IL-1α Enhancement of Platinum-Mediated Anti-Tumor Activity

  • Candace S. Johnson
  • Ming-Jei Chang
  • Wei-Dong Yu
  • Ruth A. Modzelewski
  • Derick M. Russell
  • Theodore F. Logan
  • Daniel R. Vlock
  • Leonard M. Reyno
  • Merrill J. Egorin
  • Kadir Erkmen
  • Philip Furmanski


Cytokines or biological response modifiers have been utilized in combination with conventional chemotherapeutic agents to increase cytotoxic drug-mediated efficacy and to reduce the associated toxic side effects. Interleukin-1 (IL-1) is a multifunctional cytokine, primarily produced by monocyte/macrophages1–4, that plays a central role in the activation of T and B cells3,4, potentiates hematopoiesis both in vitro and in vivo5–9, and induces the synthesis of other cytokines and regulatory molecules3,10,11. Studies in our laboratories have demonstrated that IL-1α induces acute tumor hemorrhagic necrosis, changes in tumor blood flow, an increase of tumor clonogenic cell kill and enhancement of cytotoxic drug-mediated anti-tumor effects in murine tumor model systems12–20. We focus our discussion here on IL-1’s activities in the treatment of solid tumors either alone or in combination with the platinum agents, cisplatin or carboplatin.


Tumor Cell Kill Tumor Blood Flow Murine Tumor Model Hemorrhagic Necrosis Human Vascular Endothelium 
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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  1. 1.
    I. Gery, R.K. Gershon, and B.H. Waksman, Potentiation of the T-lymphocyte response to mitogens: I. The responding cell, J. Exp. Med. 136:128 (1972).CrossRefPubMedGoogle Scholar
  2. 2.
    C.A. Dinarello, Interleukin-1, Rev. Infect. Dis. 6:51 (1984).CrossRefPubMedGoogle Scholar
  3. 3.
    J. Le, and J. Vilcek, Biology of disease: tumor necrosis factor and inter-leukin 1. Cytokines with multiple overlapping biological activities, Lab. Invest. 56:234 (1987).PubMedGoogle Scholar
  4. 4.
    K.A. Smith, L.B. Lachman, J.J. Oppenheim, and M.J. Favata, The functional relationship of the interleukins, J. Exp. Med. 151:1551 (1980).CrossRefPubMedGoogle Scholar
  5. 5.
    C.S. Johnson, DJ. Keckler, M.I. Topper, P.G. Braunschweiger, and P. Furmanski, In vivo hematopoietic effects of recombinant interleukin-1α in mice: stimulation of granulocytic, monocytic, megakaryocytic, and early erythroid progenitors, suppression of late-stage erythropoiesis, and reversal of erythroid suppression with erythropoietin. Blood 73:678 (1989).PubMedGoogle Scholar
  6. 6.
    L.C. Stork, U.M. Peterson, C.H. Rundus, and W.A. Robinson, Interleukin-1 enhances murine granulopoiesis in vivo. Exp. Hematol. 16:163 (1988).PubMedGoogle Scholar
  7. 7.
    M.A.S. Moore, and DJ. Warren, Synergy of interleukin 1 and granulocyte colony-stimulating factor: in vivo stimulation of stem-cell recovery and hematopoietic regeneration following 5-fluorouracil treatment of mice, Proc. Natl. Acad. Sci. 84:7134 (1987).CrossRefPubMedGoogle Scholar
  8. 8.
    D.Y. Mochizuki, J.R. Eisenman, P.J. Conlon, A.D. Larsen, and R.J. Tushinski, Interleukin 1 regulates hematopoietic activity, a role previously ascribed to hemopoietin 1, Proc. Natl. Acad. Sci. 84:5267 (1987).CrossRefPubMedGoogle Scholar
  9. 9.
    J.R. Zucali, H.E. Broxmeyer, C.A. Dinarello, M.A. Gross, and R.S. Weiner, Regulation of early human hematopoietic (BFU-E and CFU-GEMM) progenitor cells in vitro by interleukin-1-induced fibroblast-conditioned medium. Blood 69:33 (1987).PubMedGoogle Scholar
  10. 10.
    R. Philip, and L.B. Epstein, Tumor necrosis factor as immunomodulator and mediator of monocyte cytotoxicity induced by itself, gamma-interferon and interleukin-1. Nature 323:86 (1986).CrossRefPubMedGoogle Scholar
  11. 11.
    J.J. Oppenheim, E.J. Kovacs, K. Matsushima, and S.K. Durum, There is more than one interleukin 1. Immunol. Today 7:45 (1986).CrossRefGoogle Scholar
  12. 12.
    P.G. Braunschweiger, C.S. Johnson, N. Kumar, V. Rod and P. Furmanski, Antitumor effects of recombinant human interleukin-1α in RIF-1 and Panc02 solid tumors. Cancer Res. 48:6011 (1988).PubMedGoogle Scholar
  13. 13.
    C.S. Johnson, M.-J. Chang, P.G. Braunschweiger and P. Furmanski, Acute hemorrhagic necrosis of tumor induced by interleukin-1α: effects independent of tumor necrosis factor, J. Natl. Cancer Inst. 12:842 (1990).Google Scholar
  14. 14.
    I. Constantinidis, P.G. Braunschweiger, J.P. Wehrle, N. Kumar, C.S. Johnson, P. Furmanski and J.D. Glickson, P-nuclear magnetic resonance studies of the effect of recombinant human interleukin-1α on the bioenergetics of RIF-1 tumors. Cancer Res. 49:6379 (1989).PubMedGoogle Scholar
  15. 15.
    P.G. Braunschweiger, N. Kumar, I. Constantinidis, J.P. Wehrle, J.D. Glickson, C.S. Johnson and P. Furmanski, Potentiation of interleukin 1α mediated antitumor effects by ketoconazole. Cancer Res. 50:4709 (1990).PubMedGoogle Scholar
  16. 16.
    P.G. Braunschweiger, C.S. Johnson, N. Kumar, V. Ord and P. Furmanski, The effect of adrenalectomy and dexamethasone on interleukin-1α induced responses in RIF-1 tumors, Br. tJ. Cancer 61:9 (1990).CrossRefGoogle Scholar
  17. 17.
    P.G. Braunschweiger, S.A. Jones, C.S. Johnson and P. Furmanski, Potentiation of mitomycin C and porfiromycin antitumor activity in solid tumor models by recombinant human interleukin 1. Cancer Res. 51:5454 (1991).PubMedGoogle Scholar
  18. 18.
    C.S. Johnson, M.J. Chang, W.D. Yu, R.A. Modzelewski, J.R. Grandis, D.R. Vlock and P. Furmanski, Synergistic enhancement by interleukin-1 α of cisplatin-mediated antitumor activity in RIF-1 tumor-bearing C3H/HeJ mice, Cancer Chemother. Pharmacol. 32:339 (1993).Google Scholar
  19. 19.
    C.S. Johnson, Interleukin-1: therapeutic potential for solid tumors. Cancer Invest. 11:600 (1993).CrossRefPubMedGoogle Scholar
  20. 20.
    M.J. Chang, W.D. Yu, L.M. Reyno, R.A. Modzelewski, M.J. Egorin, K. Erkmen, D.R. Vlock, P. Furmanski and C.S. Johnson, Potentiation by interleukin 1α of cisplatin and carboplatin antitumor activity: schedule-dependent and pharmacokinetic effects in the RIF-1 tumor model. Cancer Res. 54:5380 (1994).PubMedGoogle Scholar
  21. 21.
    M.P. Bevilacqua, J.S. Pober, G.R. Majeau, W. Fiers, R.S. Cotran, and M.A. Gimbron, Recombinant tumor necrosis factor induces precoagulant activity in cultured human vascular endothelium: characterization and comparison with the actions of interleukin 1, Proc. Natl. Acad. Sci. 83:4533 (1986).CrossRefPubMedGoogle Scholar
  22. 22.
    T.H. Pohlman, K.A. Stanness, P.G. Beatty, H.D. Ochs, and J.M. Harlan, An endothelial cell surface factor(s) induced in vitro by lipopolysaccharide, interleukin 1, and tumor necrosis factor-alpha increases neutrophil adherence by a CDw 18-dependent mechanism. J. Immunol. 136:45 (1986).Google Scholar
  23. 23.
    R.L. Nachman, K.A. Hajjar, R.L. Silverstein, and C.A. Dinarello, Interleukin 1 induces endothelial cell synthesis of plasminogen activator inhibitor, J. Exp.Med. 163:1595(1986).CrossRefPubMedGoogle Scholar
  24. 24.
    M. Gowen, and G.R. Mundy, Actions of recombinant interleukin 1, interleukin 2, and interferon-gamma on bone résorption in vitro. J. Immunol. 136:2478 (1986).PubMedGoogle Scholar
  25. 25.
    J.E. Horton, L.G. Raisz, H.A. Simmons, J.J. Oppenheim, and S.E. Mergen-hagen, Bone resorbing activity in supernatant fluid from cultured human peripheral blood leukocytes. Science 177:793 (1972).CrossRefPubMedGoogle Scholar
  26. 26.
    U. Barocos, H.P. Rodemann, C.A. Dinarello, and A.L. Goldberg, Stimulation of muscle protein degradation and prostaglandin E2 release by leukocytic pyrogen (interleukin-1). A mechanisms for the increased degradation of muscle proteins during fever, N. Eng. J. Med. 308:553 (1983).CrossRefGoogle Scholar
  27. 27.
    G. Ramadori, J.D. Sipe, C.A. Dinarello, S.B. Mizel, and H.R. Colten, Pretranslational modulation of acute phase hepatic protein synthesis by murine recombinant interleukin 1 (IL-1) and purified human IL-1, J. Exp. Med. 162:930 (1985).CrossRefPubMedGoogle Scholar
  28. 28.
    J.A. Schmidt, S.B. Mizel, D. Cohen, and I. Green, Interleukin 1, a potential regulator of fibroblast proliferation. J. Immunol. 128:2177 (1982).PubMedGoogle Scholar
  29. 29.
    M. Gowen, D.D. Wood, and R.G. Russell, Stimulation of the proliferation of human bone cells in vitro by human monocyte products with interleukin-1 activity, J. Clin. iInvest. 75:1223 (1985).CrossRefGoogle Scholar
  30. 30.
    U. Ruggiero, and C. Baglioni, Synergistic anti-proliferative activity of interleukin 1 and tumor necrosis factor. J. Immunol. 138:661 (1987).PubMedGoogle Scholar
  31. 31.
    F. Cozzolino, M. Torcia, D. Aldinucci, M. Ziehe, F. Almerigogna, D. Bani, and D.M. Stern, Interleukin 1 is an autocrine regulator of human endothelial cell growth, Proc. Natl. Acad. Sci. 87:6487 (1990).CrossRefPubMedGoogle Scholar
  32. 32.
    C.J. March, B. Mosley, A. Larsen, D.P. Cerretti, G. Braedt, V. Price, S. Gillis, C.S. Henney, S.R. Kronheim, K. Grapstein, P.J. Conlon, T.P. Hopp and D. Cosman, Cloning, sequence and expression of two distinct human interleukin-1 complementary DNAs. Nature 315:641 (1985).CrossRefPubMedGoogle Scholar
  33. 33.
    E.V. Gaffney and S.C. Tsai, Lymphocyte-activating and growth-inhibitory activities for several sources of native and recombinant interleukin 1. Cancer Res. 46:3834 (1986).PubMedGoogle Scholar
  34. 34.
    C.A. Dinarello, The interleukin-1 family: 10 years of discovery. FASEB 8:1314 (1994).Google Scholar
  35. 35.
    C.H. Hannum, C.J. Wilcox, W.P. Arend, F.G. Joslin, DJ. Dripps, P.L. Heimdal, L.G. Armes, A. Sommer, S.P. Eisenberg and R.C. Thompson, Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature 343:336 (1990).CrossRefPubMedGoogle Scholar
  36. 36.
    D.B. Carter, M.R. Deibel, C.J. Dunn, C.S.C. Tomich, et al, Purification, cloning, expression and biological characterization of an interleukin-1 receptor antagonist protein. Nature 344:633 (1990).CrossRefPubMedGoogle Scholar
  37. 37.
    C.A. Dinarello, Interleukin-1 and interleukin-1 antagonism. Blood 77:1627 (1991).PubMedGoogle Scholar
  38. 38.
    D.J. Dripps, B.J. Brandhuber, R.C. Thompson, S.P. Eisenberg, Interleukin-1 (IL-1) receptor antagonist binds to the 80-kDa IL-1 receptor but does not initiate IL-1 signal transduction, J. Biol. Chem. 266:10331 (1991).PubMedGoogle Scholar
  39. 39.
    J.R. Zucali, C.A. Dinarello, D.J. Oblon, M.A. Gross, L. Anderson, and R.S. Weiner, Interleukin 1 stimulates fibroblasts to produce granulocyte-macrophage colony-stimulating activity and prostaglandin E2, J. Clin. iInvest. 77:1857 (1986).CrossRefGoogle Scholar
  40. 40.
    R. Neta, M.B. Sztein, J.J. Oppenheim, S. Gillis, and S.D. Douches, The in vivo effects of interleukin 1: I. bone marrow cells are induced by cycle after administration of interleukin 1, J. Immunol. 139:1861 (1987).PubMedGoogle Scholar
  41. 41.
    R. Neta, S. Douches, and J.J. Oppenheim, Interleukin-1 is a radioprotector. J. Immunol. 136:2483 (1986).PubMedGoogle Scholar
  42. 42.
    T.R. Bradley, N. Williams, A.B. Kriegler, J. Fawcett, and G.S. Hodgson, In vivo effects of interleukin-1α on regenerating mouse bone marrow myeloid colony-forming cells after treatment with 5-fluorouracil. Leukemia 3:893 (1989).PubMedGoogle Scholar
  43. 43.
    M.A.S. Moore, R.L. Stolfi, and D.S. Martin, Hematologic effects of interleukin-1β, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor in tumor-bearing mice treated with fluorouracil, J. Natl. Cancer Inst. 82:1031 (1990).CrossRefPubMedGoogle Scholar
  44. 44.
    J. Moreb and J.R. Zucali, Role of interleukin-1 in 4-hydroperoxy-cyclophosphamide toxicity to bone marrow progenitor cells: a review. Biotherapy 1:273 (1989).CrossRefPubMedGoogle Scholar
  45. 45.
    M.A.S. Moore, R.L. Stolfi and D.S. Martin, Hematologic effects of interleukin-1β, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor in tumor-bearing mice treated with fluorouracil, J. Natl. Cancer Inst. 82:1031 (1990).CrossRefPubMedGoogle Scholar
  46. 46.
    V. Rossi, F. Breviario, P. Ghezzi, E. Dejana, and A. Mantovani, Prostacyclin synthesis induced in vascular cells by interleukin-1. Science 229:174 (1985).CrossRefPubMedGoogle Scholar
  47. 47.
    J.J. Emeis, and T. Kooistra, Interleukin 1 and lipopolysaccharide induce an inhibitor of tissue-type plasminogen activator in vivo and in cultured endothelial cells, J. Exp. Med. 163:1260 (1986).CrossRefPubMedGoogle Scholar
  48. 48.
    M.P. Bevilacqua, J.S. Pober, M.E. Wheeler, R.S. Cotran, and M.A. Gimbrone, Interleukin 1 acts on cultured human vascular endothelium to increase the adhesion of polymorphonuclear leukocytes, monocytes, and related leukocyte cell lines, J. Clin. iInvest. 76:2003 (1985).CrossRefGoogle Scholar
  49. 49.
    A.M. Lamas, CM. Mulroney, and R.P. Schleimer, Studies on the adhesive interaction between purified human eosinophils and cultured vascular endothelial cells. J. Immunol. 140:1500 (1988).PubMedGoogle Scholar
  50. 50.
    E.A. Carswell, L.J. Old, R.L. Kassel, S. Green, N. Fiore, and B. Williamson, An endotoxin-induced serum factor that causes necrosis of tumors, Proc. Natl. Acad. Sci. 72:3666 (1975).CrossRefPubMedGoogle Scholar
  51. 51.
    L.J. Old, Tumor necrosis factor (TNF). Science 230:630 (1985).CrossRefPubMedGoogle Scholar
  52. 52.
    K. Tracey, B. Beutler, S. Lowry, J. Merryweather, S. Wolpe, I. Milsark, R. Hariri, T. Fahey, A. Zentella, J. Albert, G. Shired, and A. Cerami, Shock and tissue injury induced by recombinant human cachectin. Science 234:470 (1987).CrossRefGoogle Scholar
  53. 53.
    P.P. Nawroth, and D.M. Stern, Modulation of endothelial cell hemostatic properties by tumor necrosis factor, J. Exp. Med. 163:740 (1986).CrossRefPubMedGoogle Scholar
  54. 54.
    P.P. Nawroth, D. Haudley, G. Matsulda, R. DeWall, H. Gerlach, D. Blohn, and D.M. Stern, Tumor necrosis factor/cachectin-induced intravascular fibrin formation in meth A fibrosarcomas, J. Exp. Med. 168:637 (1988).CrossRefPubMedGoogle Scholar
  55. 55.
    R.J. North, and E.A. Havell, The antitumor function of tumor necrosis factor (TNF) II. Analysis of the role of endogenous TNF in endotoxin-induced hemorrhagic necrosis and regression of an established sarcoma, J. Exp. Med. 167:1086 (1988).CrossRefPubMedGoogle Scholar
  56. 56.
    H.F. Dvorak, and I. Gresser, Microvascular injury in pathogenesis of interferon-induced necrosis of subcutaneous tumors in mice, J. Natl. Cancer Inst. 81:497 (1989).CrossRefPubMedGoogle Scholar
  57. 57.
    F. Belardelli, E. Proietti, J. Ciolli, P. Sestili, G. Carpinelli, M. Divito, A. Ferretti, D. Woodrow, D. Boraschi, and F. Podo, Interleukin-1 beta induces tumor necrosis and early morphologic and metabolic changes in transplantable mouse tumors. Similarities with the anti-tumor effects of tumor necrosis factor alpha or beta, Int. J. Cancer 44:116 (1989).CrossRefPubMedGoogle Scholar
  58. 58.
    E.A. Havell, W. Fiers, and R.J. North, The antitumor function of tumor necrosis factor (TNF), I. Therapeutic action of TNF against an established murine sarcoma is indirect, immunologically dependent, and limited by severe toxicity, J. Exp. Med. 167:1067 (1988).CrossRefPubMedGoogle Scholar
  59. 59.
    P.L. Kilian, K.L. Kaffka, D.A. Biondi, J.M. Lipman, W.R. Benjamin, D. Feldman and C.A. Campen, Antiproliferative effect of interleukin-1 on human ovarian carcinoma cell line. Cancer Res. 51:1823 (1991).PubMedGoogle Scholar
  60. 60.
    K. Onozaki, K. Matsushima, B.B. Aggarwal, and J.J. Oppenheim, Human interleukin-1 is a cytocidal factor for several tumor-cell lines. J. Immunol. 135:3962 (1985).PubMedGoogle Scholar
  61. 61.
    L.B. Lachman, C.A. Dinarello, N.D. Llansa, I.J. Fidler, Natural and recombinant human interleukin-1β is cytotoxic for human melanoma cells. J. Immunol. 136:3098 (1986).PubMedGoogle Scholar
  62. 62.
    R.J. North, R.H. Neubauer, J.J.H. Huang, R.C. Newton, and S.E. Loveless, Interleukin 1-induced, T cell-mediated regression of immunogenic murine tumors, J. Exp. Med. 168:2031 (1988).CrossRefPubMedGoogle Scholar
  63. 63.
    M. Pezzella, M.E. Neville, J.J. Huang, In vivo inhibition of tumor growth of B16 melanoma by recombinant interleukin-1β: I. Tumor inhibition parallels lymphocyte activating factor activity of interleukin-1β proteins. Cytokine 2:357 (1990).CrossRefPubMedGoogle Scholar
  64. 64.
    S. Nakamura, K. Nakata, S. Kashimoto, H. Yoshida, and M. Yamada, Antitumor effect of recombinant human interleukin 1 alpha against murine syngeneic tumors, Jpn. J. Cancer Res. 77:767 (1988).Google Scholar
  65. 65.
    K. Nakata, S. Kashimoto, H. Yoshida, T. Oku, and S. Nakamura, Augmented anti-tumor effect of recombinant human interleukin-1α by indomethacin. Cancer Res. 48:584 (1988).PubMedGoogle Scholar
  66. 66.
    A. Tewari, W.C., Buhles Jr. and H.F. Starnes Jr, Preliminary report: effect of interleukin-1 on platelet counts, Lancet 336:712 (1990).CrossRefPubMedGoogle Scholar
  67. 67.
    J.W. Smith, W.J. Urba, B.D. Curti, et al, The toxic and hematologic effects of interleukin-1α administered in a phase I trial to patients with advanced malignancies, J. Clin. Oncol. 10:1141 (1992).PubMedGoogle Scholar
  68. 68.
    J. Crown, A. Jakubowski, N. Kemeny, et al, A phase I trial of recombinant human interleukin-1β alone and in combination with myelosuppressive doses of 5-fluorouracil in patients with gastrointestinal cancer. Blood 78:1420 (1991).PubMedGoogle Scholar
  69. 69.
    J.W. Smith II, D.L. Longo, W.G. Alvord, J.E. Janik, et al, The effects of treatment with interleukin-la on platelet recovery after high-dose carboplatin, N. Engl. J. Med. 328:756.Google Scholar
  70. 70.
    J. Nemunaitis, F.R. Appelbaum, K. Lilleby, W.C. Buhles, C. Rosenfeld, Z.R. Zeigler, R.K. Shadduck, J.W. Singer, W. Meyer and C.D. Buckner, Phase I study of recombinant interleukin-1β in patients undergoing autologous bone marrow transplant for acute myelogenous leukemia. Blood 83:3473 (1994).PubMedGoogle Scholar
  71. 71.
    D.R. Vlock, C.S. Johnson, M.-J. Chang, L.M. Reyno, K. Erkmen, M.J. Egorin, T. Logan and C. McCauley, Phase I trial of interleukin-1 alpha (IL-1) and carboplatin (CBDCA), Proc. Amer. Assoc. Cancer Res. 34:296 (1993).Google Scholar
  72. 72.
    T.F. Logan, H. Bishop, M.A. Mintun, Y. Choi, D. Sashin, M.A. Virji, T. Billiar, D.L. Trump, D. Smith, J.M. Kirkwood, D.R. Vlock, M.-J. Chang, M.J. Egorin and C.S. Johnson, Phase I trial of interleukin-la and carboplatin in patients with metastatic disease to the lung: effects on tumor blood flow evaluated by positron emission tomography, Proc. Amer. Assoc. Cancer Res. 35:198 (1994).Google Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Candace S. Johnson
    • 1
    • 2
  • Ming-Jei Chang
    • 1
  • Wei-Dong Yu
    • 1
  • Ruth A. Modzelewski
    • 1
  • Derick M. Russell
    • 1
  • Theodore F. Logan
    • 3
  • Daniel R. Vlock
    • 4
  • Leonard M. Reyno
    • 5
  • Merrill J. Egorin
    • 5
  • Kadir Erkmen
    • 5
  • Philip Furmanski
    • 6
  1. 1.Department of OtolaryngologyUniversity of Pittsburgh School of Medicine, University of Pittsburgh Cancer InstitutePittsburghUSA
  2. 2.Department of PharmacologyUniversity of Pittsburgh School of Medicine, University of Pittsburgh Cancer InstitutePittsburghUSA
  3. 3.Department of MedicineUniversity of Pittsburgh School of Medicine, University of Pittsburgh Cancer InstitutePittsburghUSA
  4. 4.Brigham and Women’s HospitalBostonUSA
  5. 5.Department of Medicine, Division of Hematology-OncologyUniversity of Maryland School of Medicine, University of Maryland Cancer CenterBaltimoreUSA
  6. 6.Department of BiologyNew York UniversityNew YorkUSA

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