MCDB Researchers Elucidate the Mechanism of Action of DM1, an Emerging Anti-cancer Molecule
The laboratories of Dr. Mary Ann Jordan and Dr. Leslie Wilson have elucidated the mechanism of action of DM1, a synthetic derivative of the natural product maytansine, from plants of the genus Maytenus. To reduce the highly toxic side effects of the natural maytansine drug, scientists from ImmunoGen, Inc., synthesized DM1 and attached it to antibodies that specifically target cancer cells of various types. Eight drugs comprised of antibodies linked to DM1 are now in clinical trials and show as much as 100% shrinkage of the targeted tumor. However, how DM1 kills cancer cells remained unknown. In two studies published in the October issue of Molecular Cancer Therapeutics, the team showed that DM1 works by targeting microtubules, the filamentous proteins that helps cells to divide and multiply. With postdoctoral students Dr. Manu Lopus and Dr. Emin Oroudjev, they found how the antibody-linked DM1 enters cancer cells, is metabolized, and the metabolites bind the growing tips of dynamic microtubules, suppressing their natural ability to grow and shorten, a behavior essential for constructing a functional spindle and completing mitosis. Cell cycle arrest in mitosis ultimately leads to killing of the cancer cells by apoptosis.