Detection of overexpressed COX-2 in precancerous lesions of hamster pancreas and lungs by molecular imaging: implications for early diagnosis and prevention.
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.
Schuller
Hildegard M
HM
Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA. hmsch@utk.edu
Kabalka
George
G
Smith
Gary
G
Mereddy
Arjun
A
Akula
Murthy
M
Cekanova
Maria
M
D000818:Animals; D006224:Cricetinae; D051546:Cyclooxygenase 2 / Q000032:analysis*; D042241:Early Diagnosis; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000201:enzymology* / Q000628:therapy; D008647:Mesocricetus; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000628:therapy; D011230:Precancerous Conditions / Q000201:enzymology* / Q000628:therapy
D051546:Cyclooxygenase 2