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

• DOI: 10.1073/pnas.0804773105
• Publication Date: 2008-08-29T01:10:38Z
• Authors: Ting-Chao Chou; Xiuguo Zhang; Zi-Yang Zhong; Yong Li; Li Feng; Sara Eng; David R. Myles; Robert Johnson; Nian Wu; Ye Ingrid Yin; Rebecca M. Wilson; Samuel J. Danishe...
• Keywords: 0301 basic medicine; Administration, Oral; Mice, Nude; Microtubules; Xenograft Model Antitumor Assays; Tubulin Modulators; 3. Good health; Mice; 03 medical and health sciences; Drug Resistance, Neoplasm; Epothilones; Drug Design; Neoplasms; Animals; Humans; Female; Cell Proliferation

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.