Medical Oncology

, Volume 27, Issue 2, pp 185–198 | Cite as

TNF-α and its inhibitors in cancer

  • Inès ZidiEmail author
  • Souhir Mestiri
  • Aghleb Bartegi
  • Nidhal Ben Amor
Original Paper


Tumor necrosis factor (TNF)-α is implicated in the same time in apoptosis and in cell proliferation. TNF-α not only acts as pro-inflammatory cytokine conducing to wide spectrum of human diseases including inflammatory diseases, but can also induce tumor development. The molecular mechanisms of TNF-α functions have been intensively investigated. In this review we covered TNF-α, the molecule, its signaling pathway, and its therapeutic functions. We provide a particular insight in its paradoxical role in tumor promotion and in its use as anti-tumor agent. This review considers also the recent findings regarding TNF-α inhibitors, their pharmacokinetics, and their pharmacodynamics. Six TNF-α inhibitors have been considered here: Infliximab, Adalimumab, Golimumab, CDP870, CDP571, Etanercept, and Thalidomide. We discussed the clinical relevance of their functions in treatment of several diseases such as advanced inflammatory rheumatic and bowel disease, with a focus in cancer treatment. Targeting TNF-α by these drugs has many side effects like malignancies development, and the long-term sequels are not very well explored. Their efficacy and their safety were discussed, underscoring the necessity of close patients monitoring and of their caution use.


TNF-α Anti-TNF-α Inhibitors Cancer Therapy 


  1. 1.
    Carswell E, et al. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA. 1975;72:3666–70. doi: 10.1073/pnas.72.9.3666.PubMedCrossRefGoogle Scholar
  2. 2.
    Feldmann M, et al. Anti-TNFalpha therapy of rheumatoid arthritis: what can we learn about chronic disease? Novartis Found Symp. 2004;256:53–69. doi: 10.1002/0470856734.ch5.PubMedCrossRefGoogle Scholar
  3. 3.
    Locksley R, Killeen N, Lenardo M. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell. 2001;104:487–501. doi: 10.1016/S0092-8674(01)00237-9.PubMedCrossRefGoogle Scholar
  4. 4.
    Black RA, et al. A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature. 1997;385:729–33. doi: 10.1038/385729a0.PubMedCrossRefGoogle Scholar
  5. 5.
    Vandenabeele P, Declercq W, Beyaert R, Fiers W. Two tumour necrosis factor receptors: structure and function. Trends Cell Biol. 1995;5:392–9. doi: 10.1016/S0962-8924(00)89088-1.PubMedCrossRefGoogle Scholar
  6. 6.
    Bazzoni F, Beutler B. The tumor necrosis factor ligand and receptor families. N Engl J Med. 1996;334:1717–25. doi: 10.1056/NEJM199606273342607.PubMedCrossRefGoogle Scholar
  7. 7.
    Aggarwal B. Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol. 2003;3:745–56. doi: 10.1038/nri1184.PubMedCrossRefGoogle Scholar
  8. 8.
    Tartaglia L, Goeddel D. Two TNF receptors. Immunol Today. 1992;13:151–3. doi: 10.1016/0167-5699(92)90116-O.PubMedCrossRefGoogle Scholar
  9. 9.
    Varfolomeev EE, Ashkenazi A. Tumor necrosis factor: an apoptosis JuNKie? Cell. 2004;116:491–7. doi: 10.1016/S0092-8674(04)00166-7.PubMedCrossRefGoogle Scholar
  10. 10.
    Wertz IE, Dixit VM. Ubiquitin-mediated regulation of TNFR1 signaling. Cytokine Growth Factor Rev. 2008;19:313–24. doi: 10.1016/j.cytogfr.2008.04.014.PubMedCrossRefGoogle Scholar
  11. 11.
    Chen G, Goeddel D. TNF-R1 signaling: a beautiful pathway. Science. 2002;296:1634–5. doi: 10.1126/science.1071924.PubMedCrossRefGoogle Scholar
  12. 12.
    Chen ZJ. Ubiquitin signalling in the NF-kappaB pathway. Nat Cell Biol. 2005;7:758–65. doi: 10.1038/ncb0805-758.PubMedCrossRefGoogle Scholar
  13. 13.
    Basak S, Hoffmann A. Crosstalk via the NF-kappa B signaling system. Cytokine Growth Factor Rev. 2008;19:187–97. doi: 10.1016/j.cytogfr.2008.04.005.PubMedCrossRefGoogle Scholar
  14. 14.
    Brenner DA, O’Hara M, Angel P, Chojkier M, Karin M. Prolonged activation of JUN and collagenase genes by tumour necrosis factor-alpha. Nature. 1989;337:661–3. doi: 10.1038/337661a0.PubMedCrossRefGoogle Scholar
  15. 15.
    Muppidi JR, Tschopp J, Siegl RM. Life and death decisions: secondary complexes and lipid rafts in TNF receptor family signal transduction. Immunity. 2004;21:461–5. doi: 10.1016/j.immuni.2004.10.001.PubMedCrossRefGoogle Scholar
  16. 16.
    Kruyt FAE. TRAIL and cancer therapy. Cancer Lett. 2008;263:14–25. doi: 10.1016/j.canlet.2008.02.003.PubMedCrossRefGoogle Scholar
  17. 17.
    Anderson G, Nakada MT, DeWitte M. Tumor necrosis factor-alpha in the pathogenesis and treatment of cancer. Curr Opin Pharmacol. 2004;4:314–20. doi: 10.1016/j.coph.2004.04.004.PubMedCrossRefGoogle Scholar
  18. 18.
    Pfeffer K. Biological functions of tumor necrosis factor cytokines and their receptors. Cytokine Growth Factor Rev. 2003;14:185–91. doi: 10.1016/S1359-6101(03)00022-4.PubMedCrossRefGoogle Scholar
  19. 19.
    Kruglov A, et al. Physiological functions of tumor necrosis factor and the consequences of its pathologic overexpression or blockade: mouse models. Cytokine Growth Factor Rev. 2008;19:231–44. doi: 10.1016/j.cytogfr.2008.04.010.PubMedCrossRefGoogle Scholar
  20. 20.
    Idriss HT, Naismith JH. TNF alpha and the TNF receptor superfamily: structure–function relationship(s). Microsc Res Tech. 2000;50:184–95. doi: 10.1002/1097-0029(20000801)50:3<184::AID-JEMT2>3.0.CO;2-H.PubMedCrossRefGoogle Scholar
  21. 21.
    Stübgen J-P. Tumor necrosis factor-alpha antagonists and neuropathy. Muscle Nerve. 2008;37:281–92. doi: 10.1002/mus.20924.PubMedCrossRefGoogle Scholar
  22. 22.
    Cope AP, et al. Chronic tumor necrosis factor alter T cells responses by attenuating T cell receptor signalling. J Exp Med. 1997;185:1573–84. doi: 10.1084/jem.185.9.1573.PubMedCrossRefGoogle Scholar
  23. 23.
    Kodama S, Davis M, Faustman D. The therapeutic potential of tumor necrosis factor for autoimmune disease: a mechanistically based hypothesis. Cell Mol Life Sci. 2005;62:1850–62. doi: 10.1007/s00018-005-5022-6.PubMedCrossRefGoogle Scholar
  24. 24.
    Ban L, et al. Selective death of autoreactive T cells in human diabetes by TNF or TNF receptor 2 agonism. Proc Natl Acad Sci USA. 2008;105:13644–9. doi: 10.1073/pnas.0803429105.PubMedCrossRefGoogle Scholar
  25. 25.
    Manusama E, et al. Synergistic antitumour effect of recombinant human tumour necrosis factor alpha with melphalan in isolated limb perfusion in the rat. Br J Surg. 1996;83:551–5. doi: 10.1002/bjs.1800830438.PubMedCrossRefGoogle Scholar
  26. 26.
    Eggermont A, de Wilt J, ten Hagen T. Current uses of isolated limb perfusion in the clinic and a model system for new strategies. Lancet Oncol. 2003;4:429–37. doi: 10.1016/S1470-2045(03)01141-0.PubMedCrossRefGoogle Scholar
  27. 27.
    Curnis F, Sacchi A, Corti A. Improving the response of tumors to chemotherapy in mice by targeted delivery of picogram doses of tumor necrosis factor-alpha to tumor vessels. J Clin Invest. 2002;110:475–82.PubMedGoogle Scholar
  28. 28.
    Folli S, et al. Tumor-necrosis factor can enhance radio-antibody uptake in human colon carcinoma xenografts by increasing vascular permeability. Int J Cancer. 1993;53:829–36. doi: 10.1002/ijc.2910530521.PubMedCrossRefGoogle Scholar
  29. 29.
    van Horssen R, Ten Hagen T, Eggermont A. TNF-alpha in cancer treatment: molecular insights, antitumor effects, and clinical utility. Oncologist. 2006;11:397–408. doi: 10.1634/theoncologist.11-4-397.PubMedCrossRefGoogle Scholar
  30. 30.
    ten Hagen T, Seynhaeve A, Eggermont A. Tumor necrosis factor-mediated interactions between inflammatory response and tumor vascular bed. Immunol Rev. 2008;222:299–315. doi: 10.1111/j.1600-065X.2008.00619.x.PubMedCrossRefGoogle Scholar
  31. 31.
    Fraker DL, Alexander H, Andrich M, Rosenberg S. Treatment of patients with melanoma of the extremity using hyperthermic isolated limb perfusion with melphalan, tumor necrosis factor, and interferon gamma: results of a tumor necrosis factor dose-escalation study. J Clin Oncol. 1996;14:479–89.PubMedGoogle Scholar
  32. 32.
    Van Horssen R, Ten Hagen TLM, Eggermont AMM. TNF-alpha in Cancer Treatment: Molecular Insights, Antitumor Effects, and Clinical Utility. The Oncologist. 2006;11:397–408. doi: 10.1634/theoncologist.11-4-397.PubMedCrossRefGoogle Scholar
  33. 33.
    Lejeune F, Rüegg C. Recombinant human tumor necrosis factor: an efficient agent for cancer treatment. Bull Cancer. 2006;93:E90–100.PubMedGoogle Scholar
  34. 34.
    Fajardo L, Kwan H, Kowalski J, Prionas S, Allison A. Dual role of tumor necrosis factor-alpha in angiogenesis. Am J Pathol. 1992;140:539–44.PubMedGoogle Scholar
  35. 35.
    Alexander HJ, et al. Isolated hepatic perfusion with tumor necrosis factor and melphalan for unresectable cancers confined to the liver. J Clin Oncol. 1998;16:1479–89.PubMedGoogle Scholar
  36. 36.
    Borsi L, et al. Selective targeted delivery of TNF alpha to tumor blood vessels. Blood. 2003;102:4384–92. doi: 10.1182/blood-2003-04-1039.PubMedCrossRefGoogle Scholar
  37. 37.
    Corti A, Ponzoni M. Tumor vascular targeting with tumor necrosis factor alpha and chemotherapeutic drugs. Ann NY Acad Sci. 2004;1028:104–12. doi: 10.1196/annals.1322.011.PubMedCrossRefGoogle Scholar
  38. 38.
    Senzer N, et al. TNFerade biologic, an adenovector with a radiation-inducible promoter, carrying the human tumor necrosis factor alpha gene: a phase I study in patients with solid tumors. J Clin Oncol. 2004;22:592–601. doi: 10.1200/JCO.2004.01.227.PubMedCrossRefGoogle Scholar
  39. 39.
    Chang K, et al. Endoscopic ultrasound delivery of an antitumor agent to treat a case of pancreatic cancer. Nat Clin Pract Gastroenterol Hepatol. 2008;5:107–11. doi: 10.1038/ncpgasthep1033.PubMedCrossRefGoogle Scholar
  40. 40.
    Mundt AJ, et al. A Phase I trial of TNFerade biologic in patients with soft tissue sarcoma in the extremities. Clin Cancer Res. 2004;10:5747–53. doi: 10.1158/1078-0432.CCR-04-0296.PubMedCrossRefGoogle Scholar
  41. 41.
    Chung T, et al. Tumor necrosis factor-alpha-based gene therapy enhances radiation cytotoxicity in human prostate cancer. Cancer Gene Ther. 1998;5:344–9.PubMedGoogle Scholar
  42. 42.
    Staba M, Mauceru H, Kufe D, Hallahan D, Weichselbaum R. Adenoviral TNF-alpha gene therapy and radiation damage tumor vasculature in a human malignant glioma xenograft. Gene Ther. 1998;5:293–300. doi: 10.1038/ Scholar
  43. 43.
    McLoughlin JM, et al. TNFerade, an adenovector carrying the transgene for human tumor necrosis factor a, for patients with advanced solid tumors: surgical experience and long-term follow-up. Ann Surg Oncol. 2005;12:825–30. doi: 10.1245/ASO.2005.03.023.PubMedCrossRefGoogle Scholar
  44. 44.
    Asher AL, et al. Murine tumor cells transduced with the gene for tumor necrosis factor-alpha. Evidence for paracrine immune effects of tumor necrosis factor against tumors. J Immunol. 1991;146:3227–34.PubMedGoogle Scholar
  45. 45.
    Han SK, Brody SL, Crystal RG. Suppression of in vivo tumorigenicity of human lung cancer cells by retrovirus-mediated transfer of the human tumor necrosis factor-alpha cDNA. Am J Respir Cell Mol Biol. 1994;11:270–8.PubMedGoogle Scholar
  46. 46.
    Mizuguchi H, et al. Tumor necrosis factor alpha-mediated tumor regression by the in vivo transfer of genes into the artery that leads to tumors. Cancer Res. 1998;58:5727–30.Google Scholar
  47. 47.
    Larmonier N, et al. The inhibition of TNF-alpha anti-tumoral properties by blocking antibodies promotes tumor growth in a rat model. Exp Cell Res. 2007;313:2345–55. doi: 10.1016/j.yexcr.2007.03.027.PubMedCrossRefGoogle Scholar
  48. 48.
    Tselepsis C, et al. Tumour necrosis factor-alpha in Barrett’s oesophagus: a potential novel mechanism of action. Oncogene. 2002;21:6071–81. doi: 10.1038/sj.onc.1205731.CrossRefGoogle Scholar
  49. 49.
    Darai E, Detchev R, Hugol D, Quang NT. Serum and cyst fluid levels of interleukin (IL)-6, IL-8 and tumour necrosis factor alpha in women with endometriomas and benign and malignant cycstic ovarian tumours. Hum Reprod. 2003;18:1681–5. doi: 10.1093/humrep/deg321.PubMedCrossRefGoogle Scholar
  50. 50.
    Szlosarek PW, Charles KA, Balkwill FR. Tumour necrosis factor-alpha as a tumour promoter. Eur J Cancer. 2006;42:745–50. doi: 10.1016/j.ejca.2006.01.012.PubMedCrossRefGoogle Scholar
  51. 51.
    Balkwill F. Tumor necrosis factor or tumor promoting factor? Cytokine Growth Factor Rev. 2002;13:135–41. doi: 10.1016/S1359-6101(01)00020-X.PubMedCrossRefGoogle Scholar
  52. 52.
    Shealy DJ, Visvanathan S. Anti-TNF antibodies: lessons from the past, roadmap for the future. In: Chernajovsky Y, Nissim A, editors. Therapeutic antibodies. Handbook of experimental pharmacology. 2008, p. 101–129.Google Scholar
  53. 53.
    Huerta-Yepez SM, Vega M, Garban H, Bonavida B. Involvement of the TNF-alpha autocrine-paracrine loop via NF-kappaB and YY1, in the regulation of tumor cell resistance to Fas-induced apoptosis. Clin Immunol. 2006;120:297–309. doi: 10.1016/j.clim.2006.03.015.PubMedCrossRefGoogle Scholar
  54. 54.
    Mocellin S, Riccardo Rossi C, Pilati P, Nitti D. Tumor necrosis factor, cancer and anticancer therapy. Cytokine Growth Factor Rev. 2005;16:35–53. doi: 10.1016/j.cytogfr.2004.11.001.PubMedCrossRefGoogle Scholar
  55. 55.
    Hagemann T, et al. Enhanced invasiveness of breast cancer cell lines upon co-cultivation with macrophages is due to TNF-alpha dependent up-regulation of matrix metalloproteases. Carcinogenesis. 2004;25:1543–9. doi: 10.1093/carcin/bgh146.PubMedCrossRefGoogle Scholar
  56. 56.
    Lee HY, et al. A small compound that inhibits tumor necrosis factor-alpha-induced matrix metalloproteinase-9 upregulation. Biochem Biophys Res Commun. 2005;336:716–22. doi: 10.1016/j.bbrc.2005.08.154.PubMedCrossRefGoogle Scholar
  57. 57.
    Overall CM, Kleifeld O. Tumour microenvironment-opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer. 2006;6:227–39. doi: 10.1038/nrc1821.PubMedCrossRefGoogle Scholar
  58. 58.
    Nagai S, et al. Glil contributs to the invasiveness of pancreatic cancer through matrix metalloproteinase-9 activation. Cancer Sci. 2008;99:1377–84. doi: 10.1111/j.1349-7006.2008.00822.x.PubMedCrossRefGoogle Scholar
  59. 59.
    Leber TM, Balkwill FR. Regulation of monocyte MMP-9 production by TNF-alpha and a tumour-derived soluble factor (MMPSF). Br J Cancer. 1998;78:724–32.PubMedGoogle Scholar
  60. 60.
    Szlosarek PW, Balkwill FR. Tumour necrosis factor: a potential target for the therapy of solid tumours. Lancet Oncol. 2003;4:565–73. doi: 10.1016/S1470-2045(03)01196-3.PubMedCrossRefGoogle Scholar
  61. 61.
    Zidi I, et al. Increase in HLA-G1 proteolytic shedding by tumor cells: a regulatory pathway controlled by NF-kappaB inducers. Cell Mol Life Sci. 2006;63:2669–81. doi: 10.1007/s00018-006-6341-y.PubMedCrossRefGoogle Scholar
  62. 62.
    Jang W, et al. The −238 tumor necrosis factor-alpha promoter polymorphism is associated with decreased susceptibility to cancers. Cancer Lett. 2001;166:41–6. doi: 10.1016/S0304-3835(01)00438-4.PubMedCrossRefGoogle Scholar
  63. 63.
    Hajeer A, et al. Preliminary evidence of an association of tumour necrosis factor microsatellites with increased risk of multiple basal cell carcinomas. Br J Dermatol. 2000;142:441–5. doi: 10.1046/j.1365-2133.2000.03353.x.PubMedCrossRefGoogle Scholar
  64. 64.
    Marsh H, et al. Polymorphisms in tumour necrosis factor (TNF) are associated with risk of bladder cancer and grade of tumour at presentation. Br J Cancer. 2003;89:1096–101. doi: 10.1038/sj.bjc.6601165.PubMedCrossRefGoogle Scholar
  65. 65.
    Scallon BJ, Arevalo Moore M, Trinh H, Knight DM, Ghrayeb J. Chimeric anti-TNF-alpha monoclonal antibody cA2 binds recombinant transmembrane TNF-alpha and activates immune effector functions. Cytokine. 1995;7:251–9. doi: 10.1006/cyto.1995.0029.PubMedCrossRefGoogle Scholar
  66. 66.
    Mitoma H, et al. Mechanisms for cytotoxic effects of anti-tumor necrosis factor agents on transmembrane tumor necrosis factor-alpha expressing cells comparison among Infliximab, Etanercept, and Adalimumab. Arthritis Rheum. 2008;58:1248–57. doi: 10.1002/art.23447.PubMedCrossRefGoogle Scholar
  67. 67.
    Daniel PT, Pezzuto A, Dörken B. Humoral immunotherapy and the use of monoclonal antibodies. In: Degos L, LDC, Löwenberg B, editors. Textbook of malignant haematology. Martin Dunitz; 1999, p. 425–46.Google Scholar
  68. 68.
    Tracey D, Klareskog L, Sasso EH, Salfled Jg, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008;117:244–79. doi: 10.1016/j.pharmthera.2007.10.001.PubMedCrossRefGoogle Scholar
  69. 69.
    Duclos M, et al. Retention rates of tumor necrosis factor blockers in daily practice in 770 rheumatic patients. J Rheumatol. 2006;33:2433–8.PubMedGoogle Scholar
  70. 70.
    Schrumpf Heiberg M, et al. The comparative one-year performance of anti-tumor necrosis factor alpha drugs in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: results from a longitudinal, observational, multicenter study. Arthritis Rheum. 2008;59:234–40. doi: 10.1002/art.23333.CrossRefGoogle Scholar
  71. 71.
    Alonso-Ruiz A, et al. Tumor necrosis factor alpha drugs in rheumatoid arthritis: systematic review and metaanalysis of efficacy and safety. BMC Musculoskelet Disord. 2008;9:52. doi: 10.1186/1471-2474-9-52.PubMedCrossRefGoogle Scholar
  72. 72.
    Carmona L, Gomez-Reino JJS, Group B. Survival of TNF antagonists in spondylarthritis is better than in rheumatoid arthritis: data from the Spanish registry BIOBADASER. Arthritis Res Ther. 2006;8:R72. doi: 10.1186/ar1941.PubMedCrossRefGoogle Scholar
  73. 73.
    Kristensen LE, Saxne T, Nilsson JA, Geborek P. Impact of concomitant DMARD therapy on adherence to treatment with Etanercept and Infliximab in rheumatoid arthritis: results from a six-year observational study in southern Sweden. Arthritis Res Ther. 2006;8:R174. doi: 10.1186/ar2084.PubMedCrossRefGoogle Scholar
  74. 74.
    Farrell R, et al. Clinical experience with infliximab therapy in 100 patients with Crohn’s disease. Am J Gastroenterol. 2000;95:3490–7. doi: 10.1111/j.1572-0241.2000.03366.x.PubMedCrossRefGoogle Scholar
  75. 75.
    St Clair E, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum. 2004;50:3432–43. doi: 10.1002/art.20568.PubMedCrossRefGoogle Scholar
  76. 76.
    Elliott MJ, et al. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum. 1993;36:1681–90. doi: 10.1002/art.1780361206.PubMedCrossRefGoogle Scholar
  77. 77.
    Wagner C, et al. lnfliximab treatment benefits correlate with pbarmacodynamic parameters in Crohn’s disease patients. Digestion. 1998;59:124–5.Google Scholar
  78. 78.
    Nakada M, et al. Neutralization of TNF by the antibody cA2 reveals differential regulation of adhesion molecule expression on TNF-activated endothelial cells. Cell Adhes Commun. 1998;5:491–503. doi: 10.3109/15419069809005606.PubMedCrossRefGoogle Scholar
  79. 79.
    Sandborn WJ, Hanauer SB. Antitumor necrosis factor therapy for inflammatory bowel disease: a review of agents, pharmacology, clinical results, and safety. Inflamm Bowel Dis. 1999;5:119–33.PubMedGoogle Scholar
  80. 80.
    Hommes D, et al. Beneficial effect of treatment with a monoclonal anti-tumor necrosis factor-alpha antibody on markers of coagulation and fibrinolysis in patients with active Crohn’s disease. Haemostasis. 1997;27:269–77.PubMedGoogle Scholar
  81. 81.
    Van Dullemen H, et al. Reduction of circulating secretory phospholipase A, levels by anti-tumor necrosis factor chimeric monoclonal antibody in patients with severe Crohn’s disease. Relation between tumor necrosis factor and secretory phospholipase A, in healthy humans and active Crohn’s disease. Scand J Gastroenterol. 1998;33:1094–8. doi: 10.1080/003655298750026813.PubMedCrossRefGoogle Scholar
  82. 82.
    Flamant M, Bourreille A. Biothérapies et MICI: anti-TNF et nouvelles cibles thérapeutiques Biologic therapies in inflammatory bowel disease. Rev Med Interne. 2007;28:852–61. doi: 10.1016/j.revmed.2007.06.008.PubMedCrossRefGoogle Scholar
  83. 83.
    Baert F, et al. Influence of immunogenicity on the long-term efficacy of Infliximab in Crohn’s disease. N Engl J Med. 2003;348:601–8. doi: 10.1056/NEJMoa020888.PubMedCrossRefGoogle Scholar
  84. 84.
    Weinblatt M, et al. Adalimumab, a fully human antitumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 2003;48:35–45. doi: 10.1002/art.10697.PubMedCrossRefGoogle Scholar
  85. 85.
    Van der Heijde D, et al. Efficacy and safety of adalimumab in patients with ankylosing spondylitis: results of a multicenter, randomized, double blind, placebocontrolled trial. Arthritis Rheum. 2006;54:2136–46. doi: 10.1002/art.21913.PubMedCrossRefGoogle Scholar
  86. 86.
    Mease P, et al. Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a double blind, randomized, placebo-controlled trial. Arthritis Rheum. 2005;52:3279–89. doi: 10.1002/art.21306.PubMedCrossRefGoogle Scholar
  87. 87.
    Keystone E, Haraoui B. Adalimumab therapy in rheumatoid arthritis. Rheum Dis Clin North Am. 2004;30:349–64. doi: 10.1016/j.rdc.2004.02.004.PubMedCrossRefGoogle Scholar
  88. 88.
    Martin PL, Oneda S, Treacy G. Effects of an anti-TNF-alpha monoclonal antibody, administered throughout pregnancy and lactation, on the development of the Macaque immune system. Am J Reprod Immunol. 2007;58:138–49. doi: 10.1111/j.1600-0897.2007.00499.x.PubMedCrossRefGoogle Scholar
  89. 89.
    Kay J, et al. Golimumab in patients with active rheumatoid arthritis despite treatment with methotrexate a randomized, double-blind, placebo-controlled, dose-ranging study. Arthritis Rheum. 2008;58:964–75. doi: 10.1002/art.23383.PubMedCrossRefGoogle Scholar
  90. 90.
    Zhou H, et al. Pharmacokinetics and safety of golimumab, a fully human anti-TNF-alpha monoclonal antibody, in subjects with rheumatoid arthritis. J Clin Pharmacol. 2007;47:383–96. doi: 10.1177/0091270006298188.PubMedCrossRefGoogle Scholar
  91. 91.
    Inman RD, et al. Efficacy and safety of Golimumab in patients with ankylosing spondylitis results of a randomized, double-blind, placebo-controlled, phase III trial. Arthritis Rheum. 2008;58:3402–12. doi: 10.1002/art.23969.PubMedCrossRefGoogle Scholar
  92. 92.
    Hutas G. Golimumab, a fully human monoclonal antibody against TNF-alpha. Curr Opin Mol Ther. 2008;10:393–406.PubMedGoogle Scholar
  93. 93.
    Sandborn WJ, et al. Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med. 2007;357:228–38. doi: 10.1056/NEJMoa067594.PubMedCrossRefGoogle Scholar
  94. 94.
    Schreiber S, et al. Maintenance therapy with Certolizumab pegol for Crohn’s disease. N Engl J Med. 2007;357:239–50. doi: 10.1056/NEJMoa062897.PubMedCrossRefGoogle Scholar
  95. 95.
    Winter G, Harris W. Humanized antibodies. Immunol Today. 1993;14:243–6. doi: 10.1016/0167-5699(93)90039-N.PubMedCrossRefGoogle Scholar
  96. 96.
    Stack WA, et al. Randomised controlled trial of CDP571 antibody to tumor necrosis factor in Crohn’s disease. Lancet. 1997;349:521–4. doi: 10.1016/S0140-6736(97)80083-9.PubMedCrossRefGoogle Scholar
  97. 97.
    Sandborn WJ, et al. An open-label study of the human anti-TNF monoclonal antibody Adalimumab in subjects with prior loss of response or intolerance to Infliximab for Crohn’s disease. Am J Gastroenterol. 2004;99:1984–9. doi: 10.1111/j.1572-0241.2004.40462.x.PubMedCrossRefGoogle Scholar
  98. 98.
    Feagan BG, et al. CDP571, a humanized monoclonal antibody to tumour necrosis factor-alpha, for steroid-dependent Crohn’s disease: a randomized, double-blind, placebo-controlled trial. Aliment Pharmacol Ther. 2006;23:617–28. doi: 10.1111/j.1365-2036.2006.02791.x.PubMedCrossRefGoogle Scholar
  99. 99.
    Sandborn W, et al. Etanercept for active Crohn’s disease: a randomized, double blind, placebo-controlled trial. Gastroenterology. 2001;121:1088–94. doi: 10.1053/gast.2001.28674.PubMedCrossRefGoogle Scholar
  100. 100.
    Nanda S, Bathon J. Etanercept: a clinical review of current and emerging indications. Expert Opin Pharmacother. 2004;5:1175–86. doi: 10.1517/14656566.5.5.1175.PubMedCrossRefGoogle Scholar
  101. 101.
    Speirs A. Thalidomide and congenital abnormalities. Lancet. 1962;1:303–5. doi: 10.1016/S0140-6736(62)91248-5.PubMedCrossRefGoogle Scholar
  102. 102.
    Kumar S, Witzig TE, Rajkumar SV. Thalidomide as an anti-cancer agent. J Cell Mol Med. 2002;6:160–74. doi: 10.1111/j.1582-4934.2002.tb00184.x.PubMedCrossRefGoogle Scholar
  103. 103.
    Combe B. Le thalidomide: vers de nouvelles indications ? Rev Rhum. 2001;68:951–7. doi: 10.1016/S1169-8330(01)00208-3.CrossRefGoogle Scholar
  104. 104.
    Moreira AL, et al. Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation. J Exp Med. 1993;177:1675–80. doi: 10.1084/jem.177.6.1675.PubMedCrossRefGoogle Scholar
  105. 105.
    Niwayama S, Turk BE, Liu JO. Potent inhibition of tumor necrosis factor-alpha production by tetrafluorothalidomide and tetrafluorophthalimides. J Med Chem. 1996;39:3044–5. doi: 10.1021/jm960284r.PubMedCrossRefGoogle Scholar
  106. 106.
    Corral LG, et al. Differential cytokine modulation and T cell activation by two distinct classes of Thalidomide analogues that are potent inhibitors of TNF-alpha. J Immunol. 1999;163:380–6.PubMedGoogle Scholar
  107. 107.
    D’Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA. 1994;91:4082–5. doi: 10.1073/pnas.91.9.4082.PubMedCrossRefGoogle Scholar
  108. 108.
    Keifer JA, Guttridge DC, Ashburner BP, Baldwin ASJ. Inhibition of NF-kappa B activity by thalidomide through suppression of Ikappa B kinase activity. J Biol Chem. 2001;276:22382–7. doi: 10.1074/jbc.M100938200.PubMedCrossRefGoogle Scholar
  109. 109.
    Teo Steven K. Properties of Thalidomide and its analogues: implications for anticancer therapy. AAPS J. 2005;7:E14–9. doi: 10.1208/aapsj070103.PubMedCrossRefGoogle Scholar
  110. 110.
    Haslett P, Corral L, Albert M, Kaplan G. Thalidomide costimulates primary human T lymphocytes, preferentially inducing proliferation, cytokine production, and cytotoxic responses in the CD8+ subset. J Exp Med. 1998;187:1885–92. doi: 10.1084/jem.187.11.1885.PubMedCrossRefGoogle Scholar
  111. 111.
    Laber DA, et al. A phase I study of Thalidomide, Capecitabine and Temozolomide in advanced cancer. Cancer Biol Ther. 2007;6:840–5.PubMedGoogle Scholar
  112. 112.
    Joshua DE. Multiple myeloma: the present and the future. Med J Aust. 2005;183:344.PubMedGoogle Scholar
  113. 113.
    Alessandri C, et al. Autoantibody production in anti-TNF-alpha-treated patients. Ann NY Acad Sci. 2007;1110:319–29. doi: 10.1196/annals.1423.034.PubMedCrossRefGoogle Scholar
  114. 114.
    Wallis RS. Tumour necrosis factor antagonists: structure, function, and tuberculosis risks. Lancet Infect Dis. 2008;8:601–11. doi: 10.1016/S1473-3099(08)70227-5.PubMedCrossRefGoogle Scholar
  115. 115.
    Nash PT, Florin TH. Tumour necrosis factor inhibitors. Med J Aust. 2005;183:205–8.PubMedGoogle Scholar
  116. 116.
    Ozorio G, et al. Autoimmune hepatitis following Infliximab therapy for ankylosing spondylitis. Med J Aust. 2007;187:524–6.PubMedGoogle Scholar
  117. 117.
    Yazisiz V, Avci AB, Erbasan F, Yildirim B, Terzioglu E. Development of Crohn’s disease following anti-tumour necrosis factor therapy (etanercept). Colorectal Dis. 2008;10:953–4.PubMedGoogle Scholar
  118. 118.
    Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT. Randomized, double-blind, placebo-controlled, pilot trial of Infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF therapy against congestive heart failure (ATTACH) trial. Circulation. 2003;107:3133–40. doi: 10.1161/01.CIR.0000077913.60364.D2.PubMedCrossRefGoogle Scholar
  119. 119.
    Keystone EC. Advances in targeted therapy: safety of biological agents. Ann Rheum Dis. 2003;62:ii34–6. doi: 10.1136/ard.62.suppl_2.ii34.PubMedCrossRefGoogle Scholar
  120. 120.
    Askling J, et al. Haematopoietic malignancies in rheumatoid arthritis: lymphoma risk and characteristics after exposure to tumour necrosis factor antagonists. Ann Rheum Dis. 2005;64:1414–20. doi: 10.1136/ard.2004.033241.PubMedCrossRefGoogle Scholar
  121. 121.
    Bongartz T, et al. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies : systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA. 2006;295:2275–85. doi: 10.1001/jama.295.19.2275.PubMedCrossRefGoogle Scholar
  122. 122.
    Okada S, Siegel J. Risk of serious infections and malignancies with anti-TNF antibody therapy in rheumatoid arthritis. JAMA. 2006;296:2201–2. doi: 10.1001/jama.296.18.2201-b.PubMedCrossRefGoogle Scholar
  123. 123.
    Mackey AC, Green L, Liang LC, Dinndorf P, Avigan M. Hepatosplenic T cell lymphoma associated with Infliximab use in young patients treated for inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2007;44:265–7. doi: 10.1097/MPG.0b013e31802f6424.PubMedCrossRefGoogle Scholar
  124. 124.
    Zeidan A, Sham R, Shapiro J, Baratta A, Kouides P. Hepatosplenic T-cell lymphoma in a patient with Crohn’s disease who received infliximab therapy. Leuk Lymphoma. 2007;48:1410–3. doi: 10.1080/10428190701345433.PubMedCrossRefGoogle Scholar
  125. 125.
    Drini M, Prichard PJ, Brown GJ, Macrae FA. Hepatosplenic T-cell lymphoma following Infliximab therapy for Crohn’s disease. Med J Aust. 2008;189:464–5.PubMedGoogle Scholar
  126. 126.
    Geborek P, et al. Tumour necrosis factor blockers do not increase overall tumour risk in patients with rheumatoid arthritis, but may be associated with an increased risk of lymphomas. Ann Rheum Dis. 2005;64:699–703. doi: 10.1136/ard.2004.030528.PubMedCrossRefGoogle Scholar
  127. 127.
    Nair B, Raval G, Mehta P. TNF-alpha inhibitor Etanercept and hematologic malignancies: report of a case and review of the literature. Am J Hematol. 2007;82:1022–4. doi: 10.1002/ajh.20926.PubMedCrossRefGoogle Scholar
  128. 128.
    Bakland G, Nossent H. Acute myelogenous leukaemia following Etanercept therapy. Rheumatology. 2003;42:900–1. doi: 10.1093/rheumatology/keg128.PubMedCrossRefGoogle Scholar
  129. 129.
    Brown SL, Greene MH, Gershon SK, Edwards ET, Braun MMT. Tumor necrosis factor antagonist therapy and lymphoma development twenty-six cases reported to the Food and Drug Administration. Arthritis Rheum. 2002;46:3151–8. doi: 10.1002/art.10679.PubMedCrossRefGoogle Scholar
  130. 130.
    Stone JH, et al. Solid malignancies among patients in the Wegener’s Granulomatosis Etanercept trial. Arthritis Rheum. 2006;54:1608–18. doi: 10.1002/art.21869.PubMedCrossRefGoogle Scholar
  131. 131.
    Humira™ (Adalimumab), DN0735V7 CR22-05126. December 20, 2002:16p.Google Scholar
  132. 132.
    Solomon DH. The comparative safety and effectiveness of TNF-alpha antagonists. J Manag Care Pharm. 2007;13:S7–18.PubMedGoogle Scholar
  133. 133.
    Curnis F, et al. Enhancement of tumor necrosis factor alpha antitumor immunotherapeutic properties by targeted delivery to aminopeptidase N (CD13). Nat Biotechnol. 2000;18:1185–90. doi: 10.1038/81183.PubMedCrossRefGoogle Scholar
  134. 134.
    Kianmanesh A, et al. Intratumoral administration of low doses of an adenovirus vector encoding tumor necrosis factor alpha together with naïve dendritic cells elicits significant suppression of tumor growth without toxicity. Hum Gene Ther. 2001;12:2035–49. doi: 10.1089/10430340152677395.PubMedCrossRefGoogle Scholar
  135. 135.
    Manusama ER, et al. Tumor necrosis factor-alpha in isolated perfusion systems in the treatment of cancer: the Rotterdam Preclinical-Clinical Program. Semin Surg Oncol. 1998;14:232–7. doi: 10.1002/(SICI)1098-2388(199804/05)14:3<232::AID-SSU7>3.0.CO;2-9.PubMedCrossRefGoogle Scholar
  136. 136.
    Lewis JD. Anti-TNF antibodies for Crohn’s disease- In pursuit of the perfect clinical trial. N Engl J Med. 2007;357:296–8. doi: 10.1056/NEJMe078111.PubMedCrossRefGoogle Scholar
  137. 137.
    Graves JE, Nunley K, Heffernan MP. Off-label uses of biologics in dermatology: Rituximab, Omalizumab, Infliximab, Etanercept, Adalimumab, Efalizumab, and Alefacept (Part 2 of 2). J Am Acad Dermatol. 2007;56:e55–79. doi: 10.1016/j.jaad.2006.07.019.PubMedCrossRefGoogle Scholar
  138. 138.
    Hochberg MC, Tracy JK, Hawkins-Holt M, Flores RH. Comparison of the efficacy of the tumour necrosis factor blocking agents Adalimumab, Etanercept, and Infliximab when added to methotrexate in patients with active rheumatoid arthritis. Ann Rheum Dis. 2003;62(Suppl II):ii13–6. doi: 10.1136/ard.62.suppl_2.ii13.PubMedGoogle Scholar
  139. 139.
    Doan QV, Chiou C-F, Dubois RW. Review of eight pharmacoeconomic studies of the value of biologic DMARDs (Adalimumab, Etanercept, and Infliximab) in the management of rheumatoid arthritis. J Manag Care Pharm. 2006;12:555–69.PubMedGoogle Scholar
  140. 140.
    Chen Y-F, et al. A systematic review of the effectiveness of Adalimumab, Etanercept and Infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness. Health Technol Assess 2006;10:iii–iv, xi–xiii, 1–229.Google Scholar
  141. 141.
    Thiéfin G, Morelet A, Heurgué A, Diebold M-D, Eschard J-P. Infliximab-induced hepatitis: absence of cross-toxicity with Etanercept. Joint Bone Spine. 2008;75:737–9. doi: 10.1016/j.jbspin.2007.12.009.PubMedCrossRefGoogle Scholar
  142. 142.
    Chang J, Girgis L. Clinical use of anti-TNF-alpha biological agents: A guide for GPs. Aust Fam Physician. 2007;36:1035–8.PubMedGoogle Scholar
  143. 143.
    Fonseca JE, et al. Recommendations for the diagnosis and treatment of latent and active tuberculosis in inflammatory joint diseases candidates for therapy with tumor necrosis factor alpha inhibitors—March 2008 update. Acta Reumatol Port. 2008;33:77–85.PubMedGoogle Scholar
  144. 144.
    Theis VS, Rhodes JM. Minimizing tuberculosis during anti-tumour necrosis factor-alpha treatment of inflammatory bowel disease. Aliment Pharmacol Ther. 2008;27:19–30.PubMedCrossRefGoogle Scholar
  145. 145.
    Gupta A, Street AC, Macrae FA. Tumour necrosis factor alpha inhibitors: screening for tuberculosis infection in inflammatory bowel disease. MJA. 2008;188:168–70.PubMedGoogle Scholar
  146. 146.
    Tayal V, Kalra B. Cytokines and anti-cytokines as therapeutics—an update. Eur J Pharmacol. 2008;579:1–12. doi: 10.1016/j.ejphar.2007.10.049.PubMedCrossRefGoogle Scholar
  147. 147.
    Schreiber S, et al. A randomized, placebo-controlled trial of Certolizumab pegol (CDP870) for treatment of Crohn’s disease. Gastroenterology. 2005;129:807–18. doi: 10.1053/j.gastro.2005.06.064.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2009

Authors and Affiliations

  • Inès Zidi
    • 1
    Email author
  • Souhir Mestiri
    • 1
  • Aghleb Bartegi
    • 1
  • Nidhal Ben Amor
    • 1
  1. 1.Laboratory of Biochemistry, Research Unit 02/UR/09-01High Institute of Biotechnology (Institut Supérieur de Biotechnologie)MonastirTunisia

Personalised recommendations