Document Detail


Maytansinoid-antibody conjugates induce mitotic arrest by suppressing microtubule dynamic instability.
MedLine Citation:
PMID:  20937595     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Maytansine and its analogues (maytansinoids) are potent microtubule-targeted compounds that inhibit proliferation of cells at mitosis. Antibody-maytansinoid conjugates consisting of maytansinoids (DM1 and DM4) attached to tumor-specific antibodies have shown promising clinical results. To determine the mechanism by which the antibody-DM1 conjugates inhibit cell proliferation, we examined the effects of the cleavable anti-EpCAM-SPP-DM1 and uncleavable anti-EpCAM-SMCC-DM1 conjugates on MCF7 human breast tumor cells. We also examined the effects of the free maytansinoids, maytansine and S-methyl DM1 (a version of DM1 that is stable in cell culture medium), for comparison. Both the conjugates and free maytansinoids potently inhibited MCF7 cell proliferation at nanomolar and subnanomolar concentrations, respectively, by arresting the cells in mitotic prometaphase/metaphase. Arrest occurred in concert with the internalization and intracellular processing of both conjugates under conditions that induced abnormal spindle organization and suppressed microtubule dynamic instability. Microtubule depolymerization occurred only at significantly higher drug concentrations. The results indicate that free maytansinoids, antibody-maytansinoid conjugates, and their metabolites exert their potent antimitotic effects through a common mechanism involving suppression of microtubule dynamic instability.
Authors:
Emin Oroudjev; Manu Lopus; Leslie Wilson; Charlene Audette; Carmela Provenzano; Hans Erickson; Yelena Kovtun; Ravi Chari; Mary Ann Jordan
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  9     ISSN:  1538-8514     ISO Abbreviation:  Mol. Cancer Ther.     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-10-12     Completed Date:  2011-03-10     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2700-13     Citation Subset:  IM    
Affiliation:
Department of Molecular, Cellular, and Developmental Biology, and Neuroscience Research Institute, University of California, Santa Barbara, California 93106-9610, USA.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents, Phytogenic / immunology,  pharmacology*
Cell Cycle
Cell Line, Tumor
Cell Proliferation
Chromatography, High Pressure Liquid
Humans
Immunoconjugates / immunology,  pharmacology*
Maytansine / immunology,  pharmacology*
Microscopy, Fluorescence
Microtubules / drug effects*
Mitosis / drug effects*,  immunology
Grant Support
ID/Acronym/Agency:
CA 57291/CA/NCI NIH HHS; NS13560/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents, Phytogenic; 0/Immunoconjugates; 35846-53-8/Maytansine
Comments/Corrections

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