Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We performed a detailed analysis of immune responses in a hepatocellular carcinoma (HCC) cell line and effector cells obtained from a patient with HCC. We examined the cytotoxic activity of natural killer (NK) cells, lymphokine-activated killer (LAK) cells and cytotoxic T lymphocytes (CTL) against an autologous tumour cell line (SUHC-1) to investigate the immune mechanism of human lymphocytes against HCC cells. Cytotoxic T lymphocytes were induced by co-culturing of peripheral blood lymphocytes (PBL) and SUHC-1 cells, mixed lymphocyte and tumour cell culture (MLTC). The susceptibility of SUHC-1 to NK and LAK cells was similar to that of other allogeneic cell lines, such as K562, PLC/PRF/5 and Mahlavu. Effector cells induced in the primary MLTC had high cytotoxic activity but were not specific for SUHC-1. Cytotoxic T lymphocytes with specific activity against SUHC-1 were induced after PBL were stimulated five times at 7-10 day intervals with SUHC-1 and low-dose recombinant interleukin-2 (rIL-2), suggesting that as the culture progressed, broadly reactive effector cells disappeared and specific effector cells survived. The specific effector cells were identified as CD3+/CD4+ and CD3+/CD8+ T-lymphocyte subsets. The recognition mechanisms of CD3+/CD4+ CTL remain unresolved because the cytotoxicities were not inhibited by anti-CD4 and anti-major histocompatibility complex (MHC) class II monoclonal antibodies (MoAb). Treatment of cells with anti-CD3, anti-CD8 and anti-MHC class I MoAb partially inhibited lysis. These results demonstrated that the T-cell receptor (TCR)/CD3 complex appeared to be involved in SUHC-1 specific antigen recognition and antigen recognition of CD3+/CD8+ CTL was MHC class I restricted.
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PMID:Immunological responses against an autologous human hepatocellular carcinoma cell line. 828 Aug 38

Tumor infiltrating lymphocytes (TIL) and peripheral blood lymphocytes (PBL) were isolated from 5 patients with multiple hepatocellular carcinoma (HCC) and with metastatic liver tumor. Proliferation of lymphocytes was observed following addition of interleukin-2 (700 JRU/ml) into the culture media. After analysis of LAK cells by FACS, the antitumor activities were examined. Higher levels of cytotoxic activity against tumor cells (K 562 and Daudi) have continued during the culture period ranging from 2 to 5 weeks. Adoptive immunotherapy was performed using TIL-LAK and PBL-LAK via hepatic artery for three patients with HCC and one patient with metastatic tumor. The average number of administered lymphocytes was 1 x 10(9). Reduction of tumor size was observed after this therapy, which caused no severe side effects exclusive of high fever and pleural effusion. Our results indicate that the treatment using lymphokine activated killer cells and interleukin-2 may be a promising modality for patients with multiple HCC.
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PMID:[Adoptive immunotherapy in patients with multiple hepatic cancers using lymphokine activated killer cells (LAK) and interleukin-2]. 839 96

The central question to discuss in this review is whether the results of interleukin-2 (IL-2) treatment are still disappointing or again promising. Although in the (recent) past application of high doses of systemically applied rIL-2 has led to some success, the overall results are not as one had hoped. Considering these poor results it seems clear that the application of high systemic doses rIL-2 was not a good choice. IL-2 has been used more or less as a chemotherapeutic compound in the highest tolerable dose. This has led to a great number of unwanted toxic side-effects. In addition, these doses mainly stimulated nonspecific lymphokine-activated killer activity through low-affinity IL-2 receptors, which does not lead to systemic immunity. On the other hand, several groups have shown that application of intratumoral low doses of IL-2 can be highly effective against cancer and without toxic side-effects. Significant tumor loads constituting up to 6% of the total body weight of a mouse were eradicated after treatment with low-dose rIL-2 given locally. Furthermore local treatment can lead to eradication of a tumor at a distant site. This type of therapy is effective in many systems namely against different tumor types in mice, hepatocellular carcinoma in guinea-pigs and vulval papilloma and carcinoma and ocular carcinoma in cattle. Low-dose IL-2 is very effective in experimental animals if it is given relatively late after inoculation of the tumor cells. In other words, it seems necessary that some sort of immune reaction has started or is developing before low doses of rIL-2 effectively stimulate it. In fact there is strong evidence that T lymphocytes, both CD4+ and CD8+ cells, are directly involved in the process leading to induction of specific immunity. In our opinion rIL-2 therapy should therefore aim at the stimulation of such (originally weak) specific immune reaction. Under these conditions also systemic immunity can be induced. In conclusion, application of rIL-2 as a modality for cancer treatment is still promising. High priority should be given to a further delineation of the mechanisms involved after local application. The method of giving IL-2 systemically in the highest tolerable dose should be abandoned. Specific stimulation of the immune system by low-dose rIL-2 is a much more promising option.
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PMID:Interleukin-2 in cancer treatment: disappointing or (still) promising? A review. 843 74

To evaluate the effect of two distinct adoptive immunotherapies, tumor-specific cytotoxic T-cell (CTL) therapy and lymphokine-activated killer (LAK) cell therapy, the clinical responses of patients with stage IV primary hepatocellular carcinoma (HCC) treated with these therapies were studied. Of 18 patients treated with CTL, 3 had complete regression (CR), 2 had partial regression, and 3 had minor regression (MR). Their median survival was 21 months after the end of therapy, and 1 CR patient survived for > 6 years. On the other hand, in the LAK-cell-treated group of eight patients, four had MR and their median survival was only 2 months. No survival was observed 27 months after the end of LAK cell therapy. These results indicate that tumor-specific CTL therapy is more effective than LAK cell therapy and that it might be a promising therapeutic tool for advanced HCC patients.
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PMID:Analytical study of the clinical response to two distinct adoptive immunotherapies for advanced hepatocellular carcinoma: comparison between LAK cell and CTL therapy. 881 96

We demonstrated that sodium butyrate (SB) induced differentiation of functions in human hepatocellular carcinoma (HCC) cell lines. To investigate relationship between the sensitivity for cellular cytotoxicity and the cellular differentiation of HCC cells, the effect of SB on lymphokine-activated killer (LAK) sensitivity and antigen expression of a human HCC cells were studied. SB induced LAK-resistance of human HCC cell lines, HCC-T and HCC-M, time-dependently. A flowcytometric analysis of cell surface antigens revealed that SB markedly reduced the expression of laminin and fibronectin and increased the expression of liver-specific antigen defined by a mouse monoclonal antibody time-dependently, but did not modify that of major histocompatibility complex antigens, intercellular adhesion molecule (ICAM)-1, or CEA. Leukocyte function-associated antigen (LFA)-3 expression on HCC-T was reduced slightly by SB treatment. LAK sensitivity was inhibited by anti-laminin, but not with anti-beta 2-microglobulin, anti-HLA DR, anti-ICAM-1, anti-fibronectin, or anti-CEA. Anti-LFA-3 reduced LAK sensitivity of HCC-T, but not HCC-M, although the reduction was less than that obtained by anti-laminin treatment. These results provided evidence that SB induced LAK-resistance of human HCC cells according to cellular differentiation and extracellular matrix functionality played an important role in this LAK-mediated cell killing. Moreover, the structure expressed on HCC cells, which contributed to LAK cytolysis, was different for each HCC cell.
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PMID:Reduction of LAK-sensitivity and changes in antigen expression on hepatoma cells by sodium butyrate. 893 41

Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the rate-limiting step in hepatic gluconeogenesis. Glucagon (via the second messenger cAMP), retinoic acid, and glucocorticoids stimulate transcription of the PEPCK gene, whereas insulin and phorbol esters have a dominant inhibitory effect. We now show that oxidative and chemical stress (hydrogen peroxide and sodium meta-arsenite, respectively) also produce a dominant inhibitory effect, both on the endogenous PEPCK gene and on a stably transfected PEPCK-chloramphenicol acetyl transferase (CAT) fusion gene. Wortmannin, an inhibitor of 1-phosphatidylinositol 3-kinase (PI 3-kinase), blocks the inhibition of glucocorticoid and cAMP-induced PEPCK gene transcription by insulin; however, it has no effect on the inhibition elicited by oxidative or chemical stress. Thus, the mechanism(s) used by hydrogen peroxide and sodium meta-arsenite to regulate PEPCK gene expression are PI 3-kinase independent. This suggests that these agents operate by a pathway distinct from that used by insulin or that the pathways converge at a point downstream of PI 3-kinase. The reactivating kinase (RK, also known as p38 mitogen activated protein kinase) is induced by insulin, hydrogen peroxide, or sodium meta-arsenite in hepatoma cells, and these effects are blocked by SB203580, a selective inhibitor of RK. However, SB203580 has no effect on the ability of any of these agents to regulate PEPCK-CAT fusion gene expression. Thus, although RK has a role in the regulation of lymphokine gene expression in monocytes, it is not required for the regulation of PEPCK expression by either insulin or oxidative and chemical stress in hepatoma cells.
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PMID:Oxidative and chemical stress mimic insulin by selectively inhibiting the expression of phosphoenolpyruvate carboxykinase in hepatoma cells. 897 Oct 75

Primary and metastatic liver cancers have a poor prognosis. At present, sonographically guided alcohol injection results in a partial reduction of cancer masses even if severe toxic effects (including pain and bleeding) are always present. For these reasons, a pilot study was started to evaluate the feasibility of an intralesional adoptive immunotherapeutic approach, using lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (rIL-2). Nine patients (one with primary hepatocarcinoma and eight with liver metastases) entered the study. Four cycles of weekly injections of LAK cells (ranging from 2 to 9 x 10(8)) and 10(6) IU rIL-2 were performed percutaneously under ultrasonic guidance. In the same period, 3 x 10(6) IU rIL-2/day, for 24 days, was injected subcutaneously. All patients but one completed the therapy. Side effects were limited to grade 1-2 fever and were mostly related to rIL-2 subcutaneous injections. No patients complained of having pain during intralesional therapy. Two complete responses were detected. One partial response, four stable diseases, and one progressive disease were observed. One patient was not evaluable. These preliminary results suggest that sonographically guided intralesional adoptive immunotherapy of liver tumors is feasible, safe, and could offer promising therapeutic advantages in cancers for which conventional treatment is generally unsatisfactory.
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PMID:Intralesional sonographically guided injections of lymphokine-activated killer cells and recombinant interleukin-2 for the treatment of liver tumors: a pilot study. 908 88

A high-dose bolus regimen for interleukin(IL)-2 administration to cancer patients frequently causes serious side-effects in which various organs are involved. In order to reveal the mechanism of toxicities associated with this regimen, we compared the augmenting effect of high-dose IL-2 on murine organ-associated lymphocytes between neoplastic and non-neoplastic states. Intraperitoneal administration of IL-2 at a dose of 10(5) JRU (Japanese Reference Units) twice daily for 3 days led to the death of all the syngeneic MH134-hepatoma- or X5563-myeloma-bearing mice, whereas it had no lethal effect on non-tumor-bearing mice. Histological and morphometric analyses demonstrated that tumor-bearing mice displayed more extensive infiltration of large granular lymphocytes and agranular lymphocytes in the liver and lungs than did the non-tumor-bearing mice. Large granular lymphocytes had the ultrastructural characteristics of lymphokine-activated killer cells. Lymphocytes often underwent extravasation into the interstitial space and exhibited local proliferation without causing any direct injury to apposed parenchymal cells. Flow-cytometric analysis of hepatic mononuclear cells demonstrated that IL-2-receptor-beta (IL-2R beta)-bearing lymphocytes, i.e., natural killer cells and intermediate CD3 cells, were increased in number in the neoplastic state before the IL-2 injection. The present study indicates that the tumor-bearing state increases the number of organ-associated IL-2R beta + lymphocytes, which are then greatly amplified by the challenge of high-dose IL-2, leading to the functional disturbance of organs. We have further demonstrated here that an intermittent low-dose IL-2 regimen has a potential therapeutic effect on tumor regression without causing lethal side-effects.
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PMID:The tumor-bearing state induces augmented responses of organ-associated lymphocytes to high-dose interleukin-2 therapy in mice. 939 Jan 96

The human multidrug resistance gene MDR1 encodes a membrane-bound protein, referred to as P-glycoprotein, that acts as a pump to extrude toxins from cells. The 3' untranslated region (3'UTR) of the human MDR1 mRNA is very AU-rich (70%) and contains AU-rich sequences similar to those shown to confer rapid decay on c-myc, c-fos, and lymphokine mRNAs. We tested the ability of the MDR1 3'UTR to act as an mRNA destabilizing element in the human hepatoma cell line HepG2. The MDR1 mRNA has an intermediate half-life of 8 h in HepG2 cells compared to a half-life of 30 min for c-myc mRNA. The MDR1 mRNA half-life was prolonged to >20 h upon treatment with the protein synthesis inhibitor cycloheximide. We constructed expression vectors containing the human beta-globin coding region with the 3'UTR from either MDR1 or c-myc. The c-myc 3'UTR increased the decay of the chimeric mRNA, but the MDR1 3'UTR had no effect. We tested the ability of MDR1 3'UTR sequences to compete for interaction with AU-binding proteins in cell extracts; MDR1 RNA probes had a fivefold lower affinity for AU-binding proteins that interact with the c-myc AU-rich 3'UTR. Overall, our data suggest that the MDR1 3'UTR does not behave as an active destabilizing element in HepG2 cells.
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PMID:The AU-rich 3' untranslated region of human MDR1 mRNA is an inefficient mRNA destabilizer. 1044 77

Malfunction of the immune system at different levels is typical for patients with liver cirrhosis. Both non-specific as well as antigen-specific functions may be compromised. The best studied and clinically most important problem is the diminished clearance capacity of the reticulo-endothelial system in liver cirrhosis. This transfers into a significantly higher rate of bacterial infections associated with a poorer prognosis in these patients. The clinical relevance of concomitant immune disorders like neutrophil dysfunction is less clear. An impaired activation of natural killer cells (NK) and lymphokine-activated killer cells (LAK) may have a role in the development of hepatocellular carcinoma but additional studies are needed. Clinically important is a moderately reduced efficacy of standard immunization protocols, which can be overcome by an increased dose in most vaccines.
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PMID:[Function of the immune system in liver cirrhosis]. 1155 65


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