DNA repair and gene therapy: Implications for translational uses

Melissa Limp-Foster, Mark R. Kelley

Research output: Contribution to journalReview article

32 Scopus citations

Abstract

Gene therapy has been proposed to have implications in the treatment of cancer. By genetically manipulating the hematopoietic stem cell compartment with genes that confer resistance to chemotherapeutic agents, the dose escalation that is necessary to effectively treat the cancers could potentially be achieved. DNA repair genes are some of the potential candidates to confer increased resistance to chemotherapeutic agents. Although initial focus in this area has been on the direct reversal protein (MGMT), its protective ability is limited to those agents that produce O6- methylGuanine cross-links-agents that are not extensively used clinically (e.g., nitrosoureas). Furthermore, most alkylating agents attack more sites in DNA other than O6-methylGuanine, such that the protections afforded by MGMT may prevent the initial cytotoxicity, but at a price of increased mutational burden and potential secondary leukemias. Therefore, some of the genes that are being tested as candidates for gene transfer are base excision repair (BER) genes. We and others have found that overexpression of selective BER genes confers resistance to chemotherapeutic agents such as thiotepa, ionizing radiation, bleomycin, and other agents. As these 'proof of concept' analyses mature, many more clinically relevant chemotherapeutic agents can be tested for BER protective ability. (C) 2000 Wiley-Liss, Inc.

Original languageEnglish (US)
Pages (from-to)71-81
Number of pages11
JournalEnvironmental and Molecular Mutagenesis
Volume35
Issue number2
DOIs
StatePublished - Apr 6 2000

Keywords

  • Cancer
  • DNA repair
  • Gene therapy
  • Hematopoiesis

ASJC Scopus subject areas

  • Environmental Science(all)
  • Environmental Chemistry
  • Genetics
  • Genetics(clinical)
  • Toxicology
  • Health, Toxicology and Mutagenesis

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