Triplex-forming oligonucleotides targeting c-MYC potentiate the anti-tumor activity of gemcitabine in a mouse model of human cancer

Mol Carcinog. 2014 Sep;53(9):744-52. doi: 10.1002/mc.22026. Epub 2013 May 16.

Abstract

Antimetabolite chemotherapy remains an essential cancer treatment modality, but often produces only marginal benefit due to the lack of tumor specificity, the development of drug resistance, and the refractoriness of slowly proliferating cells in solid tumors. Here, we report a novel strategy to circumvent the proliferation-dependence of traditional antimetabolite-based therapies. Triplex-forming oligonucleotides (TFOs) were used to target site-specific DNA damage to the human c-MYC oncogene, thereby inducing replication-independent, unscheduled DNA repair synthesis (UDS) preferentially in the TFO-targeted region. The TFO-directed UDS facilitated incorporation of the antimetabolite, gemcitabine (GEM), into the damaged oncogene, thereby potentiating the anti-tumor activity of GEM. Mice bearing COLO 320DM human colon cancer xenografts (containing amplified c-MYC) were treated with a TFO targeted to c-MYC in combination with GEM. Tumor growth inhibition produced by the combination was significantly greater than with either TFO or GEM alone. Specific TFO binding to the genomic c-MYC gene was demonstrated, and TFO-induced DNA damage was confirmed by NBS1 accumulation, supporting a mechanism of enhanced efficacy of GEM via TFO-targeted DNA damage-induced UDS. Thus, coupling antimetabolite chemotherapeutics with a strategy that facilitates selective targeting of cells containing amplification of cancer-relevant genes can improve their activity against solid tumors, while possibly minimizing host toxicity.

Keywords: DNA-reactive agents; combination chemotherapy; oncogenes; triplex-forming oligonucleotides; xenograft models.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols
  • Chromatin Immunoprecipitation
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / pathology
  • Colonic Neoplasms / prevention & control*
  • DNA, Neoplasm / genetics*
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Drug Synergism*
  • Female
  • Gemcitabine
  • Humans
  • Mice
  • Mice, Nude
  • Oligonucleotides / pharmacology*
  • Proto-Oncogene Proteins c-myc / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Antimetabolites, Antineoplastic
  • DNA, Neoplasm
  • MYC protein, human
  • Oligonucleotides
  • Proto-Oncogene Proteins c-myc
  • Deoxycytidine
  • Gemcitabine