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1 Medical Research Council, Toxicology Unit, Hodgkin Building, University of Leicester, Leicester and 2 Manchester Interdisciplinary Biocentre, School of Chemical Engineering and Analytical Science, University of Manchester, The Mill, Manchester, United Kingdom
Requests for reprints: Gerald M. Cohen, Medical Research Council, Toxicology Unit, Hodgkin Building, University of Leicester, P.O. Box 138, Lancaster Road, Leicester LE1 9HN, United Kingdom. Phone: 44-116-252-5601; Fax: 44-116-252-5616; E-mail: gmc2{at}le.ac.uk.
Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and its agonistic antibodies, which are currently in early clinical trials for treating various malignancies, induce apoptosis through triggering of either TRAIL-R1 or TRAIL-R2. Based on studies using agonistic monoclonal antibodies, we recently proposed that primary chronic lymphocytic leukemic cells seem to signal apoptosis primarily through TRAIL-R1. We have now synthesized mutant forms of TRAIL specific for TRAIL-R1 or TRAIL-R2. The selectivity of these mutants to induce apoptosis in cell lines is due to selective binding to their cognate receptors resulting in apoptosis via formation of a death-inducing signaling complex. Using these mutants, we now unequivocally show that primary cells from patients with chronic lymphocytic leukemia and mantle cell lymphoma signal to apoptosis almost exclusively through TRAIL-R1. Thus, no significant therapeutic benefit can be anticipated from treating such patients with agents currently in clinical trials that signal predominantly through TRAIL-R2, such as HGS-ETR2 or Apo2L/TRAIL. Our study highlights the necessity to determine whether primary cells from a particular tumor signal via TRAIL-R1 or TRAIL-R2. Such information will provide a rational approach to optimize TRAIL therapy. (Cancer Res 2005; 65(24): 11265-70)
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 K. H. Young, D. D. Weisenburger, B. J. Dave, L. Smith, W. Sanger, J. Iqbal, E. Campo, J. Delabie, R. D. Gascoyne, G. Ott, et al. Mutations in the DNA-binding codons of TP53, which are associated with decreased expression of TRAILreceptor-2, predict for poor survival in diffuse large B-cell lymphoma Blood, December 15, 2007; 110(13): 4396 - 4405. [Abstract] [Full Text] [PDF]
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R. M. Locklin, E. Federici, B. Espina, P. A. Hulley, R. G. G. Russell, and C. M. Edwards Selective targeting of death receptor 5 circumvents resistance of MG-63 osteosarcoma cells to TRAIL-induced apoptosis Mol. Cancer Ther., December 1, 2007; 6(12): 3219 - 3228. [Abstract] [Full Text] [PDF]
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 M. J.S. Dyer, M. MacFarlane, and G. M. Cohen Barriers to Effective TRAIL-Targeted Therapy of Malignancy J. Clin. Oncol., October 1, 2007; 25(28): 4505 - 4506. [Full Text] [PDF]
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L. Bin, J. Thorburn, L. R. Thomas, P. E. Clark, R. Humphreys, and A. Thorburn Tumor-derived Mutations in the TRAIL Receptor DR5 Inhibit TRAIL Signaling through the DR4 Receptor by Competing for Ligand Binding J. Biol. Chem., September 21, 2007; 282(38): 28189 - 28194. [Abstract] [Full Text] [PDF]
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G. Roue, P. Perez-Galan, M. Lopez-Guerra, N. Villamor, E. Campo, and D. Colomer Selective Inhibition of I{kappa}B Kinase Sensitizes Mantle Cell Lymphoma B Cells to TRAIL by Decreasing Cellular FLIP Level J. Immunol., February 1, 2007; 178(3): 1923 - 1930. [Abstract] [Full Text] [PDF]
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S. Inoue, A. Mai, M. J.S. Dyer, and G. M. Cohen Inhibition of Histone Deacetylase Class I but not Class II Is Critical for the Sensitization of Leukemic Cells to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis. Cancer Res., July 1, 2006; 66(13): 6785 - 6792. [Abstract] [Full Text] [PDF]
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