Improved effectiveness of nanoparticle albumin-bound (nab) paclitaxel versus polysorbate-based docetaxel in multiple xenografts as a function of HER2 and SPARC status
Improved effectiveness of nanoparticle albumin-bound (nab) paclitaxel versus polysorbate-based docetaxel in multiple xenografts as a function of HER2 and SPARC status
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DOI：
10.1097/cad.0b013e32830f9046
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发表时间：
2008-10-01
影响因子：
2.3
通讯作者：
Gradishar, William J.
中科院分区：
文献类型：
--
作者：
Desai, Neil P.;Trieu, Vuong;Gradishar, William J.
纳米颗粒白蛋白结合 (nab)-紫杉醇 (Abraxane) 是一种白蛋白结合的 130 nm 紫杉醇颗粒形式，在转移性乳腺癌的临床试验中，与溶剂型紫杉醇 (Taxol) 和多西紫杉醇 (Taxotere) 相比，其疗效更高且耐受性良好。白蛋白结合型紫杉醇通过 gp60 和小窝介导的内皮转胞吞作用以及与肿瘤微环境中的白蛋白结合蛋白 SPARC（分泌蛋白，酸性且富含半胱氨酸）的关联来增强肿瘤靶向。乳腺癌中人表皮生长因子受体 2 (HER2) 的过度表达已被证明与紫杉醇耐药性相关。为了评估 HER2 和 SPARC 状态在确定白蛋白结合型紫杉醇与基于聚山梨醇酯的多西他赛相比的相对疗效中的重要性，用白蛋白结合型紫杉醇治疗携带六种不同人类肿瘤异种移植物的裸鼠（MX-1：15 mg/kg，每周一次，持续 3 周；LX-1、MDA-MB-231/HER2+、PC3 和 HT29：50 120mg/kg，每4天3次； MDA-MB-231：120 和 180 mg/kg，每 4 天 3 次）和基于聚山梨酯的多西紫杉醇（15 mg/kg）。通过 RT-PCR 和免疫组织化学染色分析 HER2 和 SPARC 状态。 MDA-MB-231 和 MX-1 乳腺癌以及 LX-1 肺癌为 HER2 阴性且 SPARC 表达较低。在这三种 HER2 阴性肿瘤中，次最大耐受剂量的白蛋白结合型紫杉醇明显比最大耐受剂量的基于聚山梨酯的多西紫杉醇更有效。 HER2 阳性肿瘤具有可变的 SPARC 表达，MDA-MB-231/HER2+
Nanoparticle albumin-bound (nab)-paclitaxel (Abraxane) is an albumin-bound 130-nm particle form of paclitaxel that demonstrated higher efficacy and was well tolerated compared with solvent-based paclitaxel (Taxol) and docetaxel (Taxotere) in clinical trials for metastatic breast cancer. Nab-paclitaxel enhances tumor targeting through gp60 and caveolae-mediated endothelial transcytosis and the association with the albumin-binding protein SPARC (secreted protein, acidic and rich in cysteine) in the tumor microenvironment. The overexpression of human epidermal growth factor receptor-2 (HER2) in breast cancer has been shown to correlate with resistance to paclitaxel. To evaluate the importance of HER2 and SPARC status in determining the relative efficacy of nab-paclitaxel compared with polysorbate-based docetaxel, nude mice bearing six different human tumor xenografts were treated with nab-paclitaxel (MX-1: 15 mg/kg, once a week for 3 weeks; LX-1, MDA-MB-231/HER2+, PC3, and HT29: 50 and 120 mg/kg, every 4 days three times; MDA-MB-231: 120 and 180 mg/kg, every 4 days three times) and polysorbate-based docetaxel (15 mg/kg). HER2 and SPARC status were analyzed by RT-PCR and immunohistochemical staining. MDA-MB-231 and MX-1 breast and LX-1 lung cancers were HER2 negative and low in SPARC expression. Nab-paclitaxel at submaximum-tolerated dosage was significantly more effective than polysorbate-based docetaxel at its maximum-tolerated dosage in these three HER2-negative tumors. The HER2-positive tumors had variable SPARC expression, with MDA-MB-231/HER2+