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

We developed a tumor vaccine consisting of fixed hepatocellular carcinoma (HCC) cells/tissue fragments, biodegradable microparticles encapsulating granulocyte-macrophage-colony stimulating factor and interleukin-2, and an adjuvant. The vaccine protected 33% of syngeneic mice from HCC cell challenge. The vaccine containing human autologous HCC fragments showed essentially no adverse effect in a phase I/IIa clinical trial and 8/12 patients developed a delayed-type hypersensitivity (DTH) response against the fragments. Although 2 of 4 DTH-response-negative patients had recurrence after curative resection, the DTH-response-positive patients had no recurrence. The time before the first recurrence in the vaccinated patients was significantly longer than that in 24 historical control patients operated in the same department (P < 0.05). This formulation is a promising candidate to prevent recurrence of human HCC.
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PMID:Autologous fixed tumor vaccine: a formulation with cytokine-microparticles for protective immunity against recurrence of human hepatocellular carcinoma. 1198 84

At present, no effective therapy is available for hepatocellular carcinoma, when local treatments have failed. We reported the results obtained with prolonged, ultra-low-dose (1 MIU/d until progression), subcutaneous interleukin-2 (IL-2) in a series of 18 consecutive patients (14 men and 4 women, median age 66 years, range 49-82 years) with advanced, histologically proven HCC on liver cirrhosis. During a median follow-up time of 19.5 months, two complete responses (11.1%), lasting 35 and 46 months, respectively, and one partial response (5.5%) were recorded (overall response rate: 16.6%; 95% CI: 0-33.8%). Thirteen patients (72.3%; 95% CI: 61.6-82.7) had stable disease lasting at least 4 months; 1 of these patients obtained a complete response on lung metastases. Median time to progression was 15.3 months (95% CI: 10-33). Median overall survival was 24.5 months (95% CI: 12-43). Two patients (11.1%) progressed during therapy. Toxicity was only local (usually pain and pomphus in the site of injection). Low-dose IL-2 can be considered an active and well-tolerated treatment for unresectable hepatocellular carcinoma. Future studies on large numbers of patients are necessary to confirm these results.
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PMID:Ultra-low-dose interleukin-2 in unresectable hepatocellular carcinoma. 1204 Feb 76

Hepatocellular carcinoma remains a disease with a poor and dismal prognosis, and all forms of currently available conventional therapies are rarely beneficial. However, in recent years, combined targeting locoregional immunochemotherapy has been reported with very promising results. Adoptive immunotherapy with LAK cells (lymphokine-activated killer cells) and recombinant interleukin-2 is becoming one of the new modalities to reconstitute the depressed immune status of the tumor-bearing host. Interleukin-2, gamma-interferon, and interleukin-12 induce cytolytic activity of LAK and natural killer cells and are considered for cellular activation to locoregional immunotherapy before, after resection or even in unresectable hepatocellular carcinomas. Spleen is a suitable organ for LAK cell induction because it has densely packed lymphocytes. The strategy of administration of both interleukin-2 and gamma-interferon into the spleen for in vivo immunostimulation is based on the well-known synergism of the above cytokines. LAK cells have cytotoxic activity against a variety of tumor cells. In particular, LAK cells exhibit efficacy against lung and liver malignant lesions, as suggested by their trafficking pattern; activated killer cells injected i.v. into humans appeared in the lung early and were subsequently rapidly redistributed to the liver and spleen. Lipiodol-Urografin emulsion is probably an ideal cytokine/anti-cancer drug carrier suitable for the combined locoregional immunochemotherapy because during its preferential retention in the vascular network of the spleen and tumor, a gradual release of both immuno- and chemotherapeutical drugs bound to emulsion droplets is achieved ensuring a prolong half life for these drugs. Recent data point to the potential of considering intratumoral or intravascular use of adenovirus carrying interleukin-12 gene, and/or p53-based gene therapy as possible therapeutic strategies in patients with hepatocellular carcinoma.
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PMID:Locoregional immunochemotherapy in hepatocellular carcinoma. 1214 14

We have previously reported that transforming growth factor beta (TGF-beta) produced by rat hepatoma cell line KDH-8 cells suppressed the interleukin-2 (IL-2) production of T cells and the tumoricidal activity of macrophages in KDH-8 tumor-bearing rats and that the inhibition of TGF-beta production by low-dose bleomycin restored these activities significantly. In this study, we established three transfectant clones with stable expression of soluble TGF-beta receptor type II (sTRII), namely KT1, KT2 and KT3, and one with an empty vector used as control vector (KV), and then investigated the effects of sTRII on the tumorigenicity of KDH-8 cells and immune responses in syngeneic Wistar King Aptekman/Hok (WKAH) rats. We found that sTRII expressed in sTRII transfectants could abolish growth inhibition of Mv1Lu cells by TGF-beta1 produced by the cells themselves, and that tumor growth of KT2 and KT3 clones in vivo was suppressed significantly compared with that of parent, KV and KT1 clones. Furthermore, we demonstrated that IL-2 production of splenocytes and IL12p40 mRNA expression in tumor tissues were restored in rats inoculated with KT2 and KT3 clones, whereas such restoration was not observed in rats inoculated with parent, KV and KT1 clones. Combined with a low expression of sTRII in KT1 tumor tissues, these results suggest that sTRII may to some extent be able to abolish the tumor-promoting activity of TGF-beta, and imply that sTRII might have a therapeutic effect on TGF-beta-producing tumors.
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PMID:Suppression of in vivo tumorigenicity of rat hepatoma cell line KDH-8 cells by soluble TGF-beta receptor type II. 1219 38

A case of an inoperable hepatocellular carcinoma due to liver cirrhosis is presented. Surgical treatment was not clinically warranted. So we decided to induce tumor necrosis by intratumoral injections of 10 mL of ethanol followed by two treatments with 9 x 10(6) U Chiron interleukin-2 with an interval of 1 month. This ethanol-interleukin-2 cycle was repeated three times with intervals of 6 months. Interleukin-2 injections were given by a fine needle, under ultrasound control in the periphery and in the center of the tumor. The initial size of the tumor was 55-60 mm. During the follow-up period of 2 years the tumor size remained relatively unchanged. The patient died due to gastric hemorrhage. The treatment elicited no adverse clinical effects. The clinical status improved greatly after this treatment. Local interleukin-2 application after alcohol-induced tumor ablation might be an alternative if surgical treatment is not warranted.
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PMID:A case of hepatocellular carcinoma (HCC): treatment with local application of alcohol and interleukin 2 (IL-2). 1457 7

Chronic hepatitis B virus infection is a serious problem because of its worldwide distribution and possible adverse chronic sequelae, such as cirrhosis and hepatocellular carcinoma. Chronic hepatitis B infection is a dynamic state of interactions between the virus, hepatocyte and host immune response. Interferon-alpha and direct antiviral agents, such as lamivudine (Epivir, GlaxoSmithKline), are effective in the therapy of chronic HBV infection but the efficacy is far from satisfactory. Thymalfasin (thymosin alpha1; Talpha1, Zadaxintrade mark, SciClone Pharmaceuticals, Inc.) is a 28-amino acid polypeptide produced synthetically but originally isolated from thymosin fraction 5, a bovine thymus extract containing a number of immunologically active peptides. In vitro studies have shown that Talpha1 can influence T-cell production and maturation, stimulate production of Th1 cytokines such as interferon-gamma and interleukin-2, and activate natural killer cell-mediated cytotoxicity. Seven randomized controlled studies on Talpha1 monotherapy in patients with chronic hepatitis B showed that 6 months treatment with Talpha1 (1.6 mg twice-weekly) resulted in a significantly higher sustained response rate than untreated controls. The benefits of Talpha1 therapy is usually not immediately apparent during therapy. There is a trend for complete virological response to increase or accumulate gradually after the end of thymosin therapy. The results of Talpha1 and interferon combination therapy in two open-label trials were also promising. In terms of the mechanisms of action, a combination of Talpha1 and nucleoside or nucleotide analogs is a logical approach in the control of chronic HBV infection and a randomized control study is ongoing.
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PMID:Thymalfasin for the treatment of chronic hepatitis B. 1548 67

Alterations of cytokine responses are thought to favor the establishment of persistent hepatitis C virus (HCV) infections, enhancing the risk of liver cirrhosis and hepatocellular carcinoma. Here we demonstrate that the expression of the HCV core (C) protein in stably transfected T cells correlates with a selective reduction of interleukin-2 (IL-2) promoter activity and IL-2 production in response to T-cell receptor triggering, whereas the activation of IL-4, IL-10, gamma interferon, and tumor necrosis factor alpha was moderately increased. This altered cytokine expression profile was associated with a perturbation of mitogen-activated protein (MAP) kinase responses. Extracellular regulated kinase and p38 were constitutively phosphorylated in C-expressing cells, while triggering of the costimulatory c-Jun N-terminal kinase (JNK) signaling cascade and activation of the CD28 response element within the IL-2 promoter appeared to be impaired. The perturbations of MAP kinase phosphorylation could be eliminated by cyclosporine A-mediated inhibition of nuclear factor of activated T cells, suggesting that the inactivation of JNK signaling and hyporesponsiveness to IL-2 induction were downstream consequences of C-induced Ca(2+) flux in a manner that mimics the induction of clonal anergy.
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PMID:Hepatitis C virus core protein induces an anergic state characterized by decreased interleukin-2 production and perturbation of mitogen-activated protein kinase responses. 1568 25

Natural killer T (NKT) cells share features of both classical T cells and NK cells. NKT are heterogenous populations, and recognize glycolipids associated with CD1d molecule. We investigated Th1/Th2 cytokine production as well as frequency and phenotype of circulating NKT cells in 14 healthy subjects and in patients during therapy with type C chronic hepatitis (CH; 14 cases) and hepatocellular carcinoma (HCC; 13 cases). Peripheral blood mononuclear cells (PBMC) were obtained before and 2 weeks later interferon (IFN)/ribavirin and radiofrequency ablation therapy for CH and HCC, respectively. PBMC were cultured for 10 days with alpha-galactosylceramide (alpha-GalCer) and interleukin-2 (IL-2). Frequencies and IFN-gamma/IL-4 production of NKT cells were analyzed using flow cytometry. Intrahepatic lymphocytes were analyzed in seven CH patients with liver biopsy specimen. Prevalence of circulating Valpha24+CD3+ T cells was 0.9+/-0.9% of PBMC for controls and increased to 8.5+/-8.9% (p<0.001) in response to alpha-GalCel. Similar frequency and expansion were noted in CH. The frequency increased during therapy. The prevalence in HCC tended to be high compared to controls and response to alpha-GalCel was well. Although frequency of Valpha24+Vbeta11+CD3+ T cells was low in all groups, the distribution pattern was similar to Valpha24+Vbeta11-CD3+ T cells. Prevalence of CD56+CD3+ T cells was low independent of therapy in CH (2-3%) compared to 5.0+/-4.0% of controls, although response to alpha-GalCel was not impaired. IFN-gamma production of Valpha24+CD3+ T cells did not differ among groups, but became greater after treatment in contrast to lowered IL-4 production. Frequencies of NKT populations were higher in liver than in peripheral blood. Our study suggests that CD1d-reactive T cells have distinct distribution in different populations and therapy for patients alters cytokine response of NKT cells.
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PMID:Changes in natural killer T cells subsets during therapy in type C hepatitis and hepatocellular carcinoma. 1590 21

Interleukin-2 (IL-2) is a lymphokine produced by T cells whose main function is to stimulate the growth and cytotoxic response of activated T lymphocytes. It has been used to stimulate the immune system for the treatment of multiples tumors. This article is intended to review the reports published from 1990 to 2004 on the IL-2 treatment of tumors other than melanoma and renal carcinoma. A literature search was made in various databases (MEDLINE, EMBASE and BioAssay), focused on IL-2 clinical efficacy in such tumors. A selection was made over 150 publications reporting on administration of IL-2 in multiple tumors: lung carcinoma (small cell and non-small cell), colorectal, gastric, pancreatic, ovarian and breast cancer, sarcomas, hepatocarcinoma, mesothelioma, and brain, urological, and head and neck tumors. IL-2 was mainly used in metastatic disease, associated with other immunotherapy or chemotherapy schedules. We conclude that adjuvant IL-2 may be of value in early stages combined with standard treatment for colon and pancreas cancers. In other neoplasms, the indication for adjuvant IL-2 has been sporadic and does not allow conclusions to be drawn. Assessment of the efficacy of IL-2 combined with chemotherapy as treatment for advanced stages is complex, due to the lack of a control, and the variety of dosages and schemes. The activity of IL-2 in monotherapy or in association with immunotherapy is clinically relevant in hepatocarcinoma, mesothelioma and in malignant overflows as palliative treatment. Randomized trials would be required in order to be able to draw conclusions about its indication in other tumors.
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PMID:Interleukin-2 for the treatment of solid tumors other than melanoma and renal cell carcinoma. 1631 84

Vascular leak syndrome (VLS) is the major dose-limiting toxicity of immunotoxin and interleukin-2 therapy. It has been evidenced that VLS-inducing molecules share a three-amino acid consensus motif, (x)D(y), which may be responsible for initiating VLS. Here we have constructed a recombinant immunotoxin (SMFv-PE38KDEL) by genetically fusing PE38KDEL to a single-chain antibody derived from SM5-1 monoclonal antibody, which has a high specificity for melanoma, hepatocellular carcinoma and breast cancer. In order to eliminate VLS induced by this PE38KDEL-based immunotoxin, a panel of mutants were generated by changing amino acid residues adjacent to its three (x)D(y) motifs in the three-dimensional structure. One of the SMFv-PE38KDEL mutants, denoted as mut1, displayed a similar protein synthesis inhibitory in a reticulocyte lysate translation assay compared to the wild-type SMFv-PE38KDEL (wt). The in vitro cytotoxicity assay indicated that mut1 specifically killed SM5-1 binding protein-positive tumor cells, although its cytotoxicity was slightly less than wt. In contrast, mut1 was shown to be much weaker in inducing VLS in mice than wt. The LD(50) values of wt and mut1 in mice were investigated with the result that the LD(50) of mut1 was about tenfold higher than that of wt. The in vivo antitumor activity of wt and mut1 were also compared in tumor-bearing nude mice. Both wt and mut1 were effective in inhibiting the tumor growth but mut1 showed improved therapeutic efficacy. These studies suggest mut1 may be a novel PE-based immunotoxin with much less toxicity for clinical use.
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PMID:Treatment of hepatocellular carcinoma in a mouse xenograft model with an immunotoxin which is engineered to eliminate vascular leak syndrome. 1743 17


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