Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer.
Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer.
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DOI：
10.1158/1078-0432.ccr-10-1564
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发表时间：
2010-12-01
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影响因子：
--
通讯作者：
Smith QR
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作者：
Lockman PR;Mittapalli RK;Taskar KS;Rudraraju V;Gril B;Bohn KA;Adkins CE;Roberts A;Thorsheim HR;Gaasch JA;Huang S;Palmieri D;Steeg PS;Smith QR
乳腺癌脑转移的发病率似乎在增加，具有显著的发病率，并威胁到全身化疗所取得的成果。血液-肿瘤屏障(BTB)在许多脑转移瘤中受到损害，然而，这对化疗药物的传递和疗效的影响程度尚不清楚。在这里，我们通过在两个优先脑转移的乳腺癌模型中测量BTB被动完整性、化疗药物摄取和体内抗癌效果来回答这个问题。使用新的荧光和磷光成像技术同时测量免疫受损小鼠的实验性脑转移、药物摄取和BTB通透性。用免疫荧光显微镜检测药物诱导的细胞凋亡和血管特性。对来自两个模型(人231-BR-Her2和小鼠4T1-BR5)的>；2000脑转移瘤的分析表明，在>；的病灶中，部分血结核通透性受损，在转移内和转移之间的大小不同。脑转移瘤对~(14)C-紫杉醇和~(14)C-阿霉素的摄取一般高于正常脑组织，但仅为其他组织或周围转移瘤的15%，且仅在最具渗透性的转移瘤中的一小部分(~10%)达到细胞毒浓度。两种药物均未显著降低231-BR-Her2肿瘤细胞的实验性脑转移能力。BTB通透性与血管重塑相关，并与周细胞蛋白结蛋白的过度表达相关。这项工作表明，在乳腺癌实验性脑转移中，BTB仍然是标准化疗药物传递和疗效的重要障碍。将需要新的脑透性药物。BTB通透性改变中存在血管重塑的证据。
Brain metastases of breast cancer appear to be increasing in incidence, confer significant morbidity, and threaten to compromise gains made in systemic chemotherapy. The blood-tumor barrier (BTB) is compromised in many brain metastases, however, the extent to which this influences chemotherapeutic delivery and efficacy is unknown. Herein, we answer this question by measuring BTB passive integrity, chemotherapeutic drug uptake, and anticancer efficacy in vivo in two breast cancer models that metastasize preferentially to brain. Experimental brain metastasis drug uptake and BTB permeability were simultaneously measured using novel fluorescent and phosphorescent imaging techniques in immune compromised mice. Drug-induced apoptosis and vascular characteristics were assessed using immunofluorescent microscopy. Analysis of >2000 brain metastases from two models (human 231-BR-Her2 and murine 4T1-BR5) demonstrated partial BTB permeability compromise in >89% lesions, varying in magnitude within and between metastases. Brain metastasis uptake of 14C- paclitaxel and 14C- doxorubicin was generally greater than normal brain but <15% of that of other tissues or peripheral metastases, and only reached cytotoxic concentrations in a small subset (~10%) of the most permeable metastases. Neither drug significantly decreased the experimental brain metastatic ability of 231-BR-Her2 tumor cells. BTB permeability was associated with vascular remodeling and correlated with over expression of the pericyte protein, desmin. This work demonstrates that the BTB remains a significant impediment to standard chemotherapeutic delivery and efficacy in experimental brain metastases of breast cancer. New brain permeable drugs will be needed. Evidence is presented for vascular remodeling in BTB permeability alterations.