Zhang Qi, Li Ruichao, Chen Xu, Lee Sang Beom, Pan Jing, Xiong Donghai, Hu Jiaqi, Miller Mark Steven, Szabo Eva, Lubet Ronald A, Wang Yian, You Ming
Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Oncotarget. 2017 Aug 2;8(42):72447-72456. doi: 10.18632/oncotarget.19785. eCollection 2017 Sep 22.
Gefitinib showed response in phase II clinical trials and with better clinical response in lung cancer with activating mutations in the tyrosine kinase domain of the EGFR. Questions of toxicity and potential dosing regimens impede the use in a prevention setting. This study will provide scientific evidence for the utility of testing and comparing weekly and daily dosing regimens in clinical trials. We employed the adenocarcinoma (AD) and squamous cell carcinoma (SCC) models to compare the efficacy of Gefitinib in daily or weekly dosing regimens. We also assessed the effectiveness of Gefitinib in altering growth of the H3255 xenograft. Bioluminescent imaging (BLI) and tumor size was evaluated. Relative expression of phospho-EGFR, phospho-ERK and phospho-AKT in the xenograft were evaluated by Western Blot analysis. In the lung AD model, Gefitinib showed significant inhibition of tumor load when treated with weekly or weekly intermittent dosing regimens in AJ/p53 mice whereas a daily dosing regimen did not decrease the tumor load significantly. In the H3255-Luciferase xenograft model, weekly treatment demonstrated better inhibition than daily treatment. The weekly dosing regimen exhibited greater inhibition of phospho-EGFR, phospho-ERK and phospho-AKT than the daily dosing regimen, which may be correlated with the antitumor effects of the different dosing regimens. Weekly dosing with Gefitinib had similar or better efficacy than the daily dosing regimen in pre-clinical models of NSCLC. The data provide scientific evidences for the utility of testing and comparing weekly and intermittent dosing regimens in clinical trials.
吉非替尼在II期临床试验中显示出疗效，并且在表皮生长因子受体（EGFR）酪氨酸激酶结构域发生激活突变的肺癌患者中具有更好的临床反应。毒性问题和潜在的给药方案阻碍了其在预防方面的应用。本研究将为在临床试验中测试和比较每周给药方案和每日给药方案的效用提供科学依据。我们采用腺癌（AD）和鳞状细胞癌（SCC）模型来比较吉非替尼每日或每周给药方案的疗效。我们还评估了吉非替尼改变H3255异种移植瘤生长的有效性。对生物发光成像（BLI）和肿瘤大小进行了评估。通过蛋白质免疫印迹分析评估异种移植瘤中磷酸化EGFR、磷酸化ERK和磷酸化AKT的相对表达。在肺腺癌模型中，在AJ/p53小鼠中采用每周或每周间歇性给药方案治疗时，吉非替尼显示出对肿瘤负荷的显著抑制作用，而每日给药方案并未显著降低肿瘤负荷。在H3255-荧光素酶异种移植瘤模型中，每周治疗显示出比每日治疗更好的抑制效果。每周给药方案对磷酸化EGFR、磷酸化ERK和磷酸化AKT的抑制作用大于每日给药方案，这可能与不同给药方案的抗肿瘤作用相关。在非小细胞肺癌临床前模型中，吉非替尼每周给药的疗效与每日给药方案相似或更好。这些数据为在临床试验中测试和比较每周给药方案和间歇性给药方案的效用提供了科学证据。
