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

Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Impact Factor: 2.02). 06/2012; 66(6):409-13. DOI: 10.1016/j.biopha.2012.06.001
Source: PubMed


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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    • "Immunosuppressive drugs increase the risk of posttransplant cancer. Inparticular cyclosporines reduce UV-induced DNA repair by peripheral blood mononuclear cells [23, 24]. Without prompt and adequate treatment of a BLT there is a risk of local invasiveness leading to various complications such as abscess formation, fistulas, and defecation problems by ingrowth in or pressure to the rectum [3, 9]. "
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    ABSTRACT: Giant condyloma acuminatum or Buschke-Lowenstein tumour is a very rare disease which usually is located in the genital, anorectal, and perianal regions. It is regarded as a type of verrucous carcinoma occurring on anogenital mucosal surfaces where it is locally invasive but displays a benign cytology. We describe a case of a 24-year-old woman with persisting condyloma acuminata progressing to a large intra-abdominal Buschke-Lowenstein tumour. To our knowledge such an advanced stage has only been reported once before. The severity and extent of the tumour both determine the treatment and patient outcome. Treatment was impeded by cachexia, an immunosuppressive state after kidney transplantation and difficulties in establishing a reliable diagnose. Interferon treatment was started which initially led to tumour reduction but was complicated by an interferon-induced pancreatitis, pneumonia, and fasciitis necroticans resulting in death. We present a literature overview on the treatment options for a Buschke-Lowenstein tumour, with emphasis on interferon therapy, with all the advantages and disadvantages.
    Full-text · Article · Sep 2013
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    • "H2O2 induces double strand breaks (DSBs), which are followed by DNA repair [1], [2]. The H2O2-induced DNA repair measured in peripheral blood mononuclear cells (PBMC) has been previously used in our laboratory [1], [3], [4]. Phosphorylation of the histone H2AX is an early response to DNA damage, especially DSBs. "
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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.
    Full-text · Article · Jul 2013 · PLoS ONE
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    • "In recent years new cancer treatments have been developed [1,2]. Everolimus is an inhibitor of the mammalian target of rapamycin (mTOR) and has been approved for the prevention of organ transplant rejection as well as for the treatment of subependymal giant cell astrocytoma, neuroendocrine tumors, renal cell carcinoma and breast cancer [3-8]. mTOR inhibitors are increasingly administered for the treatment of neuroendocrine tumors [9,10]. "
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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.
    Full-text · Article · Jul 2013
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