A Comparative Study of Maytansine and a Derivative, Maysine

Abstract

Maytansine, an ansa macrolide now in clinical trial with significant antitumor activity against a variety of rodent neoplasms, was compared in several experimental systems with maysine, a structural congener lacking the ester side-chain of C-3. The effects of both drugs on cell growth, mitotic index, cell survival and tubulin-binding activity were examined in vitro. Maytansine was found to be about 100 times more potent in inhibiting the growth of L1210 cells in culture and more potent as a mitotic inhibitor. Maytansine also exhibited greater cytotoxicity in cell cloning assays after a 2-48 hr exposure. It also was shown that both maytansine and maysine bound to crude rat brain tubulin using a Sephadex column technique, and that maytansine competed with vinblastine but not colchicine for a common binding site on tubulin. The results suggested that the relative lack of potency observed for maysine was due to the absence of the ester side chain, which may have affected its uptake by cells and/or its interaction with tubulin. Due to a supply problem, it was not possible to quantify or characterize the binding characteristics of maysine to tubulin.