High-Affinity Accumulation of a Maytansinoid in Cells via Weak Tubulin Interaction

摘要: The microtubule-targeting maytansinoids accumulate in cells and induce mitotic arrest at 250- to 1000-fold lower concentrations than those required for their association with tubulin or microtubules. To identify the mechanisms of this intracellular accumulation exceptional cytotoxicity we studied interaction a highly cytotoxic maytansinoid, S-methyl DM1 several other cells. accumulated inside markedly higher apparent affinity affinities correlated cytotoxicities. number binding sites MCF7 was comparable molecules per cell (~ 4–6 × 107 copies). Efflux 3 [H]-S-methyl from enhanced presence an excess non-labeled DM1, indicating that re-binding contributed its retention. Liposomes loaded non-polymerized recapitulated high-affinity We propose model which compounds diffuse into associate tubulin. Affinities individual are weak, but high concentration favors, after dissociation compound-tubulin complex, molecule, tip microtubule same cell, over efflux. As result, significant fraction tips is occupied maytansinoid when added sub-nanomolar concentrations, inducing death.