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Evaluation of selective cyclooxygenase-2 (COX-2) inhibitors as radiosensitizing agents for cancer therapy Open Access


Other title
cancer therapy
cyclooxygenase-2 inhibitor
COX-2 inhibitor
Type of item
Degree grantor
University of Alberta
Author or creator
Marshall, Alison
Supervisor and department
Wuest, Frank (Oncologic Imaging)
Examining committee member and department
Mirzayans, Razmik (Oncology)
Murray, David (Oncology)
Velazquez-Martinez, Carlos (Pharmacy and Pharmaceutical Sciences)
Department of Oncology
Experimental Oncology
Date accepted
Graduation date
Master of Science
Degree level
Tumour resistance to chemo- and radiotherapy often prevents successful cancer therapy. This has promoted the search for novel agents that target specific molecular pathways linked to tumour resistance to cancer therapy. Among these novel agents are inhibitors of the inducible isoform of the cyclooxygenase (COX) enzyme, COX-2, which is involved in the regulation of angiogenesis, migration and invasion of cells, and the inhibition of apoptosis.The aim of the project is to study novel selective COX-2 inhibitors to enhance the efficacy of radiotherapy and chemotherapy. COX-2 expression levels in various cell lines were determined via western blot. HCA-7 cells, a human colorectal cell line, were found to have a high baseline expression of COX-2, while HCT-116 cells, also a human colorectal cell line, were not found to express COX-2. The metabolic and proliferative activity of HCA-7 and HCT-116 cellswere characterized through cell uptake studies involving 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG), and 3’-deoxy-3’-[18F]fluorothymidine ([18F]FLT). The cells were treated with varying concentrations of selective COX-2 inhibitors in combination with radiotherapy. Inhibitors included celecoxib, the current “gold standard” for selective COX-2 inhibitors as radiosensitizers, and a novel pyrimidine-based selective COX-2 inhibitor, pyricoxib. Toxicity of the compounds was examined through the methylthiazoltetrazolium(MTT) assay. Occurrence of apoptotic events were measured by labelling cells with annexin V-FITC and propidium iodide (PI) followed by flow cytometry. Cells were treated with GIEMSA stain and β-galactosidase stain to examine cell morphology and level of senescence. HCA-7 and HCT-116 cells were found to have high metabolic and proliferative activity based on their [18F]FDG and [18F]FLT cell uptake profile, respectively. Pyricoxib was found to be less toxic to cells than celecoxib. Cells were resistant to radiation-induced cell death at doses up to 20 Gy. Cells treated with selective COX-2 inhibitors did not exhibit decreased cell metabolic activity indicative of increased cell death after irradiation compared to non-irradiated cells based on the MTT assay. Neither compound appeared to produce a significant radiosensitization response based on apoptotic events, but in fact appeared to produce a radioprotective effect. When examined by GIEMSA stain in HCA-7 cells, both drugs produced more large cells with less tumour-like populations when combined with irradiation compared to the control and to HCT-116 cells. Finally, chemoradiation with coxibs did not result in an increased number of senescent cells compared to either therapy alone. Only pyricoxib in the COX-2 positive cells produced an enhanced level of senescence, but it was not greater than an additive effect.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
O. Tietz, M. Wang, A. Marshall, S.K. Sharma, J. Way, M. Wuest, F. Wuest. F-18-Labelled radiotracers for molecular imaging of cyclooxygenase-2 (COX-2) expression in cancer. 2014. Journal of Labelled Compounds and Radiopharmaceuticals. vol. 56, S3-S3.

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