title: Effect of immunosuppressive drugs on DNA repair in human peripheral blood mononuclear cells.
abstract: BACKGROUND
  Cancer is a major cause of mortality among transplant recipients. Immunosuppressive treatment is a modifiable factor contributing to this phenomenon. Cyclosporine in kidney transplant recipients was associated with reduced UV-induced DNA repair by peripheral blood mononuclear cells (PBMC) and increased cancer rate. H(2)O(2) is a common cellular reactive oxygen species (ROS), which induces DNA damage followed by DNA repair.
  
  
  OBJECTIVE
  To investigate the effect of currently used immunosuppressive drugs on DNA repair.
  
  
  METHODS
  H(2)O(2)-induced DNA repair by human PBMC was tested in vitro in the presence of the calcineurin inhibitors (CNI) cyclosporine and tacrolimus, mycophenolic acid (MPA), and the mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus, at low to high non-toxic concentrations. The effect of combination therapy at maintenance levels was also tested.
  
  
  RESULTS
  Cyclosporine and tacrolimus suppressed DNA repair throughout the tested dose range. In contrast, MPA, sirolimus and everolimus did so only at the high doses. Maintenance doses of a combination of tacrolimus and MPA, the most frequent treatment regimen, reduced DNA repair, while MPA with sirolimus or everolimus did not.
  
  
  CONCLUSIONS
  In an attempt to reduce the risk of post-transplantation malignancy, treatment protocols may be modified by reducing CNI dose.
authors.affiliation: Department of Nephrology and Hypertension, Rabin Medical Center, Petah Tikva, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Herman-Edelstein
authors.forename: Benaya
authors.initials: B
authors.lastname: Rozen-Zvi
authors.forename: Boris
authors.initials: B
authors.lastname: Zingerman
authors.forename: Shelly
authors.initials: S
authors.lastname: Lichtenberg
authors.forename: Tsipora
authors.initials: T
authors.lastname: Malachi
authors.forename: Uzi
authors.initials: U
authors.lastname: Gafter
authors.forename: Yaacov
authors.initials: Y
authors.lastname: Ori
mesh_terms: D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000494:pharmacology; D004260:DNA Repair / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006801:Humans; D006861:Hydrogen Peroxide / Q000008:administration & dosage / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D017382:Reactive Oxygen Species; D016572:Cyclosporine; D006861:Hydrogen Peroxide; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases