Discovery and Development of the G-rich Oligonucleotide AS1411 as a Novel Treatment for Cancer

By P. Bates, D. Laber, Donald M Miller, S. Thomas, John O. Trent. Experimental and molecular pathology (Print), 2009

801 citations recorded by the source corpus.

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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/c25b1875b2ad15109489ae00e1573a639cccbf11

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In Molecular Biology

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2. Changill Ban
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4. Bo-Shiun Lai
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6. Jinho Park
7. Yang Zhang
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Citations in the corpus

• Recent Advances in Aptamer Discovery and Applications (2019, background): “The anti-tumor activity of AS1411 stems from its ability to bind cell surface nucleolin, thereby inhibiting DNA synthesis, preventing cell growth signaling, and inducing apoptosis [156].”
• Targeting Strategies for Multifunctional Nanoparticles in Cancer Imaging and Therapy (2012, background): “AS1411, a nucleolin targeted aptamer, is in phase II of clinical development [112-114].”
• Aptamers as therapeutics (2010, background): “AS1411 is thought to elicit its therapeutic effects through its interaction with nucleolin 71 .”
• Nanomedicine in cancer therapy (2023, background): “235 236 – 238 AS1411 is a 26-mer G-quadruplex DNA oligonucleotide that was discovered owing to its robust cancer-selective antiproliferative activity and subsequently identi fi ed as an aptamer targeting nucleolin, a multifunctional protein that is overexpressed in the nucleolus, cytoplasm as well…”
• Aptamers and Their Biological Applications (2012, background): “In addition, many aptamer-based drugs, such as AS1411 (a nuclein-specific aptamer) for acute myeloid leukemia, ARC1779 (a vonWillebrand factor-specific aptamer) for carotid artery disease, and NU172 (a thrombin-specific aptamer) for anticoagulation, are currently in a clinical trials [80–86].”
• Aptamers in the Therapeutics and Diagnostics Pipelines (2018, background): “AS1411, previously named ARGO100, forms a G-quadruplex structure and is the first aptamer in clinical trials for the treatment of human cancer [40-42].”