NPI-2358 is a tubulin-depolymerizing agent: in-vitro evidence for activity as a tumor vascular-disrupting agent

被引：208
|
作者：
Nicholson, B
Lloyd, GK
Miller, BR
Palladino, MA
Kiso, Y
Hayashi, Y
Neuteboom, STC
机构：
[1] Nereus Pharmaceut Inc, San Diego, CA 92121 USA
[2] Kyoto Pharmaceut Univ, Kyoto 607, Japan
来源：
ANTI-CANCER DRUGS | 2006年 / 17卷 / 01期
关键词：
cancer; natural product; NPI-2358; tubulin-depolymerizing agent; vascular-disrupting agent;
D O I：
10.1097/01.cad.0000182745.01612.8a
中图分类号：
R73 [肿瘤学];
学科分类号：
100214 ;
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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页码：25 / 31
页数：7
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