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Treatment of cholangiocarcinoma with oncolytic herpes simplex virus combined with external beam radiation therapy.
- Source :
-
Cancer gene therapy [Cancer Gene Ther] 2006 Mar; Vol. 13 (3), pp. 326-34. - Publication Year :
- 2006
-
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 gamma(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 gamma(1)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 gamma(1)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 (10(3) or 10(4) 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 gamma(1)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.
- Subjects :
- Animals
Bile Duct Neoplasms pathology
Bile Duct Neoplasms radiotherapy
Bile Duct Neoplasms therapy
Bile Ducts, Intrahepatic radiation effects
Bile Ducts, Intrahepatic virology
Cell Survival physiology
Cell Survival radiation effects
Cholangiocarcinoma pathology
Combined Modality Therapy
Humans
L-Lactate Dehydrogenase metabolism
Male
Mice
Mice, Nude
Tumor Cells, Cultured metabolism
Tumor Cells, Cultured radiation effects
Tumor Cells, Cultured virology
Cholangiocarcinoma radiotherapy
Cholangiocarcinoma therapy
Oncolytic Virotherapy
Simplexvirus physiology
Virus Replication
Subjects
Details
- Language :
- English
- ISSN :
- 0929-1903
- Volume :
- 13
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cancer gene therapy
- Publication Type :
- Academic Journal
- Accession number :
- 16138120
- Full Text :
- https://doi.org/10.1038/sj.cgt.7700890