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

Bates, Paula J.; Laber, Damian A.; Miller, Donald M.; Thomas, Shelia D.; Trent, John O.

doi:10.1016/j.yexmp.2009.01.004

Cited by 874DNA and Nucleic Acid ChemistryAdvanced biosensing and bioanalysis techniquesRNA Interference and Gene Delivery

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

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Bates, Paula J., Laber, Damian A., Miller, Donald M., Thomas, Shelia D., Trent, John O.·2009·Experimental and Molecular Pathology

DOI 10.1016/j.yexmp.2009.01.004PMC PMC2716701

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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.

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AS1411 aptamer specifically binds to nucleolin, which is highly expressed on nucleus and tumor cell membranes.
“AS1411 aptamer is a 26-molecule DNA oligonucleotide accidentally discovered by Bates et al.253 It can specifically bind to nucleolin, which is highly expressed on the nucleus and on the surface of tumor cell membranes.254”
From Smart nanoparticles for cancer therapy (2023) · cites this paper as [253]

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[119]Girvan AC 2006 Mechanistic studies of guanine-rich oligonucleotides (Doctoral Dissertation) University of Louisville Electronic Theses and Dissertations

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Authors: Bates, P. J., Laber, D. A., Miller, D. M., Thomas, S. D., & Trent, J. O.
Affiliations: University of Louisville (US)
Corresponding author: Bates, Paula J.
ORCID: Bates, Paula J.
Laber, Damian A.
Miller, Donald M.
Thomas, Shelia D.
Trent, John O.
Venue: Experimental and Molecular Pathology
Publisher: Elsevier BV
Published: 2009-06
Volume: 86
Issue: 3
Pages: 151-164
ISSN: 0014-4800 (ISSN-L)
DOI: 10.1016/j.yexmp.2009.01.004
PMC: PMC2716701
OpenAlex: W2041919391
Cited by: 874
References: 172
Citations by year: 2026: 40 · 2025: 50 · 2024: 48 · 2023: 60 · 2022: 65 · 2021: 61 · 2020: 59 · 2019: 68 · 2018: 67 · 2017: 55 · 2016: 54 · 2015: 65 · 2014: 41 · 2013: 44 · 2012: 40
FWCI: 2.39
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Experimental and Molecular Pathology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Cancer Institute (R01CA113735, R01CA122383, R21CA104230, R21CA091115)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Advanced biosensing and bioanalysis techniques
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Keywords: AS1411, G-rich oligonucleotides, G-quadruplex, aptamers, nucleolin, anticancer agents, phosphodiester oligonucleotides, cancer therapy
MeSH terms: Nucleolin, Animals, Antineoplastic Agents, Clinical Trials as Topic, Drug Screening Assays, Antitumor, Humans, Neoplasms, Oligodeoxyribonucleotides, Phosphoproteins, Molecular Structure, RNA-Binding Proteins, Cell Proliferation, Aptamers, Nucleotide, Drug Discovery

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

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