Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of Cremophor-free, albumin-bound paclitaxel, ABI-007, compared with Cremophor-based paclitaxel
Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of Cremophor-free, albumin-bound paclitaxel, ABI-007, compared with Cremophor-based paclitaxel
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DOI：
10.1158/1078-0432.ccr-05-1634
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发表时间：
2006-02-15
影响因子：
11.5
通讯作者：
Soon-Shiong, P
中科院分区：
文献类型：
--
作者：
Desai, N;Trieu, V;Soon-Shiong, P
ABI-007是一种白蛋白结合的130 nm颗粒形式的紫杉醇，旨在避免Cremophor基紫杉醇（Taxol）中的Cremophor/乙醇相关毒性，并利用白蛋白受体介导的内皮转运。我们研究了ABI-007和基于Cremophor的紫杉醇的抗肿瘤活性、肿瘤内紫杉醇积累和内皮转运。在用ABI-007或基于Cremophor的紫杉醇处理的携带人肿瘤异种移植物[肺（H522）、乳腺（MX-1）、卵巢（SK-0 V-3）、前列腺（PC-3）和结肠（HT 29）]的裸鼠中评估抗肿瘤活性和死亡率。比较放射性标记的ABI-007和基于Cremophor的紫杉醇的肿瘤内紫杉醇浓度（MX-1肿瘤小鼠）。比较ABI-007和基于Cremophor的紫杉醇对紫杉醇与细胞和白蛋白结合的体外内皮转胞吞作用和Cremophor抑制。ABI-007和基于Cremophor的紫杉醇均引起肿瘤消退和延长生存期;敏感性顺序为肺>乳腺与卵巢一致>前列腺>结肠。ABI-007和基于Cremophor的紫杉醇的LD 50和最大耐受剂量分别为47和30 mg/kg/d以及30和13.4 mg/kg/d。在等毒性剂量下，ABI-007治疗组显示出更完全的消退、更长的复发时间、更长的倍增时间和更长的生存期。在相同剂量下，ABI-007的肿瘤紫杉醇曲线下面积比基于Cremophor的紫杉醇高33%，表明ABI-007的更有效的肿瘤内积累。ABI-007与基于Cremophor的紫杉醇相比，紫杉醇的内皮结合和转胞吞作用显著更高，并且这种差异被已知的内皮gp 60受体/小窝转运抑制剂消除。此外，发现Cremophor抑制紫杉醇与内皮细胞和白蛋白的结合。ABI-007的增强的内皮细胞结合和转胞吞作用以及Cremophor在基于Cremophor的紫杉醇中的抑制作用可能部分地解释了ABI-007的更大功效和肿瘤内递送。
ABI-007, an albumin-bound, 130-nm particle form of paclitaxel, was developed to avoid Cremophor/ethanol-associated toxicities in Cremophor-based paclitaxel (Taxol) and to exploit albumin receptor-mediated endothelial transport. We studied the antitumor activity, intratumoral paclitaxel accumulation, and endothelial transport for ABI-007 and Cremophor-based paclitaxel. Antitumor activity and mortality were assessed in nude mice bearing human tumor xenografts [lung (H522), breast (MX-1), ovarian (SK-OV-3), prostate (PC-3), and colon (HT29)] treated with ABI-007 or Cremophor-based paclitaxel. Intratumoral paclitaxel concentrations (MX-1-tumored mice) were compared for radiolabeled ABI-007 and Cremophor-based paclitaxel. In vitro endothelial transcytosis and Cremophor inhibition of paclitaxel binding to cells and albumin was compared for ABI-007 and Cremophor-based paclitaxel. Both ABI-007 and Cremophor-based paclitaxel caused tumor regression and prolonged survival; the order of sensitivity was lung > breast congruent to ovary > prostate > colon. The LD50 and maximum tolerated dose for ABI-007 and Cremophor-based paclitaxel were 47 and 30 mg/kg/d and 30 and 13.4 mg/kg/d, respectively. At equitoxic dose, the ABI-007-treated groups showed more complete regressions, longer time to recurrence, longer doubling time, and prolonged survival. At equal dose, tumor paclitaxel area under the curve was 33% higher for ABI-007 versus Cremophor-based paclitaxel, indicating more effective intratumoral accumulation of ABI-007. Endothelial binding and transcytosis of paclitaxel were markedly higher for ABI-007 versus Cremophor-based paclitaxel, and this difference was abrogated by a known inhibitor of endothelial gp60 receptor/caveolar transport. In addition, Cremophor was found to inhibit binding of paclitaxel to endothelial cells and albumin. Enhanced endothelial cell binding and transcytosis for ABI-007 and inhibition by Cremophor in Cremophor-based paclitaxel may account in part for the greater efficacy and intratumor delivery of ABI-007.