Non-steroidal anti-inflammatory drugs have been shown to effectively prevent tumors of several sites in humans and experimental animals. Because i) these class of agents act by inhibiting cyclooxigenase (COX-1/COX-2) metabolism of arachidonic acid to prostaglandins, and ii) prostaglandin synthesis is also elicited by tumor promoters, there is a need to understand the mechanisms by which tumor promoters regulate the enzymes involved. Using the mouse skin multistage carcinogenesis model, the principal investigator has found that the tumor promoter TPA induces the expression of COX-2 (but not COX-1) thereby increasing prostaglandin synthesis, and also that COX-2, and sometimes COX-1, are constitutively overexpressed in papillomas and carcinomas. These data have been taken as the basis to put forward the hypothesis that elevated COX is required for specific keratinocyte and dermal responses involved in tumor promotion and that constitutive high expression of COX is also required for subsequent tumor promoter-independent tumor development and progression. Experiments are designed to answer the following questions: 1) What are the patterns of COX-1 and COX-2 expression after single or multiple treatment with tumor promoters and in specific stages of carcinogenesis?; 2) how do arachidonate and prostaglandins induce COX-1 and COX-2, and are eicosanoids involved in phorbol ester-induction of COX-2?; 3) what is the mechanistic basis for the constitutive high expression of COX-1 and COX-2 in tumors?; and, 4) does elevated expression of COX-2 (high prostaglandin production) in tumors affect tumor growth, angiogenesis or invasiveness?
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