title: Increased oncolytic efficacy for high-grade gliomas by optimal integration of ionizing radiation into the replicative cycle of HSV-1.
abstract: Oncolytic viruses have been combined with standard cancer therapies to increase therapeutic efficacy. Given the sequential activation of herpes viral genes (herpes simplex virus-1, HSV-1) and the temporal cellular changes induced by ionizing radiation, we hypothesized an optimal temporal sequence existed in combining oncolytic HSV-1 with ionizing radiation. Murine U-87 glioma xenografts were injected with luciferase encoding HSV-1, and ionizing radiation (IR) was given at times before or after viral injection. HSV-1 replication and tumor-volume response were followed. Radiation given 6-9 h after HSV-1 injection resulted in maximal viral luciferase expression and infectious viral production in tumor xenografts. The greatest xenograft regression was also seen with radiation given 6 h after viral injection. We then tested if HSV-1 replication had a dose response to ionizing radiation. HSV-1 luciferase expression exhibited a dose response as xenografts were irradiated from 0 to 5 Gy. There was no difference in viral luciferase expression as IR dose increased from 5 Gy up to 20 Gy. These results suggest that the interaction of IR with the HSV-1 lytic cycle can be manipulated for therapeutic gain by delivering IR at a specific time within viral replicative cycle.
authors.affiliation: Department of Radiation Oncology and Center for Advanced Radiotherapy Technologies, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. sjadvani@ucsd.edu
authors.forename: S J
authors.initials: SJ
authors.lastname: Advani
authors.forename: J M
authors.initials: JM
authors.lastname: Markert
authors.forename: R F
authors.initials: RF
authors.lastname: Sood
authors.forename: S
authors.initials: S
authors.lastname: Samuel
authors.forename: G Y
authors.initials: GY
authors.lastname: Gillespie
authors.forename: M Y
authors.initials: MY
authors.lastname: Shao
authors.forename: B
authors.initials: B
authors.lastname: Roizman
authors.forename: R R
authors.initials: RR
authors.lastname: Weichselbaum
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000628:therapy*; D003131:Combined Modality Therapy; D004307:Dose-Response Relationship, Radiation; D005910:Glioma / Q000628:therapy*; D018259:Herpesvirus 1, Human / Q000254:growth & development* / Q000528:radiation effects; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000254:growth & development / Q000528:radiation effects; D011839:Radiation, Ionizing; D014779:Virus Replication / Q000235:genetics / Q000528:radiation effects*