Assessment of cyclooxygense-2 expression with 99mTc-labeled celebrex

Abstract

Cyclooxygenase-2 (COX-2) plays an important role in angiogenesis and cancer progression. Since many tumor cells exhibit COX-2 expression, functional imaging of COX-2 expression using celebrex (CBX, a COX-2 inhibitor) may provide not only a non-invasive, reproducible, quantifiable alternative to biopsies, but it also greatly complements pharmacokinetic studies by correlating clinical responses with biological effects. Moreover, molecular endpoints of anti-COX-2 therapy could also be assessed effectively. This study aimed at measuring uptake of Tc-EC-CBX in COX-2 expression in tumor-bearing animal models. In vitro Western blot analysis and cellular uptake assays were used to examine the feasibility of using Tc-EC-CBX to measure COX-2 activity. Tissue distribution studies of Tc-EC-CBX were evaluated in tumor-bearing rodents at 0.5-4 h. Dosimetric absorption was then estimated. Planar scintigraphy was performed in mice, rats and rabbits bearing tumors. In vitro cellular uptake indicated that cells with higher COX-2 expression (A549 and 13762) had higher uptake of Tc-EC-CBX than lower COX-2 expression (H226). In vivo biodistribution of Tc-EC-CBX in tumor-bearing rodents showed increased tumor:tissue ratios as a function of time. In vitro and biodistribution studies demonstrated the possibility of using Tc-EC-CBX to assess COX-2 expression. Planar images confirmed that the tumors could be visualized with Tc-EC-CBX from 0.5 to 4 h in tumor-bearing animal models. We conclude that Tc-EC-CBX may be useful to assess tumor COX-2 expression. This may be useful in the future for selecting patients for treatment with anti-COX-2 agents.

Detection of Overexpressed COX‐2 in Precancerous Lesions of Hamster Pancreas and Lungs by Molecular Imaging: Implications for Early Diagnosis and Prevention

“…Studies using the 18F-labelled COX-1 and COX-2 inhibitors SC63217 (COX-1) and SC58125 (COX-2) reported in vitro uptake and [25] COX-2 overexpression in animals with fully developed tumors was detected with 99 m Tc-labeled celebrex. [26] In contrast, the current experimental protocol revealed tracer accumulation in pre-malignant lesions of the lungs and pancreas. Notably, the relatively low dose of tracer used (3.7 MBq) allowed for the selective detection of only organ sites with significantly overexpressed COX-2 levels (premalignant lesions in lungs and pancreas, elevated COX-2 levels in the liver, and at the subcutaneous injection site), whereas organs with physiologically slightly elevated COX-2 levels (brain, kidneys, airway epithelia) did not show detectable tracer accumulation.…”

Tumor Specific Imaging Using Tc-99m and Ga-68 Labeled Radiopharmaceuticals

“…We have developed 99m Tc-EC-Celecoxib (EC-CBX) for measurement of COX-2 expression in tumor bearing animal models. We conclude that 99m Tc-EC-CBX may be useful to assess tumor COX-2 expression [19]. This may be useful in the future for selecting patients for treatment with anti-COX-2 agents.…”

“…Tc efficiently with high radiochemical purity and the preparation remains stable for several hours [12][13][14][15][16][17][18][19][20][21][22].…”

Molecular Imaging Kits for Hexosamine Biosynthetic Pathway in Oncology

“…These are also known to form very stable Tc(V)Ocomplexes on the basis of efficient binding of the oxotechnetium group to two thiosulfur and two amine nitrogen atoms. Therefore, L,L-ethylenedicysteine (EC) is the most successful example of N 2 S 2 chelates [30][31][32][33] of this combination. In addition, EC can be labeled with radiometals efficiently with high radiochemical purity and the preparation remains stable for several hours [34][35][36].…”