Preclinical Assessment Of Gefitinib On The Treatment Of NSCLC Brain Metastases

Background&Objective:brain metastases (BM) are a common occurrence in patients with non-small-cell lung cancer (NSCLC). Whole-brain radiotherapy (WBRT) is the standard therapy; more aggressive approaches such as surgery or radiosurgery are indicated in a subset of patients only. The role of systemic treatments remains controversial. Gefitinib is an oral, highly tolerable, specific inhibitor of epidermal growth factor receptor-associated tyrosine kinase, which has shown activity in chemotherapy pretreated NSCLC. The aim of these studys was to characterize the mechanism and PK parameters of Gefitinib in plasma, brain and CSF at different dosages in healthy nude mice, and evaluate the efficacy-brain concentration correlation of p.o.-administered Gefitinib for the treatment of established BM expressing EGFR.Material&Methods:To characterize the BBB permeability of Gefitinib, its transcellular transport and drug-transporter interaction were investigated by MDCK-MDR1cell monolayers. Nu/nu mice were sacrificed to evaluate the abilities of Gefitinib to cross the BBB by measuring the penetration of Gefitinib into brain at different dosage (50mg/kg,100mg/kg and200mg/kg) respectively. Finally, we established human PC-9BM model in nude mice to evaluate the anti-tumor activity (50mg/kg and200mg/kg, single dose, p.o.) and analyze the concentration-response correlation in brain.Result:Apical to basal transport through MDCK-MDR1cell monolayer was greater at a concentration of10uM than1uM (Papp(Aâ†'B)3.48±0.22vs2.05±0.14×10-6cm/s, P<0.01), with RE4.12and4.05respectively. CsA markedly inhibited the basal-to-apical Gefitinib transport and turned the RE down to nearly1. Gefitinib Cplasma, Cbrain and CCSF showed highly linear correlations(all P<0.01) in nude mice, Gefitinib could easily penetrate the BBB with the AUCbrain/AUCplasma1.26,1.32and0.86for each dosage respectively. In BM model, treatment with Gefitinib (single dose, p.o.) resulted in significant reduction of pEGFR (Tyr1068) signal in BM (32-87%in inhibition percentage, P<0.05), better response was seen with200mg/kg, in accordant to a higher Cmax,brain and AUCbrain.Conclusions:These studies provided the first evidence that Gefitinib could effectively cross BBB, accumulate in the brain parenchyma and markedly inhibit EGFR signal pathway in human PC-9BM model. It suggested a significant strategy for offering Gefitinib for the treatment of NSCLC BM.