A phase 1 trial of the herpes simplex virus HSV1716 in patients with high grade glioma plus an in vitro investigation of the interaction between HSV1716 and ionising radiation

Harrow, Stephen (2006) A phase 1 trial of the herpes simplex virus HSV1716 in patients with high grade glioma plus an in vitro investigation of the interaction between HSV1716 and ionising radiation. PhD thesis, University of Glasgow.

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Abstract

HSV1716 is a mutant herpes simplex virus with a deletion in both copies of the RL1 gene, that encodes the protein ICP34.5, a specific determinant of virulence. Section one presents a phase I study in which it has been demonstrated that herpes simplex virus 1716 (HSV1716) does not generate toxicity following injection into brain adjacent to excised high-grade glioma, in patients who proceeded to receive further immunosuppressive radiotherapy or chemotherapy. The survival and imaging data, in addition to the lack of toxicity, were encouraging. Section two investigates the possibility of enhanced cell kill when ionising radiation is employed in conjunction with the ICP34.5 null mutant HSV1716 in a tissue culture model and the possible mechanisms responsible for enhanced cell kill. Using the MTS assay, experiments combining HSV1716 and ionising radiation demonstrated additional cell kill in 373 and MOG cells by day six compared to either modality in isolation. Isobologram analysis confirmed a synergistic relationship between ionising radiation and HSV1716 in 373 cells and an additive relationship in the MOG cell line when the cells were irradiated one hour prior to inoculation. Lastly, stable 3T6 cells expressing ICP34.5 were developed with the aim of elucidating the mechanism of action of the ICP34.5 in the replication cycle of HSV. Functional ICP34.5 and ICP34.5-GFP in the transfected 3T6 cells was detected and able to support the replication of HSV1716. These cells were analysed with respect to HSV1716 infection and were seen to support replication with the appearance of characteristic plaque morphology.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: S M Brown
Keywords: Pharmacology
Date of Award: 2006
Depositing User: Enlighten Team
Unique ID: glathesis:2006-71429
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 10 May 2019 10:49
Last Modified: 10 May 2019 10:49
URI: http://theses.gla.ac.uk/id/eprint/71429

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