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


OBJECTIVE
To investigate the effect of currently used immunosuppressive drugs on spontaneous DNA repair.


METHODS
Spontaneous 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.


RESULTS
Cyclosporine and tacrolimus suppressed spontaneous DNA repair throughout the tested dose range. In contrast, MPA, sirolimus and everolimus did so only at the high doses.


CONCLUSIONS
A reduction in CNI dosage may lead to a decrease in the occurrence of post-transplant malignancy.
Department of Nephrology and Hypertension, Rabin Medical Center, Petah-Tikva, Israel.
Yaacov
Y
Ori
Michal
M
Herman-Edelstein
Boris
B
Zingerman
Benaya
B
Rozen-Zvi
Uzi
U
Gafter
Tsipora
T
Malachi
Anat
A
Gafter-Gvili
D000328:Adult; D001771:Blood Banks; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D015197:Carcinogenicity Tests; D016572:Cyclosporine / Q000009:adverse effects / Q000494:pharmacology*; D004260:DNA Repair / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D000068338:Everolimus; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D009173:Mycophenolic Acid / Q000009:adverse effects / Q000494:pharmacology; D009994:Osmolar Concentration; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016559:Tacrolimus / Q000009:adverse effects / Q000494:pharmacology*
D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D019703:Calcineurin; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus