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Thus COX expression is induced in cancerous epithelium, and, importantly, in tumor invading neovasculature.In Glimepiride vascular endothelium, COX immunostaining appeared only in normal, established vessels not associated with cancerous lesions.Taken together, these data show that COX, but not COX, is induced in malignant epithelium, and is also expressed in cells that comprise the angiogenic response to Glimepiride cancer.Wealso exam ined COX staining of metastatic nodules.COX posit ive ang iogen icblood vesse ls were clearly detected in livers containing metastatic colon carcinoma, and in lymph nodes invaded by pancreatic metastatic lesions.COX was also strongly expressed in the neoplastic cells comprising the metastatic nodes.Thus, COX is present in the angiogenic vasculature that occurs in rheumatoid arthritis, primary tumors, and in metastatic disease. Reducing the levels of COX derivedpros tag land ins in arthritis relieves the symptoms of this disease, symptoms which include angiogenesis.Wewondered whether inhibition of COX derived prostaglandins would have a direct inhibitory effect on in vivo angiogenesis.These tumors from animals treated with indomethacin exhibit a reduction in vascularity among other antitumor effects.This study suggests that endogenous prostaglandins promote the development, growth, neovascularization and metastasis of spontaneous mammary tumors and that all these effects are reduced by indomethacin.Angiogenesis can be observed through the cover slip, and use of labeled sulphate allows quantitation of the angiogenesis following harvest of the membrane two days later.Interestingly, we used, as a experimental control, a matrigel plug containing basic fibroblast growth factor. Four days later, we observed the plug full of new blood vessels; an effect that was dramatically augmented compared to the carrageenan plug.Sim ilar to our finding, another COX inhibitor significantly reduces the hemoglobin content of bFGF injected rat sponge implants indicating that angiogenesis is reduced by COX inhibition.Taken toge ther, these results suggest that bFGF may require the induction of COX, not COX, to generate neovascularization in vivo, and led us to further evaluate the role of COX in angiogenesis.A clear, quantitative model of angiogenesis in vivo is the cornealmicropocket assay.Matrigel plugs containing either saline, carrageenan, or bFGF were implated subcutaneously in mice.Dosing by gavage BID with indomethecin, dexamethasone, or SC was performed for the duration of the experiment.After days the plugs were resected and photographed.Both carrageenan and bFGF induced neovascularization, however bFGF was more effective.Cyclooxygenase inhibitors were adm inistered by gavage beginning the day before surgery and continuing the length of the study.Four days after surgery, the corneas were exam ined under a slit lampmicroscope and the neovascular response was calculated by measuring the area of the cornea covered by new blood vessels.Wealso used immunohistochem istry to localize COX expression in the cells of the angiogenic corneas.COX was clearly detected in the angiogenic blood vessels and vascular associated cells, but was not expressed in the preexisting limbic vessels within the cornea.In contrast, COX was observed in the existing limbic vasculature, but not in the new blood vessel cells invading the corneal stroma.Taken together, these observations suggest that COX is the enzyme present in mature endothelial cells while COX expression is associated with the generation of new blood vessels.

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