Synthesis of daunomycin-conjugated triplex-forming oligonucleotides that act as selective repressor of c-myc gene expression (Abstract/Poster in atti di convegno)

Type
Label
  • Synthesis of daunomycin-conjugated triplex-forming oligonucleotides that act as selective repressor of c-myc gene expression (Abstract/Poster in atti di convegno) (literal)
Anno
  • 2001-01-01T00:00:00+01:00 (literal)
Alternative label
  • Carlo V. Catapano, Eileen M. McGuffie, Giuseppina M. Carbone, Coutney E. Flanagan, Chiara Dembech, Federico Arcamone and Massimo L. Capobianco (2001)
    Synthesis of daunomycin-conjugated triplex-forming oligonucleotides that act as selective repressor of c-myc gene expression
    in 92nd Annual Meeting of the American Association for Cancer Research, New Orleans, 24-28 march 2001
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Carlo V. Catapano, Eileen M. McGuffie, Giuseppina M. Carbone, Coutney E. Flanagan, Chiara Dembech, Federico Arcamone and Massimo L. Capobianco (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#altreInformazioni
  • contribute #4563 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#volumeInCollana
  • 42 (literal)
Note
  • Abstract (literal)
  • Poster (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • ICOCEA-CNR, Bologna, Italy Medicinal University of South Carolina, Charleston (SC) (literal)
Titolo
  • Synthesis of daunomycin-conjugated triplex-forming oligonucleotides that act as selective repressor of c-myc gene expression (literal)
Abstract
  • Triplex-forming oligonucleotides (TFOs) that bind to homopurine:homopyrimidine sequences in DNA in a sequence specific manner can be used to selectively inhibit gene expression,. This strategy has proven to be successful in various experimental systems and may provide the opportunity for rational design of novel DNA sequence specific cancer therapeutics. Chemical modification of the TFO that would enhance triplex stability without affecting sequence specificity may further increase the efficacy of this approach. In the present study we evaluated DNA binding and anti-gene activity of daunomycin c-conjugated TFOs (D-TFOs) targeted to a sequence near the major P2 promoter in the c-myc gene. Daunomycin is an antitumoral drug and a potent DNA intercalator. GT-rich 11-mer TFOs (2S, 2Z and 2Z') were covalently attached to ring D of the anthraquinone mojety of daunomycin. This would correctly position the TFO in the major groove of the duplex and allow it to form Hoogsteen hydrogen bonds with the complementary bases of the purine rich strand of the target DNA. As shown by EMSA and DMS footprinting, the D-TFO 2S had high binding affinity and formed a much more stable triplex than the non-conjugated TFO. Binding of D-TFO 2S was also higly sequence-specific as indicated by the fact that it protected a single region corresponding to the 11-bp target sequence in the c-myc promoter. D-TFOs 2Z and 2Z' which were partially complementary to the c-myc target sequence, bound very weakly and with much lower affinity than D-TFO 2S. D-TFO 2S inhibited transcription in luciferase reporter assays, when co-trasfected into prostate cancer cells along with a pGL-myc promoter reporter plasmid. These data indicated that the attachment of daunomycin to the TFO increased its binding affinity and allowed formatio of a very stable complex with the duplex DNA. The presence of daunomycin did not affect bindng specificity, even with the short 11-mer TFO tested herein. Moreover, D-TFO 2S was able to selectively inhibit transcription of the c-myc gene both in vitro and in cells. These results encourage further testing of this approach for development of novel anti-gene therapeutics. (literal)
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