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Cardiovascular Alterations associated with Interleukin-2 Therapy

  • G. A. Fonseca
  • R. G. Kilbourn
Part of the Update in Intensive Care and Emergency Medicine book series (UICM, volume 24)

Abstract

Renal cell carcinoma affects approximately 28000 patients per year in the United States. The prognosis of patients with this malignancy is poor with a 5-year survival of approximately 15% in patients with metastatic disease. Two major characteristics of the disease contribute to the low survival. First, patients usually present with advanced disease because of the lack of early clinical symptoms and the lack of cost effective screening tests. Second, this neoplasia possesses innate resistance to conventional chemotherapeutic agents. Interleukin-2 (IL-2) is among the most active agents for the treatment of disseminated renal cell carcinoma. The antitumor activity against renal cell carcinoma was first reported during early, phase I studies at the National Institute of Health [1]. Subsequent clinical trials confirmed the activity of IL-2 which lead to approval by the U.S. Food and Drug Administration for the treatment of patients with metastatic kidney cancer. Approval was based on the finding that significant, durable responses were observed (17-33%) and that some patients were cured of their disease (approximately 5%).

Keywords

Nitric Oxide Renal Cell Carcinoma Septic Shock Capillary Leak Syndrome Cardiovascular Alteration 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Lotze MT, Chang AE, Seipp CA, et al (1986) High-dose recombinant interleukin-2 in the treatment of patients with disseminated cancer. JAMA 256:3117–3124PubMedCrossRefGoogle Scholar
  2. 2.
    Lee R, Lotze M, Skibber J, et al (1989) Cardiorespiratory effects of immunotherapy with interleukin-2. J Clin Oncol 7:7–20PubMedGoogle Scholar
  3. 3.
    Ognibene F, Rosenberg S, Skibber J, et al (1986) Interleukin-2 hemodynamics mimic septic shock. Clin Res 34:413A (Abst)Google Scholar
  4. 4.
    Rosenberg SA (1988) The development of new immunotherapies for the treatment of cancer using interleukin-2. A review. Ann Surg 208:121–135PubMedCrossRefGoogle Scholar
  5. 5.
    Suffredini A, Fromm R, Parker M, et al (1989) The cardiovascular response of normal humans to the administration of endotoxin. N Engl J Med 321:280–287PubMedCrossRefGoogle Scholar
  6. 6.
    Chong ASF, Scuderi P, Gremes WJ, et al (1989) Tumor targets stimulate IL-2 activated killer cells to produce interferon-7 and human tumor necrosis factor. J Immunol 142: 2133–2139PubMedGoogle Scholar
  7. 7.
    Gemlo B, Palladino M, Jaffe H, et al (1988) Circulating cytokines in patients with metastatic cancer treated with recombinant interleukin-2 and lymphokine-activated killer cells. Cancer Res 48:5864–5867PubMedGoogle Scholar
  8. 8.
    Mier JW, Vachino G, Van der Meer J WM, et al (1988) Induction of circulating tumor necrosis factor (TNFa) as the mechanism for the febrile response to interleukin-2 (IL- 2) in cancer patients. J Clin Immunol 8:426–436PubMedCrossRefGoogle Scholar
  9. 9.
    Rosenberg SA, Lotze MT, Yang JC, et al (1993) Prospective randomized trial of high- dose interleukin-2 alone or in conjunction with lymphokine-activated killer cells for the treatment of patients with advanced cancer. J Nat Cancer Inst 85:622–631PubMedCrossRefGoogle Scholar
  10. 10.
    Parkinson DR (1990) Lessons from the clinical trials of interleukin-2. Nat Immun Cell Growth Regul 9:242–252PubMedGoogle Scholar
  11. 11.
    Thompson JA, Benyunes MC, Fefer A (1994) Reducing IL-2 toxicity: Efforts to improve the therapeutic index of IL-2. Hem/One Annals 2:351–355Google Scholar
  12. 12.
    Mier J, Vachino G, Klempner M, et al (1990) Inhibition of interleukin-2-induced tumor necrosis factor release by dexamethasone: Prevention of an acquired neutrophil Chemotaxis defect and differential suppression of interleukin-2-associated side effects. Blood 76:1933–1940PubMedGoogle Scholar
  13. 13.
    Glauser FL, DeBlois GG, Bechard DE, et al (1988) A comparison of the cardiopulmonary effects of continuous versus bolus infusion of recombinant interleukin-2 in sheep. Cancer Res 48:2221–2225PubMedGoogle Scholar
  14. 14.
    Zeilender S, Davis D, Fairman RP, et al (1989) Inotropic and vasoactive drug treatment of interleukin-2-induced hypotension in sheep. Cancer Res 49:4423–4426PubMedGoogle Scholar
  15. 15.
    West WH, Tauer KW, Yannelli JR, et al (1987) Constant-infusion recombinant inter- leukin-2 in adoptive immunotherapy of advanced cancer. N Engl J Med 316:898–905PubMedCrossRefGoogle Scholar
  16. 16.
    Taveira da Silva AM, Kaulbach HC, Chuidian FS, et al (1993) Brief report: Shock and multiple-organ dysfunction after self-administration of Salmonella endotoxin. N Engl J Med 328:1457–1460Google Scholar
  17. 17.
    Palmer R, Ferrige A, Moncada S (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327:524–526PubMedCrossRefGoogle Scholar
  18. 18.
    Stuehr D, Griffith OW (1992) Mammalian nitric oxide synthases. Adv Enzymol Relat Areas Mol Biol 65:287–346PubMedGoogle Scholar
  19. 19.
    Hibbs J, Taintor R, Vavrin Z (1987) Macrophage cytotoxicity: Role for L-arginine de- iminase andimino nitrogen oxidation to nitrite. Science 235:473–476Google Scholar
  20. 20.
    Kilbourn RG, Belloni P (1990) Endothelial cell production of nitrogen oxides in response to interferon gamma in combination with tumor necrosis factor, interleukin-1, or endotoxin. J Natl Cancer Inst 82:772–776PubMedCrossRefGoogle Scholar
  21. 21.
    Ochoa JB, Udekwu AO, Billiar TR, et al (1991) Nitrogen oxide levels in patients after trauma and sepsis. Ann Surg 214:621–626PubMedCrossRefGoogle Scholar
  22. 22.
    Hibbs J, Westenfelder C, Taintor R, et al (1992) Evidence for cytokine-inducible nitric oxide synthesis from L-arginine in patients receiving interleukin-2 therapy. J Clin Invest 89:867–877PubMedCrossRefGoogle Scholar
  23. 23.
    Kilbourn RG, Jubran A, Gross SS, et al (1990) Reversal of endotoxin-mediated shock by NG-methyl-L-arginine, an inhibitor of nitric oxide synthesis. Biochem Biophys Res Commun 172:1132–1138PubMedCrossRefGoogle Scholar
  24. 24.
    Kilbourn RG, Gross SS, Lodato RF, et al (1992) NNG-aminoarginine inhibits inter- leukin-la-induced nitric oxide synthase in vascular smooth muscle and fully reverses interleukin-la-induced hypotension. J Natl Cancer Inst 84:1008–1016PubMedCrossRefGoogle Scholar
  25. 25.
    Fleming I, Gray G, Julou-Schaeffer G, et al (1989) Impaired vascular reactivity in the rat following endotoxin treatment can be endothelium independent, yet involves the L-arginine pathway. J Physiol 423:105P-107PGoogle Scholar
  26. 26.
    Julou-Schaeffer G, Gray G, Fleming I, et al (1990) Loss of vascular responsiveness induced by endotoxin involves L-arginine pathway. Am J Physiol 259: H1038-H1043PubMedGoogle Scholar
  27. 27.
    Rosenberg SA, Lotze MT, Muul LM, et al (1987) A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and inter- leukin-2 or high-dose interleukin-2 alone. N Engl J Med 316:889–897PubMedCrossRefGoogle Scholar
  28. 28.
    West WH, Tauer KW, Yannelli JR, et al (1987) Constant-infusion recombinant interleukin-2 in adopotive immunotherapy of advanced cancer. N Engl J Med 316: 898–905PubMedCrossRefGoogle Scholar
  29. 29.
    Rosenberg SA, Lotze MT, Yang JC, et al (1989) Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients. Ann Surg 210:474–484PubMedCrossRefGoogle Scholar
  30. 30.
    Natanson C, Danner R, Fink M, et al (1988) Cardiovascular performance with E. coli challenges in a canine model of human sepsis. Am J Physiol 254: H558-H569Google Scholar
  31. 31.
    Parker M, Shelhamer J, Bacharach S, et al (1984) Profound but reversible myocardial depression in patients with septic shock. Ann Intern Med 100:483–490PubMedGoogle Scholar
  32. 32.
    Finkel M, Oddis C, Jacob T, et al (1992) Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 257:387–389PubMedCrossRefGoogle Scholar
  33. 33.
    Lancaster J, Hibbs J (1990) EPR demonstration of iron-nitrosyl complex formation by cytotoxic activated macrophages. Proc Natl Acad Sei USA 87:1223–1227CrossRefGoogle Scholar
  34. 34.
    Gilbert EM, Haupt MT, Mandanas RY, et al (1986) The effect of fluid loading, blood transfusion, and catecholamine infusion on oxygen delivery and consumption in patients with sepsis. Am Rev Respir Dis 134:873–878PubMedGoogle Scholar
  35. 35.
    Schweizer M, Richter C (1994) Nitric oxide potently and reversibly deenergizes mito- chrondia at low oxygen tension. Biochem Biophys Res Commun 204:169–175PubMedCrossRefGoogle Scholar
  36. 36.
    Stadler J, Curran RD, Ochoa JB, et al (1991) Effect of endogenous nitric oxide on mitochondrial respiration of rat hepatocytes in vitro and in vivo. Arch Surg 126: 186–191PubMedCrossRefGoogle Scholar
  37. 37.
    Billiar T, Curran R, Harbrecht B, et al (1990) Modulation of nitrogen oxide synthesis in vivo: NG-monomethyl-L-arginine inhibits endotoxin-induced nitrate/nitrate biosynthesis while promoting hepatic damage. J Leukoc Biol 48:565–569Google Scholar
  38. 38.
    Richard V, Bernier M, Themelin L, et al (1991) Blood coagulation abnormalities during adoptive immunotherapy with interleukin-2 (r-Met Hu IL-2 [alal25]). Ann Oncol 2:67–68PubMedGoogle Scholar
  39. 39.
    Triozzi PL, Kinney P, Rinehart JJ (1990) Central nervous system toxicity of biological response modifiers. Ann NY Acad Sei (USA) 594:347–354CrossRefGoogle Scholar
  40. 40.
    Gross SS, Jaffe EA, Levi R, et al (1991) Cytokine-activated endothelial cells express an isotype of nitric oxide synthase which is tetrahydrobiopterin-dependent, calmodulin- independent and inhibited by arginine analogs with a rank order of potency characteristic of activated macrophages. Biochem Biophys Res Commun 178:823–829PubMedCrossRefGoogle Scholar
  41. 41.
    Gross S, Stuehr D, Aisaka K, et al (1990) Macrophage and endothelial cell nitric oxide synthesis. Cell-type selective inhibition by NG-amino-arginine, NG-nitro-arginine and NG-methyl-arginine. Biochem Biophys Res Commun 170:96–103Google Scholar
  42. 42.
    Zhuo M, Small SA, Kandel ER, et al (1993) Nitric oxide and carbon monoxide produce activity-dependent long-term synaptic enhancement in hippocampus. Science 260: 1946–1950PubMedCrossRefGoogle Scholar
  43. 43.
    Rosenberg SA, Lotze MT, Yang JC, et al (1993) Prospective randomized trial of high- dose interleukin-2 alone or in conjunction with lymphokine-activated killer cells for the treatment of patients with advanced cancer. J Natl Cancer Inst 85:622–632PubMedCrossRefGoogle Scholar
  44. 44.
    Damle N, Doyle L, Bender J, et al (1987) Interleukin-2 activated lymphocytes exhibit enhanced adhesion to normal vascular endothelial cells. J Immunol 138: 1779–1785PubMedGoogle Scholar
  45. 45.
    Ettinghausen SE, Moore JG, White DE, et al (1987) Hematologic effects of immunotherapy with lymphokine-activated killer cells and recombinant interleukin-2. Blood 69:1654–1660PubMedGoogle Scholar
  46. 46.
    Raefsky E, Platanias L, Zoumbos N, et al (1985) Studies of interferon as a regulator of hematopoietic cell proliferation. J Immunol 135:2507–2512PubMedGoogle Scholar
  47. 47.
    Radomski MW, Palmer RM, Moncada S (1987) The anti-aggregating properties of vascular endothelium: Interactions between prostacyclin and nitric oxide. Br J Pharmacol 92:639–646Google Scholar
  48. 48.
    Durante W, Kroll MH, Vanhoutte PM, et al (1992) Endothelium-derived relaxing factor inhibits thrombin-induced platelet aggregation by inhibiting platelet phospholipase C. Blood 79:110–116PubMedGoogle Scholar
  49. 49.
    Durante W, Schafer AI, Hrbolich JK, et al (1993) Endothelium-derived relaxing factor inhibits shear stress-induced platelet aggregation. Platelets 4:135–140PubMedCrossRefGoogle Scholar
  50. 50.
    Hôgman M, Frostell C, Arnberg H, et al (1993) Bleeding time prolongation and NO inhalation. Lancet (letter) 341:1664–1665CrossRefGoogle Scholar
  51. 51.
    Bassenge E (1991) Antiplatelet effect of endothelium-derived relaxing factor and nitric oxide donors. Eur Heart J 12 (Suppl): 12–15PubMedGoogle Scholar
  52. 52.
    Baars JW, De Boer JP, Wagstaff J, et al (1992) Interleukin-2 induces activation of coagulation and fibrinolysis: Resemblance to the changes seen during experimental endotoxemia. Brit J Haematol 82:295–301Google Scholar
  53. 53.
    Moalli R, Doyle JM, Tahhan R, et al (1989) Fibrinolysis in critically ill patients. Am Rev Respir Dis 140:287–293PubMedCrossRefGoogle Scholar
  54. 54.
    Thompson JA, Benyunes MC, Bianco JA, et al (1993) Treatment with pentoxifylline and ciprofloxacin reduces the toxicity of high-dose interleukin-2 and lymphokine- activated killer cells. Semin Oncol 20:46–51PubMedGoogle Scholar
  55. 55.
    Thompson J, Nemunitis J, Vogelzang NJ, et al (1994) Phase 1 trial of CT1501R in cancer patients receiving high-dose interleukin-2 (IL-2). Proc ASCO 13:299 (Abst)Google Scholar
  56. 56.
    Edwards MJ, Heniford BT, Klar EA, et al (1992) Pentoxifylline inhibits interleukin-2- induced toxicity in C57BL/6 mice but preserves antitumor efficacy. J Clin Invest 90: 637–641PubMedCrossRefGoogle Scholar
  57. 57.
    Boccoli G, Masciulli E, Ruggeri E, et al (1990) Adoptive immunotherapy of human cancer: The cytokine cascade and monocyte activation following high-dose interleukin- 2 bolus treatment. Cancer Res 50:5795–5800PubMedGoogle Scholar
  58. 58.
    Boldt DH, Mills BJ, Gemlo BT, et al (1988) Laboratory correlates of adoptive immunotherapy with recombinant interleukin-2 and lymphokine-activated killer cells in humans. Cancer Res 48:4409–4416PubMedGoogle Scholar
  59. 59.
    Kilbourn R, Owen-Schaub L, Cromeens D, et al (1994) NG-methyl-L-arginine, an inhibitor of nitric oxide formation, reverses IL-2 mediated hypotension in dogs. J Appl Physiol 76:1130–1137PubMedGoogle Scholar
  60. 60.
    Kilbourn R, Owen-Schaub L, Griffith O, et al (1992) Interleukin-2 mediated hypotension in dogs is reversed by NG-monomethyl-L-arginine (NMA), an inhibitor of nitric oxide (NO) formation. Proc AACR 33:328 (Abst)Google Scholar
  61. 61.
    Hoffman RA, Langrehr JM, Billiar TR, et al (1990) Alloantigen-induced activation of rat splenocytes is regulated by the oxidative metabolism of L-arginine. J Immunol 145:2220–2226PubMedGoogle Scholar
  62. 62.
    Pockaj BA, Topalian SL, Steinberg SM, et al (1993) Infectious complications associated with interleukin-2 administration: A retrospective review of 935 treatment courses. J Clin Oncol 11:136–147PubMedGoogle Scholar
  63. 63.
    Ganz W, Donoso R, Marcus HS, et al (1971) A new technique for measurement of cardiac output by thermodilution in man. Am J Cardiol 27:392–396PubMedCrossRefGoogle Scholar
  64. 64.
    Kilbourn RG, Cromeens DW, Chelly FD, et al (1994) NG-methyl-L-arginine, an inhibitor of nitric oxide formation acts synergistically with dobutamine to improve cardiovascular performance in endotoxemic dogs. Crit Care Med 22:1835–1840PubMedGoogle Scholar
  65. 65.
    Petros A, Bennett D, Vallance P (1991) Effects of nitric oxide synthase inhibitors on hypotension in patients with septic shock. Lancet 338:1557–1558PubMedCrossRefGoogle Scholar
  66. 66.
    Kilbourn RG, Belloni P (1990) Endothelial cell production of nitrogen oxides in response to interferon gamma in combination with tumor necrosis factor, interleukin-1, or endotoxin. J Natl Cancer Inst 82:772–776PubMedCrossRefGoogle Scholar
  67. 67.
    Beasley D, Schwartz JH, Brenner BM (1991) Interleukin 1 induces prolonged L-argi- nine-dependent cyclic guanosine monophosphate and nitrite production in rat vascular smooth muscle cells. J Clin Invest 87:602–608PubMedCrossRefGoogle Scholar
  68. 68.
    Kilbourn RG, Gross SS, Lodato RF, et al (1992) Nw-amino-arginine inhibits inter- leukin-la-induced nitric oxide synthase in vascular smooth muscle and fully reverses interleukin-la-induced hypotension. J Natl Cancer Inst 84:1008–1016PubMedCrossRefGoogle Scholar
  69. 69.
    Joly G, Ayres M, Chelly F, et al (1994) Effects of NG-methyl-L-arginine, NG-nitro- arginine, and aminoguanidine on constitutive and inducible nitric oxide synthase in rat aorta. Biochem Biophys Res Commun 199:147–154Google Scholar
  70. 70.
    Nava E, Palmer R, Moncada S (1991) Inhibition of nitric oxide synthesis in septic shock: How much is beneficial? Lancet 338:1555–1557PubMedCrossRefGoogle Scholar
  71. 71.
    Hutcheson IR, Whittle BJ, Boughton SNK (1990) Role of nitric oxide in maintaining vascular integrity in endotoxin-induced acute intestinal damage in the rat. Br J Pharmacol 101:815–820PubMedGoogle Scholar
  72. 72.
    Billiar TR, Curran RD, Harbrecht BG, et al (1990) Modulation of nitrogen oxide synthesis in vivo: NG-monomethyl-L-arginine inhibits endotoxin-induced nitrate/nitrate biosynthesis while promoting hepatic damage. J Leukoc Biol 48:565–569Google Scholar
  73. 73.
    Stark ME, Szurszewski JH (1992) Role of nitric oxide in gastrointestinal and hepatic function and disease. Gastroenterology 103:1928–1949PubMedGoogle Scholar
  74. 74.
    Parrillo JE (1993) Pathogenic mechanisms of septic shock. N Engl J Med 328:1428 (letter)CrossRefGoogle Scholar
  75. 75.
    Wang Q, Jacobs J, DeLeo J, et al (1991) Nitric oxide hemoglobin in mice and rats in endotoxic shock. Life Sciences 49:55–60CrossRefGoogle Scholar
  76. 76.
    Kilbourn RG, Cromeens DM, Chelly FD, et al (1994) NG-methyl-L-arginine, an inhibitor of nitric oxide formation, acts synergistically with dobutamine to improve cardiovascular performance in endotoxic dogs. Crit Care Med 22:1835–1840PubMedGoogle Scholar
  77. 77.
    Stein B, Frank P, Mulsch A (1993) Long-term treatment of cardiomyocytes with endotoxin or cytokines induce negative inotropic effects mediated by nitric oxide. Endothelium l:s63 (Abst)Google Scholar
  78. 78.
    Grocott-Mason R, Lewis M, Shah A (1993) Nitric oxide has direct myocardial relaxant effects in the isolated ejecting heart. Endothelium 1:s62 (Abst)Google Scholar
  79. 79.
    Clowes GH, Farrington GH, Zuschneid W, et al (1970) Circulating factors in the etiology of pulmonary insufficiency and right heart failure accompanying severe sepsis (peritonitis). Ann Surg 171:663–678PubMedCrossRefGoogle Scholar
  80. 80.
    Rossaint R, Falke KJ, Lopez F, et al (1993) Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 328:399–405PubMedCrossRefGoogle Scholar
  81. 81.
    Rabinovici R, Sofronski M, Renz J, et al (1992) Platelet activating factor mediates interleukin-2-induced lung injury in the rat. J Clin Invest 89:1669–1673PubMedCrossRefGoogle Scholar
  82. 82.
    Leder GH, Oppenheim M, Rosenstein M, et al (1993) Aminoguanidine decreases IL- 2-induced nitric oxide production but not the IL-2-induced capillary leak syndrome. Endothelium l:s51 (Abst)Google Scholar
  83. 83.
    Abrams JS, Rayner AA, Wiernik PH, et al (1990) High-dose recombinant interleukin- 2 alone: A regimen with limited activity in the treatment of advanced renal cell carcinoma. J Natl Cancer Inst 82:1202–1206PubMedCrossRefGoogle Scholar
  84. 84.
    Parkinson DR (1990) Interleukin-2 further progress through greater understanding. J Natl Cancer Inst 82:1374–1376PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1995

Authors and Affiliations

  • G. A. Fonseca
  • R. G. Kilbourn

There are no affiliations available

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