Targeting gene expression to hypoxic tumor cells.
Solid tumors with areas of low oxygen tension (hypoxia) have a poor prognosis, as cells in this environment often survive radiation and chemotherapy. In this report we describe how this hypoxic environment can be used to activate heterologous gene expression driven by a hypoxia-responsive element (HRE), which interacts with the transcriptional complex hypoxia-inducible factor-1 (HIF-1). Our results demonstrate that the HIF-1/HRE system of gene regulation is active in hypoxic tumor cells and show the potential of exploiting tumor-specific conditions for the targeted expression of diagnostic or therapeutic genes in cancer therapy.
Dachs
G U
GU
Experimental Oncology Division, Medical Research Council, Harwell, UK.
Patterson
A V
AV
Firth
J D
JD
Ratcliffe
P J
PJ
Townsend
K M
KM
Stratford
I J
IJ
Harris
A L
AL
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D015687:Cell Hypoxia; D043525:Cytosine Deaminase; D004268:DNA-Binding Proteins / Q000502:physiology*; D005354:Fibrosarcoma / Q000235:genetics* / Q000378:metabolism; D005437:Flucytosine / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051379:Mice; D008819:Mice, Nude; D008920:Misonidazole / Q000031:analogs & derivatives / Q000494:pharmacology; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000502:physiology*; D009700:Nucleoside Deaminases / Q000235:genetics; D010100:Oxygen / Q000494:pharmacology*; D010735:Phosphoglycerate Kinase / Q000235:genetics*; D011355:Prodrugs / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014157:Transcription Factors; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D011355:Prodrugs; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C041712:1-(2-nitro-1-imidazolyl)-3-aziridino-2-propanol; D008920:Misonidazole; D005437:Flucytosine; D010735:Phosphoglycerate Kinase; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase; D010100:Oxygen; D005472:Fluorouracil