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G-Rich Oligonucleotides for Cancer Treatment

  • Paula J. Bates
  • Enid W. Choi
  • Lalitha V. Nayak
Protocol
Part of the Methods in Molecular Biology™ book series (MIMB, volume 542)

Summary

Oligonucleotides with guanosine-rich (G-rich) sequences often have unusual physical and biological properties, including resistance to nucleases, enhanced cellular uptake, and high affinity for particular proteins. Furthermore, we have found that certain G-rich oligonucleotides (GROs) have antiproliferative activity against a range of cancer cells, while having minimal toxic effects on normal cells. We have investigated the mechanism of this activity and studied the relationship between oligonucleotide structural features and biological activity. Our results indicate that the antiproliferative effects of GROs depend on two properties: the ability to form quadruplex structures stabilized by G-quartets and binding affinity for nucleolin protein. Thus, it appears that the antiproliferative GROs are acting as nucleolin aptamers. Because nucleolin is expressed at high levels on the surface of cancer cells, where it mediates the endocytosis of various ligands, it seems likely that nucleolin-dependent uptake of GROs plays a role in their activity. One of the GROs that we have developed, a 26-nucleotide phosphodiester oligodeoxynucleotide now named AS1411 (formerly AGRO100 or GRO26B-OH), is currently being tested as an anticancer agent in Phase II clinical trials.

Keywords

Aptamer cancer G-rich oligonucleotides G-quartets quadruplex nucleolin 

Notes

Acknowledgments and Disclosures

The work described herein was funded in part by the US National Cancer Institute and the US Department of Defense Prostate Cancer Program. In addition to these sources, the authors currently receive or have previously received funding from the Kentucky Lung Cancer Research Program, the Komen Breast Cancer Foundation, the University of Louisville, and Antisoma PLC (London, England). Paula J. Bates owns shares in Antisoma.

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Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Paula J. Bates
    • 1
  • Enid W. Choi
    • 2
  • Lalitha V. Nayak
    • 3
  1. 1.Departments of Medicine and Biochemistry & Molecular BiologyBrown Cancer Center, University of LouisvilleKentuckyUSA
  2. 2.Department of Biochemistry & Molecular BiologyBrown Cancer Center, University of LouisvilleKentuckyUSA
  3. 3.Department of MedicineBrown Cancer Center, University of LouisvilleKentuckyUSA

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