Therapeutic effect against human xenograft tumors in nude mice by the third generation microtubule stabilizing epothilones

被引：47
作者：
Chou, Ting-Chao
Zhang, Xiuguo
Zhong, Zi-Yang [4 ]
Li, Yong [4 ]
Feng, Li [4 ]
Eng, Sara [4 ]
Myles, David R. [4 ]
Johnson, Robert, Jr. [4 ]
Wu, Nian [2 ]
Yin, Ye Ingrid [2 ]
Wilson, Rebecca M. [1 ]
Danishefsky, Samuel J. [1 ,3 ]
机构：
[1] Mem Sloan Kettering Canc Ctr, Bioorgan Chem Lab, Mol Pharmacol & Chem Program, New York, NY 10065 USA
[2] Mem Sloan Kettering Canc Ctr, Analyt Chem Core Labs, New York, NY 10065 USA
[3] Columbia Univ, Dept Chem, New York, NY 10027 USA
[4] Kosan Biosci Inc, Hayward, CA 94545 USA
来源：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2008年 / 105卷 / 35期
基金：
美国国家卫生研究院;
关键词：
D O I：
10.1073/pnas.0804773105
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
The epothilones represent a promising class of natural product-based antitumor drug candidates. Although these compounds operate through a microtubule stabilization mechanism similar to that of taxol, the epothilones offer a major potential therapeutic advantage in that they retain their activity against multidrug-resistant cell lines. We have been systematically synthesizing and evaluating synthetic epothilone congeners that are not accessible through modification of the natural product itself. We report herein the results of biological investigations directed at two epothilone congeners: iso-fludelone and iso-dehydelone. Iso-fludelone, in particular, exhibits a number of properties that render it an excellent candidate for preclinical development, including biological stability, excellent solubility in water, and remarkable potency relative to other epothilones. In nude mouse xenograft settings, iso-fludelone was able to achieve therapeutic cures against a number of human cancer cell lines, including mammarian-MX-1, ovarian-SK-OV-3, and the fast-growing, refractory, subcutaneous neuroblastoma-SK-NAS. Strong therapeutic effect was observed against drug-resistant lung-A549/taxol and mammary-MCF-7/Adr xenografts. In addition, iso-fludelone was shown to exhibit a significant therapeutic effect against an intracranially implanted SK-NAS tumor.
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页码：13157 / 13162
页数：6
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