PURPOSE: Afatinib maleate (AFA) is a second-generation, tyrosine kinase inhibitor (TKI) treatment for specific variants of non-small cell lung cancer exhibiting epidermal growth factor receptor (EGFR) mutations. In this study, we measured the blood AFA levels in six patients with lung cancer and investigated the association between blood levels and side effects of this drug. METHODS: The study subjects were patients who were administered AFA for non-small cell lung cancer. Of these subjects, six patients agreed to participate in the study. The starting dose of AFA was 40 mg/day. We measured trough blood AFA levels on day 1 and 3 after AFA administration, on day 8-12, and every month until AFA administration was discontinued. Side effects were evaluated according to the adverse event codialect standard (CTCAE v.4.0). RESULTS: A temporary discontinuation and/or reduction in AFA dose (within 2 months) because of diarrhea and stomatitis was needed in four patients. Mean blood AFA levels on day 8-12 in these four patients were significantly higher than in other patients (47.0 ± 9.5 vs. 24.4 ± 0.1 ng/mL, P = 0.017). In addition, mean renal function prior to AFA administration in these four patients was significantly lower than that in the other patients (49.0 ± 9.6 mL/min/1.73 m2 vs. 77.2 ± 9.0, P = 0.026). CONCLUSIONS: High blood AFA levels were associated with the early discontinuation and/or dose reduction of AFA because of untoward side effects, which may also be associated with decreased renal function.
Quinazolines/adverse effects , Afatinib , Aged , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Female , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology
PURPOSE: Epidermal growth factor receptor (EGFR) gene mutations are the most established genomic biomarkers for the efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs). The most frequent deletion in exon 19 is delE746_750, followed by del747_753insS and del747_750insP. Since investigations of delE746 have not been reported previously, it is unclear if delE746 conveys sensitivity to TKI effect of TKI on EGFR delE746. The objective was to characterize delE746 of the EGFR gene and to explore the effects of TKIs on the delE746. METHODS: We assessed the ability of gefitinib to inhibit phosphorylation of clonal L929 cell lines expressing EGFR with delE746. 3-D structures of the EGFR proteins were also used to investigate the interaction with gefitinib. RESULTS: The delE746 mutant EGFR-expressing cells exhibited gefitinib-sensitive autophosphorylation, which altered the structure of the EGFR and increased the instances of docking during docking simulations of gefitinib with the EGFR-TK. This mutant revealed that it exhibited molecular conformation alterations, and more frequent binding with gefitinib compared to wild-type EGFR. We administered EGFR-TKI, gefitinib to a Japanese woman with lung cancer that contained delE746. The patient achieved partial response after a 5 month of treatment with gefitinib. CONCLUSION: Our study revealed biological, structural, and probably clinical features of the delE746 form of EGFR.
ErbB Receptors , Gene Deletion , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Animals , Cell Line, Tumor , Codon , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Exons , Gefitinib , Lung Neoplasms/drug therapy , Lung Neoplasms/enzymology , Lung Neoplasms/genetics , Mice , Molecular Docking Simulation , Phosphorylation , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/therapeutic use , Protein Structure, Tertiary , Quinazolines/administration & dosage , Quinazolines/therapeutic use , Treatment Outcome
By using a simple optical geometry based on backward light scattering and employing a Sandercock-type tandem Fabry-Perot interferometer, we measure both the linear and the circular polarization dependences of Rayleigh-wing and Brillouin scattering in a sample of liquid-crystal 4-n-pentyl-4'-cyanobiphenyl. Observed polarization dependences are consistent with the third-order nonlinear susceptibilities, taking into account the traceless symmetric scattering tensor for Rayleigh-wing scattering and the isotropic scattering tensor for Brillouin scattering.
