Upregulation of cyclooxygenase-2 (COX-2) has been shown to be an early event in colon carcinogenesis. Multiple lines of evidence suggest that COX-2 upregulation is also an early event in the development of non-small cell lung cancer (NSCLC). In humans, COX-2 expression is upregulated in about one-third of atypical adenomatous hyperplasias and carcinoma in situ specimens obtained from lung, and in 70 percent-90 percent of invasive adenocarcinomas of the lung. The proportion of adenocarcinoma cells with increased COX-2 expression is much greater in lymph node metastases than in the corresponding primary tumors. Preclinical data indicate tumors with upregulation of COX-2 synthesize high levels of prostaglandin E2 (PGE2). High PGE2 levels are associated with increased production of proangiogenic factors and enhanced metastatic potential. These findings suggest that an increase in COX-2 expression may play a significant role in the development and growth of NSCLC and possibly with the acquisition of an invasive and metastatic phenotype. Specific inhibitors of COX-2 are now available and may prove useful in understanding the role of eicosanoids in lung cancer pathogenesis as well as in the management of established malignancies and possibly as chemopreventive agents. However, there are limited data on the function of tumor overexpression of COX-2 in lung cancer patients, and no data on whether selective inhibitors actually affect COX-2 activity within the targeted tumor in vivo. We propose to study the effects of specific inhibitors of COX-2 on COX-2 expression, serum VEGF levels and urinary metabolites of PGE2 in patients with lung cancer. Our results will serve as a prelude to clinical trials in which these agents are employed therapeutically. Our preliminary data suggest inhibitors of COX-2 rapidly reduce enzyme activity as determined by measurements of urinary metabolites of prostaglandin and assessment of enzyme activity within the tumor itself. These experiments will expand upon these preliminary results.
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