1. Application of XIAP antisense to cancer and other proliferative disorders: development of AEG35156/ GEM640.
- Author
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Lacasse EC, Kandimalla ER, Winocour P, Sullivan T, Agrawal S, Gillard JW, and Durkin J
- Subjects
- Animals, Antineoplastic Agents pharmacology, Apoptosis, Apoptosis Regulatory Proteins, Clinical Trials as Topic, Enzyme Inhibitors pharmacology, Humans, Neoplasms metabolism, Oligonucleotides pharmacology, Oligonucleotides, Antisense chemistry, RNA, Messenger metabolism, Gene Expression Regulation, Enzymologic, Neoplasms therapy, X-Linked Inhibitor of Apoptosis Protein genetics, X-Linked Inhibitor of Apoptosis Protein metabolism
- Abstract
Targeting apoptosis control provides a novel therapeutic approach to the treatment of cancer and other proliferative disorders. We summarize the evidence for apoptosis deregulation in cancer and describe the pivotal role of XIAP, the X-linked Inhibitor-of-APoptosis. XIAP is the predominant inhibitor of caspases 3, 7 and 9 in cells, which suppresses the programmed cell death effector capability of these proteases. Evidence is presented validating XIAP as a cancer target. The inhibition or downregulation of XIAP in cancer cells lowers the apoptotic threshold, thereby inducing cell death and/or enhancing the cytotoxic action of chemotherapeutic agents. We describe the development of AEG35156 (also named GEM640), a second generation antisense compound targeting XIAP, from concept to in vivo preclinical proof-of-principle studies, through formal toxicology, and to a phase 1 clinical trial in cancer patients.
- Published
- 2005
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