Discovery and development of the G-rich oligonucleotide AS1411 as a novel treatment for cancer

Exp Mol Pathol. 2009 Jun;86(3):151-64. doi: 10.1016/j.yexmp.2009.01.004. Epub 2009 Jan 20.

Abstract

Certain guanine-rich (G-rich) DNA and RNA molecules can associate intermolecularly or intramolecularly to form four stranded or "quadruplex" structures, which have unusual biophysical and biological properties. Several synthetic G-rich quadruplex-forming oligodeoxynucleotides have recently been investigated as therapeutic agents for various human diseases. We refer to these biologically active G-rich oligonucleotides as aptamers because their activities arise from binding to protein targets via shape-specific recognition (analogous to antibody-antigen binding). As therapeutic agents, the G-rich aptamers may have some advantages over monoclonal antibodies and other oligonucleotide-based approaches. For example, quadruplex oligonucleotides are non-immunogenic, heat stable and they have increased resistance to serum nucleases and enhanced cellular uptake compared to unstructured sequences. In this review, we describe the characteristics and activities of G-rich oligonucleotides. We also give a personal perspective on the discovery and development of AS1411, an antiproliferative G-rich phosphodiester oligonucleotide that is currently being tested as an anticancer agent in Phase II clinical trials. This molecule functions as an aptamer to nucleolin, a multifunctional protein that is highly expressed by cancer cells, both intracellularly and on the cell surface. Thus, the serendipitous discovery of the G-rich oligonucleotides also led to the identification of nucleolin as a new molecular target for cancer therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / therapeutic use*
  • Cell Proliferation / drug effects
  • Clinical Trials as Topic
  • Drug Discovery
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Structure
  • Neoplasms / drug therapy
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Oligodeoxyribonucleotides / chemistry
  • Oligodeoxyribonucleotides / therapeutic use*
  • Phosphoproteins / drug effects
  • Phosphoproteins / metabolism
  • RNA-Binding Proteins / drug effects
  • RNA-Binding Proteins / metabolism

Substances

  • AGRO 100
  • Antineoplastic Agents
  • Oligodeoxyribonucleotides
  • Phosphoproteins
  • RNA-Binding Proteins
  • nucleolin