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PMID: 9142119 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Targeting gene expression to hypoxic tumor cells.

Nature medicine ·Vol. 3 ·No. 5 ·1997-05-00 ·Pages 515-20

Dachs GU, Patterson AV, Firth JD, Ratcliffe PJ, Townsend KM, Stratford IJ, Harris AL

Abstract

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.

MeSH Terms

Animals Antimetabolites, Antineoplastic/pharmacology Cell Hypoxia Cytosine Deaminase DNA-Binding Proteins/physiology Fibrosarcoma/genetics,metabolism Flucytosine/pharmacology Fluorouracil/pharmacology Gene Expression Regulation, Neoplastic/drug effects,genetics Genes, Reporter/genetics Humans Hypoxia-Inducible Factor 1 Hypoxia-Inducible Factor 1, alpha Subunit Mice Mice, Nude Misonidazole/analogs & derivatives,pharmacology Neoplasm Transplantation Nuclear Proteins/physiology Nucleoside Deaminases/genetics Oxygen/pharmacology Phosphoglycerate Kinase/genetics Prodrugs/pharmacology Promoter Regions, Genetic/genetics Recombinant Fusion Proteins/biosynthesis Transcription Factors Tumor Cells, Cultured

Chemicals

Antimetabolites, Antineoplastic DNA-Binding Proteins HIF1A protein, human Hif1a protein, mouse Hypoxia-Inducible Factor 1 Hypoxia-Inducible Factor 1, alpha Subunit Nuclear Proteins Prodrugs Recombinant Fusion Proteins Transcription Factors 1-(2-nitro-1-imidazolyl)-3-aziridino-2-propanol Misonidazole Flucytosine Phosphoglycerate Kinase Nucleoside Deaminases Cytosine Deaminase Oxygen Fluorouracil

Authors & Affiliations

7 authors, click to expand affiliations / ORCID

Dachs G U

Experimental Oncology Division, Medical Research Council, Harwell, UK.

Patterson A V

Firth J D

Ratcliffe P J

Townsend K M

Stratford I J

Harris A L

Article Info

Journal

Nature medicine

Abbr.

Nat Med

ISSN

1078-8956

DOI

10.1038/nm0597-515

Published

1997-05-00

Pages

515-20

Language

English

Region

United States

NLM ID

9502015

Subset

Grants

Medical Research Council · G0500366 · United Kingdom

NCI NIH HHS · P01-CA-55165 · United States

Wellcome Trust · United Kingdom

External Links

PubMed source DOI: 10.1038/nm0597-515 View journal details

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Targeting gene expression to hypoxic tumor cells.

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