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)

Chronic hepatitis B virus (HBV) infection is a serious problem because of its world wide distribution and possible adverse chronic sequalae such as cirrhosis and hepatocellular carcinoma. Over the past 20 years, many antiviral or immunomodulatory agents, or both, have been used in patients with chronic HBV infection. Among immunomodulatory agents, levamisole, BCG, picibanil and interleukin-2 have been shown to be ineffective. Corticosteroid therapy is also ineffective and can cause deleterious effects in chronic HBV infection. Thymosin-alpha 1 therapy is currently in phase III clinical trial. Among antiviral agents, acyclovir, dideoxynucleosides, suramin, zidovudine and ganciclovir have been shown to be ineffective and have intolerable side effects. While adenine arabinoside (Ara-A) and its monophosphate derivative (Ara-AMP) are effective agents if the treatment course is long enough, they have been withdrawn from investigative use because of their substantial neuromuscular toxicity. Interferon-alpha may directly inhibit HBV replication and enhance hepatocyte HLA class I antigen expression with subsequent increase of T-cell mediated cytotoxicity. Randomized, controlled clinical trials have shown that 25% to 50% of adult patients with elevated alanine transaminase (ALT) levels lost HBeAg and HBV-DNA when treated with IFN-alpha at a dose of 5MU daily or 10 MU three times a week for 3 to 6 months. In view of the fact that the response rate is far from satisfactory, particularly in Asian patients, combination therapies including interferon alpha with Ara-AMP, acyclovir, didoxynucleoside or interferon-gamma have been studied. Most forms of combination therapy have been shown to be of limited effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Drug therapy in patients with chronic type B hepatitis]. 754 84

The therapeutic effect of the fibroblast-mediated human interferon (IFN alpha) gene therapy in combination with interleukin-2 (IL-2) activated killer cells (AK)/doxorubicin (i.e., adoptive chemoimmunotherapy) on nude mice bearing the human hepatocellular carcinoma (HCC) was investigated. A fibroblast cell clone (NIH3T3-IFN alpha+) secreting 1024 U/ml human IFN alpha was obtained from 14 positive clones by BMGNeo-IFN alpha DNA transfection, G418-resistant selection, limiting dilution and assay of IFN alpha activity. After i.p. implantation of NIH3T3-IFN alpha+ encapsulated into collagen, serum human IFN alpha activity could be detected from 12 h to day 15 with a peak at 72 h. AK were prepared from human peripheral mononuclear cells costimulated in vitro by IL-2 and inactivated human SMMC 7721 HCC cells. When the NIH3T3-IFN alpha+ cells were i.p. implanted into the HCC-bearing nude mice, the grown of HCC was inhibited and the survival time of the mice was extended. The growth of HCC was inhibited more obviously when AK was i.v. injected and IL-2 was i.p. injected after the NIH3T3-IFN alpha+ cells had been implanted. The best therapeutic effect was achieved when NIH3T3-IFN alpha+ cells were used in combination with IL-2/AK/doxorubicin. All these results suggested that the fibroblast-mediated human IFN alpha gene therapy could be used to treat the human hepatocellular carcinoma effectively and that when used in combination with IL-2-based adoptive chemoimmunotherapy, the therapeutic effect would be better.
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PMID:Treatment of human hepatocellular carcinoma by fibroblast-mediated human interferon alpha gene therapy in combination with adoptive chemoimmunotherapy. 764 87

To determine improved postresection survival in patients with hepatocellular carcinoma, two postoperative protocols were compared: adoptive chemoimmunotherapy versus chemotherapy. Following resection, 24 patients were allocated at random to receive (1) arterial infusion of Adriamycin, recombinant interleukin-2 and lymphokine-activated killer cells or (2) arterial infusion of Adriamycin alone. The spleen was removed at operation and used to prepare lymphokine-activated killer cells. Each group had 12 patients. They were followed until signs of recurrence appeared. The overall survival rates of the patients were 91.7%, 82.9%, and 72.5% at 1, 2, and 3 years, respectively, and slightly higher than would be expected with surgery alone. No statistically significant difference was found between the two groups either in the survival rate (generalized Wilcoxon test, P = .936) or in the cumulative disease free rate (P = .182). However, when patients who had had hepatic resection with negative margin (> or = 1 cm) were separated, the 2-year cumulative disease-free rate in the adoptive chemoimmunotherapy was higher (83.3%, n = 6) than that in chemotherapy (37.5%, n = 8). Toxicity to adoptive chemoimmunotherapy was moderate; no severe side effects were observed. Totally no statistical difference between the two groups was found. Although only one of six patients in adoptive chemoimmunotherapy experienced recurrence after hepatic resection with negative margin, it was not feasible to determine the role of interleukin-2 and lymphokine-activated killer cells. We conclude that the adoptive chemoimmunotherapy in this study is not an ideal adjuvant protocol after hepatic resection.
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PMID:Adjuvant chemoimmunotherapy for hepatocellular carcinoma patients. Adriamycin, interleukin-2, and lymphokine-activated killer cells versus adriamycin alone. 774 15

The efficacy of tumor therapy using polyethylene-glycol-modified interleukin-2 (PEG-IL-2), alone or in combination with cyclophosphamide, was studied in advanced metastatic disease in the guinea pig. Line 10 (L10) tumor cells appeared in the axillary lymph node only 7 days after intradermal tumor-cell inoculation, and lymph-node leukocytes were almost completely replaced by tumor cells on day 28. Local treatment of the intradermally growing L10 hepatocarcinoma in the guinea pig with a relatively low dose of PEG-IL-2 resulted in regression of the primary tumor and prevention of lymph-node metastases. Therapy was completely curative (4 out of 5 animals) when started on day 7 or 14 after tumor-cell inoculation. When started on day 21, therapy was effective in only some (2 out of 5 cured) of the treated animals. Anti-tumor effects against the primary tumor and against lymph-node metastases were observed only after intratumoral (i.t.) administration of PEG-IL-2. Injection of the agent into or near lymph-node metastases in the absence of the primary tumor had no curative effect. In PBS/BSA-treated control animals the primary tumor and metastases grew progressively. In the treatment of far advanced metastatic disease, the combination of i.t. administration of PEG-IL-2 and i.p. injection of cyclophosphamide (Cy) resulted in improved anti-tumoral effects (5/5 guinea pigs were cured) when compared with monotherapy using either agent (one and none out of 5 animals cured, respectively). PBS/BSA heated controls showed progressive tumor-growth. We conclude that large primary tumors and lymph-node metastases can be treated effectively with PEG-IL-2. The i.t. route of administration is of major importance in the treatment of metastases, since administration of PEG-IL-2 near or into the lymph node had no therapeutic effect. Combination of PEG-IL-2 therapy with systemic injections of Cy significantly improved the curative effects of the treatment of advanced metastatic cancer.
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PMID:PEG-IL-2 therapy of advanced cancer in the guinea pig. Impact of the primary tumor and beneficial effect of cyclophosphamide. 792 81

We examined whether anti-cancer cells are induced in vivo in hepatocellular carcinoma (HCC) by OK-432. Ten patients with HCC were randomly divided into two groups. The group I patient (n = 5) served as the control. In group II (n = 5), OK-432 was preoperatively administered via the hepatic artery. Tumor infiltrating lymphocytes (TILs) were collected from resected tumors. Cytotoxicity of TILs against K562 cells and Raji cells was studied with phenotypic analysis by flow cytometry. Freshly isolated TILs, whether or not treated with OK-432, showed low cytotoxicity. When TILs were co-cultured with recombinant interleukin-2 (rIL-2), the cytotoxicity was significantly activated in the OK-432 treated group, whereas untreated TILs showed no activation. The natural killer (NK) activity and the lymphokine-activated killer (LAK) activity were depressed in group I after hepatic resection, but patients in group II had no depression. Our data indicate that LAK precursor cells are induced in TILs and the prevention of post-operative immune suppression is made possible by OK-432.
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PMID:[Induction of anti-cancer cells and systemic immune response in hepatocellular carcinoma by OK-432]. 794 16

We investigated the question whether lymphokine-activated killer precursor (pre-LAK) cells are induced by OK-432 in vivo, in hepatocellular carcinoma (HCC). Ten patients with HCC were randomly divided into two groups. In group A (n = 5), OK-432 was pre-operatively administered via the hepatic artery. The group B patients (n = 5) served as controls. Tumor-infiltrating lymphocytes (TILs) were collected from the resected tumors. The cytotoxicity of TILs against natural killer (NK)-sensitive K562 cells and NK-insensitive Raji cells was examined by phenotypic analysis with flow cytometry. Freshly isolated TILs, whether treated with OK-432 or not, showed low cytotoxicity against both tumor cells. However, OK-432 pretreatment increased the T-lymphocyte population of TILs, particularly with interleukin-2 (IL-2) receptor positive cells. When TILs were co-cultured with recombinant interleukin-2 (rIL-2), the cytotoxicity was significantly activated in the OK-432 treated group, while untreated TILs showed no activation (P < 0.05). We postulate that pre-LAK cells are induced by OK-432 in TILs, mainly from the T-lymphocyte population. The possibility that LAK cells can be endogenously induced in HCC if OK-432 and rIL-2 are concomitantly administered needs to be considered for immunotherapy to HCC.
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PMID:Induction by OK-432 of lymphokine activated killer precursor cells in hepatocellular carcinoma. 795 72

An important objective for patients with unresectable hepatocellular carcinoma (HCC) is the development of effective chemotherapy. We administered a combination of biological response modifiers and anticancer agents to 24 patients with unresectable HCC. Each case had an implanted infuser port which was connected to a catheter placed in the hepatic artery for the intraarterial (i.a.) administration of chemotherapy. The following agents were administered to each patient: recombinant interleukin-2 (800,000 JRU/day infused i.a. continuously for 6 days/week); OK-432 (5 KE injected i.a. twice in 4 weeks and i.m. three times per week); Adriamycin (10 mg injected i.a. twice in 4 weeks); cyclophosphamide (300 mg injected i.a. twice in 4 weeks), and famotidine (40 mg/day administered orally). Objective response was assessed according to tumor size measured by computed tomography and angiography before and after treatment. We observed a complete response (CR) in 4, partial response (PR) in 3, minor response (MR) in 7, no change (NC) in 7, and progressive disease (PD) in 3. The response rate (CR+PR+MR) was 58.3%. The overall 2-year survival rate was 52%. The 2-year survival rate of the responders (CR+PR+MR) was 80%, while that of the non-responders (NC+PD) was 0%. There was a significant difference between the responders and non-responders in respect to survival rate (P < 0.05). The percentages of CD25+ cells, CD56+ cells, and Leu7-CD16+ cells and NK activity in the peripheral blood showed a significant increase following the regimen. Serum levels of tumor necrosis factor alpha TNF alpha rose after the initiation of OK-432. TNF alpha levels were higher in the responders than in the non-responders. Adverse effects included high fever (all patients) and severe transient hypotension (15 patients) that was controlled by conservative therapy. Combined immunochemotherapy administered intraarterially may be a new strategy for treating unresectable HCC.
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PMID:Intraarterial combined immunochemotherapy for unresectable hepatocellular carcinoma: preliminary results. 812 88

In this study we have investigated whether cytokines, critical mediators of the immune response, might have a direct effect on the expression and/or function of the human hepatic asialoglycoprotein receptor (ASGPR). Binding and uptake of asialoglycoproteins by the human hepatoma cell line, HepG2, and by freshly isolated rat hepatocytes were inhibited by 50% after 3-6 hours and completely abolished following a 24 hour exposure to tumor necrosis factor (TNF) alpha, interferon (INF) alpha or gamma, or interleukin-2 (IL-2). The loss of ASGPR binding activity mediated by IL-2 was reversible up to 4 hours of exposure and accompanied by the selective phosphorylation of the cell-surface receptor. Steady-state levels of total cellular ASGPR protein remained unchanged over the first 6 hours of IL-2 incubation but declined in a dose dependent manner thereafter. This down regulation of ASGPR expression was due to reduced synthesis as a result of reduced receptor transcript levels. No loss was detected, however, of cell surface-associated receptor protein even after 24 hours of IL-2 incubation, suggesting that cytokine induced phosphorylation constitutes a mechanism to regulate receptor activity.
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PMID:Effects of cytokines on synthesis and function of the hepatic asialoglycoprotein receptor. 812 76

A randomized study using spleen-derived lymphokine-activated killer (LAK) cells in hepatocellular carcinoma (HCC) is reported. We induced cytotoxic lymphocytes from resected spleen of HCC. The effect of recombinant interleukin-2 (rIL-2)-activated spleen cells for prevention of recurrence of HCC after hepatic resection was studied. Enough mononuclear cells could be harvested from the resected spleens. The induction of activated spleen cells was carried out by culture in fresh medium containing 1,500 JU/ml of IL-2. The cytotoxicity of the activated spleen cells maintained high levels during the culture period ranging from 3-30 days. These autologous activated spleen cells were administered to patients 2 days after the intra-arterial infusion of Adriamycin. A randomized study using these spleen LAK cells resulted in lower recurrence rates in the LAK IL-2-treated group. No severe side effects were observed. The lymphocytes derived from resected spleens were useful as the source of effector cells in clinical adoptive immunochemotherapy for HCC, because of their higher cytotoxicity and the simplicity of gaining a large amount of cells.
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PMID:Postoperative chemoimmunotherapy for the treatment of liver cancer. 821 Sep 15

Transcatheter arterial embolization (TAE) using hydroxycamptothecin, cantharidin and cisplatin which were mixed thoroughly with lipiodol, combined with large doses interferon and interleukin-2 as adoptive immunotherapy were carried out in the treatment of 48 patients with unresectable advanced stage primary hepatoma, evaluation of therapeutic effect showed that partial remission rate was 54.2%, significantly higher than that of embolization group using chemotherapeutic agents alone (cisplatin, adriamycin and mitomycin), the partial remission rate was 32.1% (P < 0.01). The side effects of camptothecin and cantharidin including hematuria, urodynia were also successfully eliminated.
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PMID:[Chinese material medica combined with cisplatin and lipiodol through transcatheter arterial embolization in the treatment of primary hepatoma]. 825 33


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