Assessment of cyclooxygense-2 expression with 99mTc-labeled celebrex.
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.
Yang
David J
DJ
Division of Diagnostic Imaging, University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA. dyang@di.mdacc.tmc.edu
Bryant
Jerry
J
Chang
Joe Y
JY
Mendez
Richard
R
Oh
Chang-Sok
CS
Yu
Dong-Fang
DF
Ito
Megumi
M
Azhdarinia
Ali
A
Kohanim
Sahar
S
Edmund Kim
E
E
Lin
Edward
E
Podoloff
Donald A
DA
D000818:Animals; D000068579:Celecoxib; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2; D004305:Dose-Response Relationship, Drug; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes / Q000032:analysis / Q000096:biosynthesis*; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis / Q000096:biosynthesis*; D011720:Pyrazoles; D011877:Radionuclide Imaging / Q000379:methods; D051381:Rats; D011916:Rats, Inbred F344; D013449:Sulfonamides / Q000378:metabolism*; D013667:Technetium; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D007527:Isoenzymes; D008565:Membrane Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D013667:Technetium; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib