Application of XIAP antisense to cancer and other proliferative disorders: development of AEG35156/ GEM640.

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.

• Authors: Eric C Lacasse, Ekambar R Kandimalla, Peter Winocour, Tim Sullivan, Sudhir Agrawal, John W Gillard, Jon Durkin
• Journal: Annals of the New York Academy of Sciences (Ann N Y Acad Sci) Vol. 1058 Pg. 215-34 (Nov 2005) ISSN: 0077-8923 [Print] United States
• PMID: 16394139 (Publication Type: Journal Article, Review)

Chemical References

• AEG 35156
• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• Enzyme Inhibitors
• Oligonucleotides
• Oligonucleotides, Antisense
• RNA, Messenger
• X-Linked Inhibitor of Apoptosis Protein

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Apoptosis Regulatory Proteins
• Clinical Trials as Topic
• Enzyme Inhibitors (pharmacology)
• Gene Expression Regulation, Enzymologic
• Humans
• Neoplasms (metabolism, therapy)
• Oligonucleotides (pharmacology)
• Oligonucleotides, Antisense (chemistry)
• RNA, Messenger (metabolism)
• X-Linked Inhibitor of Apoptosis Protein (genetics, metabolism)