RADIOSENSITIVITY ENHANCEMENT OF HUMAN GLIOBLASTOMA MULTIFORME BY A HERPES SIMPLEX VIRUS VECTOR
Ionizing radiation (IR) is the primary adjuvant treatment for glioblastoma multiforme (GBM), the most aggressive primary brain tumor in adults. Enhancement of the effects of IR may increase patient survival and quality of life in patients with GBM. The repair of DNA double strand breaks (DSBs) produced by IR proceeds along two pathways, nonhomologous end-joining (NHEJ) and homologous repair (HR). The herpes simplex virus (HSV) immediate-early protein, ICP0, has been shown to induce the degradation of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). DNA-PKcs is the primary component of NHEJ, the major DNA DSB repair pathway in mammalian cells. A replication-defective HSV-1 vector, d106, which solely expresses the immediate-early (IE) protein, ICP0, was used to determine the effect of ICP0 on GBM cell survival and DNA repair after IR treatment. Preinfection of two radioresistant GBM cells lines by d106 resulted in decreased cell survival and proliferation, protein degradation of DNA-PKcs, inhibition of DNA DSB repair, and enhanced apoptosis following IR. Optimal intracerebral delivery of the HSV-1 mutant, d106, was established by convection-enhanced delivery (CED) in a mouse model. Translation of the effects of ICP0 in combination with IR was performed with CED of d106 in a mouse glioma model. CED of d106 in combination with whole-brain irradiation significantly increased animal survival.
Advisor:Dr. Neal A. DeLuca; Dr. Paul Kinchington; Dr. Robert Sclabassi; Dr. Saleem Khan; Dr. Stephen Grant
School:University of Pittsburgh
School Location:USA - Pennsylvania
Source Type:Master's Thesis
Keywords:biochemistry and molecular genetics
Date of Publication:07/25/2005