title: Engineering death receptor ligands for cancer therapy.
abstract: CD95, TNFR1, TRAILR1 and TRAILR2 belong to a subgroup of TNF receptors which is characterized by a conserved cell death-inducing protein domain that connects these receptors to the apoptotic machinery of the cell. Activation of death receptors in malignant cells attracts increasing attention as a principle to fight cancer. Besides agonistic antibodies the major way to stimulate death receptors is the use of their naturally occurring "death ligands" CD95L, TNF and TRAIL. However, dependent from the concept followed to develop a death ligand-based therapy various limiting aspects have to be taken into consideration on the way to a "bedside" usable drug. Problems arise in particular from the cell associated transmembrane nature of the death ligands, the poor serum half life of the soluble fragments derived from the transmembrane ligands, the ubiquitous expression of the death receptors and the existence of additional non-death receptors of the death ligands. Here, we summarize strategies how these limitations can be overcome by genetic engineering.
authors.affiliation: Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany. harald.wajant@mail.uni-wuerzburg.de
authors.forename: Harald
authors.initials: H
authors.lastname: Wajant
authors.forename: Jeannette
authors.initials: J
authors.lastname: Gerspach
authors.forename: Klaus
authors.initials: K
authors.lastname: Pfizenmaier
mesh_terms: D017209:Apoptosis; D019281:Dimerization; D015195:Drug Design; D053222:Fas Ligand Protein / Q000378:metabolism; D005818:Genetic Engineering / Q000379:methods; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D008024:Ligands; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D011401:Promoter Regions, Genetic; D053218:Receptors, Death Domain / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*
chemical_list: D053222:Fas Ligand Protein; D008024:Ligands; D053218:Receptors, Death Domain; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human