Effect of immunosuppressive drugs on DNA repair in human peripheral blood mononuclear cells
ABSTRACT 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 H(2)O(2)-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.
To investigate the effect of currently used immunosuppressive drugs on spontaneous DNA repair.
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.
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.
A reduction in CNI dosage may lead to a decrease in the occurrence of post-transplant malignancy.
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ABSTRACT: The mammalian target of rapamycin inhibitors are normally favored as immunosuppressant agents for solid organ transplantation such as kidney, liver or heart. Only in recent years have they been increasingly administered for the treatment of neuroendocrine tumors. Even though mammalian target of rapamycin inhibitors are known to exhibit specific side effects, everolimus-related severe hepatic steatosis has not as yet been described in the literature. We report the case of a 76-year-old man who developed severe hepatic steatosis within four weeks of treatment with everolimus as concomitant tumor therapy for a progressively growing neuroendocrine carcinoma of the ileum. A diagnosis of hepatic steatosis was established using computer tomography and fibroscan(C). Other underlying causes for steatosis could be excluded. Further studies are warranted to explain the underlying mechanisms.07/2013; 18(1):22. DOI:10.1186/2047-783X-18-22
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ABSTRACT: Atopic dermatitis (AD) is a condition frequently encountered in medical practices across the country. Arming ourselves with appropriate and safe treatment modalities to provide relief for this chronic and relapsing inflammatory condition is of utmost importance to our patients and their families. Utilizing topical calcineurin inhibitors (TCIs) for the treatment of AD not responsive to high-potency corticosteroids, or low-potency corticosteroids and localized to the face, eyelids, and skin folds of patients >2 years, is reasonable to include in common practice. Despite the FDA¿s Black Box warning, to date no evidence has been published linking the TCIs to an increased incidence of malignancy in either children or adults that establishes causation. The Canadian Society of Allergy and Clinical Immunology (CSACI) therefore recognizes that the benefits of TCIs should be carefully weighed with the theoretical risks in advising patients, and acknowledges that long-term studies remain in progress. The safety and efficacy of topical tacrolimus and pimecrolimus should therefore be considered when treating children and adults with AD in Canadian allergy and immunology practices.Allergy Asthma and Clinical Immunology 07/2013; 9(1):24. DOI:10.1186/1710-1492-9-24
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ABSTRACT: DNA repair is a cellular defence mechanism responding to DNA damage caused in large part by oxidative stress. There is a controversy with regard to the effect of red blood cells on DNA damage and cellular response. To investigate the effect of red blood cells on H2O2-induced DNA damage and repair in human peripheral blood mononuclear cells. DNA breaks were induced in peripheral blood mononuclear cells by H2O2 in the absence or presence of red blood cells, red blood cells hemolysate or hemoglobin. DNA repair was measured by (3)H-thymidine uptake, % double-stranded DNA was measured by fluorometric assay of DNA unwinding. DNA damage was measured by the comet assay and by the detection of histone H2AX phosphorylation. Red blood cells and red blood cells hemolysate reduced DNA repair in a dose-dependent manner. Red blood cells hemolysate reduced % double-stranded DNA, DNA damage and phosphorylation of histone H2AX. Hemoglobin had the same effect as red blood cells hemolysate on % double-stranded DNA. Red blood cells, via red blood cells hemolysate and hemoglobin, reduced the effect of oxidative stress on peripheral blood mononuclear cell DNA damage and phosphorylation of histone H2AX. Consequently, recruitment of DNA repair proteins diminished with reduction of DNA repair. This suggests that anemia predisposes to increased oxidative stress induced DNA damage, while a higher hemoglobin level provides protection against oxidative-stress-induced DNA damage.PLoS ONE 07/2013; 8(7):e68341. DOI:10.1371/journal.pone.0068341 · 3.53 Impact Factor