title: Gene therapy for malignant gliomas using replication incompetent retroviral and adenoviral vectors encoding the cytochrome P450 2B1 gene together with cyclophosphamide.
abstract: Cyclophosphamide is an inactive prodrug which is converted by hepatic cytochrome P450 2B1 to cytotoxic metabolites which produce interstrand DNA cross-linking in a cell cycle-independent fashion. The limited ability of these metabolites to cross the blood-brain barrier contributes to the poor activity of cyclophosphamide against brain tumors. In this study we demonstrate that replication deficient retroviral and adenoviral vector-mediated gene transfer of cytochrome P450 2B1 into 9L glioma cells significantly increases the sensitivity of these tumor cells to cyclophosphamide in vitro, and prolongs the survival of animals bearing intracerebral 9L tumors treated with cyclophosphamide in vivo. Attempts to improve the effectiveness of retrovirally mediated transduction of the P450 2B1 gene by increasing the concentration of cyclophosphamide delivered to the tumors using intracarotid and intratumoral injections did not prolong animal survival, although survival was increased when a second treatment with P450-expressing retroviral vectors and cyclophosphamide was administered. These results suggest that in situ transduction of tumor cells with the P450 2B1 gene using retroviral and adenoviral vectors increases their sensitivity to cyclophosphamide and may have a potential role in the therapy of malignant gliomas.
authors.affiliation: Division of Cancer Pharmacology, Dana-Farber Cancer Institute Harvard Medical School, Boston, MA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Manome
authors.forename: P Y
authors.initials: PY
authors.lastname: Wen
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.forename: T
authors.initials: T
authors.lastname: Tanaka
authors.forename: Y
authors.initials: Y
authors.lastname: Dong
authors.forename: M
authors.initials: M
authors.lastname: Yamazoe
authors.forename: A
authors.initials: A
authors.lastname: Hirshowitz
authors.forename: D W
authors.initials: DW
authors.lastname: Kufe
authors.forename: H A
authors.initials: HA
authors.lastname: Fine
mesh_terms: D000256:Adenoviridae; D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003001:Cloning, Molecular; D003520:Cyclophosphamide / Q000378:metabolism* / Q000627:therapeutic use*; D019362:Cytochrome P-450 CYP2B1 / Q000096:biosynthesis* / Q000235:genetics*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D018316:Gliosarcoma / Q000473:pathology / Q000628:therapy*; D006801:Humans; D051381:Rats; D011916:Rats, Inbred F344; D012190:Retroviridae; D014162:Transfection / Q000379:methods; D014407:Tumor Cells, Cultured
chemical_list: D003520:Cyclophosphamide; D019362:Cytochrome P-450 CYP2B1