Coordination of DNA mismatch repair and base excision repair processing of chemotherapy and radiation damage for targeting resistant cancers.
DNA damage processing by mismatch repair (MMR) and/or base excision repair (BER) can determine the therapeutic index following treatment of human cancers using radiation therapy and several classes of chemotherapy drugs. Over the last decade, basic and translational cancer research in DNA repair has led to an increased understanding of how these two DNA repair pathways can modify cytotoxicity to chemotherapy and/or ionizing radiation treatments in both normal and malignant tissues. This Molecular Pathways article provides an overview of the current understanding of mechanisms involved in MMR and BER damage processing, including insights into possible coordination of these two DNA repair pathways after chemotherapy and/or ionizing radiation damage. It also introduces principles of systems biology that have been applied to better understand the complexities and coordination of MMR and BER in processing these DNA damages. Finally, it highlights novel therapeutic approaches to target resistant (or DNA damage tolerant) human cancers using chemical and molecular modifiers of chemotherapy and/or ionizing radiation including poly (ADP-ribose) polymerase inhibitors, methoxyamine and iododeoxyuridine (and the prodrug, 5-iodo-2-pyrimidinone-2'-deoxyribose).
Kinsella
Timothy J
TJ
Case Integrative Cancer Biology Program, Case Western Reserve University, Cleveland, OH, USA. tkinsella@notes.cc.sunysb.edu
D004249:DNA Damage; D053843:DNA Mismatch Repair; D004260:DNA Repair; D019008:Drug Resistance, Neoplasm; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D006898:Hydroxylamines / Q000627:therapeutic use; D007065:Idoxuridine / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors
D006898:Hydroxylamines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C005214:methoxyamine; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D007065:Idoxuridine