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

Stephen B. Boulware, Laura A. Christensen, Howard Thames, Lezlee Coghlan, Karen M. Vasquez, Rick A. Finch

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)744-752
Number of pages9
JournalMolecular Carcinogenesis
Volume53
Issue number9
DOIs
StatePublished - Sep 2014

Keywords

  • Combination chemotherapy
  • DNA-reactive agents
  • Oncogenes
  • Triplex-forming oligonucleotides
  • Xenograft models

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

MD Anderson CCSG core facilities

  • Biostatistics

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