Abstract
Brain metastasis is an increasing problem in non-small cell lung cancer (NSCLC) patients. Tyrosine kinase inhibitors (TKIs), including gefitinib, erlotinib, and icotinib, are reported to be effective in patients with brain metastases. However, direct comparative studies of the pharmacokinetics and efficacy of these three drugs in treating brain metastases are lacking. In the present investigation, we found that gefitinib penetrated the blood-tumor barrier and was distributed to brain metastases more effectively than erlotinib or icotinib in a nude mouse model. The 1-h ratio of brain metastases to plasma concentration for gefitinib, erlotinib, and icotinib was 9.82±1.03%, 4.83±0.25%, and 2.62±0.21%, respectively. The 2-h ratio of brain metastases to plasma concentration for gefitinib, erlotinib, and icotinib was 15.11±2.00%, 5.73±1.31%, and 2.69±0.31%, respectively. Gefitinib exhibited the strongest antitumor activity (pgefitinib vs. erlotinib=0.005; pgefitinib vs. icotinib=0.002). Notably, erlotinib exhibited a better treatment efficacy than icotinib (p=0.037). Consistently, immunohistochemical data showed that TKIs differentially inhibit the proliferation of metastatical tumor cells. Gefitinib and erlotinib markedly inhibited the proliferation of tumor cells, while there were more ki-67-positive tumor cells in the icotinib group. Additionally, gefitinib inhibited the phosphorylation of EGFR better than the other drugs, whereas pEGFR expression levels in erlotinib groups were lower than levels in the icotinib group (pgefitinib vs. erlotinib=0.995; pgefitinib vs. icotinib=0.028; perlotinib vs. icotinib=0.042).Altogether, our findings suggest that gefitinib and erlotinib can inhibit the growth of PC-9-luc brain tumors. Gefitinib demonstrated better antitumor activity and penetration rate in brain metastases than erlotinib or icotinib.
Highlights
Mutations in epidermal growth factor receptor (EGFR) gene activation (19 exon del/L858R) may be a risk factor for brain metastases in patients with nonsmall cell lung cancer (NSCLC) [1]
We found that gefitinib penetrated the blood-tumor barrier and was distributed to brain metastases more effectively than erlotinib or icotinib in a nude mouse model
Gefitinib inhibited the phosphorylation of EGFR better than the other drugs, whereas pEGFR expression levels in erlotinib groups were lower than levels in the icotinib group
Summary
Mutations in epidermal growth factor receptor (EGFR) gene activation (19 exon del/L858R) may be a risk factor for brain metastases in patients with nonsmall cell lung cancer (NSCLC) [1]. The invasiveness of EGFR mutations [3], prolonged survival [2], and blood-brain barrier (BBB) blockage of drug penetration [4] are potential factors that may increase the occurrence of brain metastases in EGFR mutation-positive NSCLC. Some patients show improvement using these methods, indicating that a high dose of EGFR TKIs can increase the concentration of the medication in cerebrospinal fluid (CSF). This shows that the main issue limiting drug efficacy is the distribution of EGFR TKIs in the brain, rather than resistance [13,14,15]. There may be differences in the efficacy of various EGFR TKIs in treating brain metastases
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