LU103793 (NSC D-669356) - A SYNTHETIC PEPTIDE THAT INTERACTS WITH MICROTUBULES AND INHIBITS MITOSIS

LU103793 (NSC D-669356) is a new synthetic derivative of Dolastatin 15 , an antiproliferative compound which was isolated from the mollusk Do labella auricularia, Like Dolastatin 15, LU103793 is highly cytotoxic in vitro (IC50 = 0.1 nM). To investigate the mechanism of action of LU 103793, we used a combination of biochemical and cellular methods, Tur bidity assays with bovine brain microtubules demonstrated that LU10379 3 inhibits microtubule polymerization in a concentration-dependent man ner (IC50 = 7 mu M). Treatment with this compound also induced depolym erization of preassembled microtubules. Cell cycle analysis of tumor c ell lines treated with LU103793 indicated a block in the G(2)-M phase. At the cellular level, it induced depolymerization of microtubules in interphase cells and development of abnormal spindles and chromosome distribution in mitotic cells. Although these effects are very similar to the cellular alterations caused by vinblastine, LU103793 does not inhibit vinblastine binding to unpolymerized tubulin in vitro, Our res ults suggest that LU103793 exerts its cytotoxic activity primarily thr ough disruption of microtubule organization.