Premium
Detection of Overexpressed COX‐2 in Precancerous Lesions of Hamster Pancreas and Lungs by Molecular Imaging: Implications for Early Diagnosis and Prevention
Author(s) -
Schuller Hildegard M.,
Kabalka George,
Smith Gary,
Mereddy Arjun,
Akula Murthy,
Cekanova Maria
Publication year - 2006
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200500032
Subject(s) - pancreas , carcinogen , medicine , hamster , pathology , immunostaining , biodistribution , lung , celecoxib , immunohistochemistry , in vivo , biology , biochemistry , microbiology and biotechnology
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 have 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 radiotracer 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 radiotracer 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 same treatment group. Immunostains showed selective overexpression of COX‐2 in pre‐neoplastic 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.