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Role of nitric oxide in IL-2 therapy-induced capillary leak syndrome

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Abstract

Nitric oxide (NO) is a potent short-lived and short range bioactive molecule, which plays a key role in physiological and pathological processes including inflammation and cancer. Detrimental effects of excessive NO production during septic shock have been well recognized. We tested the hypothesis that ‘capillary leak syndrome’ following systemic interleukin-2 (IL-2) therapy resulted from a cascade of events leading to the induction of NO which, directly or indirectly, injured capillaries and caused fluid leakage. Our results provided the first direct evidence that the induction of active NO synthase (NOS) leading to the overproduction of NO is instrumental in IL-2-induced capillary leakage in mice and that successful blocking of this overproduction with chronic oral administration of NOS inhibitors can mitigate this leakage without interfering with the beneficial antitumor effects of IL-2 therapy. NO blocking agents can, in fact, improve IL-2-induced antitumor effector cell activation, as well as tumor regression. In our studies, NO blocking agents alone reduced the growth and metastasis of a murine mammary carcinoma, at least in part, by mitigating the invasion and angiogenesis-stimulating role of tumor-derived NO. Thus, NOS inhibitors may be useful in treating certain tumors and serve as valuable adjuncts to systemic IL-2 based immunotherapy of cancer and infectious diseases.

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References

  1. Robb MJ, Munck A, Smith KA: T cell growth factor receptors: Quantitation, specificity and biological relevance. J Exp Med 154: 1455-1474, 1981

    Article  PubMed  Google Scholar 

  2. Aribia MHB, Moire N, Metivier D, Vaquero C, Lantz O, Olive D, Charpentier B, Senik A: IL-2 receptors on circulating natural killer cells and T lymphocytes. J Immunol 142: 490-499, 1989

    PubMed  Google Scholar 

  3. Holter W, Grunow R, Stockinger H, Knapp W: Recombinant interferon-??induces interleukin 2 receptors on human peripheral blood monocytes. J Immunol 136: 2171-2175, 1986

    PubMed  Google Scholar 

  4. Parhar RS, Lala PK: Prostaglandin E2-mediated inactivation of various killer lineage cells by tumor-bearing host macrophages. J Leukocyte Biol 44: 474-484, 1988

    PubMed  Google Scholar 

  5. Rosenberg SA, Mule JJ, Spiess PJ, Reichart CM, Schwarz SL: Regression of established pulmonary metastasis and subcutaneous tumor mediated by systemic administration of high dose recombinant interleukin 2. J Exp Med 161: 1169, 1985

    Article  PubMed  Google Scholar 

  6. Rosenberg SA: Clinical immunotherapy studies in the surgery branch of the U.S. National Cancer Institute. Cancer Treat Rev 16(Suppl A): 115-121, 1989

    Article  PubMed  Google Scholar 

  7. Fisher RI, Coltman CA, Doroshow JA, Rayner AA, Hawkins MJ, Mier JW, Wiernik P, McMannis JD, Weiss GR, Margolin KA, Gemlo BT, Hoth DF, Parkinson DR, Paietta E: A phase II study of interleukin-2 and lymphokine activated killer cells (LAK) in metastatic renal cancer. Ann Intern Med 108: 518-523, 1988

    PubMed  Google Scholar 

  8. Dutcher JP, Creekmore S, Weiss GR, Margolin K, Markowitz AB, Roper M, Parkinson D, Ciobanu N, Fisher RI, Boldt DH, Doroshow JH, Rayner AA, Hawkins M, Atkins M: A phase II study of interleukin-2 and lymphokine activated killer (LAK) cells in patients with metastatic malignant melanoma. J Clin Oncol 7: 477-485, 1989

    PubMed  Google Scholar 

  9. Parkinson DR, Fisher RI, Rayner AA, Paietta E, Margolin KA, Weiss GR, Mier JW, Sznol M, Gaynor ER, Bar MH, Gucalp R, Boldt DH, Mills B, Hawkins MJ: Therapy of renal cell carcinoma with interleukin-2 and lymphokine-activated killer cells: Phase II experience with a hybrid bolus and continuous infusion interleukin-2 regimen. J Clin Oncol 8: 1630-1636, 1990

    PubMed  Google Scholar 

  10. Bar M, Sznol M, Atkins MB, Ciobanu N, Micetich KC, Boldt DH, Margolin KA, Aronson FR, Rayner AA, Hawkins MJ, Mier JW, Paietta E, Fisher RI, Weiss GR, Doroshow JH: Metastatic malignant melanoma treated with combined bolus and continuous infusion interleukin-2 and lymphokine-activated killer cells. J Clin Oncol 8: 1138-1147, 1990

    PubMed  Google Scholar 

  11. Mertens WC, Bramwell VHC, Banerjee D, Gwadry-Sridhar F, Al-Mutter N, Parhar RS, Lala PK: Chronic oral indomethacin and ranitidine with intermittent continuous infusion interleukin-2 in advanced renal cell carcinoma. Cancer Biotherapy 8: 229-233, 1993

    PubMed  Google Scholar 

  12. Mertens WC, Bramwell VHC, Banarjee D, Gwadry-Sridhar F, Lala PK: Sustained indomethacin and ranitidine with intermittent continuous infusion interleukin-2 in advanced malignant melanoma: a phase II study. Clin Oncol 5: 197-213, 1993

    Google Scholar 

  13. Siegel JP, Puri RK: Interleukin-2 toxicity. J Clin Oncol 9: 694-704, 1991

    PubMed  Google Scholar 

  14. Oppenheim MH, Lotze MT: Interleukin-2: Solid-tumor therapy. Oncology 51: 154-169, 1994

    PubMed  Google Scholar 

  15. Lotze M, Matory Y, Ettinghausen S, Raynor A, Sharrow S, Siepp C, Custer M, Rosenberg SA: In vivoadministration of purified human interleukin-2. II. Half-life, immunologic effects, and expansion of periferal lymphoid cells in vivowith recombinant interleukin-2. J Immunol 135: 2865, 1985

    PubMed  Google Scholar 

  16. Rosenberg SA, Lotze M, Muul L, Leitman S, Chang AE, Ettinghausen SE, Matory YL, Skibber JM, Shiloni E, Vetto JT, Seipp CA, Simpson C, Reichert CM: Observation on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 313: 1485-1492, 1985

    PubMed  Google Scholar 

  17. Rosenstein M, Ettinghausen SE, Rosenberg SA: Extravasation of intravascular fluid mediated by the systemic administration of recombinant interleukin 2. J Immmunol 137: 1735-1742, 1986

    Google Scholar 

  18. Ettinghausen SE, Puri RK, Rosenberg SA: Increased vascular permeability in organs mediated by the systemic administration of lymphokine-activated killer cells and recombinant interleukin-2 in mice. J Natl Cancer Inst 80: 177-188, 1988

    PubMed  Google Scholar 

  19. Harms BA, Pahl AC, Pohlman TH, Conhaim RL, Starling JR, Storm FK: Effects of interleukin-2 on pulmonary and systemic transvascular fluid filtration. Surgery 106: 339-346, 1989

    PubMed  Google Scholar 

  20. Klausner JM, Paterson IS, Morel NML, Goldman G, Gray AD, Valeri R, Eberlein TJ, Shepro D, Hechtman HB: Role of thromboxane in interleukin 2-induced lung injury in sheep. Cancer Res 49: 3542-3549, 1989

    PubMed  Google Scholar 

  21. Jesmok GJ, Gunther RA: In vivobiology of recombinant interleukin-2 infusion in sheep. Inflammation 13: 267-284, 1989

    PubMed  Google Scholar 

  22. Edwards MJ, Miller FN, Sims DE, Abney DL, Schuschke DA, Corey TS: Interleukin 2 acutely induces platelet and neutrophil-endothelial adherence and macromolecular leakage. Cancer Res 52: 3425-3431, 1992

    PubMed  Google Scholar 

  23. Kotasek D, Vercellotti GM, Ochoa AC, Bach FH, White JG, Jacob HS: Mechanism of cultured endothelial injury induced by lymphokine-activated killer cells. Cancer Res 48: 5528-5532, 1988

    PubMed  Google Scholar 

  24. Amador J-F, Vazquez AM, Cabrera L, Barral AM, Gendelman R, Jondal M: Toxic effects of interleukin-2 activated lymphocytes on vascular endothelial cells. Nat Immun Cell Growth Regul 10: 207-215, 1991

    PubMed  Google Scholar 

  25. Aronson FR, Libby P, Brandon EP, Janicka MW, Mier JW: IL-2 rapidly induces natural killer cell adhesion to human endothelial cells. J Immunol 141: 158-163, 1988

    PubMed  Google Scholar 

  26. Montesano R, Orci L, Vassalli P: Human endothelial cell cultures: Phenotypic modulation by leukocyte interleukins. J Cell Physiol 122: 424-434, 1985

    PubMed  Google Scholar 

  27. Kahaleh MB, Smith EA, Soma Y, LeRoy EC: Effect of lymphotoxin and tumor necrosis factor in vivoand their prevention by cyclooxygenase inhibitors. Clin Immunol Immunopath 49: 261-272, 1988

    Article  Google Scholar 

  28. Palmer RMJ, Bridge L, Foxwell NA, Moncada S: The role of nitric oxide in endothelial cell damage and its inhibition by glucocorticoids. Br J Pharmacol 105: 11-12, 1992

    PubMed  Google Scholar 

  29. Estrada C, Gomez C, Martin C, Moncada S, Gonzalez C: Nitric oxide mediates tumor necrosis factor-??cytotoxicity in endothelial cells. Biochem Biophys Res Commun 186: 475-482, 1992

    PubMed  Google Scholar 

  30. Hibbs JB, Jr., Westenfelder C, Taintor R, Vavrin Z, Kablitz C, Baranowski RL, Ward JH, Menlove RL, McMurry MP, Kushner JP, Samlowski WE: Evidence for cytokine-inducible nitric oxide synthesis from L-arginine in patients receiving interleukin-2 therapy. J Clin Invest 89: 867-877, 1992

    PubMed  Google Scholar 

  31. Ochoa JB, Curti B, Peitzman AB, Simmons RL, Billiar TR, Hoffman R, Rault R, Longo DL, Urba WJ, Ochoa AC: Increased circulating nitrogen oxides after human tumor immunotherapy: correlation with toxic hemodynamic changes. J Natl Cancer Inst 84: 864-867, 1992

    PubMed  Google Scholar 

  32. Knowles RG, Moncada S: Nitric oxide synthases in mammals. Biochem J 298: 249-258, 1994

    PubMed  Google Scholar 

  33. Morris SM, Billiar TR: New insights into the regulation of inducible nitric oxide synthesis. Am J Physiol 266: E829-E839, 1994

    PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  35. Rosenberg SA, Lotze MT, Muul LM, Chang AE, Avis FP, Leitman S, Lineham M, Robertson CN, Lee RE, Rubin JT, Seipp CA, Simpson C, White DE: A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. New Engl J Med 316: 889-897, 1987

    PubMed  Google Scholar 

  36. Lotze MT, Matory YL, Rayner AA, Ettinghausen SE, Vetto JT, Seipp CA, Rosenberg SA: Clinical effects and toxicity of interleukin-2 in patients with cancer. Cancer 58: 2764-2772, 1986

    PubMed  Google Scholar 

  37. Mier J, Vadrino G, Van der Meer J, Numerof R, Adams S, Cannon J, Bernheim H, Atkins M, Parkinson D, Dinarello C: Induction of circulating tumor necrosis factor as the mechanism for the febrile response to interleukin-2. J Clin Immunol 8: 426, 1988

    PubMed  Google Scholar 

  38. Morgan DA, Ruscetti FW, Gallo R: Selective in vitrogrowth of T lymphocytes from normal human bone marrow. Science 193: 1007-1008, 1976

    PubMed  Google Scholar 

  39. Watson JD, Mochizuchi DY, Gillis S: Molecular characterization of interleukin-2. Fed Proc 42: 2447-2776, 1983

    Google Scholar 

  40. Shows T, Eddy R, Haley L, Byers M, Henry M, Fujita T, Matsui H, Taniguchi T: Interleukin-2 (IL-2) is assigned to human chromosome 4. Somat Cell Mol Genet 10: 315-318, 1984

    PubMed  Google Scholar 

  41. Taniguchi T, Matsui H, Fujita T, Takaoka C, Kashima N, Yoshimoto R, Hamuro J: Structure and expression of a cloned cDNA for human interleukin 2. Nature 302: 305-310, 1983

    PubMed  Google Scholar 

  42. Devos R, Plaetinck G, Cheroutre H, Simons G, Degrave W, Tavernier J, Remaut E, Fiers W: Molecular cloning of human interleukin 2 cDNA and its expression in E. coli. Nucleic Acid Res 11: 4307-4323, 1983

    PubMed  Google Scholar 

  43. Hatakeyama M, Tsudo M, Minamoto S, Kono T, Doi T, Miyata T, Miyasaka M, Taniguchi T: Interleukin-2 receptor beta chain gene: Generation of three receptor forms by cloned human alpha and beta chain cDNAs. Science 244: 551-556, 1989

    PubMed  Google Scholar 

  44. Takeshita T, Asao H, Ohtani K, Ishi N, Kumuki S, Tanaka N, Munakata H, Nakamura M, Sugamura K: Cloning of the gamma chain of the human IL-2 receptor. Science 257: 379-382, 1992

    PubMed  Google Scholar 

  45. Minami Y, Komo T, Mizazaki T, Taniguchi T: The IL-2 receptor complex: its structure, function and target genes. Ann Rev Immunol 11: 245-267, 1993

    Article  Google Scholar 

  46. Rosenstein M, Yron I, Kaufmann Y, Rosenberg SA: Lymphokine-activated killer cells: Lysis of fresh syngeneic NKresistant murine tumor cells by lymphocytes cultured in interleukin-2. Cancer Res 44: 1946-1953, 1984

    PubMed  Google Scholar 

  47. Lotze MT, Custer MC, Sharrow DO, Rubin LA, Nelson DL, Rosenberg SA: In vivoadministration of purified human interleukin-2 to patients with cancer: Development of interleukin-2 receptor following interleukin-2 administration. Cancer Res 47: 2188-2195, 1987

    PubMed  Google Scholar 

  48. Bonveniste EN, Merrill JE: Stimulation of oligodendroglial proliferation and maturation by interleukin-2. Nature 321: 610-613, 1986

    PubMed  Google Scholar 

  49. eSteiner G, Tschachler E, Tani M, Malek TR, Shevach EM, Holter W, Knopp W, Wolff K, Stingl G: Interleukin-2 receptors on cultured murine epidermal Langerhans cells. J Immunol 137: 155-159, 1986

    PubMed  Google Scholar 

  50. Boyd AW, Fisher DC, Fox DA, Schlossman SF, Nadler LM: Structural and functional characterization of IL-2 receptors on activated human B cells. J Immunol 134: 2387-2392, 1985

    PubMed  Google Scholar 

  51. Weidemann E, Sacchi M, Plaisance S, Heo DS, Yasumura S, Lin WC, Johnson JT, Herberman RB, Azzarone B, Whiteside TL: Receptors for interleukin-2 on human squamous cell carcinoma cell lines and tumor in situ. Cancer Res 52: 5963, 1992

    PubMed  Google Scholar 

  52. Kuribayashi K, Gillis S, Kern DE, Henney CS: Murine NK cell cultures: effects of interleukin-2 and interferon on cell growth and cytotoxic reactivity. J Immunol 126: 2321-2327, 1981

    PubMed  Google Scholar 

  53. Domzig W, Stadler BM, Herberman RB: Interleukin-2 dependence of natural killer activity. J Immunol 13: 1823-1841, 1983

    Google Scholar 

  54. Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA: Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin-2-activated autologous human peripheral blood lymphocytes. J Exp Med 155: 1823-1841, 1982

    Article  PubMed  Google Scholar 

  55. Munn DH, Cheung NKV: Interleukin-2 enhancement of monoclonal antibody-mediated cellular cytotoxicity against human melanoma. Cancer Res 47: 6600-6605, 1987

    PubMed  Google Scholar 

  56. Sondel PM, Kohler PC, Hank JA, Moore HH, Rosenthal NS, Sosman JA, Bechhofer R, Storer B: Clinical and immunological effects of recombinant interleukin-2 given by repetitive weekly cycles to patient with cancer. Cancer Res 48: 2561-2567, 1988

    PubMed  Google Scholar 

  57. Mule JJ, Shu S, Schwarz SL, Rosenberg SA: Adoptive immunotherapy of established pulmonary metastases with LAK cells and recombinant interleukin-2. Science 225: 1487-1489, 1984

    PubMed  Google Scholar 

  58. La Freiniere R, Rosenberg SA: Successful immunotherapy of murine experimental hepatic metastases with lymphokine-activated killer cells and recombinant interleukin-2. Cancer Res 54: 3735-3741, 1985

    Google Scholar 

  59. Paciucci PA, Holland JF, Glidewell O, Odchimar R: Recombinant interleukin-2 by continuous infusion and adoptive transfer of recombinant interleukin-2-activated cells in patients with advanced cancer. J Clin Oncol 7: 869-878, 1989

    PubMed  Google Scholar 

  60. Fisher B, Packard BS, Read EJ, Carrasquillo JA, Carter CS, Topalian SL, Yang JC, Yolles P, Larson SM, Rosenberg SA: Tumor localization of adoptively transferred Indium-111 labeled tumor infiltrating lymphocytes in patients with metastatic melanoma. J Clin Oncol 7: 250-261, 1989

    PubMed  Google Scholar 

  61. Topalian SL, Solomon D, Avis FP, Chang AE, Freerksen DL, Linehan WM, Lotze MT, Robertson CN, Seipp CA, Simon P, Simpson CG, Rosenberg SA: Immunotherapy of patients with advanced cancer using tumor-infiltrating lymphocytes and recombinant interleukin-2: a pilot study. J Clin Oncol 6: 839-853, 1988

    PubMed  Google Scholar 

  62. Kradin RL, Boyle LA, Preffer FI, Calahan RJ, Barlai-Kovach M, Strauss WH, Dubinett S, Kurnick JT: Tumor-derived interleukin-2-dependent lymphocytes in adoptive immunotherapy of lung cancer. Cancer Immunol Immunother 24: 76-85, 1987

    Article  PubMed  Google Scholar 

  63. Rosenberg SA, Packard BS, Aebersold PM, Solomon D, Topalian SL, Toy ST, Simon P, Lotze MT, Yang JC, Seipp CA, Simpson C, Carter C, Bock S, Schwartzentruber D, Wei JP, White DE: Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. N Engl J Med 319: 1676-1680, 1988

    PubMed  Google Scholar 

  64. Lala PK, Santer V, Libenson H, Parhar RS: Changes in the host natural killer cell population in mice during tumor development. Cell Immunol 93: 250-264, 1985

    PubMed  Google Scholar 

  65. Parhar RS, Lala PK: Changes in the host natural killer cell population in mice during tumor development. 2. The mechanism of suppression of NK activity. Cell Immunol 93: 265, 1985

    PubMed  Google Scholar 

  66. Young RM, Newby M, Meunier J: Relationships between morphology, dissemination, migration, and prostaglandin E2 secretion by cloned variants of Lewis lung carcinoma. Cancer Res 45: 3918-3923, 1985

    PubMed  Google Scholar 

  67. Goodwin JS, Weeb DR: Regulation of the immune response by prostaglandins. Clin Immunol Immunopath 15: 106-122, 1980

    Article  Google Scholar 

  68. Saarloos M, Lala PK: Prostaglandins and the host immune system: application of prostaglandin inhibitors for cancer immunotherapy. In: Harris JE, Braun DP, Anderson KM (eds) Prostaglandin Inhibitors in Tumor Immunology and Immunotherapy. CRC Press, Boca Raton, chapter 7, 1994, pp 187-227

    Google Scholar 

  69. Walker C, Kristensen F, Bettens F, de Weck AL: Lymphokine regulation of activated (G1) lymphocytes. I. Prostaglandin E2-induced inhibition of interleukin-2 production. J Immunol 130: 1770-1773, 1983

    PubMed  Google Scholar 

  70. Lala PK, Kennedy TG, Parhar RS: Suppression of lymphocyte alloreactivity by early gestational human decidua. II. Characterization of suppressor mechanisms. Cell Immunol 116: 411, 1988

    PubMed  Google Scholar 

  71. Parhar RS, Lala PK: Amelioration of B16F10 melanoma lung metastasis in mice by a combination therapy with indomethacin and interleukin 2. J Exp Med 165: 14-28, 1987

    Article  PubMed  Google Scholar 

  72. Fulton AM: In vivoeffects of indomethacin on the growth of murine mammary tumours. Cancer Res 44: 2416-2420, 1984

    PubMed  Google Scholar 

  73. Lala PK, Parhar RS, Singh P: Indomethacin therapy abrogates the prostaglandin-mediated suppression of natural killer activity in tumor-bearing mice and prevents tumor metastasis. Cell Immunol 99: 108-118, 1986

    PubMed  Google Scholar 

  74. Lala PK, Parhar RS: Cure of B16F10 melanoma lung metastasis in mice by chronic indomethacin therapy combined with repeated rounds of interleukin-2: characteris141 tics of killer cells generated in situ. Cancer Res 48: 1072-1079, 1988

    PubMed  Google Scholar 

  75. Lala PK, Parhar RS: Eradication of spontaneous and experimental adenocarcinoma metastases with chronic indomethacin and intermittent IL-2 therapy. Int J Cancer 54: 677-684, 1993

    PubMed  Google Scholar 

  76. Lala PK, Elkashab M, Kerbel RS, Parhar RS: Cure of human melanoma lung metastases in nude mice with chronic indomethacin therapy combined with multiple rounds of IL-2: characteristics of killer cells generated in situ. Int Immunol 2: 1149-1158, 1990

    PubMed  Google Scholar 

  77. Lala PK, Al-Mutter N, Parhar R, Saarloos MN, Banerjee D, Bramwell V, Mertens WC: Combination of chronic indomethacin and intermittent IL-2 therapy in the treatment of disseminated cancer. In: Garaci E, Goldstein A (eds) Combination Therapies II. Planum Publishing Company, New York, 1983, pp 155-165

    Google Scholar 

  78. Mertens WC, Bramwell VHC, Gwadry-Sridhar F, Romano W, Banerjee D, Lala PK: Effect of indomethacin and ranitidine in advanced melanoma patients on high dose interleukin-2. Lancet 340: 397-398, 1992

    Article  PubMed  Google Scholar 

  79. Mertens WC, Banerjee D, Al-Mutter N, Stiff L, Bramwell VHC, Lala PK: High dose venous infusion of interleukin-2: influence of dose and infusion rate on tumoricidal function and lymphocyte subset. Cancer Immunol Immunother 41: 271-279, 1995

    Article  PubMed  Google Scholar 

  80. Kilbourn RG, Owen-Schaub LB, Cromeens DM, Gross SS, Flaherty MJ, Santee SM, Alak AM, Griffith OW: NGMethyl-L-Arginine, an inhibitor of nitric oxide formation, reverses IL-2-mediated hypotension in dogs. J Appl Physiol 76: 1130-1137, 1994

    PubMed  Google Scholar 

  81. Margolin KA, Rayner AA, Hawkins MJ, Atkins MB, Dutcher JP, Fisher RI, Weiss GR, Doroshow JH, Jaffe HS, Roper M, Parkinson DR, Wiernik PH, Creekmore SP, Boldt DH: Interleukin-2 and lymphokine-activated killer cell therapy of solid tumors: analysis of toxicity and management guidelines. J Clin Oncol 7: 486-498, 1989

    PubMed  Google Scholar 

  82. Moncada S, Higgs A: The L-arginine-nitric oxide pathway. N Engl J Med 329: 2002-2012, 1993

    Article  PubMed  Google Scholar 

  83. Puri PK, Travis WD, Rosenberg SA: Decrease in interleukin-2-induced vascular leakage in the lungs of mice by administration of recombinant interleukin 1a?in vivo. Cancer Res 49: 969-976, 1989

    PubMed  Google Scholar 

  84. Welbourn R, Goldman G, Kobzik L, Valeri CR, Hechtman HB, Shepro D: Attenuation of IL-2-induced multisystem organ edema by phaloidin and antamanide. J Appl Physiol 70: 1364-1368, 1991

    PubMed  Google Scholar 

  85. Orucevic A, Lala PK: Effects of NG-Methyl-L-Arginine and indomethacin on IL-2 induced pulmonary edema and pleural effusion. Proceedings of the American Association for Cancer Research 33: 322, 1992 (Abstract)

    Google Scholar 

  86. Orucevic A, Lala PK: Effects of NG-Methyl-L-Arginine and indomethacin on IL-2 induced capillary leakage in tumor-bearing mice. Proceedings of the American Association for Cancer Research 34: 459, 1993 (Abstract)

    Google Scholar 

  87. Damie NK, Doyle LV, Bender JR, Bradley EC: Interleukin-2-activated human lymphocytes exhibit enhanced adhesion to normal vascular endothelial cells and cause their lysis. J Immunol 138: 1779-1785, 1987

    PubMed  Google Scholar 

  88. Savion N, Vlodavski I, Fuks Z: Interaction of T lymphocytes and macrophages with cultured vascular endothelial cells: attachment, invasion, and subsequent degradation of the subendothelial extracellular matrix. J Cell Physiol 118: 169-178, 1984

    PubMed  Google Scholar 

  89. Collins T, Lapierre LA, Fiers W, Strominger JL, Prober JS: Recombinant human tumor necrosis factor increases mRNA levels and surface expression of HLA-A,B antigens in vascular endothelial cells and dermal fibroblasts in vitro.Proc Natl Acad Sci USA 83: 446-450, 1986

    PubMed  Google Scholar 

  90. Doukas J, Prober JS: IFN-??enhanced endothelial activation induced by tumor necrosis factor but not IL-1. J Immunol 145: 1727-1733, 1990

    PubMed  Google Scholar 

  91. Leewenberg JFM, Von Asmuth EJU, Jeunhomme TMAA, Buurman WA: IFN-??regulates the expression of adhesion molecule ELAM-1 and IL-6 production by human endothelial cells in vitro.J Immunol 145: 2110-2114, 1990

    PubMed  Google Scholar 

  92. Mier JW, Brandon PE, Libby P, Janicka MW, Aronson FR: Activated endothelial cells resist lymphokine-activated killer cell-mediated injury. J Immunol 143: 2407-2414, 1989

    PubMed  Google Scholar 

  93. Hibbs JB Jr, Traintor RR, Vavrin Z, Rachlin EM: Nitric oxide: a cytotoxic activated macrophage effector molecule. Biochem Biophys Res Commun 157: 87-94, 1988

    PubMed  Google Scholar 

  94. Stuehr DJ, Nathan CF: Nitric oxide: a macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells. J Exp Med 469: 1543-1555, 1989

    Article  Google Scholar 

  95. Kilbourn RG, Belloni P: Endothelial cell production of nitrogen oxides in response to interferon ??in combination with tumor necrosis factor, interleukin-1 or endotoxin. J Natl Cancer Inst 82: 772-776

  96. Kilbourn RG, Gross SS, Jubran A, Adams J, Griffith OW, Levi R, Lodato RF: NG-Methyl-L-arginine inhibits tumor necrosis factor-induced hypotension: Implications for the involvement of nitric oxide. Proc Natl Acad Sci USA 87: 3629-3632, 1990

    PubMed  Google Scholar 

  97. 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, 1990

    PubMed  Google Scholar 

  98. Kelm M, Feelisch M, Grube R, Motz W, Stauer BE: Metabolism of endothelium-derived nitric oxide in human blood. In: Moncada S, Marletta MA, Hibbs JB Jr., Higgs EA (eds) The Biology of Nitric Oxide. Portland Press, London, 1992, pp 319-322

    Google Scholar 

  99. Miles D, Thomsen L, Balkwill F, Thavasu P, Moncada S: Association between biosynthesis of nitric oxide and changes in immunological and vascular parameters in patients treated with interleukin-2. Eur J Clin Invest 24: 287-290, 1994

    PubMed  Google Scholar 

  100. Kilbourn R, Fonseca G, Griffith OW: NG-Monomethyl-Larginine, an inhibitor of nitric oxide production, reverses interleukin-2 mediated hypotension. Crit Care Med 23: 1018-1024, 1995

    Article  PubMed  Google Scholar 

  101. Orucevic A, Lala PK: Effects of NG-Methyl-L-Arginine, an inhibitor of nitric oxide synthesis, on IL-2 induced capillary leakage and anti-tumor responses in healthy and tumor bearing mice. Cancer Immunol Immunother 42: 38-46, 1996

    Article  PubMed  Google Scholar 

  102. Orucevic A, Lala PK: NG-Nitro-L-Arginine methyl ester, an inhihitor of nitric oxide synthesis, ameliorates interleukin-2-induced capillary leak syndrome in healthy mice. J Immunother 18: 210-220, 1996

    Google Scholar 

  103. Samlowski WE, Yim CY, McGregor JR, Kwon OD, Gonzales S, Hibbs JB Jr: Effectiveness and toxicity of protracted nitric oxide synthesis inhibition during IL-2 treatment of mice. J Immunother 18: 166-178, 1995

    Google Scholar 

  104. Leder GH, Oppenheim M, Rosenstein M, Shah N, Hoffman R, Lotze MT, Beger HG: Inhibition of nitric oxide does not improve IL-2 mediated antitumor effects in vivo.Eur Sur Res 329: 1-6, 1995

    Google Scholar 

  105. Orucevic A, Hearn S, Lala PK: The role of active inducible nitric oxide synthase expression in the pathogenesis of capillary leak syndrome resulting from interleukin-2 therapy in mice. Lab Investigation 76: 53-65, 1997

    Google Scholar 

  106. Orucevic A, Lala PK: NG-Nitro-L-Arginine methyl ester, an inhibitor of nitric oxide synthesis, ameliorates interleukin-2 induced capillary leakage and reduces tumor growth in adenocarcinoma bearing mice. Br J Cancer 72: 189-197, 1996

    Google Scholar 

  107. Orucevic A, Lala PK: Effects of NG-Nitro-L-Arginine methyl ester, an inhibitor of nitric oxide synthesis, on IL-2 induced LAK cell generation in vivoand in vitroin healthy and tumor bearing mice. Cell Immunol 169: 125-132, 1996

    Article  PubMed  Google Scholar 

  108. Gutman M, Laufer R, Eisenthal A, Goldman G, Ravid A, Inbar M, Klausner JM: Increased microvascular permeability induced by prolonged interleukin-2 administration is attenuated by the oxygen-free-radical scavanger dimethylthiourea. Cancer Immunol Immunother 43: 240-244, 1996

    Article  PubMed  Google Scholar 

  109. Griffith OW, Stuehr DJ: Nitric oxide synthases: properties and catalytic mechanism. Ann Rev Physiol 57: 707-736, 1995

    Article  Google Scholar 

  110. Garvey EP, Oplinger JA, Furfine ES, Kiff RJ, Laszlo F, Whittle BJR, Knowles RG: 1400W is a slow tight binding, and highly selective inhibitor of inducible nitric oxide synthase in vitroand in vivo.J Biol Chem 272: 4959-4963, 1997

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania

    Amila Orucevic

  2. Department of Anatomy and Cell Biology, The University of Western Ontario, London, Ontario, Canada

    Peeyush K. Lala

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  1. Amila Orucevic
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  2. Peeyush K. Lala
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Orucevic, A., Lala, P.K. Role of nitric oxide in IL-2 therapy-induced capillary leak syndrome. Cancer Metastasis Rev 17, 127–142 (1998). https://doi.org/10.1023/A:1005969024182

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