Novel Microtubule-Stabilizing Reagents
Final rept. 1 Sep 2003-31 Aug 2005
COLUMBIA UNIV NEW YORK
Pagination or Media Count:
Many chemotherapeutic drugs most effective in combating breast cancer work by altering microtubule MT dynamics, i.e., MT assembly and disassembly from tubulin protomers. The taxanes, Taxol paclitaxel and Taxotere docetaxel, increase MT stability along the entire length of MTs 1. Taxanes are widely used to halt breast tumors, because they block mitosis and metastasis, and promote apoptosis, though some breast cancers are unpredictably refractory to taxanes, even at levels high enough that toxic side-effects ensue 2. We set out to test for MT- stabilizing drugs that act in all cell types and are mechanistically distinct from taxanes, as potentially promising new therapies. Also, if such a novel MT-stabilizing agents and Taxol were used in combination, tumor cells would be unlikely to escape or adapt to the effects of both, and additive or synergistic action of the two compounds would permit therapeutic regimens in which each was administered at low levels that precluded toxicity. Our initial working hypothesis was that histone deacetylation inhibitors could serve as novel MT-stabilizing agents that would work like Taxol, but via mechanisms distinct from Taxol.
- Medicine and Medical Research