Oct 13, 2010

Maytansinoid-antibody conjugates induce mitotic arrest by suppressing microtubule dynamic instability

Molecular Cancer Therapeutics
Emin OroudjevMary Ann Jordan

Abstract

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 c...Continue Reading

  • References33
  • Citations60

References

Mentioned in this Paper

TAGLN gene
Exertion
Protoplasm
Mitotic Metaphase
Antineoplastic Agents, Phytogenic
Cell Culture Techniques
Spindle Organization
Immunofluorescence Microscopy
Microtubule Depolymerization Process
Metaphase

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