Efficiency of recombinant human TNF in human cancer therapy.
Recombinant human tumour necrosis factor (TNF) has a selective effect on angiogenic vessels in tumours. Given that it induces vasoplegia, its clinical use has been limited to administration through isolated limb perfusion (ILP) for regionally advanced melanomas and soft tissue sarcomas of the limbs. When combined with the alkylating agent melphalan, a single ILP produces a very high objective response rate. In melanoma, the complete response (CR) rate is around 80% and the overall objective response rate greater than 90%. In soft tissue sarcomas that are inextirpable, ILP is a neoadjuvant treatment resulting in limb salvage in 80% of the cases. The CR rate averages 20% and the objective response rate is around 80%. The mode of action of TNF-based ILP involves two distinct and successive effects on the tumour-associated vasculature: first, an increase in endothelium permeability leading to improved chemotherapy penetration within the tumour tissue, and second, a selective killing of angiogenic endothelial cells resulting in tumour vessel destruction. The mechanism whereby these events occur involves rapid (of the order of minutes) perturbation of cell-cell adhesive junctions and inhibition of alphavbeta3 integrin signalling in tumour-associated vessels, followed by massive death of endothelial cells and tumour vascular collapse 24 hours later. New, promising approaches for the systemic use of TNF in cancer therapy include TNF targeting by means of single chain antibodies or endothelial cell ligands, or combined administration with drugs perturbing integrin-dependent signalling and sensitizing angiogenic endothelial cells to TNF-induced death.
Multidisciplinary Oncology Centre (CePO), Lausanne, Switzerland.
Ferdy J
FJ
Lejeune
Danielle
D
Liénard
Maurice
M
Matter
Curzio
C
Rüegg
D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D010478:Chemotherapy, Cancer, Regional Perfusion; D002986:Clinical Trials as Topic; D005260:Female; D006801:Humans; D007249:Inflammation / Q000139:chemically induced; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary; D008297:Male; D008545:Melanoma / Q000098:blood supply / Q000188:drug therapy / Q000556:secondary; D008558:Melphalan / Q000008:administration & dosage / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D009369:Neoplasms / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000503:physiopathology; D012516:Osteosarcoma / Q000188:drug therapy; D011487:Protein Conformation; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D012074:Remission Induction; D012509:Sarcoma / Q000098:blood supply / Q000188:drug therapy; D012983:Soft Tissue Neoplasms / Q000098:blood supply / Q000188:drug therapy; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D039302:Integrin alphaVbeta3; D009363:Neoplasm Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; C069521:recombinant human tumor necrosis factor-binding protein-1; D008558:Melphalan