Immunologia Ilaria Pelassa Tumor Necrosis Factor Tumor Necrosis Factor A.A. 2006- 2007
TNF Receptor Family TNF Receptor Family Dempsey P.W. et al. , The signaling adaptors and pathways activated by TNF superfamily Cytokine & Growth Factor Reviews , 14 :193 ,2003
LIFE OR DEATH ? Remco v. H. et al.,TNF-α in Cancer Treatment, The Oncologist , 11 : 397, 2006
Who decides the fate? Who decides the fate? DEATH DOMAIN MOLECULES DEATH DOMAIN MOLECULES FADD FAS Associated Death Domain ADAPTORS TRADD TNFR Associated Death Domain Locksley R.M. , et al., The TNF and TNF Receptor Superfamilies , Cell, 104 : 487, 2001
TRAFs TRAFs Wajant H. et al. TNF receptor associated factors in cytokine signaling/ Cytokine & Growth Factor Reviews, 10 : 15, 1999
ITS PLEIOTROPIC PROPERTIES LEAD TO….
TNF ANTI-NEOPLASTIC EFFECTS ANTITUMOR IMMUNITY DIRECT VASCULAR EFFECT CYTOTOXIC SYNERGISM WITH EFFECTS ANTINEOPLASTIC AGENTS
TNF TUMOR PROMOTING EFFECTS LOW DOSE TNF IN VITRO: ACTIVATION OF: NF-KB UPREGULATION RAS and C-MYC PI3K-PKB DOWNREGULATION Cdk-Inhibitors MAPK PRO-SURVIVAL K.O. EXPERIMENTS: PATHWAYS HIGHER INCIDENCE OF CANCER IN ANIMAL TNF+/+
TNF VASCULAR EFFECTS
TUMOR ANGIOGENESIS TUMOR ANGIOGENESIS Remco v. H. et al.,TNF-α in Cancer Treatment, The Oncologist , 11:397 ,2006
HYPOTHETICAL MECHANISM OF TNF-α α HYPOTHETICAL MECHANISM OF TNF- TNFR1 INTACT HEALTHY ENDOTHELIUM UPREGULATION Remco v. H. et al.,TNF-α in Cancer Treatment, The Oncologist , 11:397 ,2006
NEW AND INNOVATIVE APPROACH WHICH COMBINES : - VASCULAR EFFECT - SYNERGISM WITH ANTINEOPLASTIC AGENTS
ISOLATED LIMB PERFUSION WITH ANTICANCER AGENTS ISOLATED LIMB PERFUSION WITH ANTICANCER AGENTS (ILP) (ILP) Lejeune F.J., Efficiency of recombinant human TNF in human cancer therapy Cancer Immunity, 6: 6 , 2006
RESULTS COMBINATION TREATMENTS: Efficacy of TIM-ILP on bulky melanoma metastasis TNF , INF-γ , Melphalan (TIM-ILP) TNF , Melphalan (TM-ILP) Melphalan (M-ILP)
ISOLATED LIMB PERFUSION ISOLATED LIMB PERFUSION ADVANTAGES DISADVANTAGES ADVANTAGES DISADVANTAGES 80-90% Complete Response In metastatic stage the patient dies 80-90% Complete Response In metastatic stage the patient dies - - Avoid amputation of the limb Avoid amputation of the limb - Only local administration Only local administration - Used in Sarcoma, Melanoma and Used in Sarcoma, Melanoma and - liver with Hepatic Perfusion Low concentration of TNF liver with Hepatic Perfusion Low concentration of TNF - promotes angiogenesis promotes angiogenesis No toxicity of TNF No toxicity of TNF - Surgical Approach Surgical Approach - Selective accumulation of drugs Selective accumulation of drugs - inside the tumor inside the tumor
CANCER IMMUNOTHERAPY
Smyth M.J. et al.,Nature’s TRAIL On a Path to Cancer Immunotherapy, Immunity, 18: 1 , 2003
Lu G. et al.,Innate Direct Anticancer Effector Function of Human Immature Dendritic Cells. The Journal of Immunology, 168: 1831, 2002
WHAT HAPPENS? TRAIL TNF TRAILR TNFR LT FAS L FASLR DENDRITIC CELL LTR TUMOR CELL APOPTOSIS
“ Defining the role of TNF in cancer therapy is a challenging task. The pleiotropic nature of the cytokine, which can stimulate multiple, complexly interconnected pathways often involved in opposing phenomena, makes it difficult to discern the ultimate effect of TNF ” Mocellin S. et al. , Tumor necrosis factor, cancer and anticancer therapy, Cytokine & Growth Factor Reviews, 16:35 , 2005
BIBLIOGRAPHY BIBLIOGRAPHY Remco v. H. et al.,TNF-α in Cancer Treatment, The Oncologist , 11:397 ,2006 Pfeffer K. , Biological functions of tumor necrosis factor cytokines and their receptors, Cytokine & Growth Factor Reviews 14 : 185 , 2003 Dempsey P.W. et al. , The signaling adaptors and pathways activated by TNF superfamily, Cytokine & Growth Factor Reviews , 14 :193 ,2003 Wajant H. et al. TNF receptor associated factors in cytokine signaling / Cytokine & Growth Factor Reviews 10: 15, 1999 Locksley R.M., et al. , The TNF and TNF Receptor Superfamilies, Cell, 104:487, 2001 Mocellin S. et al. , Tumor necrosis factor, cancer and anticancer therapy, Cytokine & Growth Factor Reviews, 16:35 , 2005 Palladino M.A.et al. , Anti-Tnf-α therapies : the next generation, Nature, 2:736,2003 Atish T. P.et al., Modulating TNF-a signaling with natural products, Drug Discovery Today 11:15,2006 Lejeune F.J.,et al., Efficiency of recombinant human TNF in human cancer therapy, Cancer Immunity, 6: 6 , 2006 Smyth M.J. et al.,Nature’s TRAIL On a Path to Cancer Immunotherapy, Immunity, 18: 1 , 2003 Lu G. et al.,Innate Direct Anticancer Effector Function of Human Immature Dendritic Cells. The Journal of Immunology, 168: 1831, 2002
Kanduc D. et al, Cell death: Apoptosis versus necrosis, Int Journal of Oncology , 21: 165 , 2002 Lucas R. et al. , Tumor Necrosis Factor : How to make a killer molecule tumor- specific? , Curr Can Drug Targets, 5:381, 2005 Schreiber R.D., Cancer Vaccines 2004 opening address: The molecular and cellular basis of cancer immunosurveillance and immunoediting, Cancer Immunity, 5: 1, 2005 Dunn G. P. et al., The Immunobiology of Cancer Immunosurveillance and Immunoediting, Immunity, 21 : 137, 2004 Kumar A. et al.,Tumor Necrosis Factor et and Interleukin 1 Are Responsible for In Vitro Myocardial Cell Depression Induced by Human Septic Shock Serum, j. Exp . Med.,183 1996 EckS M.J. et al., The Structure of Tumor Necrosis Factor-alpha at 2.6 A Resolution, The Journal of Biological Chemistry, 264: 17595,1989 Wiley S. R. et al., TWEAK a member of the TNF superfamily, Cytokine & Growth Factor Reviews 14 : 241,2003 Benedict C. A..,Viruses and the TNF-related cytokines, an evolving battle, Cytokine & Growth Factor Reviews 14 : 349,2003
Recommend
More recommend
