Journal
CHEMMEDCHEM
Volume 1, Issue 6, Pages 603-610Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.200500032
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Funding
- NCI NIH HHS [R01-CA 088809, R01-CA 096128-01A1, R01-CA 042829] Funding Source: Medline
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The enzyme cyclooxygenase-2 (COX-2) is overexpressed in many cancers, cardiovascular disease, neurodegenerative disorders, and arthritis. Selective inhibitors of COX-2 have been developed as therapeutics or preventive agents for these diseases. However, recent reports hove revealed a significant increase in cardiovascular mortality in long-term users of the COX-2 inhibitors Vioxx and Celebrex, emphasizing the need for noninvasive tests that allow the identification of individuals whose COX-2 levels are overexpressed prior to assignment to treatment with these drugs. In this study, we have prepared a radioiodinated analogue of the selective COX-2 inhibitor celecoxib, and verified its binding to the COX-2 enzyme in vitro. Biodistribution studies in hamsters demonstrated significantly higher levels of rodiotracer in animals treated with the tobacco carcinogen NNK in lung, pancreas, and liver. Assessment of COX-2 levels by whole-body planar nuclear imaging two hours after injection of the rodiotracer was suggestive of a distinct increase in COX-2 in the pancreas and liver of a hamster treated for 10 weeks with NNK, in the lungs and liver of a second animal, and in the liver only, in two additional animals from the some treatment group. Immunostains showed selective overexpression of COX-2 in pre-neoplostic lesions of the pancreas and lungs in only those animals that showed tracer accumulation in these organs and in the livers of all NNK-treated hamsters. Immunostains for COX-1 yielded detectable reactions in the intestinal epithelium but not in pancreas, lungs, or liver, supporting the specificity of the tracer for COX-2. Our data provide proof of principle for the hypothesis that molecular imaging with radiolabeled COX-2 inhibitors can be used for the noninvasive monitoring of overexpressed COX-2 levels.
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