Discovery and development of the G-rich oligonucleotide AS1411 as a novel treatment for cancer.
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.
Bates
Paula J
PJ
James Graham Brown Cancer Center, Department of Medicine, University of Louisville, Louisville, Kentucky 40202, USA. paula.bates@louisville.edu
Laber
Damian A
DA
Miller
Donald M
DM
Thomas
Shelia D
SD
Trent
John O
JO
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D052157:Aptamers, Nucleotide; D049109:Cell Proliferation / Q000187:drug effects; D002986:Clinical Trials as Topic; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000627:therapeutic use*; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D000097796:Nucleolin
D000970:Antineoplastic Agents; D052157:Aptamers, Nucleotide; D009838:Oligodeoxyribonucleotides; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D000097796:Nucleolin; C513936:AGRO 100