| Large Epidemiological studies have shown a 40-50% reduction in mortality from colorectal cancer in persons taking aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) on a regular basis. One property shared by all of these drugs is their ability to inhibit COX, a key enzyme in the conversion of arachidonic acid (AA) to prostaglandins (PGs). Although the precise mechanisms for the protective effects of NSAIDs are unknown, some studies in recent years have demonstrated that the effect is related to inhibition of COX-2. COX-2 have received considerable attention in cancer chemoprevention study. COX-2 level is increased in human and anomals tumor tissues such as colorectal, pancreas, prostate and lung cancer. COX-2 is overexpressed in the early stage in carcinogenesis such as colorectal ployposis, adenoma and cellular proliferation, which indicates that COX-2 play an important role in carcinogenesis. COX-2 can stimulate tumor cell proliferation. A considerable amount of evidence indicates that COX-2 overexpression has been associated with resistance to apoptosis. COX-2 inhibitor-induced apoptosis has been correlated with down-regulation of the antiapoptosis protein Bcl-2, and regulates metastasis and angiogenesis through increasing the levels of MMP-2, uPA, VEGF, and bFGF. PGE2 has been shown to induce T cell anergy and reduce activation of natural killer cells and cytotoxic T cells, induce inhibition of interleukin-2 production and downregulation of IL-2 receptor expression on the effector cell surface, and suppress the immune reaction against tumor cells through modulation of production of such cytokines as IL-10 and IL-12 by lymphocytes and macrophages.However, several indirect lines of evidence have recently suggested that COX may not be the only target of the anti-proliferative effects of NSAIDs. Firstly, some NSAIDs can exert the anti-proliferative effects on COX-2+ and COX-2-cancer cell line, and treatment of colorectal carcinoma cell lines with PGs did not reverse the inhibitory effects of NSAIDs on cell growth. Secondly, COX-2 inhibitor can't inhibit cell growth although it can inhibit COX-2 activity at the same concentration. Thirdly, sulindac sulphone (a metabolite of sulindac which does not inhibit either COX isoform) inhibited azoxymethane-induced colonic carcinogenesis in rats and is also chemopreventive in a murine model ocarcinogenesis. R-enantiomer of flurbiprofen (which does not inhibit COX) has chemopreventative activity in the Min mouse model of intestinal polyposis. These evidence suggest that NSAIDs can act via both COX-dependent and COX-independent mechanisms.However, standard NSAIDs are nonselective in their inhibition, affecting both COX-1 and COX-2, treatment with these agents is limited by normal tissue toxicity. Of particular sensitivity is the gastrointestinal tract, which is especially dependent on COX-1 for normal function. Therefore, because it is COX-2 that is overexpressed in many tumor types, the recently developed selective COX-2 inhibitors may be more amenable for use in antineoplastic therapy. Valdecoxib is the second generation of selective COX-2 inhibitor. It has been used to relieve the inflammation reaction and pain and has fewer side effects. But it is unknown that if it has antitumor effect like asipirin. We study the antitumor effect of valdecoxib and related mechanisms in vivo and in vitro. Part 1 The relationship between antitumor effect of slectiveCOX-2 inhibitor valdecoxib and COX-2Aim: To evaluate inhibitory effect of valdecoxib on the growth of the cancer cell lines and involvement of COX-2 in this inhibition.Methods: Western blot and immunocytochemistry were used to detect the expression of COX-2 in human gastric cancer BGC-27 and HGC-27 cells, human ovarian cancer SK-OV-3 cell and mouse colorectal cancer clone 26 cell. MTT assay was used to determine inhibitory effect of the drugs on the cell growth. The content of PGE2 in cell medium was determined with PGE2 ELASA kit.Results: (1) Our results indicate that clone 26 ce...
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