Translational Clinical Research Science & Strategy Dept., Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa, 247-8530, Japan.
Department of Molecular Pharmacology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
Sci Rep. 2017 Dec 1;7(1):16763. doi: 10.1038/s41598-017-17211-6.
Combination therapy of erlotinib plus bevacizumab improves progression-free survival of patients with epidermal growth factor receptor-mutated (EGFR-mutated) advanced non-small-cell lung cancer (NSCLC) compared with erlotinib alone. Although improved delivery and distribution of erlotinib to tumours as a result of the normalization of microvessels by bevacizumab is thought to be one of the underlying mechanisms, there is insufficient supporting evidence. B901L cells derived from EGFR-mutated NSCLC were subcutaneously implanted into mice, and mice were treated with bevacizumab or human IgG followed by treatment with erlotinib. The distribution of erlotinib in their tumours at different times after erlotinib administration was analysed by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI). We also analysed the distribution of erlotinib metabolites and the distribution of erlotinib in tumours refractory to erlotinib, which were established by long-term treatment with erlotinib. We found that erlotinib was broadly diffused in the tumours from B901L-implanted xenograft mice, independently of bevacizumab treatment. We also found that erlotinib metabolites were co-localized with erlotinib and that erlotinib in erlotinib-refractory tumours was broadly distributed throughout the tumour tissue. Multivariate imaging approaches using MALDI MSI as applied in this study are of great value for pharmacokinetic studies in drug development.
厄洛替尼联合贝伐珠单抗治疗表皮生长因子受体突变（EGFR 突变）晚期非小细胞肺癌（NSCLC）患者的无进展生存期优于厄洛替尼单药治疗。尽管认为贝伐珠单抗使微血管正常化从而改善了厄洛替尼向肿瘤的传递和分布是其潜在机制之一，但证据不足。将源自 EGFR 突变 NSCLC 的 B901L 细胞皮下植入小鼠，并给予贝伐珠单抗或人 IgG 治疗，然后给予厄洛替尼。在厄洛替尼给药后不同时间，通过基质辅助激光解吸/电离质谱成像（MALDI MSI）分析厄洛替尼在其肿瘤中的分布。我们还分析了厄洛替尼代谢物的分布以及对厄洛替尼耐药的肿瘤中厄洛替尼的分布，这些肿瘤是通过长期厄洛替尼治疗建立的。我们发现厄洛替尼在 B901L 植入的异种移植小鼠的肿瘤中广泛扩散，与贝伐珠单抗治疗无关。我们还发现厄洛替尼代谢物与厄洛替尼共定位，并且对厄洛替尼耐药的肿瘤中的厄洛替尼广泛分布于整个肿瘤组织中。本研究中应用的 MALDI MSI 等多变量成像方法对于药物开发中的药代动力学研究具有重要价值。
