Formation of complement-activating particles in aqueous solutions of Taxol: possible role in hypersensitivity reactions
Formation of complement-activating particles in aqueous solutions of Taxol: possible role in hypersensitivity reactions
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DOI：
10.1016/s1567-5769(01)00006-6
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发表时间：
2001-04-01
影响因子：
5.6
通讯作者：
Talmon, Y
中科院分区：
文献类型：
--
作者：
Szebeni, J;Alving, CR;Talmon, Y
我们早些时候报道了抗癌药物紫杉醇(Taxol)在体外激活了人血清中的补体(C)系统，增加了C激活可能在对该药物不明的超敏反应(HSRs)中起作用的可能性[J，Natl]。癌症研究所。90(1998)300]，为了探讨紫杉醇激活C的机理，本研究提供了证据表明，注射浓缩物在水溶液中稀释后会形成胶束和针状结构，这两种结构都会在体外引起C的激活。紫杉醇的非离子乳化剂载体Cremvoor EL(CrEL)主要形成胶束，紫杉醇输液中的CrEL含量超过临界胶束浓度至少400倍。准弹性光散射和低温透射电子显微镜显示CrEL胶束是球形的，直径在8-22 nm范围内；然而，与人血浆孵育后新形成的50-300 nm微滴表明血液中进一步的基本结构变化。紫杉醇诱导的C活化表现为血清C3a-Desarg、iC3b和SC5b-9的不同程度升高。通过30 kDa截滤器过滤紫杉醇或纯CrEL水溶液，消除了CrEL胶束在C活化中的作用，而过滤保留液恢复了C活化，从而证明了CrEL胶束在C活化中的作用。10 mg/ml的人免疫球蛋白(IVIG)也能抑制紫杉醇对c的激活。如果在临床上得到证实，紫杉醇的HSRs可能代表一种迄今为止模糊分类的药物不良反应，最近被称为C激活相关假过敏(CARPA)[循环99(1999)2302]。(C)2001年，爱思唯尔科学公司出版。
We reported earlier that the anticancer drug paclitaxel (Taxol) activated the complement (C) system in human serum in vitro, raising the possibility that C activation might play a role in the ill-understood hypersensitivity reactions (HSRs) to this drug [J, Natl. Cancer Inst. 90 (1998) 300], In pursuing the mechanism of C activation by Taxol, the present study provided evidence that dilution of the injection concentrate in aqueous solvents led to the formation of micelles and needle-like structures, both of which caused C activation in vitro. Micelles were formed mainly from Cremophor EL (CrEL), the nonionic emulsifier vehicle of paclitaxel, whose level in Taxol infusion exceeded its critical micelle concentration by at Least 400-fold. CrEL micelles were shown by quasi-elastic light scattering and cryo-transmission electron microscopy (cryo-TEM) to be spherical with diameters in the 8-22 nm range; however, de novo formation of 50-300 nm microdroplets following incubation with human plasma suggested further fundamental structural transformation in blood. The needle-like structures extended to the multimicron range and were shown by electron diffraction to be crystalline paclitaxel, Taxol-induced C activation was manifested in varying rises of serum C3a-desarg, iC3b and SC5b-9. The causal role of CrEL micelles in C activation was demonstrated by the fact that filtration of aqueous solutions of Taxol or pure CrEL via 30-kDa cutoff filters eliminated, while the filter retentate restored C activation. C activation by Taxol was also inhibited by 10 mg/ml human immunoglobulin (IVIG). If proven clinically, HSRs to Taxol may represent a hitherto vaguely classified adverse drug reaction recently called C activation-related pseudoallergy (CARPA) [Circulation 99 (1999) 2302]. (C) 2001 Published by Elsevier Science B.V.