Therapeutic effect against human xenograft tumors in nude mice by the third generation microtubule stabilizing epothilones Journal Article
| Authors: | Chou, T. C.; Zhang, X.; Zhong, Z. Y.; Li, Y.; Feng, L.; Eng, S.; Myles, D. R.; Johnson, R. Jr; Wu, N.; Yin, Y. I.; Wilson, R. M.; Danishefsky, S. J. |
| Article Title: | Therapeutic effect against human xenograft tumors in nude mice by the third generation microtubule stabilizing epothilones |
| Abstract: | 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 SKNAS tumor. © 2008 by The National Academy of Sciences of the USA. |
| Keywords: | controlled study; treatment outcome; unclassified drug; human cell; drug efficacy; nonhuman; capecitabine; paclitaxel; temozolomide; neoplasms; cell proliferation; mouse; animals; mice; animal tissue; low drug dose; animal experiment; animal model; cancer cell culture; drug potency; tumor xenograft; drug resistance, neoplasm; xenograft model antitumor assays; drug design; carmustine; vinblastine; mus musculus; docetaxel; nude mouse; tissue distribution; mice, nude; neuroblastoma; breast carcinoma; ovary carcinoma; lung carcinoma; therapy effect; water; administration, oral; microtubule; microtubules; drug stability; isofludelone; epothilones; epothilone derivative; tubulin modulators; drug solubility; fludelone; 12,13 desoxy epothilone b; dehydelone; isodehydelone; mammaria |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 105 |
| Issue: | 35 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2008-09-02 |
| Start Page: | 13157 |
| End Page: | 13162 |
| Language: | English |
| DOI: | 10.1073/pnas.0804773105 |
| PUBMED: | 18755900 |
| PROVIDER: | scopus |
| PMCID: | PMC2529025 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 16" - "Export Date: 17 November 2011" - "CODEN: PNASA" - "Source: Scopus" |
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