G-rich oligonucleotides for cancer treatment.
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.
Bates
Paula J
PJ
University of Louisville, Louisville, KY, USA.
Choi
Enid W
EW
Nayak
Lalitha V
LV
D002470:Cell Survival / Q000187:drug effects; D002942:Circular Dichroism; D003851:Deoxyribonucleases / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D006151:Guanosine / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008967:Molecular Biology / Q000379:methods*; D009369:Neoplasms / Q000628:therapy*; D009691:Nucleic Acid Denaturation / Q000187:drug effects; D009695:Nucleic Acid Renaturation / Q000187:drug effects; D009841:Oligonucleotides / Q000032:analysis / Q000494:pharmacology*; D011868:Radioisotopes; D013194:Staining and Labeling; D013242:Sterilization
D009841:Oligonucleotides; D011868:Radioisotopes; D006151:Guanosine; D003851:Deoxyribonucleases