, 1996

    Article  PubMed  Google Scholar 

  67. 67.

    Park CS, Pardhasaradhi K, Gianotti C, Villegas E, Krishna G: Human retina expresses both constitutive and inducible isoforms of nitric oxide synthase mRNA. Biochem Biophys Res Commun 205: 85-91, 1994

    Article  PubMed  Google Scholar 

  68. 68.

    Sirsjo A, Karlsson M, Gidlof A, Rollman O, Torma H: Increased expression of inducible nitric oxide synthase in psoriatic skin and cytokine-stimulated cultured keratonocytes. Br J Dermatol 134: 643-648, 1996

    PubMed  Google Scholar 

  69. 69.

    Kolios G, Brown Z, Robson RL, Robertson DA, Westwick J: Inducible nitric oxide synthase activity and expression in a human colonic epithelial cell line, HT-29. Br J Pharmacol 116: 2866-2872, 1995

    PubMed  Google Scholar 

  70. 70.

    Wang R, Ghahary A, Shen YJ, Scott PG, Tredget EE: Human dermal fibroblasts produce nitric oxide and express both constitutive and inducible nitric oxide synthase isoforms. J Invest Dermatol 106: 419-427, 1996

    Article  PubMed  Google Scholar 

  71. 71.

    Furukawa K, Harrison DG, Saleh D, Shennib H, Chagnon FP, Giaid A: Expression of nitric oxide synthase in the human nasal mucosa. Am J Resp Crit Care Med 153: 847-850, 1996

    PubMed  Google Scholar 

  72. 72.

    Mehta JL, Chen LY, Kone BC, Mehta P, Turner P: Identification of constitutive and inducible forms of nitric oxide synthase in human platelets. J Lab Clin Med 125: 370-377, 1995

    PubMed  Google Scholar 

  73. 73.

    Asano K, Chee CB, Gaston B, Lilly CM, Gerard C, Drazen JM, Stamler JS: Constitutive and inducible nitric oxide synthase gene expression, regulation, and activity in human lung epithelial cells. Proc Natl Acad Sci USA 91: 10089-10093, 1994

    PubMed  Google Scholar 

  74. 74.

    Palmer RM, Hickery MS, Charles IG, Moncada S, Bayliss MT: Induction of nitric oxide synthase in human chondrocytes. Biochem Biophys Res Commun 193: 398-405, 1993

    Article  PubMed  Google Scholar 

  75. 75.

    Berrazueta JR, Salas E, Amado JA, Sanchez de Vega MJ, Poveda JJ: Induction of nitric oxide synthase in human mammary arteries in vitro.Eur J Pharmacol 251: 303-305, 1994

    Article  PubMed  Google Scholar 

  76. 76.

    Nicolson AG, Haites NE, McKay NG, Wilson HM, Macleod AM, Benjamin N: Induction of nitric oxide synthase in human mesangial cells. Biochem Biophys Res Commun 193: 1269-1274, 1993

    Article  PubMed  Google Scholar 

  77. 77.

    Lelchuk R, Radomski MW, Martin JF, Moncada S: Constitutive and inducible nitric oxide synthases in human megakaryoblastic cells. J Pharmacol Exp Ther 262: 1220-1224, 1992

    PubMed  Google Scholar 

  78. 78.

    Thoenes M, Forstermann U, Tracey WR, Bleese NM, Nussler AK, Scholz H, Stein B: Expression of inducible nitric oxide synthase in failing and non-failing human heart. J Mol Cell Cardiol 28: 165-169, 1996

    Article  PubMed  Google Scholar 

  79. 79.

    Buttery LD, Springall DR, Chester AH, Evans TJ, Standfield EN, Parums DV, Yacoub MH, Polak JM: Inducible nitric oxide synthase is present within human atherosclerotic lesions and promotes the formation and activity of peroxynitrite. Lab Invest 75: 77-85, 1996

    PubMed  Google Scholar 

  80. 80.

    Lewis NP, Tsao PS, Rickenbacher PR, Xue C, Johns RA, Haywood GA, von der Leyen H, Trindade PT, Cooke JP, Hunt SA, Billingham ME, Valantine HA, Fowler MB: Induction of nitric oxide synthase in the human cardiac allograft is associated with contractile dysfunction of the left ventricle. Circulation 93: 720-729, 1996

    PubMed  Google Scholar 

  81. 81.

    Schonfelder G, John M, Hopp H, Fuhr N, van der Giet M, Paul M: Expression of inducible nitric oxide synthase in placenta of women with gestational diabetes. FASEB J 10: 777-784, 1996

    PubMed  Google Scholar 

  82. 82.

    Sakurai H, Kohsaka H, Liu MF, Higashiyama H, Hirata Y, Kanno K, Saito I, Miyasaka N: Nitric oxide production and inducible nitric oxide synthase expression in inflammatory arthritides. J Clin Invest 96: 2357-2363, 1995

    PubMed  Google Scholar 

  83. 83.

    Bo L, Dawson TM, Wesselingh S, Mork S, Choi S, Kong PA, Hanley D, Trapp BD: Induction of nitric oxide synthase in demyelinating regions of multiple sclerosis brains. Ann Neurol 36: 778-786, 1994

    PubMed  Google Scholar 

  84. 84.

    Tracey WR, Xue C, Klinghofer V, Barlow J, Pollock JS, Forstermann U, Johns RA: Immunochemical detection of inducible NO synthase in human lung. Am J Physiol 266: L722-L727, 1994

    PubMed  Google Scholar 

  85. 85.

    Ellie E, Loiseau H, Lafond F, Arsaut J, Demotes-Mainard J: Differential expression of inducible nitric oxide synthase mRNA in human brain tumours. Neuroreport 7: 294-296, 1995

    PubMed  Google Scholar 

  86. 86.

    Hokari A, Zeniya M, Esumi H: Cloning and functional expression of human inducible nitric oxide synthase (NOS) cDNA from a glioblastoma cell line A-172. J Biochem 116: 575-581, 1994

    PubMed  Google Scholar 

  87. 87.

    Moochhala S, Chhatwall VJ, Chan ST, Ngoi SS, Chia YW, Rauff A: Nitric oxide synthase activity and expression in human colorectal cancer. Carcinogenesis 17: 1171-1174, 1996

    PubMed  Google Scholar 

  88. 88.

    Jenkins DC, Charles IG, Baylis SA, Lelchuk R, Radomski MW, Moncada S: Human colon cancer cell lines show a diverse pattern of nitric oxide synthase gene expression and nitric oxide generation. Br J Cancer 70: 847-849, 1994

    PubMed  Google Scholar 

  89. 89.

    Sherman PA, Laubach VE, Reep BR, Wood ER: Purification and cDNA sequence of an inducible nitric oxide synthase from a human tumor cell line. Biochemistry 32: 11600-11605, 1993

    PubMed  Google Scholar 

  90. 90.

    Rosbe KW, Prazma J, Petrusz P, Mims W, Ball SS, Weissler MC: Immunohistochemical characterization of nitric oxide synthase activity in squamous cell carcinoma of the head and neck. Otolaryngology - Heck Neck Surg 113: 541-549, 1995

    Google Scholar 

  91. 91.

    Thomsen LL, Miles DW, Happerfield L, Bobrow LG, Knowles RG, Moncada S: Nitric oxide synthase activity in human breast cancer. Br J Cancer 72: 41-44, 1995

    PubMed  Google Scholar 

  92. 92.

    Zhang X, Laubach VE, Alley EW, Edwards KA, Sherman PA, Russell SW, Murphy WJ: Transcriptional basis for hyporesponsiveness of the human inducible nitric oxide synthase gene to lipopolysaccharide/interferon-gamma. J Leukocyte Biol 59: 575-585, 1996

    PubMed  Google Scholar 

  93. 93.

    Tzeng E, Yoneyama T, Hatakeyama K, Shears LL II, Billiar TR: Vascular inducible nitric oxide synthase gene therapy: requirement for guanosine triphosphate cyclohydrolase I. Surgery 120: 315-321, 1996

    Google Scholar 

  94. 94.

    Rocha M, Kruger A, Van Rooijen N, Schirrmacher V, Umansky V: Liver endothelial cells participate in T-cell-dependent host resistance to lymphoma metastasis by production of nitric oxide in vivo.Int J Cancer 63: 405-411, 1995

    PubMed  Google Scholar 

  95. 95.

    Farias-Eisner R, Sherman MP, Aeberhard E, Chaudhuri G: Nitric oxide is an important mediator for tumoricidal activity in vivo.Proc Natl Acad Sci USA 91: 9407-9411, 1994

    PubMed  Google Scholar 

  96. 96.

    Yamamoto T, Terada N, Nishizawa Y, Tanaka H, Akedo H, Seiyama A, Shiga T, Kosaka H: Effects of NG-nitro-L-arginine and/or L-arginine on experimental pulmonary metastasis in mice. Cancer Lett 87: 115-120, 1994

    Article  PubMed  Google Scholar 

  97. 97.

    Pipili-Synetos E, Papageorgiou A, Sakkoula E, Sotiropoulou G, Fotsis T, Karakiulakis G, Maragoudakis ME: Inhibition of angiogenesis, tumor growth and metastasis by the NO-releasing vasodilators, isosorbide mononitrate and dinitrate. Brit J Pharmacol 116: 1829-1834, 1995

    Google Scholar 

  98. 98.

    Xie K, Wang Y, Huang S, Xu L, Bielenberg D, Salas T, McConkey DJ, Jiang W, Fidler IJ: Nitric oxide-mediated apoptosis of K-1735 murine melanoma cells is associated with down-regulation of Bcl-2. Oncogene, in press, 1997

  99. 99.

    Murata J, Corradin SB, Janzer RC, Juillerat-Jeanneret L: Tumor cells suppress cytokine-mediated nitric-oxide (NO) production in cerebral endothelial cells. Int J Cancer 59: 699-705, 1994

    PubMed  Google Scholar 

  100. 100.

    Denhardt DT, Chambers AF: Overcoming obstacles to metastasis - defenses against host defenses: osteopontin (OPN) as a shield against attack by cytotoxic host cells (Review). J Cell Biochem 56: 48-51, 1994

    PubMed  Google Scholar 

  101. 101.

    Kripke ML: Speculations on the role of ultraviolet radiation in the development of malignant melanoma. J Natl Cancer Inst 63: 541-545, 1979

    PubMed  Google Scholar 

  102. 102.

    Staroselsky AH, Pathak S, Chernajovsky Y, Tucker SI, Fidler IJ: Predominance of the metastatic phenotype in somatic cell hybrids of the K-1735 murine melanoma. Cancer Res 51: 6292-6297, 1991

    PubMed  Google Scholar 

  103. 103.

    Dong Z, Staroselsky AH, Qi X, Xie K, Fidler IJ: Inverse correlation between expression of inducible nitric oxide synthase activity and production of metastasis in K-1735 murine melanoma cells. Cancer Res 54: 789-793, 1994

    PubMed  Google Scholar 

  104. 104.

    Radomski MW, Palmer RMJ, Moncada S: An L-arginine/nitric oxide pathway present in human platelets regulates aggregation. Proc Natl Acad Sci USA 87: 5193-5197, 1990

    PubMed  Google Scholar 

  105. 105.

    Tsuruo T, Kawabata H, Iida H, Yomori T: Tumor-induced platelet aggregation and growth promoting factors as determinants for successful tumor metastasis. Clin Exp Metastasis 7: 25-29, 1986

    Google Scholar 

  106. 106.

    De Caterina R, Libby P, Peng HB, Thannickal VJ, Rajavashisth TB, Gimbrone MA Jr, Shin WS, Liao JK: 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, 1995

    PubMed  Google Scholar 

  107. 107.

    Shin WS, Hong YH, Peng HB, De Caterina R, Libby P, Liao JK: Nitric oxide attenuates vascular smooth muscle cell activation by interferon-gamma. The role of constitutive NF-?B activity. J Biol Chem 271: 11317-11324, 1996

    Article  PubMed  Google Scholar 

  108. 108.

    Korbut R, Gryglewski RJ: Nitric oxide from polymorphonuclear leukocytes modulates red blood cell deformability in vitro.Eur J Pharmacol 234: 17-22, 1993

    Article  PubMed  Google Scholar 

  109. 109.

    Sakkoula E, Haralabopoulos G, Andriopoulou P, Magoudakis ME: Evidence that nitric oxide is an endogenous anti-angiogenic mediator. Br J Pharmacol 111: 894-902, 1994

    PubMed  Google Scholar 

  110. 110.

    Perretti M, Szabo C, Thiemermann C: Effect of interleukin-4 and interleukin-10 on leukocyte migration and nitric oxide production in the mouse. Br J Pharmacol 116: 2251- 2257, 1995

    PubMed  Google Scholar 

  111. 111.

    Pipili-Synetos E, Sakkoula E, Maragoudakis ME: Nitric oxide is involved in the regulation of angiogenesis. Br J Pharmacol 108: 855-857, 1993

    PubMed  Google Scholar 

  112. 112.

    Xie K, Fidler IJ: Decreased matrix metalloproteinase-2 (MMP-2) expression correlates with suppression of tumorigenicity and metastasis of K-1735 murine melanoma cells transfected with the inducible nitric oxide synthase (iNOS) gene. Proc Am Assoc Cancer Res 38: 1113, 1997

    Google Scholar 

  113. 113.

    Nunokawa Y, Tanaka S: Interferon-gamma inhibits proliferation of rat vascular smooth muscle cells by nitric oxide generation. Biochem Biophys Res Commun 188: 409-415, 1992

    PubMed  Google Scholar 

  114. 114.

    Sarkar R, Meinberg EG, Stanley JC, Gordon D, Webb RC: Nitric oxide reversibly inhibits the migration of cultured vascular smooth muscle cells. Circulation Res 78: 225-230, 1996

    PubMed  Google Scholar 

  115. 115.

    Kourembanas S, McQuillan LP, Leung GK, Faller DV: Nitric oxide regulates the expression of vasoconstrictors and growth factors by vascular endothelium under both normoxia and hypoxia. J Clin Invest 92: 99-104, 1993

    PubMed  Google Scholar 

  116. 116.

    Tuder RM, Flook BE, Voelkel NF: Increased gene expression for VEGF and the VEGF receptors KDR/Flk and Flt in lungs exposed to acute or to chronic hypoxia. Modulation of gene expression by nitric oxide. J Clin Invest 95: 1798-1807, 1995

    PubMed  Google Scholar 

  117. 117.

    Doi K, Akaike T, Horie H, Noguchi Y, Fujii S, Beppu T, Ogawa M, Maeda H: Excessive production of nitric oxide in rat solid tumor and its implication in rapid tumor growth. Cancer 77: 1598-1604, 1996

    PubMed  Google Scholar 

  118. 118.

    Ziche M, Morbidelli L, Masini E, Amerini S, Granger HJ, Maggi CA, Geppetti P, Ledda F: Nitric oxide mediates angiogenesis in vivoand endothelial cell growth and migration in vitropromoted by substance P. J Clin Invest 94: 2036-2044, 1994

    PubMed  Google Scholar 

  119. 119.

    Leibovich SJ, Polverini PJ, Fong TW, Harlow LA, Koch CJ: Production of angiogenic activity by human monocytes requires an L-arginine/nitric oxide-synthase-dependent effector mechanism. Proc Natl Acad Sci USA 91: 4190-4194, 1994

    PubMed  Google Scholar 

  120. 120.

    Fukuo K, Inoue T, Morimoto S, Nakahashi T, Yasuda O, Kitano S, Sasada R, Ogihara T: Nitric oxide mediates cytotoxicity and basic fibroblast growth factor release in cultured vascular smooth muscle cells. A possible mechanism of neovascularization in atherosclerotic plaques. J Clin Invest 95: 669-676, 1995

    PubMed  Google Scholar 

  121. 121.

    Andrew PJ, Harant H, Lindley IJ: Nitric oxide regulates IL-8 expression in melanoma cells at the transcriptional level. Biochem Biophys Res Commun 214: 949-956, 1995

    Article  PubMed  Google Scholar 

  122. 122.

    Xie K, Huang S, Dong Z, Juang S-H, Gutman M, Xie Q-W, Nathan C, Fidler IJ: Transfection with the inducible nitric oxide synthase gene suppresses tumorigenicity and abrogates metastasis in K-1735 murine melanoma cells. J Exp Med 181: 1333-1343, 1995

    Article  PubMed  Google Scholar 

  123. 123.

    Xie Q-W, Cho HJ, Calaycay J, Mumford RA, Swiderek KM, Lee TD, Ding A, Troso T, Nathan C: Cloning and characterization of inducible nitric oxide synthase from mouse macrophages. Science 256: 225-228, 1992

    PubMed  Google Scholar 

  124. 124.

    Karupiah G, Xie Q-W, Mark R, Buller L, Nathan C: Inhibition of viral replication by interferon-?-induced nitric oxide synthase. Science 261: 1445-1449, 1993

    PubMed  Google Scholar 

  125. 125.

    Xie K, Fidler IJ: TNF-mediated cytotoxicity in sensitive and resistant L929 fibroblasts correlates with nitric oxide-independent and-dependent mechanisms, respectively (Abstract). J Leukocyte Biol 3: 45, 1992

    Google Scholar 

  126. 126.

    Xie K, Huang S, Dong Z, Fidler IJ: Cytokine-induced apoptosis in transformed murine fibroblasts involves synthesis of endogenous nitric oxide. Int J Oncol 3: 1043-1047, 1993

    Google Scholar 

  127. 127.

    Xie K, Huang S, Dong Z, Gutman M, Fidler IJ: Direct correlation between expression of endogenous inducible nitric oxide synthase and regression of M5076 reticulum cell sarcoma hepatic metastases in mice treated with liposomes containing lipopeptide CGP 31362. Cancer Res 55: 3123-3131, 1995

    PubMed  Google Scholar 

  128. 128.

    Sarih M, Souvannavong V, Adam A: Nitric oxide synthase induces macrophages death by apoptosis. Biochem Biophys Res Commun 191: 503-508, 1993

    Article  PubMed  Google Scholar 

  129. 129.

    Albina JE, Cui S, Mateo RB, Reichner JS: Nitric oxide-mediated apoptosis in murine peritoneal macrophages. J Immunol 150: 5080-5085, 1993

    PubMed  Google Scholar 

  130. 130.

    Kamijo R, Harada H, Matsuyama T, Bosland M, Gerecitano J, Shapiro D, Le J, Im KS, Kimuar T, Green S, Mak TW, Taniguchi T, Vilcek J: Requirement for transcription factor IRF-1 in NO synthase induction in macrophages. Science 263: 1612-1615. 1994

    PubMed  Google Scholar 

  131. 131.

    Blanco FJ, Ochs RL, Schwarz H, Lotz M: Chondrocyte apoptosis induced by nitric oxide. Am J Pathol 146: 75-85, 1995

    PubMed  Google Scholar 

  132. 132.

    Campbell IL, Samimi A, Chiang C-S: Expression of the inducible nitric oxide synthase: Correlation with neuropathology and clinical features in mice with lymphocytic choriomeningitis. J Immunol 153: 3622-3629, 1994

    PubMed  Google Scholar 

  133. 133.

    Cui S, Reichner JS, Mateo RB, Albina JE: Activated murine macrophages induce apoptosis in tumor cells through nitric oxide-dependent or-independent mechanisms. Cancer Res 54: 2462-2467, 1994

    PubMed  Google Scholar 

  134. 134.

    Fehsel K, Kroncke K-D, Meyer KL, Huber H, Wahn V, Kolb-Bachofen V: Nitric oxide induces apoptosis in murine thymocytes. J Immunol 155: 2858-2865, 1995

    PubMed  Google Scholar 

  135. 135.

    Kitajima I, Kawahara K, Nakajima T, Soejima Y, Matsuyama T, Maruyama I: Nitric oxide-mediated apoptosis in murine mastocytoma. Biochem Biophys Res Commun 204: 244-251, 1995

    Article  Google Scholar 

  136. 136.

    Paul-Eugene N, Kolb JP, Damais C, Dugas B: Heterogenous nitrite production by IL-4-stimulated human monocytes and peripheral blood monocluear cells. Immunol Lett 42: 31-34, 1994

    Article  PubMed  Google Scholar 

  137. 137.

    Corradin SB, Fasel N, Buchmuller-Rouiller Y, Ransijn A, Smith J, Mauel J: Induction of macrophage nitric oxide production by interferon-gamma and tumor necrosis factor-alpha is enhanced by interleukin-10. Eur J Immunol 23: 2045-2048, 1993

    PubMed  Google Scholar 

  138. 138.

    Waldburger KE, Hastings RC, Schaub RG, Goldman SJ, Leonard JP: Adoptive transfer of experimental allergic encephalomyelitis after in vitrotreatment with recombinant murine interleukin-12. Preferential expansion of interferon-gamma-producing cells and increased expression of macrophage-associated inducible nitric oxide synthase as immunomodulatory mechanisms. Am J Pathol 148: 375-382, 1996

    PubMed  Google Scholar 

  139. 139.

    Mustafa SB, Howard KM, Olson MS: Platelet-activating factor augments lipopolysaccharide-induced nitric oxide formation by rat. Kupffer cells. Hepatology 23: 1622-1630, 1996

    Article  PubMed  Google Scholar 

  140. 140.

    Ding A, Nathan CF, Graycar J, Derynck R, Stuehr DJ, Srimal S: Macrophage deactivation factor and transforming growth factor-β1,-β2, and-β3 inhibit induction of macrophage nitrogen oxide synthesis by IFN-?. J Immunol 145: 940-947, 1990

    PubMed  Google Scholar 

  141. 141.

    Beck KF, Mohaupt MG, Sterzel RB: Endothelin-1 inhibits cytokine-stimulated transcription of inducible nitric oxide synthase in glomerular mesangial cells. Kidney Int 48: 1893-1899, 1995

    PubMed  Google Scholar 

  142. 142.

    Heck DE, Laskin DL, Gardner CR, Laskin JD: Epidermal growth factor suppresses nitric oxide and hydrogen peroxidase production by keratinocytes: Potential role for nitric oxide in the regulation of wound healing. J Biol Chem 267: 21277-21284, 1992

    PubMed  Google Scholar 

  143. 143.

    Schini VB, Catovsky S, Schray-Utz B, Busse R, Vanhoutte PM: Insulin-like growth factor I inhibits induction of nitric oxide synthase in vascular smooth muscle cells. Circulation Res 74: 24-32, 1994

    PubMed  Google Scholar 

  144. 144.

    Liew FY, Li Y, Severn A, Millott S, Schmidt J, Salter M, Moncada S: A possible novel pathway of regulation by murine T helper type 21 (Th2) of a Th1 cell activity via the modulation of the induction of nitric oxide synthase on macrophages. Eur J Immunol 2: 2489-2496, 1991

    Google Scholar 

  145. 145.

    Bogdan C, Vodovotz Y, Paik J, Xie QW, Nathan C: Mechanism of suppression of nitric oxide synthase expression by interleukin-4 in primary mouse macrophages. J Leukocyte Biol 55: 227-233, 1994

    PubMed  Google Scholar 

  146. 146.

    McCall TB, Palmer RMJ, Moncada S: Interleukin-8 inhibits the induction of nitric oxide synthase in rat peritoneal neutrophils. Biochem Biophys Res Commun 186: 680-687, 1992

    PubMed  Google Scholar 

  147. 147.

    Cuhna FQ, Moncada S, Liew FY: Interleukin-10 inhibits the induction of nitric oxide synthase by interferon-?????????in murine macrophages. Biochem Biophys Res Commun 182: 1155-1159, 1992

    PubMed  Google Scholar 

  148. 148.

    Becherel PA, Le Goff L, Ktorza S, Ouaaz F, Mencia-Huerta JM, Dugas B, Debre P, Mossalayi MD, Arock M: Inter leukin-10 inhibits IgE-mediated nitric oxide synthase induction and cytokine synthesis in normal human keratinocytes. Eur J Immunol 25: 2992-2995, 1995

    PubMed  Google Scholar 

  149. 149.

    Doyle AG, Herbein G, Montaner LJ, Minty AJ, Caput D, Ferrara P, Gordon S: Interleukin-13 alters the activation state of murine macrophages in vitro: Comparison with interleukin-4 and interferon-?. Eur J Immunol 24: 1441-1445, 1994

    PubMed  Google Scholar 

  150. 150.

    Melillo G, Musso T, Sica A, Taylor LS, Cox GW, Varesio L: A hypoxia-responsive element mediates a novel pathway of activation of the inducible nitric oxide synthase promoter. J Exp Med 182: 1683-1693, 1995

    Article  PubMed  Google Scholar 

  151. 151.

    Xie K, Huang S, Dong Z, Juang S-H, Wang Y, Fidler IJ: Destruction of bystander cells by tumor cells transfected with inducible nitric oxide synthase gene. J Natl Cancer Inst 89: 421-427, 1997

    Article  PubMed  Google Scholar 

  152. 152.

    Pestka S, Langer JA, Zoon KC, Samuel CE: Interferons and their action. Annu Rev Biochem 56: 727-777, 1987

    Article  PubMed  Google Scholar 

  153. 153.

    Schmidt HHHW, Watter U: NO at work. Cell 78: 919-925, 1994

    Article  PubMed  Google Scholar 

  154. 154.

    Haddad EK, Duclos AJ, Baines MG: Early embryo loss is associated with local production of nitric oxide by decidual mononuclear cells. J Exp Med 182: 1143-1153, 1995

    Article  PubMed  Google Scholar 

  155. 155.

    Kaneto H, Fujii J, Seo HG, Suzuki K, Matsuoka T, Nakamura M, Tatsumi H, Yamasaki Y, Kamada T, Taniguchi N: Apoptotic cell death triggered by nitric oxide in pancreatic beta cells. Diabetes 44: 733-738, 1995

    PubMed  Google Scholar 

  156. 156.

    Dunger A, Augstein P, Schmidt S, Fischer U: Identification of interleukin 1-induced apoptosis in rat islets using in situspecific labelling of fragmented DNA. J Autoimmunity 9: 309-313, 1996

    Article  Google Scholar 

  157. 157.

    Sveinbjornsson B, Olsen R, Seternes OM, Seljelid R: Macrophage cytotoxicity against murine meth A sarcoma involves nitric oxide-mediated apoptosis. Biochem Biophys Res Commun 223: 643-649, 1996

    Article  PubMed  Google Scholar 

  158. 158.

    Geng YJ, Hellstrand K, Wennmalm A, Hansson GK: Apoptotic death of human leukemic cells induced by vascular cells expressing nitric oxide synthase in response to IFN-??and TNF-a. Cancer Res 56: 866-874, 1996

    PubMed  Google Scholar 

  159. 159.

    Filep JG, Baron C, Lachance S, Perreault C, Chan JS: Involvement of nitric oxide in target-cell lysis and DNA fragmentation induced by murine natural killer cells. Blood 87: 5136-5143, 1996

    PubMed  Google Scholar 

  160. 160.

    Xiao L, Eneroth PH, Qureshi GA: Nitric oxide synthase pathway may mediate human natural killer cell cytotoxicity. Scand J Immunol 42: 505-511, 1995

    PubMed  Google Scholar 

  161. 161.

    Cifone MG, Festuccia C, Cironi L, Cavallo G, Chessa MA, Pensa V, Tubaro E, Santoni A: Induction of the nitric oxide-synthesizing pathway in fresh and interleukin 2-cultured rat natural killer cells. Cell Immunol 157: 181-194, 1994

    Article  PubMed  Google Scholar 

  162. 162.

    Stangel M, Zettl UK, Mix E, Zielasek J, Toyka KV, Hartung HP, Gold R: H2O2 and nitric oxide-mediated oxidative stress induce apoptosis in rat skeletal muscle myoblasts. J Neuropathol Exp Neurol 55: 36-43, 1996

    PubMed  Google Scholar 

  163. 163.

    Palluy O, Rigaud M: Nitric oxide induces cultured cortical neuron apoptosis. Neurosci Lett 208: 1-4, 1996

    Article  PubMed  Google Scholar 

  164. 164.

    Martin-Sanz P, Diaz-Guerra MJ, Casado M, Bosca L: Bacterial lipopolysaccharide antagonizes transforming growth factor beta 1-induced apoptosis in primary cultures of hepatocytes. Hepatology 23: 1200-1207, 1996

    Article  PubMed  Google Scholar 

  165. 165.

    Fukuo K, Hata S, Suhara T, Nakahashi T, Shinto Y, Tsujimoto Y, Morimoto S, Ogihara T: Nitric oxide induces upregulation of Fas and apoptosis in vascular smooth muscle. Hypertension 27: 823-826, 1996

    PubMed  Google Scholar 

  166. 166.

    Shimaoka M, Iida T, Ohara A, Taenaka N, Mashimo T, Honda T, Yoshiya I: NOC, a nitric-oxide-releasing compound, induces dose dependent apoptosis in macrophages. Biochem Biophys Res Commun 209: 519-526, 1995

    Article  PubMed  Google Scholar 

  167. 167.

    Messmer UK, Lapetina EG, Brune B: Nitric oxideinduced apoptosis in RAW264.7 macrophages is antagonized by protein kinase C-and protein kinase A-activating compounds. Mol Pharmacol 47: 757-765, 1995

    PubMed  Google Scholar 

  168. 168.

    Xia Y, Dawson VL, Dawson TM, Snyder SH, Zweier JL: Nitric oxide synthase generates superoxide and nitric oxide in arginine-depleted cells leading to peroxynitrite-mediated cellular injury. Proc Natl Acad Sci USA 93: 6770-6774, 1996

    Article  PubMed  Google Scholar 

  169. 169.

    Ankarcrona M, Dypbukt JM, Brune B, Nicotera P: Interleukin-1β-induced nitric oxide production activates apoptosis in pancreatic RINm5F cells. Exp Cell Res 213: 172-177, 1994

    Article  PubMed  Google Scholar 

  170. 170.

    Chun SY, Eisenhauer KM, Kubo M, Hsueh AJ: Interleukin-1β?suppresses apoptosis in rat ovarian follicles by increasing nitric oxide production. Endocrinology 136: 3120-3127, 1995

    Article  PubMed  Google Scholar 

  171. 171.

    Mannick JB, Asano K, Izumi K, Kieff E, Stamler JS: Nitric oxide produced by human B lymphocytes inhibits apoptosis and Epstein-Barr virus reactivation. Cell 79: 1137-1146, 1994

    Article  PubMed  Google Scholar 

  172. 172.

    Lin KT, Xue JY, Nomen M, Spur B, Wong PV: Peroxynitrite-induced apoptosis in HL-60 cells. J Biol Chem 270: 16487-16490, 1995

    PubMed  Google Scholar 

  173. 173.

    Mitrovic B, Ignarro LJ, Vinters HV, Akers MA, Schmid I, Uittenbogaart C, Merrill JE: Nitric oxide induces necrotic but not apoptotic cell death in oligodendrocytes. Neuroscience 65: 531-539, 1995

    Article  PubMed  Google Scholar 

  174. 174.

    Mackenzie-Graham AJ, Mitrovic B, Smoll A, Merrill JE: Differential sensitivity to nitric oxide in immortalized, cloned murine oligodendrocyte cell lines. Developmental Neurosci 16: 162-171, 1994

    Google Scholar 

  175. 175.

    Bonfoco E, Krainc D, Ankarcrona M, Nicotera P, Lipton SA: Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-Daspartate or nitric oxide/superoxide in cortical cell cultures. Proc Natl Acad Sci USA 92: 7162-7166, 1995

    PubMed  Google Scholar 

  176. 176.

    Beckman JS: Oxidative damage and tyrosine nitration from peroxynitrite (Review). Chem Res Toxicol 9: 836-844, 1996

    Article  PubMed  Google Scholar 

  177. 177.

    Estevez AG, Radi R, Barbeito L, Shin JT, Thompson JA, Beckman JS: Peroxynitrite-induced cytotoxicity in PC12 cells: Evidence for an apoptotic mechanism differentially modulated by neurotrophic factors. J Neurochem 65: 1543-1550, 1995

    PubMed  Google Scholar 

  178. 178.

    Kong SK, Yim MB, Stadtman ER, Chock PB: Peroxynitrite disables the tyrosine phosphorylation regulatory mechanism: Lymphocyte-specific tyrosine kinase fails to phosphorylate nitrated cdc2(6-20)NH2 peptide. Proc Natl Acad Sci USA 93: 3377-3382, 1996

    Article  PubMed  Google Scholar 

  179. 179.

    Kuo ML, Chau YP, Wang JH, Shiah SG: Inhibitors of poly (ADP-ribose) polymerase block nitric oxide-induced apoptosis but not differentiation in human leukemia HL-60 cells. Biochem Biophys Res Commun 219: 502-508, 1996

    Article  PubMed  Google Scholar 

  180. 180.

    Szabo C, Zingarelli B, O'Connor M, Salzman AL: DNA strand breakage, activation of poly (ADP-ribose)synthetase, and cellular energy depletion are involved in the cytotoxicity of macrophages and smooth muscle cells exposed to peroxynitrite. Proc Natl Acad Sci USA 93: 1753-1758, 1996

    Google Scholar 

  181. 181.

    Pou S, Nguyen SY, Gladwell T, Rosen GM: Does peroxynitrite generate hydroxyl radical? Biochim Biophys Acta 1244: 62-68, 1995

    PubMed  Google Scholar 

  182. 182.

    Lizasoain I, Moro MA, Knowles RG, Darley-Usmar V, Moncada S: Nitric oxide and peroxynitrite exert distinct effects on mitochondrial respiration which are differentially blocked by glutathione or glucose. Biochem J 314: 877-880, 1996

    PubMed  Google Scholar 

  183. 183.

    Walker MW, Kinter MT, Roberts RJ, Spitz DR: Nitric oxide-induced cytotoxicity: involvement of cellular resistance to oxidative stress and the role of glutathione in protection. Pediatric Res 37: 41-49, 1995

    Google Scholar 

  184. 184.

    Hata Y, Ota S, Hiraishi H, Terano A, Ivey KJ: Nitric oxide enhances cytotoxicity of cultured rabbit gastric mucosal cells induced by hydrogen peroxide. Biochim Biophys Acta 1290: 257-260, 1996

    PubMed  Google Scholar 

  185. 185.

    Ioannidis I, de Groot H: Cytotoxicity of nitric oxide in Fu5 rat hepatoma cells: evidence for cooperative action with hydrogen peroxide. Biochem J 296: 341-345, 1993

    PubMed  Google Scholar 

  186. 186.

    Wink DA, Cook JA, Pacelli R, Liebmann J, Krishna MC, Mitchell JB: NO protects against cellular damage by reactive oxygen species (Review). Toxicol Lett 82-83: 221-226, 1995

    Article  PubMed  Google Scholar 

  187. 187.

    Brown GC: Reversible binding and inhibition of catalase by nitric oxide. Eur J Biochem 232: 188-191, 1995

    PubMed  Google Scholar 

  188. 188.

    Farias-Eisner R, Chaudhuri G, Aeberhard E, Fukuto JM: The chemistry and tumoricidal activity of nitric oxide/hydrogen peroxide and the implications to cell resistance/susceptibility. J Biol Chem 271: 6144-6151, 1996

    Article  PubMed  Google Scholar 

  189. 189.

    Petit JF, Nicaise M, Lepoivre M, Guissani A, Lemaire G: Protection by glutathione against the antiproliferative effects of nitric oxide. Dependence on kinetics of no release. Biochem Pharmacol 52: 205-212, 1996

    Article  PubMed  Google Scholar 

  190. 190.

    Schwarz MA, Lazo JS, Yalowich JC, Allen WP, Whitmore M, Bergonia HA, Tzeng E, Billiar TR, Robbins PD, Lancaster Jr JR: Metallothionein protects against the cytotoxic and DNA-damaging effects of nitric oxide. Proc Natl Acad Sci USA 92: 4452-4456, 1995

    PubMed  Google Scholar 

  191. 191.

    Asahi M, Fujii J, Suzuki K, Seo HG, Kuzuya T, Hori M, Tada M, Fujii S, Taniguchi N: Inactivation of glutathione peroxidase by nitric oxide. Implications for cytotoxicity. J Biol Chem 270: 21035-21039, 1995

    Article  PubMed  Google Scholar 

  192. 192.

    Walker MW, Kinter MT, Roberts RJ, Spitz DR: Nitric oxide-induced cytotoxicity: involvement of cellular resistance to oxidative stress and the role of glutathione in protection. Pediatric Res 37: 41-49, 1995

    Google Scholar 

  193. 193.

    Noronha-Dutra AA, Epperlein MM, Woolf N: Reaction of nitric oxide with hydrogen peroxide to produce potentially cytotoxic singlet oxygen as a model for nitric oxide-mediated killing. FEBS Lett 321: 59-62, 1993

    Article  PubMed  Google Scholar 

  194. 194.

    Lepoivre M, Chenais B, Yapo A, Lemaire G, Thelander L, Tenu J-P: Alterations of ribonucleotide reductase activity following induction of the nitrite-generating pathway in adenocarcinoma cells. J Biol Chem 265: 14143-14149, 1990

    PubMed  Google Scholar 

  195. 195.

    Richter C, Schweizer M, Cossarizza A, Franceschi C: Control of apoptosis by the cellular ATP level (Review). FEBS Lett 378: 107-110, 1996

    Article  PubMed  Google Scholar 

  196. 196.

    Xie K, Huang S, Dong Z, Fidler IJ: Nitric oxide-mediated apoptosis occurs by a decrease in intracellular pH (Abstract). J Leukocyte Biol 5: 126, 1995

    Google Scholar 

  197. 197.

    Richter C, Gogvadze V, Laffranchi R, Schlapbach R, Schweizer M, Suter M, Walter P, Yaffer M: Oxidants in mitochondria: From physiology to diseases. Biochem Biophys Acta 1271: 67-74, 1995

    PubMed  Google Scholar 

  198. 198.

    Eastman A: Assays for DNA fragmentation, endonucleases, and intracellular pH and Ca2??associated with apoptosis. Meth Cell Biol 46: 41-55, 1995

    Google Scholar 

  199. 199.

    Nathan CF: Natural resistance and nitric oxide. Cell 82: 873-876, 1995

    Article  PubMed  Google Scholar 

  200. 200.

    Nishio E, Fukushima K, Shiozaki M, Watanabe Y: Nitric oxide donor SNAP induces apoptosis in smooth muscle cells through cGMP-independent mechanism. Biochem Biophys Res Commun 221: 163-168, 1996

    Article  PubMed  Google Scholar 

  201. 201.

    Brune B, Mohr S, Messmer UK: Protein thiol modification and apoptotic cell death as cGMP-independent nitric oxide (NO) signaling pathways. Rev Physiol Biochem Pharmacol 127: 1-30, 1996

    PubMed  Google Scholar 

  202. 202.

    Ho YS, Wang YJ, Lin JK: Induction of p53 and p21/WAF1/CIP1 expression by nitric oxide and their association with apoptosis in human cancer cells. Mol Carcinogen 16: 20-31, 1996

    Google Scholar 

  203. 203.

    Xie K, Huang S, Wang Y, Beltran PJ, Juang SH, Dong Z, Reed JC, McDonnell TJ, McConkey DJ, Fidler IJ: Bcl-2 protects cells from cytokine-induced nitric-oxide-dependent apoptosis. Cancer Immunol Immunother 43: 109-115, 1996

    Article  PubMed  Google Scholar 

  204. 204.

    Albina JE, Martin BA, Henry WL Jr, Louis CA, Reichner JS: B cell lymphoma-2 transfected P815 cells resist reactive nitrogen intermediate-mediated macrophage-dependent cytotoxicity. J Immunol 157: 279-283, 1996

    PubMed  Google Scholar 

  205. 205.

    Messmer UK, Reed UK, Brune B: Bcl-2 protects macrophages from nitric oxide-induced apoptosis. J Biol Chem 271: 20192-20197, 1996

    Google Scholar 

  206. 206.

    Genaro AM, Hortelano S, Alvarez A, Martinez C, Bosca L: Splenic B lymphocyte programmed cell death is prevented by nitric oxide release through mechanisms involving sustained Bcl-2 levels. J Clin Invest 95: 1884-1890, 1995

    PubMed  Google Scholar 

  207. 207.

    Fidler IJ, Kleinerman ES: Clinical application of phospholipid liposomes containing macrophage activators for therapy of cancer metastasis. Adv Drug Del Rev 13: 325-240, 1994

    Article  Google Scholar 

  208. 208.

    Hart IR, Talmadge JE, Fidler IJ: Metastatic behavior of a murine reticulum cell sarcoma exhibiting organ-specific growth. Cancer Res 41: 1281-1287, 1980

    Google Scholar 

  209. 209.

    Calderon C, Huang ZH, Gage DA, Sotomayor EM, Lopez DM: Isolation of a nitric oxide inhibitor from mammary tumor cells and its characterization as phosphatidylserine. J Exp Med 180: 945-958, 1995

    Article  Google Scholar 

  210. 210.

    Juang S-H, Xie K, Wang Y, Dong Z, Fidler IJ: Suppression of tumorigenicity and metastasis by murine melanoma cells infected with the PLXSN retrovirus carrying the inducible nitric synthase gene. Proc Am Assoc Cancer Res 37: 2328, 1996

    Google Scholar 

Download references

Author information

Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Xie, K., Fidler, I.J. Therapy of cancer metastasis by activation of the inducible nitric oxide synthase. Cancer Metastasis Rev 17, 55–75 (1998). https://doi.org/10.1023/A:1005956721457

Download citation

  • iNOS
  • apoptosis
  • metastasis
  • therapy