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Features that determine telomere homolog oligonucleotide-induced therapeutic DNA damage-like responses in cancer cells.

Abstract
Cancer is the second leading cause of death in the USA, with metastatic disease proving a particular management challenge. Treatment modalities for patients with metastatic disease are limited, and survival beyond 5 years is uncommon. We have reported that an 11-base DNA oligonucleotide 100% homologous to the telomere 3' overhang can induce apoptosis, senescence and/or differentiation of several types of malignant cells in vitro and in vivo, while having minimal effect on normal cells. We now report that 22 oligonucleotides, 9-20 bases in length, with or without a 5' phosphate group and with varying homology (40-100%) to the 3' overhang, inhibit growth and induce apoptosis of human cell lines derived from breast cancers, pancreatic and ovarian carcinomas, and malignant melanoma, lines that lack p53 and/or p16 and harbor a variety of other abnormalities in key regulatory signaling pathways. Cytosine (C) content adversely affected oligonucleotide efficacy, decreasing their effect on cellular apoptosis by > or =80%. These data confirm and expand our earlier work suggesting that such telomere homolog oligonucleotides (T-oligos) target an innate anti-cancer defense system in human cells and may provide an effective treatment for cancers of multiple different cellular origins and genetic profile.
AuthorsNorio Ohashi, Mina Yaar, Mark S Eller, Francesca Truzzi, Barbara A Gilchrest
JournalJournal of cellular physiology (J Cell Physiol) Vol. 210 Issue 3 Pg. 582-95 (Mar 2007) ISSN: 0021-9541 [Print] United States
PMID17133364 (Publication Type: Journal Article)
CopyrightCopyright 2006 Wiley-Liss, Inc.
Chemical References
  • DNA, Neoplasm
  • H2AX protein, human
  • Histones
  • Oligonucleotides
Topics
  • Aging (drug effects)
  • Apoptosis (drug effects)
  • Cell Line, Tumor
  • Cell Nucleus (pathology)
  • Cell Proliferation (drug effects)
  • Cell Transformation, Neoplastic (drug effects)
  • DNA Damage (genetics)
  • DNA, Neoplasm (drug effects, genetics)
  • Histones (metabolism)
  • Humans
  • Neoplasms (drug therapy, genetics, pathology)
  • Oligonucleotides (chemistry, genetics, pharmacology)
  • Phosphorylation (drug effects)
  • S Phase (drug effects)
  • Telomere (genetics)

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