論文 - 詳細
| RRC ID | 61302 |
|---|---|
| 著者 | Kodama T, Hasegawa M, Takanashi K, Sakurai Y, Kondoh O, Sakamoto H. |
| タイトル | Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases. |
| ジャーナル | Cancer Chemother Pharmacol |
| Abstract |
PURPOSE:The clinical efficacy of the anaplastic lymphoma kinase (ALK) inhibitor crizotinib has been demonstrated in ALK fusion-positive non-small cell lung cancer (NSCLC); however, brain metastases are frequent sites of initial failure in patients due to poor penetration of the central nervous system by crizotinib. Here, we examined the efficacy of a selective ALK inhibitor alectinib/CH5424802 in preclinical models of intracranial tumors. METHODS:We established intracranial tumor implantation mouse models of EML4-ALK-positive NSCLC NCI-H2228 and examined the antitumor activity of alectinib in this model. Plasma distribution and brain distribution of alectinib were examined by quantitative whole-body autoradiography administrating a single oral dose of (14)C-labeled alectinib to rats. The drug permeability of alectinib was evaluated in Caco-2 cell. RESULTS:Alectinib resulted in regression of NCI-H2228 tumor in mouse brain and provided a survival benefit. In a pharmacokinetic study using rats, alectinib showed a high brain-to-plasma ratio, and in an in vitro drug permeability study using Caco-2 cells, alectinib was not transported by P-glycoprotein efflux transporter that is a key factor in blood-brain barrier penetration. CONCLUSIONS:We established intracranial tumor implantation models of EML4-ALK-positive NSCLC. Alectinib showed potent efficacy against intracranial EML4-ALK-positive tumor. These results demonstrated that alectinib might provide therapeutic opportunities for crizotinib-treated patients with brain metastases. |
| 巻・号 | 74(5) |
| ページ | 1023-8 |
| 公開日 | 2014-11-1 |
| DOI | 10.1007/s00280-014-2578-6 |
| PMID | 25205428 |
| MeSH | Anaplastic Lymphoma Kinase Animals Brain Neoplasms / drug therapy* Brain Neoplasms / metabolism Brain Neoplasms / secondary Caco-2 Cells Carbazoles / blood Carbazoles / pharmacokinetics Carbazoles / pharmacology* Carcinoma, Non-Small-Cell Lung / drug therapy* Carcinoma, Non-Small-Cell Lung / genetics Carcinoma, Non-Small-Cell Lung / metabolism Cell Line, Tumor Humans Luciferases / genetics Luciferases / metabolism Luminescent Measurements / methods Lung / drug effects Lung / metabolism Lung / pathology Lung Neoplasms / drug therapy* Lung Neoplasms / genetics Lung Neoplasms / metabolism Mice, Nude Mice, SCID Oncogene Proteins, Fusion / antagonists & inhibitors Oncogene Proteins, Fusion / metabolism Piperidines / blood Piperidines / pharmacokinetics Piperidines / pharmacology* Protein Kinase Inhibitors / blood Protein Kinase Inhibitors / pharmacokinetics Protein Kinase Inhibitors / pharmacology Rats Receptor Protein-Tyrosine Kinases / antagonists & inhibitors* Receptor Protein-Tyrosine Kinases / metabolism Tissue Distribution Xenograft Model Antitumor Assays |
| IF | 2.967 |
| リソース情報 | |
| ヒト・動物細胞 | CACO-2(RCB0988) |