Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Herpes simplex virus type-1 (HSV1) in which the neurovirulence factor ICP34.5 is inactivated has been shown to direct tumour-specific cell lysis in several tumour models. Such viruses have also been shown to be safe in Phase I clinical trials by intra-tumoral injection in glioma and melanoma patients. Previous work has used serially passaged laboratory isolates of HSV1 which we hypothesized may be attenuated in their lytic capability in human tumour cells as compared to more recent clinical isolates. To produce ICP34.5 deleted HSV with enhanced oncolytic potential, we tested two clinical isolates. Both showed improved cell killing in all human tumour cell lines tested compared to a laboratory strain (strain 17+). ICP34.5 was then deleted from one of the clinical isolate strains (strain JS1). Enhanced tumour cell killing with ICP34.5 deleted HSV has also been reported by the deletion of ICP47 by the up-regulation of US11 which occurs following this mutation. Thus to further improve oncolytic properties, ICP47 was removed from JS1/ICP34.5-. As ICP47 also functions to block antigen processing in HSV infected cells, this mutation was also anticipated to improve the immune stimulating properties of the virus. Finally, to provide viruses with maximum oncolytic and immune stimulating properties, the gene for human or mouse GM-CSF was inserted into the JS1/34.5-/47- vector backbone. GM-CSF is a potent immune stimulator promoting the differentiation of progenitor cells into dendritic cells and has shown promise in clinical trials when delivered by a number of means. Combination of GM-CSF with oncolytic therapy may be particularly effective as the necrotic cell death accompanying virus replication should serve to effectively release tumour antigens to then induce a GM-CSF-enhanced immune response. This would, in effect, provide an in situ, patient-specific, anti-tumour vaccine. The viruses constructed were tested in vitro in human tumour cell lines and in vivo in mice demonstrating significant anti-tumour effects. These were greatly improved compared to viruses not containing each of the modifications described. In vivo, both injected and non-injected tumours showed significant shrinkage or clearance and mice were protected against re-challenge with tumour cells. The data presented indicate that JS1/ICP34.5-/ICP47-/GM-CSF acts as a powerful oncolytic agent which may be appropriate for the treatment of a number of solid tumour types in man.
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PMID:ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties. 1259 88

One major problem associated with application of gene therapy to treatment of tumors is poor transgene expression. Although suicide gene therapy with the herpes simplex virus-thymidine kinase gene (HSV-tk) followed by administration of ganciclovir (GCV) was effective in the treatment of melanoma, it was still difficult to induce complete remission to cancer. A novel histone deacetylase inhibitor drug FR901229 was found to enhance transgene expression in tumor cells both in vitro and in vivo. Combination therapy with HSV-tklGCV and FR901228 by direct injection into tumor enhanced antimelanoma effects. The number of apoptotic cells in melanoma tumors was increased significantly (P<.05) after combined suicide gene therapy and FR901228. Six times injection of HSV-tk/GCV and FR901228 prolonged mice survival compared to that of HSV-tk/GCV injection alone (P=.021). In total, 56% (10 of 18) of the mice survived 120 days after combined suicide gene therapy and FR901228 treatment, and no new tumors appeared in the surviving mice. However, only 19% (3 of 16) of the mice survived when treated with suicide gene therapy alone. This novel strategy may be applicable as a therapeutic regimen for the treatment of aggressive types of cancers.
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PMID:A novel combination of suicide gene therapy and histone deacetylase inhibitor for treatment of malignant melanoma. 1263 38

Tegument proteins of herpes simplex virus type 1 (HSV-1) are hypothesized to contain the functional information required for the budding or envelopment process proposed to occur at cytoplasmic compartments of the host cell. One of the most abundant tegument proteins of HSV-1 is the U(L)49 gene product, VP22, a 38-kDa protein of unknown function. To study its subcellular localization, a VP22-green fluorescent protein chimera was expressed in transfected human melanoma (A7) cells. In the absence of other HSV-1 proteins, VP22 localizes to acidic compartments of the cell that may include the trans-Golgi network (TGN), suggesting that this protein is membrane associated. Membrane pelleting and membrane flotation assays confirmed that VP22 partitions with the cellular membrane fraction. Through truncation mutagenesis, we determined that the membrane association of VP22 is a property attributed to amino acids 120 to 225 of this 301-amino-acid protein. The above results demonstrate that VP22 contains specific information required for targeting to membranes of acidic compartments of the cell which may be derived from the TGN, suggesting a potential role for VP22 during tegumentation and/or final envelopment.
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PMID:Membrane association of VP22, a herpes simplex virus type 1 tegument protein. 1266 95

Neuroattenuated herpes simplex virus ICP34.5 mutants slow progression of preformed tumors and lead to complete regression of some tumors. Although this was previously thought to be due to viral lysis of infected tumor cells, it is now understood that there is an immune component to tumor destruction. We have previously shown that no difference in survival is seen in lymphocyte-depleted mice after viral or mock therapy of syngeneic intracranial melanomas. We have also demonstrated the presence of a wide spectrum of immune cells following viral therapy, including larger percentages of CD4+ T cells and macrophages. In this paper, the contribution of the immune system to tumor destruction has been further delineated. Viral therapy of intracranial melanoma induces a tumor-specific cytotoxic and proliferative T cell response. However, there is no increase following viral therapy in either serum tumor antibody levels or viral-neutralizing antibodies. Thus specific T cell responses appear to mediate viral-elicited prolongation in survival. These data suggest that designing new viruses capable of augmenting T cell responses may induce stronger tumor destruction upon viral therapy.
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PMID:Requirement of an integrated immune response for successful neuroattenuated HSV-1 therapy in an intracranial metastatic melanoma model. 1278 47

H11, the eukaryotic homologue of a herpes simplex virus protein, has the crystallin motif of heat shock proteins (Hsp), but it differs from canonical family members in that mRNA and protein levels were reduced in various tumor tissues and cell lines (viz. melanoma, prostate cancer and sarcoma) relative to their normal counterparts. In these cells, expression was not restored by heat shock, but rather by the demethylating agent 5-aza-2'-deoxycytidine (Aza-C). Forced H11 expression by Aza-C treatment, transient transfection with H11 expression vectors, or retrovirus-mediated delivery of H11 under the control of a tetracycline-sensitive promoter triggered apoptosis. This is evidenced by a significant (p < 0.001) increase in the percentage of cells positive for terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) and for activation of caspase-3 and p38MAPK and by the co-localization of TUNEL+ nuclei with increased H11 levels. Apoptosis was partially inhibited by the pancaspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone or the p38MAPK inhibitor SB203580. It was abrogated by co-treatment with both inhibitors, suggesting that H11-triggered apoptosis is both caspase- and p38MAPK-dependent. A single site mutant (H11-W51C) had cytoprotective activity related to MEK/ERK activation, and it blocked H11-induced apoptosis in co-transfected and Aza-C-treated cells, indicating that it is a dominant negative mutant. This is the first report of a heat shock protein with proapoptotic activity.
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PMID:Forced expression of the H11 heat shock protein can be regulated by DNA methylation and trigger apoptosis in human cells. 1283 17

We examined the possible involvement of human herpes viruses in sporadic non-melanoma skin cancer of Greek patients. Polymerase chain reaction (PCR) based detection assays were utilized for the detection of viral cytomegalovirus (CMV), herpes simplex virus (HSV) and Epstein-Barr virus (EBV) genomes in 24 squamous cell carcinomas (SCC), five Bowen's disease, 72 basal cell carcinomas (BCC) specimens and eight premalignant lesions. Forty-two of 109 (38.5%) skin lesions were found positive for CMV DNA. The highest incidence was 6/8 (75%) observed in specimens with premalignant lesions. The incidence was 37.5% (27/72) in BCC, 33% (8/24) in SCC and 20% (1/5) in extragenital Bowen's disease. All samples were negative for HSV-1/2 and EBV DNA as assessed by our PCR based assay. The CMV infection showed no statistically significant correlation with the histological type, age, site of lesion or sex. Our results give a strong indication of the possible involvement of CMV in non-melanoma skin cancer development.
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PMID:Human herpes viruses in non-melanoma skin cancers. 1289 33

Expression of chemokines within tumors can be used to recruit immature dendritic cells (DCs) for the initiation of antitumor T-cell responses. Here, we describe the chemokine receptor expression on murine bone marrow-derived immature DCs. On the basis of these receptor studies, we chose to express the chemokines CCL3 (Mip-1alpha) or CCL20 (Mip-3alpha) in tumors. We show that expression of these chemokines in the colorectal tumor model CMT93 significantly decreases tumorigenesis. This decrease is associated with an increase in CD8 T cells, natural killer cells, and Class II DCs in the tumor within the first 24 h. Furthermore, studies in immunodeficient mice show that both natural killer cells and T cells are required for this decrease in immunogenicity. CCL3 and CCL20 expression alone did not significantly inhibit the development of the B16 melanoma tumor. However, coexpression of the Herpes Simplex Virus thymidine kinase gene (HSVtk) and CCL20, cured large established tumors where HSVtk expression alone was not sufficient. Finally, coexpression of HSVtk with either CCL3 or CCL20 was able to significantly increase protection against subsequent tumor rechallenge.
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PMID:Expression of inflammatory chemokines combined with local tumor destruction enhances tumor regression and long-term immunity. 1450 Mar 87

Impression cytology, either using cellulose acetate strips or the Biopore membrane device, is a simple, noninvasive technique that aids in the diagnosis of several disorders of the ocular surface. These disorders include ocular surface squamous neoplasia, dry eye syndrome, limbal stem-cell deficiency, specific viral infections, vitamin A deficiency, allergic disorders, conjunctival melanosis, and malignant melanoma. Another advantage is the preservation of limbal stem cells, which occur in the basal layer of the limbal epithelium and are responsible for renewal of the corneal epithelium. The Biopore membrane device is particularly user friendly, with little expertise required and adequate specimens obtained in a very high percentage of cases. The most common applications in diagnostic ocular pathology are:(i) primary diagnosis and follow-up of ocular surface squamous neoplasia, including after therapy with topical mitomycin C. The sensitivity is high (78-87%); and (ii) dry eye syndrome where squamous metaplasia and/ or hyperkeratosis are noted. Certain limitations of the technique for diagnosis of squamous neoplasia include the fact that dysplasias are often keratinizing and may yield very few or even no dysplastic cells with impression cytology. Secondly, no definite cytologic criteria reliably distinguish invasive SCC of ocular surface from in situ disease. Other applications include the rapid specific diagnosis of ocular surface infections with herpes simplex, adeno-, and varicella zoster viruses. Impression cytology samples may also be used to obtain mRNA, cells for phenotyping by flow cytometry, and proteins for Western blotting for research studies.
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PMID:Ocular surface impression cytology. 1458 22

An impediment encountered in many viral-based gene therapy clinical trials has been the rapid destruction of the transgene by the host's immune response. The processing and presentation of antigens through the class I major histocompatibility complex (MHC) pathway is the initial specific response to viral infection. Disruption of the class I MHC pathway by herpes simplex virus (HSV) or the human cytomegalovirus (HCMV) results in a decrease of the CD8(+) cytotoxic T lymphocyte (CTL) response and prolongs survival of infected cells in the host. Two viral immune suppression genes that interfere with the class I MHC presentation pathway, the HSV type I ICP47 gene and HCMV US11 gene, were cloned and each incorporated into a retroviral vector. HSV ICP47 and HCMV US11 transgenes were expressed in multiple cells lines and compared for their abilities to reduce antigen presentation on the cell surface by class I MHC. Retroviral supernatants were used to transduce human, canine, and rat cell lines. Fluorescence-activated cell sorter (FACS) analysis of US11- and ICP47-transduced cell lines demonstrated substantial reductions in class I MHC cell surface expression in most cell lines except in rodent cells where ICP47 is nonfunctional. The decrease in the level of class I MHC expression for ICP47 transduced cell lines ranged from 31-98% relative to negative controls. US11 decreased class I cell surface MHC by 67-96%. When both ICP47 and US11 are expressed in human cells, a further reduction of class I MHC was observed. Next, human A375 melanoma cells were tested to determine if the resulting reduction in cell surface class I MHC would reduce in vitro cytotoxicity by CTL. A375 cells expressing either ICP47 or US11 demonstrated a twofold to threefold reduction of specific lysis by primed CD8(+) CTL. These data clearly establish an ability to convey immune protection to human cells by viral genes. However, further analysis demonstrated that interferon (IFN)-gamma could reverse part or all of the downregulation of class I MHC induced by the ICP47 or US11 genes. The ICP47 and US11 genes, when expressed in target cells, decrease class I MHC presentation and as such might be used in strategies to create local immunosuppression against transgenes or allografts.
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PMID:Effective suppression of class I major histocompatibility complex expression by the US11 or ICP47 genes can be limited by cell type or interferon-gamma exposure. 1467 Jan 27

Selective killing of tumors can be achieved by targeting the transcription of suicide genes via specific DNA control elements to malignant cells. Three different enhancer-promoter systems were constructed and evaluated for their capability to direct gene expression to melanoma. Two tissue-specific (tyrosine and MIA) promoters and one weak viral promoter were fused to multiple tandem copies of a melanocyte-specific enhancer element. Reporter gene assays revealed a maximum increase in transcription by combining each promoter with 3-4 copies of the enhancer and demonstrated that all enhancer-promoter combinations exhibited tissue-specific activity. Though this activity was still significantly less than that of the strong but unspecific cytomegalovirus (CMV) promoter. In contrast, when those combinations were employed to drive the expression of two suicide genes, encoding the diptheria toxin A chain (DT-A) and the prodrug-activating herpes simplex virus thymidine kinase (TK), respectively, only those constructs in which transcription was under control of tissue-specific promoter elements mediated selective killing of melanoma cells. This killing was in the range of cell death induced by CMV promoter activity. Our data indicate that the enhancer/tyrosinase and enhancer/MIA promoter constructs but not the viral promoter constructs can provide a valuable tool for selective suicide gene expression in melanoma.
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PMID:Evaluation of combined gene regulatory elements for transcriptional targeting of suicide gene expression to malignant melanoma. 1471 61


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