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)

The therapeutic efficacy of herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system in many types of tumors is unsatisfactory due to the insufficient spread of gene transfer and insufficient cell killing. In the current study, we investigated whether adenovirally delivered monocyte chemoattractant protein (MCP)-1 potentiates the antitumor effects of the HSV-tk/GCV system in hepatocellular carcinoma (HCC) cells. Subcutaneous tumor foci of the human HCC cell line, HuH7, established in athymic mice were directly transduced with a recombinant adenovirus (rAd) harboring an HSV-tk gene driven by a human alpha-fetoprotein promoter, followed by GCV administration. Subsequently, another rAd expressing MCP-1 under the universal CAG promoter was injected. The growth of tumors was markedly suppressed by codelivering HSV-tk and MCP-1 genes compared to that by either HSV-tk/GCV or MCP-1 delivery. In the tumor tissues, monocyte/macrophage infiltration was detected immunohistochemically. The antitumor effects of the rAd expressing MCP-1 were markedly reduced by the administration of carrageenan, a compound known to inactivate macrophage. These results indicate that adenovirally delivered MCP-1 enhanced the antitumor effects of the HSV-tk/GCV system synergistically by recruitment/activation of macrophages in tumor tissues, suggesting an effective immunotherapy for HCC and other lineages of tumors when used adjuvantly with a suicide gene.
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PMID:Enhanced anti-tumor effects of herpes simplex virus thymidine kinase/ganciclovir system by codelivering monocyte chemoattractant protein-1 in hepatocellular carcinoma. 1168 92

Gene therapy for hepatocellular carcinoma (HCC) may be achieved by introducing a therapeutic gene under the control of transcriptional regulatory sequences of the alpha-fetoprotein (AFP) gene. Transcription of the human AFP gene is controlled positively by the promoter and the enhancer and negatively by the silencer. The AFP promoter is a 200-bp region immediately upstream of the AFP gene, and the enhancer is present between 3 and 4.9 kb upstream of the transcription initiation site. Two silencer regions have been identified upstream of the gene, one at -0.31 kb and the other at -1.75 kb. To achieve specific killing of HCC, adenoviral vectors carrying AFP regulatory sequences have been constructed. In this article, we describe the details of the preparation of an adenoviral vector designed to express the herpes simplex virus thymidine kinase gene under the control of the 4.9-kb AFP 5'-regulatory sequence. Treatment with this viral vector followed by ganciclovir resulted in specific killing of AFP-positive HCC transplanted in nude mice. Other viral vectors containing AFP-regulatory sequences are also discussed.
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PMID:Gene therapy vectors harboring AFP regulatory sequences. Preparation of an adenoviral vector. 1172 28

The present study aimed to establish a novel efficient nonviral strategy for suicide gene transfer in hepatocellular carcinoma (HCC) in vivo. We employed branched polyethylenimine (PEI) and combined it with Epstein-Barr virus (EBV)-based plasmid vectors. The HCC cells transfected with an EBV-based plasmid carrying the herpes simplex virus-1 thymidine kinase (HSV-1 Tk) gene (pSES.Tk) showed up to 30-fold higher susceptibilities to ganciclovir (GCV) than those transfected with a conventional plasmid vector carrying the HSV-1 Tk gene (pS.Tk). The therapeutic effect in vivo was tested by intratumoral injection of the plasmids into HuH-7 hepatomas transplanted into C.B-17 scid/scid mutant (SCID) mice and subsequent GCV administrations. Treatment with pSES.Tk, but not pS.Tk, markedly suppressed growth of hepatomas in vivo, resulting in a significantly prolonged survival period of the mice. These findings suggest that PEI-mediated gene transfer system can confer efficient expression of the suicide gene in HCC cells in vivo by using EBV-based plasmid vectors.
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PMID:Polyethylenimine-mediated suicide gene transfer induces a therapeutic effect for hepatocellular carcinoma in vivo by using an Epstein-Barr virus-based plasmid vector. 1182 60

The herpes simplex virus (HSV) recombinant virus R7020 is an attenuated virus designed as a candidate for immunization against both HSV-1 and HSV-2 infections. It was extensively tested in an experimental animal system and in a healthy human adult population without significant untoward effects. We report on the use of R7020 with ionizing radiation as an oncolytic agent for hepatomas. Two hepatoma cell lines were studied, Hep3B and Huh7. R7020 replicated to higher titers in Hep3B cells than in Huh7 cells. Tissue culture studies correlated with hepatoma xenograft responses to R7020. R7020 was more effective in mediating Hep3B tumor xenograft regression compared with Huh7. Ionizing radiation combined with R7020 also showed differential results in antitumor efficacy between the two cell lines in tumor xenografts. Ionizing radiation enhanced the replication of R7020 in Hep3B xenografts. Moreover, the combination of ionizing radiation and virus caused a greater regression of xenograft volume than either R7020 or radiation alone. Ionizing radiation had no effect on the replication of R7020 virus in Huh7 xenografts. These results indicate that a regimen involving infection with an appropriate herpesvirus such as R7020 in combination with ionizing radiation can be highly effective in eradicating certain tumor xenografts.
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PMID:The use of a genetically engineered herpes simplex virus (R7020) with ionizing radiation for experimental hepatoma. 1185 Jul 25

Herpes simplex virus type 1 (HSV-1) deleted for the immediate-early gene was applied for treatment of hepatoma cells of SKHep 1 and Huh-7. Hepatoma cells were cultured in medium containing HSV1 expressing GFP gene (QOZ/HG) to determine its transfection rate, and both cell lines infected by MOI 1 of QOZ/HG were found to have high expression of GFP without cytotoxicity. Subcutaneous growth of SKHep 1 cell tumor in nude mice was significantly reduced by injection of replicative-deficient herpes virus (TOZ.1) containing Tk-gene with administration of GCV, in comparison with that of noninjected tumor. SCID mice of peritonitis carcinomatosis due to Huh-7 hepatoma cells infected with TOZ.1 could survive longer under administration of GCV than those without TOZ.1. Therefore replicative-deficient HSV1 is a useful vector for treatment of human hepatoma cells, and TOZ.1 with GCV may be applied to suicide gene therapy for hepatoma and peritonitis carcinomatosis of hepatoma cells.
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PMID:Suicide gene therapy of human hepatoma and its peritonitis carcinomatosis by a vector of replicative-deficient herpes simplex virus. 1186 43

The adenomatous polyposis coli (APC) or beta-catenin genes are frequently mutated in colorectal cancers, leading to activation of downstream genes with beta-catenin/T-cell factor (Tcf)-responsive promoters. We have developed a gene therapy approach selectively targeting colorectal cancer cells in which beta-catenin/Tcf4 pathway is activated by using a recombinant adenovirus AdTOP-CMV-TK, which carries a herpes simplex virus thymidine kinase gene (HSV TK) under the control of a beta-catenin/Tcf-response promoter linking to a minimum CMV promoter. AdTOP-CMV-TK and ganciclovir (GCV) treatment significantly suppressed the growth of human DLD-1 colon cancer cells in nude mice. Furthermore, no significant tumor suppression effect was observed in human hepatoma cell line SK-HEP-1, in which the beta-catenin/Tcf pathway is not activated, as a control experiment. In summary, we demonstrated the selective targeting of colorectal cancers with activated beta-catenin by AdTOP-CMV-TK and GCV treatment in animal models, as well as its therapeutic potential for colon cancer metastasized to liver.
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PMID:The suppression of colon cancer cell growth in nude mice by targeting beta-catenin/TCF pathway. 1244 97

Common viral agents known to cause inflammation of the liver (hepatitis) are hepatitis A virus (HAV), hepatitis B virus (HBV), and hepatitis C virus (HCV). Some other viral agents that can cause hepatitis are Epstein Barr virus, herpes simplex virus, and cytomegalovirus. Some patients infected with these viral agents progress to develop chronic viral hepatitis. Approximately 45% of chronic hepatitis cases are associated with hepatitis C and approximately 15% are associated with hepatitis B. In addition to being a leading cause of chronic hepatitis, HCV is most frequently associated with liver cirrhosis and hepatocellular carcinoma. Although much has been published about HAV and HBV, health professionals have learned about HCV only in recent years. For this reason, this article will emphasize the epidemiologic challenges and current treatments for hepatitis C; hepatitis A and B will be discussed in brief.
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PMID:Current treatments for hepatitis. 1246 95

The objective of the study was to evaluate the utility of NV1042, a replication competent, oncolytic herpes simplex virus (HSV) containing the interleukin-12 (IL-12) gene, as primary treatment for hepatic tumors and to further assess its ability to reduce tumor recurrence following resection. Resection is the most effective therapy for hepatic malignancies, but is not possible in the majority of the patients. Furthermore, recurrence is common after resection, most often in the remnant liver and likely because of microscopic residual disease in the setting of postoperative host cellular immune dysfunction. We hypothesize that, unlike other gene transfer approaches, direct injection of liver tumors with replication competent, oncolytic HSV expressing IL-12 will not only provide effective control of the parent tumor, but will also elicit an immune response directed at residual tumor cells, thus decreasing the risk of cancer recurrence after resection. Solitary Morris hepatomas, established in Buffalo rat livers, were injected directly with 10(7) particles of NV1042, NV1023, an oncolytic HSV identical to NV1042 but without the IL-12 gene, or with saline. Following tumor injection, the parent tumors were resected and measured and the animals were challenged with an intraportal injection of 10(5) tumor cells, recreating the clinical scenario of residual microscopic cancer. In vitro cytotoxicity against Morris hepatoma cells was similar for both viruses at a multiplicity of infection of 1 (MOI, ratio of viral particles to target cells), with >90% tumor cell kill by day 6. NV1042 induced high-level expression of IL-12 in vitro, peaking after 4 days in culture. Furthermore, a single intratumoral injection of NV1042, but not NV1023, induced marked IL-12 and interferon-gamma (IFN-gamma) expression. Both viruses induced a significant local immune response as evidenced by an increase in the number of intratumoral CD4(+) and CD8(+) lymphocytes, although the peak of CD8(+) infiltration was later with NV1042 compared with NV1023. NV1042 and NV1023 reduced parent tumor volume by 74% (P<.003) and 52% (P<.03), respectively, compared to control animals. Treatment of established tumors with NV1042, but not with NV1023, significantly reduced the number of hepatic tumors after resection of the parent tumor and rechallenge (16.8+/-11 (median=4) vs. 65.9+/-15 (median=66) in control animals, P<.025). In conclusion, oncolytic HSV therapy combined with local immune stimulation with IL-12 offers effective control of parent hepatic tumors and also protects against microscopic residual disease after resection. The ease of use of this combined modality approach, which appears to be superior to either approach alone, suggests that it may have clinical relevance, both as primary treatment for patients with unresectable tumors and also as a neoadjuvant strategy for reducing recurrence after resection.
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PMID:Neoadjuvant treatment of hepatic malignancy: an oncolytic herpes simplex virus expressing IL-12 effectively treats the parent tumor and protects against recurrence-after resection. 1263 43

The efficacy of the suicide gene therapy using the herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system for the treatment of cancer is limited because of the insufficient gene transfer and the low killing activity. To enhance the antitumor activity, we determined whether recombinant adenovirus vector (rAd)s expressing both HSV-tk and monocyte chemoattractant protein-1 (MCP-1) genes could potentiate the destruction of hepatocellular carcinoma (HCC). The rAd Ad-tk-MCP1 harboring HSV-tk and MCP-1 genes in sequence under the universal CAG promoter was constructed with a bicistronic unit including the encephalomyocarditis virus-internal ribosomal entry site. The levels of HSV-tk expression and GCV-sensitive tumoricidal activity of Ad-tk-MCP1 were comparable to those of rAd expressing HSV-tk alone. The growth of subcutaneous tumors in athymic nude mice was markedly suppressed when tumors were treated with Ad-tk-MCP1 as opposed to another bicistronic vector Ad-MCP1-tk, rAd expressing either HSV-tk or MCP-1, or both of these vectors. The antitumor effects of Ad-tkMCP1 may be dependent on the activation of macrophages, since the recruitment of macrophages was observed tumor necrosis factor-alpha production was enhanced in the tumor tissue. Furthermore, the enhanced antitumor effect was abolished by inactivating macrophages with carrageenan treatment. These results demonstrated that a bicistronic rAd harboring both suicide and chemokine genes in sequence exerted the enhanced, macrophage-dependent, antitumor effects in a model of HCC and support the use of this strategy for the treatment of HCC.
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PMID:Enhanced antitumor effects of a bicistronic adenovirus vector expressing both herpes simplex virus thymidine kinase and monocyte chemoattractant protein-1 against hepatocellular carcinoma. 1267 98

Tissue- or cell-specific targeting of vectors is critical to the success of gene therapy. I describe a novel approach to viral-mediated gene therapy, where viral replication and associated cytotoxicity are limited to a specific cell-type by the regulated expression of an essential immediate-early viral gene product. This is illustrated with two herpes simplex virus type 1 vectors (G92A and d12.CALP) whose growth are restricted to albumin- or calponin-expressing cells, respectively. G92A was constructed by inserting an albumin enhancer/promoter--ICP4 transgene into the thymidine kinase gene of mutant herpes simplex virus type 1 d120, deleted for both copies of the ICP4 gene. This vector also contains the Escherichia coli lacZ gene under control of the thymidine kinase promoter, a viral early promoter, to permit easy detection of infected cells containing replicating vector. In the adult, albumin is expressed uniquely in the liver and in hepatocellular carcinoma and is transcriptionally regulated. G92A efficiently replicated in vitro in two human hepatoma cell lines expressing albumin, but not in three human non-hepatoma, albumin-non-expressing tumor cell lines, while all cell lines were equally susceptible to a tissue non-specific HSV recombinant, hrR3. In vivo, G92A replicated well in subcutaneous xenografts of human hepatoma cells (Hep3B) in athymic mice, but not in non-hepatoma subcutaneous tumors (PC3 and HeLa), whereas, hrR3 replicated well in both tumor types. Intratumoral inoculation of G92A inhibited the growth of established subcutaneous hepatoma tumors in nude mice, but not prostate tumors. D12CALP also revealed the cell-specific replication to leiomyosarcoma in which calponin expression was augmented. Using hrR3, we demonstrated inhibition of re-stenosis of rat carotid arteries caused by balloon injury. The antiproliferative effects of this virus was marked in the proliferating smooth muscle cells, however, there still remained the fear for the injury of the endothelial cells. Confining a productive, cytotoxic viral infection to a specific cell-type should be useful for tumor therapy and the ablation of specific cell-types for the generation of animal models of disease. Further experiments using d12CALP will be focused on the arteriosclerosis due to balloon angioplasty or organ transplantation.
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PMID:Gene therapy using tissue-specific replication competent HSV. 1270 43


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