Hypoxia- and radiation-inducible, breast cell-specific targeting of retroviral vectors.
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.
Lipnik
Karoline
K
Research Institute of Virology and Biomedicine, University of Veterinary Medicine, Veterinaerplatz 1, A-1210 Vienna, Austria.
Greco
Olga
O
Scott
Simon
S
Knapp
Elzbieta
E
Mayrhofer
Elisabeth
E
Rosenfellner
Doris
D
Günzburg
Walter H
WH
Salmons
Brian
B
Hohenadl
Christine
C
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
D008894:Milk Proteins; C485184:enhanced green fluorescent protein; C024471:whey acidic proteins; D049452:Green Fluorescent Proteins