Overexpression of Cyclooxygenase-2 (COX-2) is observed in most tumor types. Increased COX-2 activity and synthesis of prostaglandins stimulates proliferation, angiogenesis, invasiveness and inhibits apoptosis. Many stress and proinflammatory signals induce COX-2 expression, including oxyradicals or DNA-damaging agents. The latter also induces p53, a transcription factor often inactivated by mutation in cancer. Several studies have identified complex cross-talks between p53 and COX-2, whereby p53 can either up-or down-regulate COX-2, which in turn controls p53 transcriptional activity. However, the molecular basis of these effects are open to debate, in particular since no p53 binding sequences have been identified in COX-2 regulatory regions. In this review, we summarize the molecular mechanisms by which COX-2 contributes to carcinogenesis and discuss the experimental set-up, results and conclusions of studies analyzing cross-talks between p53 and COX-2. We propose 2 scenarios accounting for overexpression of COX-2 in precursor and cancer lesions. In the ''inflammatory'' scenario, p53, activated by DNA damage induced by oxygen and nitrogen species, recruits NF-kappaB to activate COX-2, resulting in antiapoptotic effects that contribute to cell expansion in inflammatory precursor lesions. In the ''constitutive proliferation'' scenario, oncogenic stress due to activation of growth signaling cascades may upregulate COX-2 promoter independently of NF-kappaB and p53, synergizing with TP53 mutation to promote cancer progression. These 2 scenarios, although not mutually exclusive, may account for the diversity of the correlations between COX-2 expression and TP53 mutation, which vary according to cancer types and biological contexts, and have implications for the use of COX-2 inhibitors in cancer prevention and therapy. ' 2007 Wiley-Liss, Inc.

The diversity of interventions and outcomes addressed across studies and differences in settings, populations and comparisons made it difficult to summarise results across studies. Cap and co-payment polices may reduce the use of medicines and reduce medicine expenditures for health insurers. However, they may also reduce the use of life-sustaining medicines or medicines that are important in treating chronic, including symptomatic, conditions and, consequently, could increase the use of healthcare services. Fixed co-payment with a ceiling and tiered fixed co-payment may be less likely to reduce the use of essential medicines or to increase the use of healthcare services.

Overexpression of cyclooxygenase-2 (Cox-2) is thought to exert antiapoptotic effects in cancer. Here we show that the tumor suppressor p53 upregulated Cox-2 in esophageal and colon cancer cell lines by inducing the binding of nuclear factor-kappaB (NF-kappaB) to its response element in the COX-2 promoter. Inhibition of NF-kappaB prevented p53 induction of Cox-2 expression. Cooperation between p53 and NF-kappaB was required for activation of COX-2 promoter in response to daunomycin, a DNAdamaging agent. Pharmacological inhibition of Cox-2 enhanced apoptosis in response to daunomycin, in particular in cells containing active p53. In esophageal cancer, there was a correlation between Cox-2 expression and wild-type TP53 in Barrett's esophagus (BE) and in adenocarcinoma, but not in squamous cell carcinoma (Po0.01). These results suggest that p53 and NF-kappaB cooperate in upregulating Cox-2 expression, promoting cell survival in inflammatory precursor lesions such as BE.