Effect of immunosuppressive drugs on spontaneous DNA repair in human peripheral blood mononuclear cells

Abstract

IntroductionImmunosuppressive treatment increases the risk of post-transplant cancer. Cyclosporine reduced UV-induced DNA repair by peripheral blood mononuclear cells (PBMC) and increased cancer incidence in kidney transplant recipients. Calcineurin inhibitors (CNI), but not mammalian target of rapamycin (mTOR) inhibitors or mycophenolic acid, suppressed H2O2-induced DNA repair in human peripheral blood mononuclear cells (PBMC) in vitro at maintenance drug concentrations. DNA repair, when measured in quiescent cells, is named spontaneous DNA repair, and represents a basal ongoing DNA repair in response to endogenous DNA damage. The effect of immunosuppressive drugs on spontaneous DNA repair has not been investigated. AimTo investigate the effect of currently used immunosuppressive drugs on spontaneous DNA repair. MethodsSpontaneous DNA repair by human PBMC was tested in vitro in the presence of the CNI–cyclosporine and tacrolimus; mycophenolic acid (MPA); and the mTOR inhibitors–sirolimus and everolimus, at low to high nontoxic concentrations. ResultsCyclosporine and tacrolimus suppressed spontaneous DNA repair throughout the tested dose range. In contrast, MPA, sirolimus and everolimus did so only at the high doses. ConclusionA reduction in CNI dosage may lead to a decrease in the occurrence of post-transplant malignancy.