Effect of weekly or daily dosing regimen of Gefitinib in mouse models of lung cancer
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Qi Zhang1,2, Ruichao Li2, Xu Chen1,2, Sang Beom Lee2, Jing Pan1,2, Donghai Xiong1,2, Jiaqi Hu2, Mark Steven Miller3, Eva Szabo3, Ronald A. Lubet3, Yian Wang1,2 and Ming You1,2
1Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
2Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
3Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville, MD 20850, USA
Ming You, email: [email protected]
Keywords: weekly, daily, intermittent, Gefitinib, lung cancer
Received: February 16, 2017 Accepted: June 27, 2017 Published: August 02, 2017
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/p53val135/wtmice 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.
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