Center for Preclinical Safety and Efficacy, The Hamner Institutes for Health Sciences, Six Davis Drive, Research Triangle Park, NC 27709, USA.
Cancer Prev Res (Phila). 2011 Aug;4(8):1233-42. doi: 10.1158/1940-6207.CAPR-10-0117. Epub 2011 May 11.
Our previous study comparing inhalation and aspiration to administer agents directly to lung indicated that aspiration route is as effective as inhalation while reducing costs for equipment and chemopreventive agent. This study evaluated the chemopreventive efficacy and mechanism of licofelone, a dual inhibitor of COX-2 and 5-lipoxygenase (5-Lox), via oropharyngeal aspiration against mouse lung adenoma. Eight-week-old female A/J mice were given three doses of benzo[a]pyrene (B[a]P; 2 mg/dose, gavage) to induce lung adenomas. After dysplasia developed, the mice were given licofelone (0, 0.03, 0.1, or 0.3 mg/kg) for 16 weeks, and tumor incidence and multiplicity in lung were measured. In addition, the expression of a series of biomarkers in lung cancer progression was evaluated at 2 and 16 weeks. Licofelone showed dose-related inhibition of B[a]P-induced tumor incidence and multiplicity at 0.03 and 0.1 mg/kg following 16-week treatment. Licofelone also showed dose-dependent inhibition of COX-2 (25%-41%) and 5-Lox (35%-61%) at 2 and 16 weeks and proliferating cell nuclear antigen (PCNA; 41%-61%) at 16 weeks. A dose-dependent increase in apoptosis (1.5- to 2.4-fold) was also observed in licofelone groups. A marginal inhibition of survivin was observed at one dose. In conclusion, this study showed that licofelone via aspiration showed chemopreventive efficacy against mouse lung adenoma with good correlation to early and late biomarkers of lung cancer progression. This is the first study to show that the aspiration route can be an excellent inexpensive alternative to inhalation for direct delivery of drugs to rodent lungs for efficacy testing of potential chemopreventive agents.
我们之前的研究比较了吸入和抽吸两种将药物直接输送到肺部的方法，结果表明，抽吸途径与吸入途径同样有效，同时还降低了设备和化学预防剂的成本。本研究通过口腔抽吸评估了 COX-2 和 5-脂氧合酶（5-Lox）双重抑制剂昔乐福林（licofelone）对小鼠肺腺癌的化学预防效果及其机制。将 8 周龄雌性 A/J 小鼠给予 3 次苯并[a]芘（B[a]P；2 mg/剂量，灌胃）以诱导肺腺癌。在发育不良发生后，将小鼠给予昔乐福林（0、0.03、0.1 或 0.3 mg/kg）16 周，并测量肺中的肿瘤发生率和多发性。此外，在 2 周和 16 周时评估了肺癌进展过程中一系列生物标志物的表达。在 16 周治疗后，昔乐福林在 0.03 和 0.1 mg/kg 时显示出与剂量相关的抑制 B[a]P 诱导的肿瘤发生率和多发性。昔乐福林还在 2 周和 16 周时显示出对 COX-2（25%-41%）和 5-Lox（35%-61%）以及增殖细胞核抗原（PCNA；41%-61%）的剂量依赖性抑制，在 16 周时观察到凋亡（1.5-至 2.4 倍）也呈剂量依赖性增加。在一个剂量下观察到生存素的轻微抑制。总之，本研究表明，昔乐福林通过抽吸显示出对小鼠肺腺癌的化学预防效果，与肺癌进展的早期和晚期生物标志物具有良好的相关性。这是第一项表明抽吸途径可以成为向啮齿动物肺部直接输送药物以测试潜在化学预防剂疗效的廉价替代吸入途径的研究。
