X-2 inhibitors had been investi-Table 1. Clinical trials of cyclooxygenase-2 (COX-2) inhibitors for the treatment of cervical neoplasiaAuthors or protocol ID Weppelmann and MonkemeierSample size 76 vs. 84 (control)Interventions OxyphenbutazoneTargeted disease Cervical cancerResponse rate 5-year survival rate : 70 vs. 55 10-year survival rate : 62 vs. 44 25 vs.12.5 75 vs. 31 81 Toxicity: 48 -Hefler et al.57 58 Farley et al. 59 Herrera et al. Gaffney et al.60 NCT00081263 (GOG-0207) NCT00152828 NCT00072540 (SWOG-S0212) *Cervical intraepithelial neoplasia;8 vs. 8 (control) 12 vs. 13 (control) 31 84 100 45Rofecoxib Celecoxib Celecoxib Celecoxib Celecoxib Celecoxib CelecoxibCIN* 2-3 CIN* 2-3 Cervical cancer Cervical cancer CIN* 2-3 Cervical cancer CIN* 2-Active clinical trials (available at http://clinicaltrials.gov).Journal of Cancer Prevention Vol. 18, No. 2,gated for chemoprevention because some studies have demonstrated that inhibiting COX-2 could prevent the formation of premalignant colorectal adenomas.61-inhibition may reduce the production of prostacyclin, which normally inhibits platelet aggregation and vasodilation, while still allowing COX-1 mediated synthesis of TX A2 to induce platelet aggregation and vasoconstric67 tion. After withdrawal of rofecoxib, the safety of celeco-How-ever, rofecoxib was withdrawn from the market on September 2004 because of the serious adverse event found in Adenomatous Polyp Prevention on Vioxxxib has also been investigated for cardiovascular adverse effects. Celecoxib has been shown to be safer than rofecoxib in most studies. The first reason is that the degree of COX-2 selectivity of celecoxib is a fifth of that of rofecoxib. Actually, the degree of COX-2 selectivity is known to correlate with cardiovascular and renal risks.68,(APPROVe) trial, demonstrating that the group assigned to rofecoxib had a fourfold increased risk of serious thromboembolic events including acute myocardial infarction and cerebrovascular accident compared with the placebo group.Furthermore, rofecoxib has been shown toincrease cardiovascular adverse effects by meta-analysis when compared to placebo or NSAIDs (Table 2). Benefit and risk by COX-2 inhibitors are summarized in Fig. 2. In spite of markedly less GI damage than NSAIDs, selective COX-2 inhibitors are doomed to increase cardiovascular adverse effects because selective COX-The second reason is that a reactive metabolite of rofecoxib, a maleic anhydride derivative which contributes to atherothrombosis, cannot be derived from other COX-2 inhibitors including celecoxib, valdecoxib and lumaricoxib.Clindamycin hydrochloride Furthermore, the Celecoxib Long-term Arthritis Safety Study (CLASS) demonstrated no significant difference inTable 2.Lucanthone Cardiovascular adverse effect of selective cyclooxygenase-2 (COX-2) inhibitors by meta-analysisAdverse effects Serious cardiovascular eventsMeta-analysis Kearney et alparison Control Placebo Naproxen Non-naproxen Naproxen Control Non-naproxen – Diclofenac – Nabumetone – Arthrotec Placebo Naproxen Control Naproxen Non-naproxen Placebo Naproxen Non-naproxen Placebo Naproxen Non-naproxen – Diclofenac Placebo Naproxen Non-naproxen Control Naproxen Intervention Selective COX-2 inhibitors Selective COX-2 inhibitors Selective COX-2 inhibitors Rofecoxib Rofecoxib Rofecoxib Rofecoxib Rofecoxib Selective COX-2 Selective COX-2 Rofecoxib Selective COX-2 Selective COX-2 Rofecoxib Rofecoxib Rofecoxib Rofecoxib RofecoxibRelative risk* with 95 CI 1.PMID:24257686 42 1.57 0.88 1.89.