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 tetrahydroisoquinoline 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 progress through S phase more slowly than control cells and then accumulate in the G2M phase. The sensitivity to ET-743 of G1 synchronised cells was much higher than that of cells synchronised in S phase and even higher than that of cells synchronised in G2M. ET-743 concentrations up to four times higher than the IC(50) value caused no detectable DNA breaks or DNA-protein 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 p53 (-/-) 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 lines proficient or deficient in nucleotide excision repair (NER), and it was found that ET-743 was approximately 7-8 times less active in ERCC3/XPB and ERCC1-deficient cells than control cells. The findings that G1 phase cells 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 that of other DNA-interacting drugs.
Erba
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Department of Oncology, Istituto di Ricerche Farmacologiche 'Mario Negri' Via Eritrea 62, 20157, Milan, Italy. erba@marionegri.it
Bergamaschi
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Bassano
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Damia
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Ronzoni
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Faircloth
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D'Incalci
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D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016213:Cyclins / Q000378:metabolism; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000032:analysis; D004149:Dioxoles / Q000494:pharmacology / Q000627:therapeutic use*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology / Q000627:therapeutic use*; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; D014407:Tumor Cells, Cultured / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D018906:Antineoplastic Agents, Alkylating; D016213:Cyclins; D004273:DNA, Neoplasm; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D016159:Tumor Suppressor Protein p53; D000077606:Trabectedin