康布雷他汀
微管蛋白
秋水仙碱
体外
长春新碱
微管
体内
解聚
癌症研究
药理学
医学
生物
化学
生物化学
内科学
细胞生物学
化疗
环磷酰胺
生物技术
有机化学
作者
Benjamin Nicholson,G. Kenneth Lloyd,Brian R. Miller,Michael A. Palladino,Yoshiaki Kiso,Yoshio Hayashi,Saskia Neuteboom
出处
期刊:Anti-Cancer Drugs
[Lippincott Williams & Wilkins]
日期:2005-11-24
卷期号:17 (1): 25-31
被引量:239
标识
DOI:10.1097/01.cad.0000182745.01612.8a
摘要
The diketopiperazine NPI-2358 is a synthetic analog of NPI-2350, a natural product isolated from Aspergillus sp., which depolymerizes microtubules in A549 human lung carcinoma cells. Although structurally different from the colchicine-binding site agents reported to date, NPI-2358 binds to the colchicine-binding site of tubulin. NPI-2358 has potent in-vitro anti-tumor activity against various human tumor cell lines and maintains activity against tumor cell lines with various multidrug-resistant (MDR) profiles. In addition, when evaluated in proliferating human umbilical vein endothelial cells (HUVECs), concentrations as low as 10 nmol/l NPI-2358 induced tubulin depolymerization within 30 min. Furthermore, NPI-2358 dose dependently increases HUVEC monolayer permeability--an in-vitro model of tumor vascular collapse. NPI-2358 was compared with three tubulin-depolymerizing agents with vascular-disrupting activity: colchicine, vincristine and combretastatin A-4 (CA4). Results showed that the activity of NPI-2358 in HUVECs was more potent than either colchicine or vincristine; the profile of CA4 approached that of NPI-2358. Altogether, our data show that NPI-2358 is a potent anti-tumor agent which is active in MDR tumor cell lines, and is able to rapidly induce tubulin depolymerization and monolayer permeability in HUVECs. These data warrant further evaluation of NPI-2358 as a vascular-disrupting agent in vivo. Currently, NPI-2358 is in preclinical development for the treatment of cancer.
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