Lung Cancer Chemoprevention with Enzastaurin

肺癌占美国所有癌症相关死亡的近三分之一，治愈率 保持低位。因此，有必要开发能够在有风险的个人中预防这种疾病的化合物。 吸烟、阻塞性肺病和年龄是压倒性的危险因素。符合条件的人 戒烟的人患肺癌的风险终生增加，与吸烟量成正比 抽了多少支香烟。前吸烟者是化学预防的特别有吸引力的目标人群 用药理药剂。已经对一些化合物进行了测试，但到目前为止试验还没有结果 肺癌发病率的下降。事实上，两项大规模的化学预防试验，评估了 现在和以前吸烟者中的β-胡萝卜素，导致肺部发病率和死亡率的增加 癌症。对这些研究和其他相关已发表报告的亚组分析表明，临床 而且，对化学预防药物的生物反应在吸烟者和吸烟者之间有所不同。全国范围内， 肺癌化学预防的重点是炎症反应途径和生长的抑制物 因子信号通路和使用中间生物标记物作为主要试验终点。一种新型药剂 具有抗增殖、促凋亡和最小毒性作用的是苯扎托林(LY317615)。它是一种口服蛋白质 激酶C(PKC)抑制剂目前正在进行II期和III期临床疗效测试 各种恶性肿瘤。为了测试这种制剂在预防肺癌方面的临床效用，我们将进行一项 既往吸烟者的双盲、安慰剂对照、随机化的Lib期试验。肺的代用标记物 癌症风险，增殖标记Ki-67，将被用作主要终点。之前的其他标记 目前正在由我们和其他人调查，特别是DMA复制起源许可的组件 复杂，也将被探索作为代孕试验的终点。这些调查所产生的数据将 不仅确定了苯扎托林作为肺癌化学预防药物的疗效，而且还提供了 未来研究的重要分析线索。

Lung cancer is responsible for nearly one-third of all cancer-related death in the U.S., and the cure rates remain low. Thus, there is a need to develop compounds that can prevent the disease in individuals at risk. Cigarette smoking, obstructive pulmonary disease, and age are the overwhelming risk factors. Persons that have quit smoking remain at an increased risk for lung cancer for lifetime that is proportional to the amount of cigarettes smoked. Former smokers are a particularly attractive target population for chemoprevention with pharmacological agents. A number of compounds have been tested but trials to date have not resulted in a decrease of lung cancer incidence. In fact, two large-scale chemoprevention trials, which evaluated beta-carotene in current and former smokers, resulted in an increase of incidence and mortality from lung cancer. Subgroup analyses of these studies and other related published reports suggest that the clinical and biologic responses to chemopreventive agents differ between active and former smokers. Nationally, the focus of lung cancer chemoprevention is on inhibitors of inflammatory response pathways and growth factor signaling pathways and the use of intermediate biomarkers as primary trial endpoints. A novel agent with antiproliferative, proapoptotic, and minimal toxic effects is enzastaurin (LY317615). It is an oral protein kinase C (PKC) inhibitor currently undergoing clinical efficacy testing in phase II and III trials in patients with a variety of malignancies. To test the clinical utility of this agent in lung cancer prevention, we will conduct a double-blind, placebo-controlled, randomized phase lib trial in former smokers. A surrogate marker of lung cancer risk, the proliferation marker Ki-67, will be used as the primary endpoint. Other markers previously and currently investigated by us and others, in particular components of the DMA replication origin licensing complex, will also be explored as surrogate trial endpoints. The data generated by these investigations will not only determine the efficacy of enzastaurin as a chemopreventive agent for lung cancer, but also provide important analytical leads for future studies.