title: Clinical relevance of the homologous recombination machinery in cancer therapy.
abstract: Cancer chemotherapy and radiotherapy kill cancer cells by inducing DNA damage, unless the lesions are repaired by intrinsic repair pathways. DNA double-strand breaks (DSB) are the most deleterious type of damage caused by cancer therapy. Homologous recombination (HR) is one of the major repair pathways for DSB and is thus a potential target of cancer therapy. Cells with a defect in HR have been shown to be sensitive to a variety of DNA-damaging agents, particularly interstrand crosslink (ICL)-inducing agents such as mitomycin C and cisplatin. These findings have recently been applied to clinical studies of cancer therapy. ERCC1, a structure-specific endonuclease involved in nucleotide excision repair (NER) and HR, confers resistance to cisplatin. Patients with ERCC1-negative non-small-cell lung cancer were shown to benefit from adjuvant cisplatin-based chemotherapy. Imatinib, an inhibitor of the c-Abl kinase, has been investigated as a sensitizer in DNA-damaging therapy, because c-Abl activates Rad51, which plays a key role in HR. Furthermore, proteins involved in HR have been shown to repair DNA damage induced by a variety of other chemotherapeutic agents, including camptothecin and gemcitabine. These findings highlight the importance of HR machinery in cancer therapy.
authors.affiliation: Department of Radiation Biology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. miyag-tky@umin.ac.jp
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Miyagawa
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D053903:DNA Breaks, Double-Stranded; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000235:genetics* / Q000628:therapy*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic; D059005:Topoisomerase II Inhibitors
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D059005:Topoisomerase II Inhibitors; D011505:Protein-Tyrosine Kinases; D051135:Rad51 Recombinase; D004250:DNA Topoisomerases, Type II