title: Hypoxia- and radiation-inducible, breast cell-specific targeting of retroviral vectors.
abstract: To facilitate a more efficient radiation and chemotherapy of mammary tumours, synthetic enhancer elements responsive to hypoxia and ionizing radiation were coupled to the mammary-specific minimal promoter of the murine whey acidic protein (WAP) encoding gene. The modified WAP promoter was introduced into a retroviral promoter conversion (ProCon) vector. Expression of a transduced reporter gene in response to hypoxia and radiation was analysed in stably infected mammary cancer cell lines and an up to 9-fold increase in gene expression demonstrated in comparison to the respective basic vector. Expression analyses in vitro, moreover, demonstrated a widely preserved mammary cell-specific promoter activity. For in vivo analyses, xenograft tumours consisting of infected human mammary adenocarcinoma cells were established in SCID/beige mice. Immunohistochemical analyses demonstrated a hypoxia-specific, markedly increased WAP promoter-driven expression in these tumours. Thus, this retroviral vector will facilitate a targeted gene therapeutic approach exploiting the unique environmental condition in solid tumours.
authors.affiliation: Research Institute of Virology and Biomedicine, University of Veterinary Medicine, Veterinaerplatz 1, A-1210 Vienna, Austria.
authors.forename: Karoline
authors.initials: K
authors.lastname: Lipnik
authors.forename: Olga
authors.initials: O
authors.lastname: Greco
authors.forename: Simon
authors.initials: S
authors.lastname: Scott
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Knapp
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mayrhofer
authors.forename: Doris
authors.initials: D
authors.lastname: Rosenfellner
authors.forename: Walter H
authors.initials: WH
authors.lastname: Günzburg
authors.forename: Brian
authors.initials: B
authors.lastname: Salmons
authors.forename: Christine
authors.initials: C
authors.lastname: Hohenadl
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000628:therapy*; D015687:Cell Hypoxia; D002460:Cell Line; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D008894:Milk Proteins / Q000235:genetics*; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000528:radiation effects; D012190:Retroviridae; D012680:Sensitivity and Specificity; D014183:Transplantation, Heterologous; D014965:X-Rays
chemical_list: D008894:Milk Proteins; C485184:enhanced green fluorescent protein; C024471:whey acidic proteins; D049452:Green Fluorescent Proteins