title: DNA repair targeted therapy: The past or future of cancer treatment?
abstract: The repair of DNA damage is a complex process that relies on particular pathways to remedy specific types of damage to DNA. The range of insults to DNA includes small, modest changes in structure including mismatched bases and simple methylation events to oxidized bases, intra- and interstrand DNA crosslinks, DNA double strand breaks and protein-DNA adducts. Pathways required for the repair of these lesions include mismatch repair, base excision repair, nucleotide excision repair, and the homology directed repair/Fanconi anemia pathway. Each of these pathways contributes to genetic stability, and mutations in genes encoding proteins involved in these pathways have been demonstrated to promote genetic instability and cancer. In fact, it has been suggested that all cancers display defects in DNA repair. It has also been demonstrated that the ability of cancer cells to repair therapeutically induced DNA damage impacts therapeutic efficacy. This has led to targeting DNA repair pathways and proteins to develop anti-cancer agents that will increase sensitivity to traditional chemotherapeutics. While initial studies languished and were plagued by a lack of specificity and a defined mechanism of action, more recent approaches to exploit synthetic lethal interaction and develop high affinity chemical inhibitors have proven considerably more effective. In this review we will highlight recent advances and discuss previous failures in targeting DNA repair to pave the way for future DNA repair targeted agents and their use in cancer therapy.
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
authors.forename: Navnath S
authors.initials: NS
authors.lastname: Gavande
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
authors.forename: Pamela S
authors.initials: PS
authors.lastname: VanderVere-Carozza
authors.affiliation: Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
authors.forename: Hilary D
authors.initials: HD
authors.lastname: Hinshaw
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
authors.forename: Shadia I
authors.initials: SI
authors.lastname: Jalal
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
authors.forename: Catherine R
authors.initials: CR
authors.lastname: Sears
authors.affiliation: NERx Biosciences, Indianapolis, IN 46202, United States.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Pawelczak
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States; NERx Biosciences, Indianapolis, IN 46202, United States; Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, United States. Electronic address: jturchi@iu.edu.
authors.forename: John J
authors.initials: JJ
authors.lastname: Turchi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004247:DNA / Q000187:drug effects*; D018736:DNA Adducts / Q000187:drug effects; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; D004247:DNA
keywords: Cancer; DNA damage; DNA repair; Radiation; Replication protein A