Selective Visualization of Cyclooxygenase-2 in Inflammation and Cancer by Targeted Fluorescent Imaging Agents

Uddin, Md. Jashim; Crews, Brenda C.; Blobaum, Anna L.; Kingsley, Philip J.; Gorden, D. Lee; McIntyre, J. Oliver; Matrisian, Lynn M.; Subbaramaiah, Kotha; Dannenberg, Andrew J.; Piston, David W.; Marnett, Lawrence J.

doi:10.1158/0008-5472.can-09-2664

Cited by 159 publications

(276 citation statements)

References 33 publications

(24 reference statements)

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“…S530A/S530A huPGHS-2), significant accumulation of unreacted [1-14 C]AA occurred and was attributable to the binding of unreacted [1-14 C]AA in the COX site of E allo . [1-14 C]AA was displaced from S530A/S530A huPGHS-2 by PA, but PA was unable to displace [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]AA from Y385F S530A/ Native huPGHS-2. Again, this is consistent with a lack of stimulation of this latter mutant heterodimer by PA. We interpret these results to mean that Ser-530 partners with Tyr-385 in the allosteric regulation of huPGHS-2 by nonsubstrate FAs.…”

Section: Effects Of Fas Nsnsaids and Coxibs On Pghs-2 Dimersmentioning

confidence: 95%

“…Various amounts of guanidine hydrochloride were then added, and the samples were incubated at room temperature for 30 min. After centrifugation, the denaturant-treated proteins were incubated again with 1 mM [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]acetylsalicylate for 30 min at room temperature. Total aspirin acetylation was quantified by liquid scintillation counting as described above.…”

Section: Quantification Of Hupghs-2 Variants By Western Transfermentioning

confidence: 99%

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Pre-existent Asymmetry in the Human Cyclooxygenase-2 Sequence Homodimer

Sharma

Jurban

Smith

2013

Journal of Biological Chemistry

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Background: Cyclooxygenase-2 (COX-2), a target of coxibs, aspirin, and related drugs, is a sequence homodimer that functions as a conformational heterodimer. Results: Kinetic and aspirin labeling studies indicate that COX-2 is composed of two equivalent, stable populations of conformational heterodimers. Conclusion: COX-2 is processed and folds into a pre-existent conformational heterodimer. Significance: COX-2 half-site functionality results from COX-2 folding into a stable conformational heterodimer.

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Section: Effects Of Fas Nsnsaids and Coxibs On Pghs-2 Dimersmentioning

confidence: 95%

Section: Quantification Of Hupghs-2 Variants By Western Transfermentioning

confidence: 99%

Pre-existent Asymmetry in the Human Cyclooxygenase-2 Sequence Homodimer

Sharma

Jurban

Smith

2013

Journal of Biological Chemistry

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“…24) More recently, using organic fluorophores tethered to indomethacin through an amide linkage, the feasibility of specific in vivo targeting of COX-2 in inflammatory lesions in mice has been demonstrated by the same group. 25) The purpose of this study is to find suitable radioligands for imaging brain COX-2 in vivo by PET. We initially chose two potent and selective COX-2 inhibitors of indomethacin ester analog for 11 C-radiolabeling: N-Pentyl-(1-p-chlorobenzoyl-5-methoxy-2-methylindole)-3-acetate (1) (COX-1, IC 50 Ͼ66 mM; COX-2, IC 50 ϭ50 nM) 21) and N-octyl-(1-pchlorobenzoyl-5-methoxy-2-methylindole)-3-acetate (2) (COX-1, IC 50 ϭ66 mM; COX-2, IC 50 ϭ40 nM).…”

Section: )mentioning

confidence: 99%

11C-Labeled Analogs of Indomethacin Esters and Amides for Brain Cyclooxygenase-2 Imaging: Radiosynthesis, in Vitro Evaluation and in Vivo Characteristics in Mice

Yamamoto

Toyohara

Ishiwata

et al. 2011

CHEMICAL & PHARMACEUTICAL BULLETIN

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Cyclooxygenase (COX) is the crucial enzyme in the conversion of arachidonic acid to prostaglandins. It exists at least in two isoforms, a constitutive form (COX-1) and an inducible form (COX-2), 1-3) although a third distinct COX isozyme has also been reported.4) The COX-1 enzyme is responsible for maintaining homeostasis whereas COX-2 is induced during inflammation by various stimuli and, in some tissues including the brain, kidney and placenta, is also constitutively expressed. Recent studies indicate that elevated expression of COX-2 has been implicated in many pathological events, including rheumatoid arthritis, cancer, heart disease, and neurodegenerative disorders. 5)In the brain, COX-2 is mainly expressed in the cortex, hypothalamus, and hippocampus, 6) and is upregulated in neurological disorders such as Parkinson's disease and Alzheimer's disease, [7][8][9] although the functions of COX-2 in pathophysiological processes are not yet well-understood. There is great potential that COX-2-targeted imaging by positron emission tomography (PET) may provide useful information on the role of this enzyme, especially in various neurological disorders, and also may help to evaluate the efficacy of selective COX-2 inhibitors. 10) Thus, many COX-2 inhibitors have been labeled with a suitable radionuclide for mapping the enzymes in vivo. However, previously evaluated PET radiotracers, including 11 C-labeled COX inhibitors of the diarylheterocyclic class which were synthesized by us, 11,12) have only achieved limited success, due to a lack of sufficient specific-binding to the COX-2 enzyme and/or sufficient brain penetration, in spite of promising in vitro pharmacological data. [13][14][15][16][17][18] There is a need for systematic studies correlating the physicochemical properties of agents with their in vivo behavior for a better design of COX-2 imaging probes.Currently, many selective COX-2 inhibitors with various structural features, as exemplified by vicinal diaryl heterocycles such as celecoxib and refecoxib, have been developed as non-steroidal anti-inflammatory drugs (NSAIDs) with improved gastric safety profiles.19) Most of them have high lipophilicity. Indomethacin is a traditional non-selective inhibitor of the COX isozyme which is widely used as a NSAID, but with poor brain penetration largely due to the presence of the carboxylic acid moiety. 20) Interestingly, recent studies concerning ester and amide derivatives of indomethacin have found very high COX-2 inhibition potency and a high degree of COX-2-selectivity.21-23) Marnett and colleagues synthesized 123 I-labeled N-iodobenzyl-containing amide derivative of indomethacin as a COX-2 imaging agent, which exhibited sufficient stability in COX-2 expressing nude mouse tumor.24) More recently, using organic fluorophores tethered to indomethacin through an amide linkage, the feasibility of specific in vivo targeting of COX-2 in inflammatory lesions in mice has been demonstrated by the same group. 25)The purpose of this study is to find suitable radioligands ...

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“…19,20 In addition, novel derivatives of nonsteroidal anti-inflammatory drugs (NSAIDs) fluorescently labeled with 5-carboxy-X-rhodamine dyes, fluorocoxibs have been synthesized and evaluated as optical imaging agents in rodent models of inflammation and cancer. 21,22 Fluorocoxib A, N-[(5-carboxy-X-rhodaminyl)but-4-yl]-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide, is a fluorescent indomethacin derivative (λ ex ¼ 580 nm and λ em ¼ 605 nm) that selectively binds to COX-2. 21 Fluorocoxib's potential for optical in vivo imaging was evaluated using carrageenan-induced acute inflammation in the mouse footpad, COX-2-expressing human tumor xenografts in nude mice and in mice with spontaneous tumors.…”

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confidence: 99%

Single-dose safety and pharmacokinetic evaluation of fluorocoxib A: pilot study of novel cyclooxygenase-2-targeted optical imaging agent in a canine model

et al. 2012

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Abstract. We evaluated preclinical single-dose safety, pharmacokinetic properties, and specific uptake of the new optical imaging agent fluorocoxib A in dogs. Fluorocoxib A, N-[(5-carboxy-X-rhodaminyl)but-4-yl]-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide, selectively binds and inhibits the cyclooxygenase-2 (COX-2) enzyme, which is overexpressed in many cancers. Safety pilot studies were performed in research dogs following intravenous (i.v.) administration of 0.1 and 1 mg∕kg fluorocoxib A. Blood and urine samples collected three days after administration of each dose of fluorocoxib A revealed no evidence of toxicity, and no clinically relevant adverse events were noted on physical examination of exposed dogs over that time period. Pharmacokinetic parameters were assessed in additional research dogs from plasma collected at several time points after i.v. administration of fluorocoxib A using high-performance liquid chromatography analysis. The pharmacokinetic studies using 1 mg∕kg showed a peak of fluorocoxib A (92 AE 28 ng∕ml) in plasma collected at 0.5 h. Tumor specific uptake of fluorocoxib A was demonstrated using a dog diagnosed with colorectal cancer expressing COX-2. Our data support the safe single-dose administration and in vivo efficacy of fluorocoxib A, suggesting a high potential for successful translation to clinical use as an imaging agent for improved tumor detection in humans.

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Selective Visualization of Cyclooxygenase-2 in Inflammation and Cancer by Targeted Fluorescent Imaging Agents

Cited by 159 publications

References 33 publications

Pre-existent Asymmetry in the Human Cyclooxygenase-2 Sequence Homodimer

Pre-existent Asymmetry in the Human Cyclooxygenase-2 Sequence Homodimer

11C-Labeled Analogs of Indomethacin Esters and Amides for Brain Cyclooxygenase-2 Imaging: Radiosynthesis, in Vitro Evaluation and in Vivo Characteristics in Mice

Single-dose safety and pharmacokinetic evaluation of fluorocoxib A: pilot study of novel cyclooxygenase-2-targeted optical imaging agent in a canine model

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