UMLS:C0019204 - FACTA Search

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Query: UMLS:C0019204 (hepatocellular carcinoma)
71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor recurrence after liver transplantation still remains a significant problem in patients with hepatocellular carcinoma. The small GTPase Rho/Rho-associated kinase (ROCK) pathway is involved in the motility and invasiveness of cancer cells. We investigated whether tacrolimus activated the Rho/ROCK signal pathway to promote the invasiveness of rat hepatocellular carcinoma cells. We also investigated whether the ROCK inhibitor Y-27632 suppressed tumor recurrence after experimental liver transplantation in a rat hepatocellular carcinoma model. Orthotopic liver transplantation was performed in hepatocellular carcinoma cell line McA-RH7777-bearing rats. Tacrolimus was administered to liver transplant rats and these rats were divided into two groups: the Y-27632-treated (10 mg/kg, for 28 days) group and the Y-27632-untreated group. Tacrolimus enhanced the cancer cell migration and stimulated phosphorylation of the myosin light chain (MLC), a downstream effector of Rho/ROCK signaling. Y-27632 suppressed the cancer cell migration and tacrolimus-induced MLC phosphorylation. Suppression of tumor recurrence after liver transplantation and significant prolongation of survival were observed in the Y-27632-treated rats in comparison with theY-27632-untreated rats. Tacrolimus stimulates the Rho/ROCK signal pathway to enhance the invasiveness of hepatocellular carcinoma, and the ROCK inhibitor Y-27632 can be used as a new antimetastatic agent for the prevention of tumor recurrence after liver transplantation.
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PMID:Rho-associated kinase inhibitor reduces tumor recurrence after liver transplantation in a rat hepatoma model. 1722 77

Allogeneic bone-marrow transplantation (BMT) can induce a powerful graft-vs.-tumor (GVT) effect not only on hematological malignancies but also on solid tumors. However, graft-vs.-host disease (GVHD) is a major complication of allogeneic BMT. We assessed GVT effect on hepatocellular carcinoma (HCC) and the effects of hepatocyte growth factor (HGF) gene transduction on GVHD in HCC transplanted mice. (C57BL/6 x C3H/HeJ)F(1)(B6C3F1, H-2(bxk)) mice were used as recipients and C3H/HeJ(H-2(k)) mice were used as donors. Hepa1-a (a C57L mouse-derived hepatoma cell, H-2(b)) was subcutaneously injected into the recipient mice. Tumor bearing mice were treated in the following ways: group 1, no treatment; group 2, total body irradiation (TBI); group 3, TBI and BMT; group 4, TBI and BMT with empty vector; group 5, TBI and BMT with HGF gene transduction; group 6, TBI and BMT with administration of FK506, a representative immunosuppressive agent. Acute GVHD was assessed by histological examination of the liver, small intestines, and large intestines. Tumor growth was markedly suppressed in mice that received an allogeneic BMT. Donor-derived CD8(+) T cells had infiltrated into the tumor, and cytotoxic CD8(+) T cells against HCC were present. However, among the four groups that received a BMT, this suppressive effect was weaker in group 6 compared with the other three groups (groups 3, 4, and 5). HGF gene transduction improved GVHD while preserving the GVT effects. Allogeneic BMT markedly suppresses the growth of HCC. Simultaneous HGF gene transfer can suppress GVHD while preserving the GVT effect.
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PMID:Allogeneic bone marrow transplantation for hepatocellular carcinoma: hepatocyte growth factor suppresses graft-vs.-host disease. 1776 34

Hepatic steatosis and insulin resistance are factors that aggravate the progression of liver disease caused by hepatitis C virus (HCV) infection. In the pathogenesis of liver disease and metabolic disorders in HCV infection, oxidative stress due to mitochondrial respiratory chain dysfunction plays a pivotal role. Tacrolimus (FK506) is supposed to protect mitochondrial respiratory function. We studied whether tacrolimus affects the development of HCV-associated liver disease using HCV core gene transgenic mice, which develop hepatic steatosis, insulin resistance, and hepatocellular carcinoma. Administration of tacrolimus to HCV core gene transgenic mice three times per week for 3 months led to a significant reduction in the amounts of lipid in the liver as well as in serum insulin. Tacrolimus treatment also ameliorated oxidative stress and DNA damage in the liver of the core gene transgenic mice. Tacrolimus administration reproduced these effects in a dose-dependent manner in HepG2 cells expressing the core protein. The intrahepatic level of tumor necrosis factor-alpha, which may be a key molecule for the pathogenesis in HCV infection, was significantly decreased in tacrolimus-treated core gene transgenic mice. Tacrolimus thus reversed the effect of the core protein in the pathogenesis of HCV-associated liver disease. These results may provide new therapeutic tools for chronic hepatitis C, in which oxidative stress and abnormalities in lipid and glucose metabolism contribute to liver pathogenesis.
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PMID:Tacrolimus ameliorates metabolic disturbance and oxidative stress caused by hepatitis C virus core protein: analysis using mouse model and cultured cells. 1972 76

Living donor liver transplantation (LDLT) has become one of the chief methods of saving patients with end-stage liver disease due to liver cirrhosis. Accumulation of knowledge about indication and perioperative managements improve outcome of this treatment. In this study, we elucidate the risk factors of LDLT, which still exist today. Sixty-one patients received LDLT in our institute between 2003 and 2009 were included in this study. Recipient age and sex, donor age and sex, etiology, preoperative model of end-stage liver disease (MELD) score, hepatocellular carcinoma (HCC), graft versus recipient weight ratio (GRWR), cold and warm ischemic time, operation time, blood loss, ABO compatibility, rejection, cytomegalovirus (CMV) infection, biliary stricture, and calcineurin inhibitor (FK506 or cyclosporin A) were the factors investigated. p < 0.05 was considered as statistically significant in the proportional hazard model. In univariate analysis, the recipients' age (p = 0.024) and rejection episode (p = 0.046) were selected as significant risk factors. In multivariate analysis including the factors that showed p < 0.2 (recipient age, GRWR, ABO compatibility, rejection episode) in univariate analysis, recipient age (p = 0.008, HR: 1.40; 95% CI: 1.09-1.80) and rejection episodes (p = 0.002, HR: 13.33; 95% CI: 2.53-71.43) were still selected as significant independent risk factors after LDLT. Recipient age was shown to be 1.40 times risk per 1 year older and the rejection episode was shown to be 13.33 times risk in the recent era with comprehensive indication and preoperative management for LDLT. Indication must be cautious for elderly patients, and prevention of rejection is crucial for the improvement of results for LDLT.
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PMID:Risk factors of recipient receiving living donor liver transplantation in the comprehensive era of indication and perioperative managements. 2094 66

FK506 binding proteins (FKBPs) are the intracellular ligands of FK506 and rapamycin, two natural compounds with powerful and clinically efficient immunosuppressive activity. In recent decades, a relevant role for immunosuppressants as anticancer agents has emerged. Especially, rapamycin and its derivatives are used, with successful results, across a variety of tumors. Of note, rapamycin and FK506 bind to FKBP12, and the resulting complexes interfere with distinct intracellular signaling pathways driven, respectively, by the mammalian target of rapamycin and calcineurin phosphatase. These pathways are related to T-cell activation and growth. Hyperactivation of the mammalian target of rapamycin (mTOR), particularly in cancers that have lost the tumor suppressor gene PTEN, plays an important pathogenetic role in tumor transformation and growth. The signaling pathway involving calcineurin and nuclear factors of activated T-lymphocytes is also involved in the pathogenesis of different cancer types and in tumor metastasis, providing a rationale for use of FK506 in anticancer therapy. Recent studies have focused on FKBPs in apoptosis regulation: Targeting of FKBP12 promotes apoptosis in chronic lymphocytic leukemia, FKBP38 knockdown sensitizes hepatoma cells to apoptosis, and FKBP51 silencing overcomes resistance to apoptosis in acute lymphoblastic leukemia, prostate cancer, melanoma, and glioma. Interestingly, derivatives of FK506 that have the same FKBP12-binding properties as FK506 but lack functional immunosuppressant activity, exert the same apoptotic effect as FK506 in chronic lymphocytic leukemia.These findings suggest that a direct FKBP inhibition represents a further mechanism of immunosuppressants.' anticancer activity. In this review, we focus on the role of FKBP members in apoptosis control and summarize the data on the antitumor effect of selective targeting of FKBP.
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PMID:FK506 binding proteins as targets in anticancer therapy. 2118 72

No effective therapeutic approaches have been available for early recurrences following liver transplantation for hepatocellular carcinoma (HCC). The prognosis for such patients has been poor. We encountered two patients with recurrent HCC following liver transplantation, and in the prescribed sorafenib after the failure of various therapeutic approaches. In vitro experiments have shown sorafenib to be metabolized by the drug-metabolizing enzyme cytochrome P450 3A4 (CYP3A4) and glucuronosyltransferase (UGT1A9). The metabolic pathway is predicted to overlap that of calcineurin inhibitors (CNIs). In the two cases in which we used sorafenib, tacrolimus (FK506) was used in case 1 and cyclosporine, in case 2. We therefore have also reported the blood levels of the CNI at the time of sorafenib use. Patients with recurrent HCC following liver transplantation were less tolerant of sorafenib than advanced HCC patients who had not undergone transplantation. Poor tolerance was believed to be due to pharmacological interactions of sorafenib and CNIs. Likewise in our patients, determining blood levels of sorafenib, including the area under the blood concentration-time curve of at least the CNI, in each case allowed us to determine the optimal sorafenib dose for each patient. In the future, when administering sorafenib to treat recurrent liver cancers following liver transplantation, the dose of sorafenib should be started at 200 mg/d and gradually increased while measuring CNI blood levels.
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PMID:Using sorafenib for recurrent hepatocellular carcinoma after liver transplantation--interactions between calcineurin inhibitor: two case reports. 2191 Nov 67

By analyzing 26,414 patients [12,589 with hepatitis C virus (HCV)] in the Scientific Registry of Transplant Recipients Database, we sought to determine comparative risk factors (including primary immunosuppression) predictive of death and graft loss among patients with HCV and patients without HCV. Immunosuppression was examined at the baseline and as a time-dependent variable, and the results were stratified by the transplant center and were adjusted for variables well known to affect patient and graft survival. A multivariate analysis of patient mortality demonstrated that recipient age, donor age, hepatocellular carcinoma, diabetes, and creatinine were significantly associated with increased 3-year mortality for both groups. Tacrolimus-based immunosuppression was associated with superior survival in both groups. In contrast, the use of sirolimus was strongly associated with increased mortality in the HCV group, and cyclosporine was associated with increased mortality in the non-HCV group. Adjusting for known and unknown factors predictive of posttransplant outcomes, a propensity analysis confirmed the association of sirolimus use with an increased risk of death in HCV patients as well as the association of tacrolimus use with a decreased risk of death in all patients. In conclusion, this study suggests a novel association between sirolimus use and an increased risk of death and graft loss after liver transplantation in HCV patients that is not seen in patients without HCV. This study confirms the association of tacrolimus with superior outcomes. Sirolimus should be used sparingly in recipients with HCV infections.
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PMID:Impact of sirolimus and tacrolimus on mortality and graft loss in liver transplant recipients with or without hepatitis C virus: an analysis of the Scientific Registry of Transplant Recipients Database. 2322 19

To provide a basis for improved prevention and treatment of hepatitis B virus (HBV) re-infection after liver transplantation, variations in the S and P genes of HBV under immunosuppression in vitro and their association with patient prognosis were investigated. For the in vitro study, HepG2.2.15 hepatocellular carcinoma cells stably producing HBV particles were treated with the immunosuppressants methylprednisolone (MP) and tacrolimus (FK506) at doses found to be non-toxic by the methylthiazolyl tetrazolium (MTT) cell viability assay. MP dose-dependently inhibited HBV DNA expression in HepG2.2.15 cells, while FK506 did not, as determined by quantitative real-time PCR (qRT-PCR). By gene sequencing, both MP and FK506 were found to cause variations in HBV S, P, and S/P overlapping regions. MP- but not FK506-induced mutations were common in the glucocorticoid response element of the P region, while both immunosuppressants caused mutations outside the nucleoside analogue resistance sites. For the in vivo study, 14 patients with HBV-related end-stage liver disease re-infected after liver transplantation, and 20 cases without HBV re-infection as controls, were studied. Seventy-five percent of re-infected recipients showed multi-loci amino acid mutations at different sites besides lamivudine (LAM)-resistant loci in the P region, including in the glucocorticoid response element. Fifty percent of re-infected recipients had mutations in the "a" determinant region and flanking sequences. Re-infection was associated with negative serum hepatitis B immunoglobulin (HBIG), as measured by a microparticle capture enzyme immunoassay. Nucleotide mutations in the S region caused missense or synonymous mutations, which caused synonymous mutations in the overlapping P region. These results showed that effects of immunosuppressants on HBV genes in vitro were different from those in clinical recipients. Positive HBV DNA and gene mutations pre-transplantation were factors affecting re-infection post-transplantation. Multiple mutations found in the P and S genes suggest that the formation of quasispecies contributes to HBV re-infection after liver transplantation.
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PMID:Variations in the S and P regions of the hepatitis B virus genome under immunosuppression in vitro and in vivo. 2294 68

The development of immunosuppression has significantly affected the development of liver transplantation and has helped to switch from the experimental method to a standard treatment of life threatening liver conditions. Tacrolimus is the basic immunosuppressant for patients after a liver transplant and thanks to its prolonged-release dosage form, which due to its simplicity and reliability of use, replaces tacrolimus twice daily early after the transplant and in the longterm administration, will apparently, for a while, defend its position. Other widely used medicines include mycophenolic acid and mTOR inhibitors, sirolimus and everolimus. The induction with antilymphocyte antibodies is used in less than 10% of liver recipients. Only a few new immunosuppresants in this century have passed later stages of clinical studies; the last 2 medicines registered for patients after liver transplantation include Advagraf (Astellas) and Certican (Novartis). Personalised immunosuppression should respect at least the following basic clinical situations: recipients renal function, hepatitis C virus infection, and hepatocellular carcinoma as the liver transplant indication. The results of immunotolerance bio-marker research are necessary for a more successful conduct of protocols minimising immunosuppression and leading to immunotolerance, especially under the efforts of complete withdrawal of immunosupression.
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PMID:[Immunosuppression after liver transplant, now and in future]. 2400 21

Hepatocellular carcinoma is the fifth most common cancer worldwide and shows a complex clinical course, poor response to pharmacological treatment, and a severe prognosis. Thus, the aim of this study was to investigate whether tacrolimus (FK506) has synergistic antitumor effects with doxorubicin on two human hepatocellular carcinoma cell lines, Huh7 and HepG2. Cell viability was analyzed by Sulforhodamine B assay and synergic effect was evaluated by the software CalcuSyn. Cell apoptosis was evaluated using Annexin V and Dead Cell assay. Apoptosis-related protein PARP-1 cleaved and autophagy-related protein expressions (Beclin-1 and LC3B) were measured by western blotting analysis. Cytokines concentration in cellular supernatants after treatments was studied by Bio-Plex assay. Interestingly the formulation with doxorubicin and tacrolimus induced higher cytotoxicity level on tumor cells than single treatment. Moreover, our results showed that the mechanisms involved were (i) a strong cell apoptosis induction, (ii) contemporaneous decrease of autophagy activation, understood as prosurvival process, and (iii) downregulation of proinflammatory cytokines. In conclusion, future studies could relate to the doxorubicin/tacrolimus combination effects in mice models bearing HCC in order to see if this formulation could be useful in HCC treatment.
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PMID:Synergistic antitumor effect of Doxorubicin and tacrolimus (FK506) on hepatocellular carcinoma cell lines. 2470 Nov 68

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