Randomized study of paclitaxel and tamoxifen deposition into human brain tumors: Implications for the treatment of metastatic brain tumors
Randomized study of paclitaxel and tamoxifen deposition into human brain tumors: Implications for the treatment of metastatic brain tumors
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DOI：
10.1158/1078-0432.ccr-05-2356
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发表时间：
2006-10-01
影响因子：
11.5
通讯作者：
Fetell, Michael R.
中科院分区：
文献类型：
--
作者：
Fine, Robert L.;Chen, Johnson;Fetell, Michael R.
目的：脑肿瘤的耐药性部分是由血脑屏障介导的，血脑屏障的关键成分是P-糖蛋白，P-糖蛋白在脑毛细血管中高表达。他莫昔芬是一种无毒的P-糖蛋白抑制剂。这项试验评估了紫杉醇在原发和转移性脑瘤中的不同沉积，以及他莫昔芬是否可以增加紫杉醇的沉积。实验设计：将接受手术切除原发或转移性脑瘤的患者前瞻性地随机分配到之前的紫杉醇(175 mg/m(2)/iv)。或他莫昔芬，连服5天，然后用紫杉醇。中心和周围肿瘤，周围正常脑和血浆，分析紫杉醇和他莫昔芬。结果：27名患者完成研究。基于多元线性回归模型，在调整治疗组(他莫昔芬与对照组)后，两个研究组之间的紫杉醇浓度没有显著差异。然而，在肿瘤类型分析中，转移性脑肿瘤的肿瘤中心紫杉醇浓度(1.93倍，P=0.10)和肿瘤周边紫杉醇浓度(2.46倍，P=0.039)高于原发脑肿瘤。药代动力学分析显示紫杉醇在两个治疗臂之间的血药浓度下具有相似的区域。结论：紫杉醇的沉积没有增加，因为低的血药浓度可能是同时使用P-450诱导药物所致。然而，转移性脑肿瘤周边紫杉醇沉积的统计学上较高，为证实转移性脑肿瘤与原发脑肿瘤相比P-糖蛋白表达降低的报道提供了功能证据。这表明，如果紫杉醇对原发肿瘤的组织病理学有临床疗效，转移性脑瘤可能对紫杉醇有反应。
Purpose: Drug resistance in brain tumors is partially mediated by the blood-brain barrier of which a key component is P-glycoprotein, which is highly expressed in cerebral capillaries. Tamoxifen is a nontoxic inhibitor of P-glycoprotein. This trial assessed, in primary and metastatic brain tumors, the differential deposition of paclitaxel and whether tamoxifen could increase paclitaxel deposition.Experimental Design: Patients for surgical resection of their primary or metastatic brain tumors were prospectively randomized to prior paclitaxel alone (175 mg/m(2)/i.v.) or tamoxifen for 5 days followed by paclitaxel. Central and peripheral tumor, surrounding normal brain and plasma, were analyzed for paclitaxel and tamoxifen.Results: Twenty-seven patients completed the study. Based on a multivariate linear regression model, no significant differences in paclitaxel concentrations between the two study arms were found after adjusting for treatment group (tamoxifen versus control). However, in analysis for tumor type, metastatic brain tumors had higher paclitaxel concentrations in the tumor center (1.93-fold, P = 0.10) and in the tumor periphery (2.46-fold, P = 0.039) compared with primary brain tumors. Pharmacokinetic analyses showed comparable paclitaxel areas under the serum concentration between treatment arms.Conclusions: Paclitaxel deposition was not increased with this tamoxifen schedule as the low plasma concentrations were likely secondary to concurrent use of P-450-inducing medications. However, the statistically higher paclitaxel deposition in the periphery of metastatic brain tumors provides functional evidence corroborating reports of decreased P-glycoprotein expression in metastatic versus primary brain tumors. This suggests that metastatic brain tumors may respond to paclitaxel if it has proven clinical efficacy for the primary tumor's histopathology.