Targeted induction of apoptosis in cancer management: the emerging role of tumor necrosis factor-related apoptosis-inducing ligand receptor activating agents.
Targeted induction of programmed cell death or apoptosis via the extrinsic apoptotic pathway represents an unexploited therapeutic strategy to destroy cancer cells. The activation of cell surface receptors by the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) results in direct stimulation of apoptotic signaling pathways (extrinsic stimulation). Molecules that directly activate these receptors, such as agonistic monoclonal antibodies to the TRAIL receptors and recombinant TRAIL, are being developed as monotherapies and as part of combination therapies with existing chemotherapeutic drugs and other therapeutic modalities. This article examines the TRAIL receptors as potential targets for activating the TRAIL-mediated apoptosis pathway and presents the current status of novel therapeutics that exploit this pathway, particularly focusing on agonistic monoclonal antibodies to the TRAIL receptors. The preclinical activity, the status of ongoing evaluations, and the potential clinical impact of these novel agents are reviewed.
Rowinsky
Eric K
EK
ImClone Systems, Branchburg, NJ 08876, USA. erowinsky@oncodrugs.com
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D002986:Clinical Trials as Topic; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D009369:Neoplasms / Q000188:drug therapy / Q000503:physiopathology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000502:physiology; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha