Gefitinib治疗肺癌脑转移药代动力学基础研究
摘要
研究背景：肺癌是脑转移(BM)发生率最高的恶性肿瘤,约40-50%非小细胞肺癌(NSCLC)患者会出现脑转移。出现脑转移与预后不良相关。除少部分患者可行手术外,目前的标准疗法为全脑放疗(WBRT)联合激素治疗,治疗后中位生存期为3-6月。传统的化疗方案疗效也并不理想。小分子EGFR-TKI Gefitinib细胞透过性好,临床应用于脑转移治疗观察到一定疗效。250mg/d标准剂量无效的患者加大剂量(500-1000mg/d)仍可获益,但此时测得脑脊液药物浓度很低。这是否意味着Gefitinib可透过血脑屏障,并在脑实质浓聚(而非脑脊液),且与血药浓度有较好相关性?都需要进一步探讨。
研究目的：本研究将探讨Gefitinib与血脑屏障(BBB)上转运子间的相互作用,说明Gefitinib穿透血脑屏障(BBB)的部分机制,明确Gefitinib在血浆、脑实质和CSF药代动力学特点,评价Gefitinib对正常脑组织BBB和脑转移灶的穿透能力,并分析局部组织药物浓度与疗效的相关性。
材料和方法：研究采用MDCK-MDR1单细胞层检测Gefitinib与BBB上最常见的转运子P-gp的相互作用及其对药物跨细胞转运的影响。分别予以健康裸小鼠50mg/kg、100mg/kg和200mg/kg Gefitinib单剂量口服,绘制不同剂量组Gefitinib血浆、脑实质和CSF浓度-时间曲线,计算药代动力学参数。建立人肺腺癌细胞PC-9脑转移裸小鼠模型,以50mg/kg和200mg/kg单次口服给药后检测荷瘤状态对Gefitinib血浆、脑实质和CSF分布的影响,行脑组织病理切片IHC染色,检测脑转移灶pEGFR (Tyr1068)信号的改变,分析脑组织药物浓度与疗效的相关性。
结果：在MDCK-MDR1单细胞层双向运输实验中,lOuM Gefitinib Papp (A→B)显著高于luM (3.48±0.22vs2.05±0.14×10-6cm/s, P<0.01),相应RE为4.12和4.05。P-gp转运子抑制剂CsA使Gefitinib Papp (A→B)增加、Papp (B→A)下降,RE分别下降为1和1.35。Gefitinib在健康裸小鼠血浆、脑组织和CSF的浓度随剂量增加,Cplasma、C brain和CCSF之间两两线性相关(P均<0.01),所有剂量Kp,uu均小于1。50mg/kg、100mg/kg和200mg/kg剂量下小鼠AUCbrain/AUCplasma分别为1.26,1.32和0.86。人肺腺癌细胞PC-9在裸小鼠模型上表现为播散性小灶性脑转移。与50mg/kg相比,口服200mg/kg Gefitinib的小鼠Cmax,brain和AUCbrain显著增加(P均<0.01)。与阴性对照相比,Gefitinib对小鼠脑转移灶pEGFR信号的抑制率为32-87%,200mg/kg疗效好于50mg/kgo
结论：Gefitinib可穿透正常BBB,但一定程度受到P-gP外排的限制。Gefitinb在PC-9脑转移模型小鼠脑组织浓度较高,显著阻断EGFR信号通路,与剂量相关。本研究首次提出了Gefitinib治疗脑转移过程中脑组织浓度-疗效的关系,为临床使用Gefitinib治疗NSCLC脑转移提供了依据。
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(A→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.
研究目的：本研究将探讨Gefitinib与血脑屏障(BBB)上转运子间的相互作用,说明Gefitinib穿透血脑屏障(BBB)的部分机制,明确Gefitinib在血浆、脑实质和CSF药代动力学特点,评价Gefitinib对正常脑组织BBB和脑转移灶的穿透能力,并分析局部组织药物浓度与疗效的相关性。
材料和方法：研究采用MDCK-MDR1单细胞层检测Gefitinib与BBB上最常见的转运子P-gp的相互作用及其对药物跨细胞转运的影响。分别予以健康裸小鼠50mg/kg、100mg/kg和200mg/kg Gefitinib单剂量口服,绘制不同剂量组Gefitinib血浆、脑实质和CSF浓度-时间曲线,计算药代动力学参数。建立人肺腺癌细胞PC-9脑转移裸小鼠模型,以50mg/kg和200mg/kg单次口服给药后检测荷瘤状态对Gefitinib血浆、脑实质和CSF分布的影响,行脑组织病理切片IHC染色,检测脑转移灶pEGFR (Tyr1068)信号的改变,分析脑组织药物浓度与疗效的相关性。
结果：在MDCK-MDR1单细胞层双向运输实验中,lOuM Gefitinib Papp (A→B)显著高于luM (3.48±0.22vs2.05±0.14×10-6cm/s, P<0.01),相应RE为4.12和4.05。P-gp转运子抑制剂CsA使Gefitinib Papp (A→B)增加、Papp (B→A)下降,RE分别下降为1和1.35。Gefitinib在健康裸小鼠血浆、脑组织和CSF的浓度随剂量增加,Cplasma、C brain和CCSF之间两两线性相关(P均<0.01),所有剂量Kp,uu均小于1。50mg/kg、100mg/kg和200mg/kg剂量下小鼠AUCbrain/AUCplasma分别为1.26,1.32和0.86。人肺腺癌细胞PC-9在裸小鼠模型上表现为播散性小灶性脑转移。与50mg/kg相比,口服200mg/kg Gefitinib的小鼠Cmax,brain和AUCbrain显著增加(P均<0.01)。与阴性对照相比,Gefitinib对小鼠脑转移灶pEGFR信号的抑制率为32-87%,200mg/kg疗效好于50mg/kgo
结论：Gefitinib可穿透正常BBB,但一定程度受到P-gP外排的限制。Gefitinb在PC-9脑转移模型小鼠脑组织浓度较高,显著阻断EGFR信号通路,与剂量相关。本研究首次提出了Gefitinib治疗脑转移过程中脑组织浓度-疗效的关系,为临床使用Gefitinib治疗NSCLC脑转移提供了依据。
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(A→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.
引文
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[1]Matthias P, David C, A. IM, et al.Brain metastases:pathobiology and emerging targeted therapies[J]. Acta Neuropathol,2012,123(2):205-222.
[2]Law A, Karp DD and D. T.Emergence of increased cerebral metastasis after high-dose preoperative radiotherapy with chemotherapy in patients with locally advanced non-small cell lung carcinoma[J].Cancer,2001,92(1):160-164.
[3]Shaw E, Scott C, Souhami L, et al.Radiosurgery for the treatment of previously irradiated recurrent primary brain tumors and brain metastases:Initial report of Radiation Therapy Oncology Group protocol (90-05)[J].Int J Radiat Oncol Biol Phys,1996,34(3):647-654.
[4]McKillop D, Raab G and E. H.Intratumoral and plasma concentrations of gefitinib (Iressa) in breast cancer patients:preliminary results from a presurgical investigatory study (BCIRG 103)[J].Proc Annu Meet Am Soc Clin Oncol,2004,23(22):581.
[5]M. D.Tumor penetration of gefitinib (Iressa), an epidermal growth factor receptor tyrosine kinase inhibitor[J].Molecular Cancer Therapeutics,2005,4(4):641-649.
[6]Chiu CH, Tsai CM, Chen YM, et al. Gefitinib is active in patients with brain metastases from non-small cell lung cancer and response is related to skin toxicity[J].lung cancer,2005,47(1):129-138.
[7]Isamu Okamoto, Tetsuya Mitsudomi, Kazuhiko Nakagawa, et al. The emerging role of epidermal growth factor receptor (EGFR) inhibitors in first-line treatment for patients with advanced non-small cell lung cancer positive for EGFR mutations[J].Therapeutic Advances in Medical Oncology,2010,2(5):301-307.
[8]Tiseo M, Bartolotti M, Gelsomino F, et al. Emerging role of gefitinib in the treatment of non-small-cell lung cancer (NSCLC)[J].Drug Design, Development and Therapy, 2010,4:81-98.
[9]Amy B. Heimberger, Chris A. Learn and G E. Archer.Brain tumors in mice are susceptible to blockade of epidermal growth factor Receptor (EGFR) with the Oral Specific, EGFR-Tyrosine Kinase Inhibitor ZD1839 (Iressa)[J].Clin Cancer Res,2002,8:3496-3502.
[10]Federico Cappuzzoa, Andrea Ardizzonib, Hector Soto-Parrac, et al. Epidermal growth factor receptor targeted therapy by ZD 1839 (Iressa) in patients with brain metastases from non-small cell lung cancer (NSCLC)[J].lung cancer,2003,41(2):227-231.
[11]Hotta K, Kiura K, Ueoka H, et al.Effect of gefitinib ('Iressa', ZD1839) on brain metastases in patients with advanced non-small-cell lung cancer[J].lung cancer,2004, 46(2):255-261.
[12]Poon AN, Ho SS, Yeo W, et al.Brain metastasis responding to gefitinib alone[J]. Oncology,2004,67(2):174-178.
[13]Namba Y, Kijima T and Y. S.Gefitinib in Patients with Brain Metastases from Non-Small-Cell Lung Cancer:Review of 15 Clinical Cases [J]. Clinical Lung Cancer, 2004,6(2):123-128.
[14]Ceresoli GL, Cappuzzo F, Gregorc V, et al. Gefitinib in patients with brain metastases from non-small-cell lung cancer:a prospective trial [J]. Ann Oncol,2004,15(7):1402-1407.
[15]Wu C, Li LY, Wang MZ, et al. Gefitinib as palliative therapy for lung adenocarcinoma metastatic to the brain[J].lung cancer,2007,57(3):359-364.
[16]Valerie G, Marie W, Virginie P, et al. Subsequent brain metastasis responses to epidermal growth factor receptor tyrosine kinase inhibitors in a patient with non-small-cell lung cancer[J].lung cancer,2007,58(3):425-428.
[17]H. J. Stemmlera, O. Weigerta, M. Krycha, et al. Brain metastases in metastatic non-small cell lung cancer responding to single-agent gefitinib:a case report[J].Anti-Cancer Drugs,2005,16(7):747-749.
[18]Villano JL, Mauer AM and V. EE.A case study documenting the anticancer activity of ZD1839 (Iressa) in the brain[J].Ann Oncol,2003,14(4):656-658.
[19]Kim JE, Lee DH and C. Y.Epidermal growth factor receptor tyrosine kinase inhibitors as a first-line therapy for never-smokers with adenocarcinoma of the lung having asymptomatic synchronous brain metastasis[J].lung cancer,2009,65(3):351-354.
[20]Wenhao Tang, Jiahong Chen, Renhua Ye, et al.Near Total Regression of Diffuse Brain Metastases in Adenocarcinoma of the Lung with an EGFR Exon 19 Mutation:A Case Report and Review of the Literature[J].Case Rep Oncol,2011,4(3):445-451.
[21]Katz A and Z. P.Quality-of-life benefits and evidence of antitumour activity for patients with brain metastases treated with gefitinib[J].Br J Cancer,2003,89 suppl 2:S15-S18.
[22]McKillop D, Hutchison M and Partridge EA.Metabolic disposition of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in rat, dog and man[J].Xenobiotica,2004,34:917-934.
[23]Jackman DM, Holmes AJ, Lindeman N, et al. Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose gefitinib[J].J Clin Oncol,2006,24(27):4517-4520.
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[1]Matthias P, David C, A. IM, et al.Brain metastases:pathobiology and emerging targeted therapies[J]. Acta Neuropathol,2012,123(2):205-222.
[2]Law A, Karp DD and D. T.Emergence of increased cerebral metastasis after high-dose preoperative radiotherapy with chemotherapy in patients with locally advanced non-small cell lung carcinoma[J].Cancer,2001,92(1):160-164.
[3]Shaw E, Scott C, Souhami L, et al.Radiosurgery for the treatment of previously irradiated recurrent primary brain tumors and brain metastases:Initial report of Radiation Therapy Oncology Group protocol (90-05)[J].Int J Radiat Oncol Biol Phys,1996,34(3):647-654.
[4]McKillop D, Raab G and E. H.Intratumoral and plasma concentrations of gefitinib (Iressa) in breast cancer patients:preliminary results from a presurgical investigatory study (BCIRG 103)[J].Proc Annu Meet Am Soc Clin Oncol,2004,23(22):581.
[5]M. D.Tumor penetration of gefitinib (Iressa), an epidermal growth factor receptor tyrosine kinase inhibitor[J].Molecular Cancer Therapeutics,2005,4(4):641-649.
[6]Chiu CH, Tsai CM, Chen YM, et al. Gefitinib is active in patients with brain metastases from non-small cell lung cancer and response is related to skin toxicity[J].lung cancer,2005,47(1):129-138.
[7]Isamu Okamoto, Tetsuya Mitsudomi, Kazuhiko Nakagawa, et al. The emerging role of epidermal growth factor receptor (EGFR) inhibitors in first-line treatment for patients with advanced non-small cell lung cancer positive for EGFR mutations[J].Therapeutic Advances in Medical Oncology,2010,2(5):301-307.
[8]Tiseo M, Bartolotti M, Gelsomino F, et al. Emerging role of gefitinib in the treatment of non-small-cell lung cancer (NSCLC)[J].Drug Design, Development and Therapy, 2010,4:81-98.
[9]Amy B. Heimberger, Chris A. Learn and G E. Archer.Brain tumors in mice are susceptible to blockade of epidermal growth factor Receptor (EGFR) with the Oral Specific, EGFR-Tyrosine Kinase Inhibitor ZD1839 (Iressa)[J].Clin Cancer Res,2002,8:3496-3502.
[10]Federico Cappuzzoa, Andrea Ardizzonib, Hector Soto-Parrac, et al. Epidermal growth factor receptor targeted therapy by ZD 1839 (Iressa) in patients with brain metastases from non-small cell lung cancer (NSCLC)[J].lung cancer,2003,41(2):227-231.
[11]Hotta K, Kiura K, Ueoka H, et al.Effect of gefitinib ('Iressa', ZD1839) on brain metastases in patients with advanced non-small-cell lung cancer[J].lung cancer,2004, 46(2):255-261.
[12]Poon AN, Ho SS, Yeo W, et al.Brain metastasis responding to gefitinib alone[J]. Oncology,2004,67(2):174-178.
[13]Namba Y, Kijima T and Y. S.Gefitinib in Patients with Brain Metastases from Non-Small-Cell Lung Cancer:Review of 15 Clinical Cases [J]. Clinical Lung Cancer, 2004,6(2):123-128.
[14]Ceresoli GL, Cappuzzo F, Gregorc V, et al. Gefitinib in patients with brain metastases from non-small-cell lung cancer:a prospective trial [J]. Ann Oncol,2004,15(7):1402-1407.
[15]Wu C, Li LY, Wang MZ, et al. Gefitinib as palliative therapy for lung adenocarcinoma metastatic to the brain[J].lung cancer,2007,57(3):359-364.
[16]Valerie G, Marie W, Virginie P, et al. Subsequent brain metastasis responses to epidermal growth factor receptor tyrosine kinase inhibitors in a patient with non-small-cell lung cancer[J].lung cancer,2007,58(3):425-428.
[17]H. J. Stemmlera, O. Weigerta, M. Krycha, et al. Brain metastases in metastatic non-small cell lung cancer responding to single-agent gefitinib:a case report[J].Anti-Cancer Drugs,2005,16(7):747-749.
[18]Villano JL, Mauer AM and V. EE.A case study documenting the anticancer activity of ZD1839 (Iressa) in the brain[J].Ann Oncol,2003,14(4):656-658.
[19]Kim JE, Lee DH and C. Y.Epidermal growth factor receptor tyrosine kinase inhibitors as a first-line therapy for never-smokers with adenocarcinoma of the lung having asymptomatic synchronous brain metastasis[J].lung cancer,2009,65(3):351-354.
[20]Wenhao Tang, Jiahong Chen, Renhua Ye, et al.Near Total Regression of Diffuse Brain Metastases in Adenocarcinoma of the Lung with an EGFR Exon 19 Mutation:A Case Report and Review of the Literature[J].Case Rep Oncol,2011,4(3):445-451.
[21]Katz A and Z. P.Quality-of-life benefits and evidence of antitumour activity for patients with brain metastases treated with gefitinib[J].Br J Cancer,2003,89 suppl 2:S15-S18.
[22]McKillop D, Hutchison M and Partridge EA.Metabolic disposition of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in rat, dog and man[J].Xenobiotica,2004,34:917-934.
[23]Jackman DM, Holmes AJ, Lindeman N, et al. Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose gefitinib[J].J Clin Oncol,2006,24(27):4517-4520.
[24]Lee YJ, Choi HJ and K. SK.Frequent central nervous system failure after clinical benefit with epidermal growth factor receptor tyrosine kinase inhibitors in Korean patients with nonsmall-cell lung cancer[J].Cancer,2010,116(5):1336-1343.
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