Ecteinascidin-743 (ET-743), a natural marine compound, with a unique mechanism of action

The mode of action of Ecteinascidin-743 (ET-743), a marine tetrahydroisoqui noline alkaloid isolated from Ecteinascidia turbinata. which has shown very potent antitumour activity in preclinical systems and encouraging results in Phase I clinical trials was investigated at a cellular level. Both SW620 and LoVo human intestinal carcinoma cell lines exposed For 1 h to ET-743 p rogress through S phase more slowly than control cells and then accumulate in the G(2)M phase. The sensitivity to ET-743 of G(1) synchronised cells wa s much higher than that of cells synchronised in S phase and even higher th an that of cells synchronised in G(2)M. ET-743 concentrations up to Four ti mes higher than the IC50 value caused no detectable DNA breaks or DNA-prote in cross-links as assessed by alkaline elution techniques. ET-743 induced a significant increase in p53 levels in cell lines expressing wild-type (wt) (p53). However, the p53 status does not appear to be related to the ET-743 cytotoxic activity as demonstrated by comparing the drug sensitivity in p5 3 (-/-) or (+/+) mouse embryo fibroblasts and in A2780 ovarian cancer cells or the A2780/CX3 sub-line transfected with a dominant-negative mutant TP53 . The cytotoxic potency of ET-743 was comparatively evaluated in CHO cell l ines proficient or deficient in nucleotide excision repair (NER), and it na s found that ET-743 was approximately 7-8 times less active in ERCC3/XPB an d ERCC1-deficient cells than control cells. The findings that G(1) phase ce lls are hypersensitive and that NER-deficient cells are resistant to ET-743 indicate that the mode of action of ET-743 is unique and different from th at of other DNA-interacting drugs. (C) 2001 Published by Elsevier Science L td.