Document Detail

Discovery and development of the epothilones : a novel class of antineoplastic drugs.
MedLine Citation:
PMID:  18095749     Owner:  NLM     Status:  MEDLINE    
The epothilones are a novel class of antineoplastic agents possessing antitubulin activity. The compounds were originally identified as secondary metabolites produced by the soil-dwelling myxobacterium Sorangium cellulosum. Two major compounds, epothilone A and epothilone B, were purified from the S. cellulosum strain So ce90 and their structures were identified as 16-member macrolides. Initial screening with these compounds revealed a very narrow and selective antifungal activity against the zygomycete, Mucor hiemalis. In addition, strong cytotoxic activity against eukaryotic cells, mouse L929 fibroblasts and human T-24 bladder carcinoma cells was observed. Subsequent studies revealed that epothilones induce tubulin polymerization and enhance microtubule stability. Epothilone-induced stabilisation of microtubules was shown to cause arrest at the G2/M transition of the cell cycle and apoptosis. The compounds are active against cancer cells that have developed resistance to taxanes as a result of acquisition of beta-tubulin overexpression or mutations and against multidrug-resistant cells that overexpress P-glycoprotein or multidrug resistance-associated protein. Thus, epothilones represent a new class of antimicrotubule agents with low susceptibility to key tumour resistance mechanisms. More recently, a range of synthetic and semisynthetic epothilone analogues have been produced to further improve the adverse effect profile (or therapeutic window) and to maximize pharmacokinetic and antitumour properties. Various epothilone analogues have demonstrated activity against many tumour types in preclinical studies and several compounds have been and still are being evaluated in clinical trials. This article reviews the identification and early molecular characterization of the epothilones, which has provided insight into the mode of action of these novel antitumour agents in vivo.
Hans Reichenbach; Gerhard Höfle
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Review    
Journal Detail:
Title:  Drugs in R&D     Volume:  9     ISSN:  1174-5886     ISO Abbreviation:  Drugs R D     Publication Date:  2008  
Date Detail:
Created Date:  2007-12-21     Completed Date:  2008-05-06     Revised Date:  2009-11-03    
Medline Journal Info:
Nlm Unique ID:  100883647     Medline TA:  Drugs R D     Country:  New Zealand    
Other Details:
Languages:  eng     Pagination:  1-10     Citation Subset:  IM    
Helmholtz-Zentrum für Infektionsforschung, Braunschweig, Germany.
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MeSH Terms
Antineoplastic Agents / pharmacology*
Drug Design
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Epothilones / isolation & purification,  pharmacokinetics,  pharmacology*
Myxococcales / metabolism
Tubulin Modulators / pharmacology*
Reg. No./Substance:
0/Antineoplastic Agents; 0/Epothilones; 0/Tubulin Modulators

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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