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Using Human Observations to Gain Biologic Insights and New Treatments; Discovery of a Quadruplex-Forming DNA Aptamer as an Anticancer Agent

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The Primo Vascular System

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Abstract

The discovery and characterization of the primo vascular system represents a major new development in our understanding of human biology. The current understanding of this novel system is based on careful observations over an extended period of time. We have, in an analogous fashion, used clinical observations in patients with malignant diseases to develop new insights which have led to novel types of therapies. Beginning with the observation, in 1979, of in vivo differentiation of chronic myelogenous leukemia cells in a patient treated with the RNA synthesis inhibitor, mithramycin, we have characterized the ability of DNA binding compounds to inhibit gene expression. As a result of this work, we have discovered a quadruplex-forming, DNA aptamer, AS1411, which has significant anticancer activity with very little toxicity. AS1411 is currently in Phase IIb studies. We have recently shown that genomic quadruplex-forming sequences are selectively toxic to transformed cells and have therapeutic potential.

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References

  1. Koller CA et al (1985) In vivo differentiation of blast-phase chronic granulocytic leukemia. Expression of c-myc and c-abl protooncogenes. J Clin Invest 76(1):365–369

    Article  PubMed  CAS  Google Scholar 

  2. Koller CA, Miller DM (1986) Preliminary observations on the therapy of the myeloid blast phase of chronic granulocytic leukemia with plicamycin and hydroxyurea. N Engl J Med 315(23):1433–1438

    Article  PubMed  CAS  Google Scholar 

  3. Ray R et al (1989) Mithramycin blocks protein binding and function of the SV40 early promoter. J Clin Invest 83(6):2003–2007

    Article  PubMed  CAS  Google Scholar 

  4. Miller DM et al (1987) Mithramycin selectively inhibits transcription of G-C containing DNA. Am J Med Sci 294(5):388–394

    Article  PubMed  CAS  Google Scholar 

  5. Snyder RC et al (1991) Mithramycin blocks transcriptional initiation of the c-myc P1 and P2 promoters. Biochemistry 30(17):4290–4297

    Article  PubMed  CAS  Google Scholar 

  6. Snyder RC, Miller DM (1992) Regulation of c-myc transcription initiation and elongation. Crit Rev Oncog 3(3):283–291

    PubMed  CAS  Google Scholar 

  7. Chen SJ et al (1994) Mithramycin inhibits myointimal proliferation after balloon injury of the rat carotid artery in vivo. Circulation 90(5):2468–2473

    PubMed  CAS  Google Scholar 

  8. Blume SW et al (1991) Mithramycin inhibits SP1 binding and selectively inhibits transcriptional activity of the dihydrofolate reductase gene in vitro and in vivo. J Clin Invest 88(5):1613–1621

    Article  PubMed  CAS  Google Scholar 

  9. Felsenfeld G, Rich A (1957) Studies on the formation of two- and three-stranded polyribonucleotides. Biochim Biophys Acta 26(3):457–468

    Article  PubMed  CAS  Google Scholar 

  10. Jain A, Wang G, Vasquez KM (2008) DNA triple helices: biological consequences and therapeutic potential. Biochimie 90(8):1117–1130

    Article  PubMed  CAS  Google Scholar 

  11. Ebbinghaus SW et al (1993) Triplex formation inhibits HER-2/neu transcription in vitro. J Clin Invest 92(5):2433–2439

    Article  PubMed  CAS  Google Scholar 

  12. Gee JE et al (1992) Triplex formation prevents Sp1 binding to the dihydrofolate reductase promoter. J Biol Chem 267(16):11163–11167

    PubMed  CAS  Google Scholar 

  13. Helm CW et al (1993) A unique c-myc-targeted triplex-forming oligonucleotide inhibits the growth of ovarian and cervical carcinomas in vitro. Gynecol Oncol 49(3):339–343

    Article  PubMed  CAS  Google Scholar 

  14. Mayfield C et al (1994) Triplex formation by the human Ha-ras promoter inhibits Sp1 binding and in vitro transcription. J Biol Chem 269(27):18232–18238

    PubMed  CAS  Google Scholar 

  15. Bates PJ et al (1999) Antiproliferative activity of G-rich oligonucleotides correlates with protein binding. J Biol Chem 274(37):26369–26377

    Article  PubMed  CAS  Google Scholar 

  16. Gellert M, Lipsett MN, Davies DR (1962) Helix formation by guanylic acid. Proc Natl Acad Sci U S A 48:2013–2018

    Article  PubMed  CAS  Google Scholar 

  17. Burge S et al (2006) Quadruplex DNA: sequence, topology and structure. Nucleic Acids Res 34(19):5402–5415

    Article  PubMed  CAS  Google Scholar 

  18. Gilbert DE, Feigon J (1999) Multistranded DNA structures. Curr Opin Struct Biol 9(3):305–314

    Article  PubMed  CAS  Google Scholar 

  19. Blume SW et al (1997) Divalent transition metal cations counteract potassium-induced quadruplex assembly of oligo(dG) sequences. Nucleic Acids Res 25(3):617–625

    Article  PubMed  CAS  Google Scholar 

  20. Du Z et al (2007) Enrichment of G4 DNA motif in transcriptional regulatory region of chicken genome. Biochem Biophys Res Commun 354(4):1067–1070

    Article  PubMed  CAS  Google Scholar 

  21. Eddy J, Maizels N (2006) Gene function correlates with potential for G4 DNA formation in the human genome. Nucleic Acids Res 34(14):3887–3896

    Article  PubMed  CAS  Google Scholar 

  22. Huppert JL, Balasubramanian S (2007) G-quadruplexes in promoters throughout the human genome. Nucleic Acids Res 35(2):406–413

    Article  PubMed  CAS  Google Scholar 

  23. Ambrus A et al (2005) Solution structure of the biologically relevant G-quadruplex element in the human c-MYC promoter. Implications for G-quadruplex stabilization Biochemistry 44(6):2048–2058

    CAS  Google Scholar 

  24. Palumbo SL et al (2008) A novel G-quadruplex-forming GGA repeat region in the c-myb promoter is a critical regulator of promoter activity. Nucleic Acids Res 36(6):1755–1769

    Article  PubMed  CAS  Google Scholar 

  25. Cogoi S, Xodo LE (2006) G-quadruplex formation within the promoter of the KRAS proto-oncogene and its effect on transcription. Nucleic Acids Res 34(9):2536–2549

    Article  PubMed  CAS  Google Scholar 

  26. Dai J et al (2006) NMR solution structure of the major G-quadruplex structure formed in the human BCL2 promoter region. Nucleic Acids Res 34(18):5133–5144

    Article  PubMed  CAS  Google Scholar 

  27. Dai J et al (2006) An intramolecular G-quadruplex structure with mixed parallel/antiparallel G-strands formed in the human BCL-2 promoter region in solution. J Am Chem Soc 128(4):1096–1098

    Article  PubMed  CAS  Google Scholar 

  28. Murchie AI, Lilley DM (1992) Retinoblastoma susceptibility genes contain 5′ sequences with a high propensity to form guanine-tetrad structures. Nucleic Acids Res 20(1):49–53

    Article  PubMed  CAS  Google Scholar 

  29. De Armond R et al (2005) Evidence for the presence of a guanine quadruplex forming region within a polypurine tract of the hypoxia inducible factor 1alpha promoter. Biochemistry 44(49):16341–16350

    Article  PubMed  Google Scholar 

  30. Fry M (2007) Tetraplex DNA and its interacting proteins. Front Biosci 12:4336–4351

    Article  PubMed  CAS  Google Scholar 

  31. Kan ZY et al (2007) G-quadruplex formation in human telomeric (TTAGGG)4 sequence with complementary strand in close vicinity under molecularly crowded condition. Nucleic Acids Res 35(11):3646–3653

    Article  PubMed  CAS  Google Scholar 

  32. Sundquist WI, Klug A (1989) Telomeric DNA dimerizes by formation of guanine tetrads between hairpin loops. Nature 342(6251):825–829

    Article  PubMed  CAS  Google Scholar 

  33. Sen D, Gilbert W (1988) Formation of parallel four-stranded complexes by guanine-rich motifs in DNA and its implications for meiosis. Nature 334(6180):364–366

    Article  PubMed  CAS  Google Scholar 

  34. Sundquist WI, Heaphy S (1993) Evidence for interstrand quadruplex formation in the dimerization of human immunodeficiency virus 1 genomic RNA. Proc Natl Acad Sci U S A 90(8):3393–3397

    Article  PubMed  CAS  Google Scholar 

  35. Fry M, Loeb LA (1994) The fragile X syndrome d(CGG)n nucleotide repeats form a stable tetrahelical structure. Proc Natl Acad Sci USA 91(11):4950–4954

    Article  PubMed  CAS  Google Scholar 

  36. Xu X et al (2001) Inhibition of DNA replication and induction of S phase cell cycle arrest by G-rich oligonucleotides. J Biol Chem 276(46):43221–43230

    Article  PubMed  CAS  Google Scholar 

  37. Anselmet A et al (2002) Non-antisense cellular responses to oligonucleotides. FEBS Lett 510(3):175–180

    Article  PubMed  CAS  Google Scholar 

  38. Buckheit RW Jr et al (1994) Potent and specific inhibition of HIV envelope-mediated cell fusion and virus binding by G quartet-forming oligonucleotide (ISIS 5320). AIDS Res Hum Retroviruses 10(11):1497–1506

    Article  PubMed  CAS  Google Scholar 

  39. Burgess TL et al (1995) The antiproliferative activity of c-myb and c-myc antisense oligonucleotides in smooth muscle cells is caused by a nonantisense mechanism. Proc Natl Acad Sci USA 92(9):4051–4055

    Article  PubMed  CAS  Google Scholar 

  40. Mata JE et al (1997) A hexameric phosphorothioate oligonucleotide telomerase inhibitor arrests growth of Burkitt’s lymphoma cells in vitro and in vivo. Toxicol Appl Pharmacol 144(1):189–197

    Article  PubMed  CAS  Google Scholar 

  41. Dapic V et al (2002) Antiproliferative activity of G-quartet-forming oligonucleotides with backbone and sugar modifications. Biochemistry 41(11):3676–3685

    Article  PubMed  CAS  Google Scholar 

  42. Girvan AC et al (2006) AGRO100 inhibits activation of nuclear factor-kappaB (NF-kappaB) by forming a complex with NF-kappaB essential modulator (NEMO) and nucleolin. Mol Cancer Ther 5(7):1790–1799

    Article  PubMed  CAS  Google Scholar 

  43. Laber DA, Taft BS, Kloecker GH, Bates PJ, Trent JO, Miller DM (2006) Extended phase I study of AS1411 in renal and non-small cell lung cancers. J Clin Oncol, ASCO Annual Meeting Proceedings. 24(No 18S):13098

    Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, 40202, USA

    Donald M. Miller

Authors
  1. Donald M. Miller
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  2. Shelia D. Thomas
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  3. Kara Sedoris
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  4. Ashraful Islam
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  5. David Muench
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  6. Cortney Clarkson
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  7. Charles A. Koller
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Corresponding author

Correspondence to Donald M. Miller .

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Editors and Affiliations

  1. , Advanced Institute of Convergence Techno, Seoul National University, Seoul, 443-270, Korea, Republic of (South Korea)

    Kwang-Sup Soh

  2. , Department of Chemical Engineering, University of Louisville, Louisville, 40292, Kentucky, USA

    Kyung A. Kang

  3. , Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE1 7RU, United Kingdom

    David K Harrison

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Miller, D.M. et al. (2012). Using Human Observations to Gain Biologic Insights and New Treatments; Discovery of a Quadruplex-Forming DNA Aptamer as an Anticancer Agent. In: Soh, KS., Kang, K., Harrison, D. (eds) The Primo Vascular System. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-0601-3_27

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