Study on growth suppression and chemoprevention of lung cancer by cyclooxygenase 2 inhibitor

我们最近报道了COX-2的表达增加在一种特定类型的肺癌，即腺癌中经常出现，并且可能与其侵袭和转移有关。我们还在一组I期疾病患者中显示了COX-2表达升高与患者生存期缩短之间的显著关系。我们在这里报道COX-2抑制剂可以在体外以剂量依赖的方式抑制非小细胞肺癌（NSCLC）细胞系的增殖，部分原因是即使在临床可达到的低浓度下也能诱导细胞凋亡。我们的观察结果还表明，非小细胞肺癌细胞中COX-2的表达状态可能影响它们对COX-2抑制剂的反应性。此外，我们发现COX-2抑制剂，当以临床可达到的浓度联合使用时，可使各种抗癌药物的IC_<50>值降低高达77%，尽管降低水平差异很大。在辐射敏感性方面，COX-2抑制剂显示出对辐照效果的加性效应。由于我们之前的研究表明，高达70%的腺癌病例中存在COX-2表达显著增加，因此目前的研究结果具有很大的临床意义，并且最近开发的下一代高选择性COX-2抑制剂应该可以在不影响其生活质量的情况下与各种抗癌药物一起辅助治疗高风险患者，从而获得更大的疗效。

We recently reported that an increased expression of COX-2 was frequently seen in a specific type of lung cancer, i.e., adenocarcinoma, and was possibly associated with its invasion and metastases. We have also shown the presence of a significant relationship between elevated COX-2 expression and shortened patient survival in a cohort of patients with stage I disease.We report here that COX-2 inhibitor could inhibit proliferation of non-small cell lung cancer (NSCLC) cell lines in vitro in a dose-dependent manner, in part by inducing apoptosis even at clinically achievable low concentrations. Our observations also suggested that the state of COX-2 expression in NSCLC cells might influence their responsiveness to COX-2 inhibitors. Moreover, we found that COX-2 inhibitor, when used in combination at clinically achievable concentrations, reduced the IC_<50> values of various anticancer agents by up to 77%, although the levels of reduction varied considerably. In radiation sensitivity, COX-2 inhibitor was shown to have an additive effect on the efficacy of irradiation. Since our previous studies have indicated that significantly increased COX-2 expression is present in up to 70% of adenocarcinoma cases, the present findings are of great clinical interest and the recent development of next generation, highly selective COX-2 inhibitors should lead to even greater efficacy for the adjunct use with various anticancer agents in the treatment of high risk patients without compromising their quality of life.