ABSTRACT
Anthracycline chemotherapeutics are well characterised as poisons of topoisomerase II, however many anthracyclines, including doxorubicin, are also capable of forming drug-DNA adducts. Anthracycline-DNA adducts present an unusual obstacle for cells as they are covalently attached to one DNA strand and stabilised by hydrogen bonding to the other strand. We now show that in cycling cells processing of anthracycline adducts through DNA replication appears dominant compared to processing via transcription-coupled pathways, and that the processing of these adducts into DNA breaks is independent of topoisomerase II. It has previously been shown that cells deficient in homologous recombination (HR) are hypersensitive to adduct forming treatments. Given that anthracycline-DNA adducts, whilst not true crosslinks, are associated with both DNA strands, the role of ICL repair pathways was investigated. Mus81 is a structure specific nuclease implicated in Holliday junction resolution and the resolution of branched DNA formed by stalled replication forks. We now show that ICL repair deficient cells (Mus81(-/-)) are hypersensitive to anthracycline-DNA adducts and ET-743, a compound which causes a chemically similar type of DNA damage. Further analysis of this mechanism showed that Mus81 does not appear to cause DNA breaks resulting from either anthracycline- or ET743-DNA adducts. This suggests Mus81 processes these novel forms of DNA damage in a fundamentally different way compared to the processing of classical covalent crosslinks. Improved understanding of the role of DNA repair in response to such adducts may lead to more effective chemotherapy for patients with BRCA1/2 mutations and other HR deficiencies.
Subject(s)
Anthracyclines/metabolism , Anthracyclines/pharmacology , DNA Adducts/metabolism , DNA Repair , DNA Replication , DNA-Binding Proteins/metabolism , Endonucleases/metabolism , Animals , Anthracyclines/chemistry , Cricetinae , Cricetulus , DNA Adducts/chemistry , DNA Breaks, Double-Stranded/drug effects , DNA Topoisomerases, Type II/metabolism , DNA-Binding Proteins/genetics , Dioxoles/pharmacology , Endonucleases/genetics , Fanconi Anemia Complementation Group D2 Protein/genetics , Fanconi Anemia Complementation Group D2 Protein/metabolism , G1 Phase/genetics , HL-60 Cells , Homologous Recombination , Humans , Tetrahydroisoquinolines/pharmacology , TrabectedinABSTRACT
Patients with mitral regurgitation are increasing while those with mitral stenosis are decreasing. In addition, percutaneous transluminal mitral commissurotomy (PTMC) technique has dramatically reduced surgical indication of mitral stenosis. At the present time, the most important topic would be the surgical indication of asymptomatic patients with severe mitral regurgitation and preserved left ventricular function. In this context, feasibility of mitral valve repair, in other words, the skill and experience of the surgeon becomes very important. In this paper, we described issues about the timing and indication of mitral valvular surgery based on "American College Cardiology/American Heart Association (ACC/AHA) 2006 practice guidelines for the management of patients with valvular heart disease".
