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

• Published in: Experimental and molecular pathology Vol. 86; no. 3; pp. 151 - 164
• Main Authors: Bates, Paula J., Laber, Damian A., Miller, Donald M., Thomas, Shelia D., Trent, John O.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.06.2009
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - therapeutic use; Aptamer; Aptamers, Nucleotide; AS1411; Cell Proliferation - drug effects; Clinical Trials as Topic; Drug Discovery; Drug Screening Assays, Antitumor; Dz13; G-quartets; G-rich oligonucleotides; Humans; Molecular Structure; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; NF-kappaB; Nucleolin; Oligodeoxyribonucleotides - chemistry; Oligodeoxyribonucleotides - therapeutic use; Phosphoproteins - drug effects; Phosphoproteins - metabolism; PRMT5; Quadruplex; RNA-Binding Proteins - drug effects; RNA-Binding Proteins - metabolism; T-oligos; T-oligos; PRMT5; G-rich oligonucleotides; AS1411; Dz13; Aptamer; NF-kappaB; Quadruplex; G-quartets; Nucleolin
• ISSN: 0014-4800; 1096-0945; 1096-0945
• DOI: 10.1016/j.yexmp.2009.01.004

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.