Lapatinib distribution in HER2 overexpressing experimental brain metastases of breast cancer.
Lapatinib distribution in HER2 overexpressing experimental brain metastases of breast cancer.
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DOI：
10.1007/s11095-011-0601-8
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发表时间：
2012-03
影响因子：
3.7
通讯作者：
Smith QR
中科院分区：
文献类型：
--
作者：
Taskar KS;Rudraraju V;Mittapalli RK;Samala R;Thorsheim HR;Lockman J;Gril B;Hua E;Palmieri D;Polli JW;Castellino S;Rubin SD;Lockman PR;Steeg PS;Smith QR
拉帕替尼是一种小分子EGFR/HER2抑制剂，在临床前和临床试验中对HER2+脑转移瘤的预后影响有限。我们研究了对MDA-MD-231-BR-HER2脑转移乳腺癌小鼠给予14c -拉帕替尼（100mg /kg口服或10mg /kg静脉注射）后，拉帕替尼在中枢神经系统中达到治疗浓度的能力。用定量放射自显影和层析法测定给药后不同时间的药物浓度。14c -拉帕替尼浓度在脑转移瘤中存在差异，并与血肿瘤屏障通透性改变相关。在口服给药后2和12小时，脑转移浓度平均比周围脑组织高7 - 9倍。然而，拉帕替尼在脑转移瘤中的平均浓度仍仅为外周转移瘤的10-20%。只有一部分脑病变（17%）的拉帕替尼浓度接近全身性转移。未发现拉帕替尼治疗后脑内残留肿瘤细胞对拉帕替尼耐药的证据。结果表明，拉帕替尼在乳腺癌脑转移中的分布受到限制，血液肿瘤屏障的通透性是影响拉帕替尼治疗效果的关键因素，而拉帕替尼的治疗效果在肿瘤内部和肿瘤之间存在差异。
Lapatinib, a small molecule EGFR/HER2 inhibitor, has limited effect on outgrowth of HER2+ brain metastases in preclinical and clinical trials. We investigated the ability of lapatinib to reach therapeutic concentrations in the CNS following 14C-lapatinib administration (100 mg/kg p.o. or 10 mg/kg, i.v.) to mice with MDA-MD-231-BR-HER2 brain metastases of breast cancer. Drug concentrations were determined at differing times after administration by quantitative autoradiography and chromatography. 14C-Lapatinib concentration varied among brain metastases and correlated with altered blood-tumor barrier permeability. On average, brain metastasis concentration was 7–9-fold greater than surrounding brain tissue at 2 and 12 hours after oral administration. However, average lapatinib concentration in brain metastases was still only 10–20% of those in peripheral metastases. Only in a subset of brain lesions (17%) did lapatinib concentration approach that of systemic metastases. No evidence was found of lapatinib resistance in tumor cells remaining in brain after lapatinib treatment. Results show that lapatinib distribution to brain metastases of breast cancer is restricted and blood-tumor barrier permeability is a key component of lapatinib therapeutic efficacy which varies within and between tumors.
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拉帕替尼对转移性乳腺癌细胞生长到大脑的影响。
影响因子：
10.3
作者：
Gril, Brunilde;Palmieri, Diane;Bronder, Julie L.;Herring, Jeanne M.;Vega-Valle, Eleazar;Feigenbaum, Lionel;Liewehr, David J.;Steinberg, Seth M.;Merino, Maria J.;Rubin, Stephen D.;Steeg, Patricia S.
通讯作者：
Steeg, Patricia S.
影响因子：
50.5
作者：
Metro, G.;Foglietta, J.;Gori, S.
通讯作者：
Gori, S.
影响因子：
3.8
作者：
Cameron, David;Casey, Michelle;Geyer, Charles E.
通讯作者：
Geyer, Charles E.
影响因子：
3.9
作者：
Polli, Joseph W.;Humphreys, Joan E.;Serabjit-Singh, Cosette J.
通讯作者：
Serabjit-Singh, Cosette J.
影响因子：
5.3
作者：
Lampson LA
通讯作者：
Lampson LA