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K. Valyi-Nagy, R. Folberg, T. Valyi-Nagy, A. J. Maniotis; Role of Tumor Invasiveness, the Extracellular Matrix, and Chromatin Sequestration in the Susceptibility of Uveal Melanoma to Herpes Simplex Virus Type 1. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4761.
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Oncolytic therapy with herpes simplex virus type 1 (HSV-1) is a promising novel approach to treat several human malignancies including melanomas. The first objective of this research was to determine whether the susceptibility of uveal melanoma cultures to HSV-1-mediated destruction was dependent on the invasive potential of melanomas and/or the presence of a laminin-rich extracellular matrix (Matrigel). The second objective was to determine whether sequestration of cellular chromatin, a characteristic feature of highly invasive uveal melanomas that is further increased by exposure to laminin, could be reversed by HSV-1 infection.
Uveal melanoma cell lines of low (OCM1a) and of high (M619, MUM2B) invasive potential were grown in vitro either in the presence or absence of Matrigel and were then infected with wild type HSV-1. The day when at least 95% of the melanoma cells were destroyed following infection was noted. The effect of HSV-1 infection on chromatin sequestration was determined by digestion of smears of infected cells with the restriction enzyme Alu I, followed by ethidium bromide staining and visualization of chromatin under an inverted fluorescence microscope.
OCM1a cultures were destroyed faster by HSV-1 than M619 and MUM2B cultures. In the presence of Matrigel, all melanoma cultures demonstrated delayed destruction by HSV-1 relative to Matrigel-free cultures. HSV-1 infection induced a global reversal of chromatin sequestration in highly invasive uveal melanoma cells. However, this viral effect was first observed only 2 hours following virus infection and required novel protein synthesis from input viral DNA.
These findings suggest that tumor invasiveness, the spatial relationship of tumor cells to laminin and chromatin sequestration are determinants of susceptibility/resistance of melanomas to HSV-1 oncolytic therapy. Furthermore, these findings indicate for the first time that HSV-1 infection is associated with global exposure of normally highly sequestered cellular DNA in malignant cells.
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