4 results on '"Hezel M"'
Search Results
2. Molecular network pathways and functional analysis of tumor signatures associated with development of resistance to viral gene therapy.
- Author
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Song, T-J, Haddad, D, Adusumilli, P, Kim, T, Stiles, B, Hezel, M, Socci, N D, Gönen, M, and Fong, Y
- Subjects
MOLECULAR biology ,CANCER treatment ,GENE therapy ,FUNCTIONAL analysis ,VIRAL genes ,CANCER cells ,CELL lines ,GENE expression ,DNA microarrays - Abstract
Replication-competent attenuated herpes simplex viruses have proven effective in killing many cancer cell lines. However, determinants of resistance to oncolytic therapy are mostly unknown. We developed viral therapy-resistant cells and examined changes in gene-expression pattern compared with therapy-sensitive parental cells. Colon cancer cell line HT29 and hepatoma cell line PLC5 were exposed to increasing concentrations of virus G207. Therapy-resistant cells were isolated and grown in vitro. Tumorigenicity was confirmed by ability of cell lines to form tumors in mice. Human Genome U133A complementary DNA microarray chips were used to determine gene-expression patterns, which were analyzed in the context of molecular network interactions, pathways and gene ontology. In parental cell lines, 90-100% of cells were killed by day 7 at 1.0 multiplicity of infection. In resistant cell lines, cytotoxicity assay confirmed 200- to 400-fold resistance. Microarray analysis confirmed changes in gene expressions associated with resistance: cell surface proteins affecting viral attachment and entry, cellular proteins affecting nucleotide pools and proteins altering apoptotic pathways. These changes would decrease viral infection and replication. Our study identifies gene-expression signatures associated with resistance to oncolytic viral therapy. These data provide potential targets to overcome resistance, and suggest that molecular assays may be useful in selecting patients for trial with this novel treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
3. Cytokine-secreting herpes viral mutants effectively treat tumor in a murine metastatic colorectal liver model by oncolytic and T-cell-dependent mechanisms.
- Author
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DeRubertis, B. G., Stiles, B. M., Bhargava, A., Gusani, N. J., Hezel, M., D'Angelica, M., and Fong, Y.
- Subjects
HERPES simplex virus ,GENE therapy ,COLON tumors ,TUMOR treatment ,T cells ,CELLULAR mechanics ,CELL proliferation ,GENETIC mutation - Abstract
In this model of hepatic micrometastases, the antitumor efficacy and role of the T-cell and natural killer (NK) cell populations were studied for oncolytic herpes simplex virus type-1 (HSV-1) viral mutants containing the granulocyte-monocyte colony stimulating factor (GM-CSF (NV1034)) or interluken-12 (IL-12 (NV1042)) cytokine genes. These were compared to saline and control virus (NV1023) in vitro and in vivo. HSV-1 mutants were assessed for cytotoxicity, replication and cytokine expression in CT-26 cells. A syngeneic micrometastatic liver model was then established in naive and immune cell-depleted animals to assess the antitumor efficacy of these viruses. In vitro cytotoxicity and viral replication were similar for each virus, resulting in greater than 80 and 98% cytotoxicity at multiplicity of infection of 1 and 10, respectively. Peak viral titers were 25- to 50-fold higher than initial titer and were not significantly different between viruses. In vivo, all three viruses reduced metastases relative to control, but cytokine-secreting viruses did so with greater efficacy compared to NV1023. This effect was abrogated by T-cell depletion, but not NK-cell depletion. Single-agent therapy with oncolytic viral agents containing GM-CSF or IL-12 is effective in a murine model of liver metastases and likely involves direct viral oncolysis and actions of specific immune effector cells.Cancer Gene Therapy (2007) 14, 590–597. doi:10.1038/sj.cgt.7701053; published online 13 April 2007 [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
4. Treatment of cholangiocarcinoma with oncolytic herpes simplex virus combined with external beam radiation therapy.
- Author
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Jarnagin, W. R., Zager, J. S., Hezel, M, Stanziale, S. F., Adusumilli, P. S., Gonen, M, Ebright, M. I., Culliford, A, Gusani, N. J., and Fong, Y
- Subjects
CHOLANGIOCARCINOMA ,CANCER treatment ,GENE therapy ,HERPES simplex virus ,RADIOTHERAPY ,CELL-mediated cytotoxicity ,VIRAL replication ,CELL lines ,COMBINATION drug therapy - Abstract
Replication-competent oncolytic herpes simplex viruses (HSV), modified by deletion of certain viral growth genes, can selectively target malignant cells. The viral growth gene γ
1 34.5 has significant homology to GADD34 (growth arrest and DNA damage protein 34), which promotes cell cycle arrest and DNA repair in response to stressors such as radiation (XRT). By upregulating GADD34, XRT may result in greater oncolytic activity of HSV strains deficient in the γ1 34.5 gene. The human cholangiocarcinoma cell lines KMBC, SK-ChA-1 and YoMi were treated with NV1023, an oncolytic HSV lacking one copy of γ1 34.5. Viral proliferation assays were performed at a multiplicity of infection (MOI, number of viral particles per tumor cell) equal to 1, either alone or after XRT at 250 or 500 cGy. Viral replication was assessed by plaque assay. In vitro cytotoxicity assays were performed using virus at MOIs of 0.01 and 0.1, with or without XRT at 250 cGy and cell survival determined with lactate dehydrogenase assay. Established flank tumors in athymic mice were treated with a single intratumoral injection of virus (103 or 104 plaque forming units), either alone or after a single dose of XRT at 500 cGy, and tumor volumes measured. RT-PCR was used to measure GADD34 mRNA levels in all cell lines after a single dose of XRT at 250 or 500 cGy. NV1023 was tumoricidal in all three cell lines, but sensitivity to the virus varied. XRT enhanced viral replication in vitro in all cell lines. Combination treatment with low-dose XRT and virus was highly tumoricidal, both in vitro and in vivo. The greatest tumor volume reduction with combination therapy was seen with YoMi cells, the only cell line with increased GADD34 expression after XRT and the only cell line in which a synergistic treatment effect was suggested. In KMBC and SK-ChA-1 cells, neither of which showed increased GADD34 expression after XRT, tumor volume reduction was less pronounced and there was no suggestion of a synergistic effect in either case. Oncolytic HSV are effective in treating human cholangiocarcinoma cell lines, although sensitivity to virus varies. XRT-enhanced viral replication occurs through a mechanism that is not necessarily dependent on GADD34 upregulation. However, XRT-induced upregulation of GADD34 further promotes tumoricidal activity in viral strains deficient in the γ1 34.5 gene, resulting in treatment synergy; this effect is cell type dependent. Combined XRT and oncolytic viral therapy is a potentially important treatment strategy that may enhance the therapeutic ratios of both individual therapies.Cancer Gene Therapy (2006) 13, 326–334. doi:10.1038/sj.cgt.7700890; published online 2 September 2005 [ABSTRACT FROM AUTHOR]- Published
- 2006
- Full Text
- View/download PDF
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