A preclinical model for noninvasive imaging of hypoxia-induced gene expression; comparison with an exogenous marker of tumor hypoxia Journal Article
| Authors: | Wen, B.; Burgman, P.; Zanzonico, P.; O'Donoghue, J.; Cai, S.; Finn, R.; Serganova, I.; Blasberg, R.; Gelovani, J.; Li, G. C.; Ling, C. C. |
| Article Title: | A preclinical model for noninvasive imaging of hypoxia-induced gene expression; comparison with an exogenous marker of tumor hypoxia |
| Abstract: | Purpose: Hypoxia is associated with tumor aggressiveness and is an important cause of resistance to radiation therapy and chemotherapy. Assays of tumor hypoxia could provide selection tools for hypoxia-modifying treatments. The purpose of this study was to develop and characterize a rodent tumor model with a reporter gene construct that would be transactivated by the hypoxia-inducible molecular switch, i.e., the upregulation of HIF-1. Methods: The reporter gene construct is the herpes simplex virus 1-thymidine kinase (HSV1-tk) fused with the enhanced green fluorescent protein (eGFP) under the regulation of an artificial hypoxia-responsive enhancer/promoter. In this model, tumor hypoxia would up-regulate HIF-1, and through the hypoxia-responsive promoter transactivate the HSV1-tkeGFP fusion gene. The expression of this reporter gene can be assessed with the 124I-labeled reporter substrate 2′-fluoro-2′-deoxy-1-β-D-arabinofuranosyl-5- iodouracil (124I-FIAU), which is phosphorylated by the HSV1-tk enzyme and trapped in the hypoxic cells. Animal positron emission tomography (microPET) and phosphor plate imaging (PPI) were used in this study to visualize the trapped 124I-FIAU, providing a distribution of the hypoxia-induced molecular events. The distribution of 124I-FIAU was also compared with that of an exogenous hypoxic cell marker, 18F-fluoromisonidazole (FMISO). Results: Our results showed that 124I-FIAU microPET imaging of the hypoxia-induced reporter gene expression is feasible, and that the intra-tumoral distributions of 124I-FIAU and 18F-FMISO are similar. In tumor sections, detailed radioactivity distributions were obtained with PPI which also showed similarity between 124I-FIAU and 18F-FMISO. Conclusion: This reporter system is sufficiently sensitive to detect hypoxia-induced transcriptional activation by noninvasive imaging and might provide a valuable tool in studying tumor hypoxia and in validating existing and future exogenous markers for tumor hypoxia. © Springer-Verlag 2004. |
| Keywords: | controlled study; unclassified drug; promoter region; dna-binding proteins; nonhuman; comparative study; positron emission tomography; radiopharmaceuticals; genetic analysis; adenocarcinoma; animal cell; animals; gene expression; gene expression profiling; image analysis; tumor markers, biological; green fluorescent protein; animal experiment; drug evaluation, preclinical; molecular imaging; cell line, tumor; cancer model; transcription factors; nuclear proteins; hypoxia; feasibility study; enzyme phosphorylation; regulatory mechanism; isotope labeling; iodine radioisotopes; feasibility studies; rat; radioactivity; fusion gene; transactivation; arabinofuranosyluracil; reporter gene; imaging; 1 fluoro 3 (2 nitro 1 imidazolyl) 2 propanol f 18; fialuridine i 124; iodine 124; thymidine kinase; cell hypoxia; rats; upregulation; misonidazole; cell marker; tumor; disease models, animal; fluorine 18; herpes simplex virus 1; tumor hypoxia; hypoxia-inducible factor 1, alpha subunit; viral proteins; gene construct; phosphorus; fluorine radioisotopes; marker; molecule; hypoxia inducible factor 1; hypoxia-inducible factor 1; fmiso; hypoxic cell; article; herpes simplex virus 1-thymidine kinase |
| Journal Title: | European Journal of Nuclear Medicine and Molecular Imaging |
| Volume: | 31 |
| Issue: | 11 |
| ISSN: | 1619-7070 |
| Publisher: | Springer |
| Date Published: | 2004-11-01 |
| Start Page: | 1530 |
| End Page: | 1538 |
| Language: | English |
| DOI: | 10.1007/s00259-004-1673-z |
| PROVIDER: | scopus |
| PUBMED: | 15378285 |
| DOI/URL: | |
| Notes: | Eur. J. Nucl. Med. Mol. Imaging -- Cited By (since 1996):44 -- Export Date: 16 June 2014 -- CODEN: EJNMA -- Source: Scopus |
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