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

Ann N Y Acad Sci. 2005 Nov;1058:215-34. doi: 10.1196/annals.1359.032.

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.

Publication types

  • Review

MeSH terms

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

Substances

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