title: Engineered herpes simplex virus expressing bacterial cytosine deaminase for experimental therapy of brain tumors.
abstract: Lack of effective therapy of primary brain tumors has promoted the development of novel experimental approaches utilizing oncolytic viruses combined with gene therapy. Towards this end, we have assessed a conditionally replication-competent, gamma(1)34.5-deleted herpes simplex virus type 1 (HSV-1) expressing cytosine deaminase (CD) for treatment of malignant brain tumors. Our results are summarized as follows: (i) a recombinant HSV (M012) was constructed in which both copies of the gamma(1)34.5 gene were replaced with the bacterial CD gene, under the control of the cellular promoter Egr-1; (ii) M012-infected cells in vitro efficiently convert 5-fluorocytosine (5-FC) to 5-fluorouracil, thereby enhancing cytotoxicity of neighboring, uninfected cells; (iii) both direct and bystander cytotoxicity of murine neuroblastoma and human glioma cell lines after infection with M012 were demonstrated; (iv) direct intracerebral inoculation of A/J mice demonstrated lack of neurotoxicity at doses similar to G207, a gamma(1)34.5-deleted HSV with demonstrated safety in human patient trials and (v) intratumoral injection of M012 into Neuro-2a flank tumors in combination with 5-FC administration significantly reduced tumor growth versus tumors treated with R3659 combined with 5-FC, or treated with M012 alone. Thus, M012 is a promising new oncolytic HSV vector with an enhanced prodrug-mediated, antineoplastic effect that is safe for intracranial administration.
authors.affiliation: Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35294-3410, USA.
authors.forename: M B
authors.initials: MB
authors.lastname: Guffey
authors.forename: J N
authors.initials: JN
authors.lastname: Parker
authors.forename: W S
authors.initials: WS
authors.lastname: Luckett
authors.forename: G Y
authors.initials: GY
authors.lastname: Gillespie
authors.forename: S
authors.initials: S
authors.lastname: Meleth
authors.forename: R J
authors.initials: RJ
authors.lastname: Whitley
authors.forename: J M
authors.initials: JM
authors.lastname: Markert
mesh_terms: D000818:Animals; D001419:Bacteria / Q000201:enzymology*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000628:therapy*; D002522:Chlorocebus aethiops; D043525:Cytosine Deaminase / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D005818:Genetic Engineering; D006801:Humans; D051379:Mice; D018139:Simplexvirus / Q000235:genetics*; D014709:Vero Cells
chemical_list: D043525:Cytosine Deaminase; D005472:Fluorouracil