Ecteinascidin-743 (ET-743), a natural marine compound, with a unique mechanism of action
Ecteinascidin-743 (ET-743), a natural marine compound, with a unique mechanism of action
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DOI：
10.1016/s0959-8049(00)00357-9
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发表时间：
2001-01-01
影响因子：
8.4
通讯作者：
D'Incalci, M
中科院分区：
文献类型：
--
作者：
Erba, E;Bergamaschi, D;D'Incalci, M
Ecteinascidin-743（ET-743）是一种从Ecteinascidia turbinata中分离的海洋四氢异喹啉生物碱。其在临床前系统中显示出非常有效的抗肿瘤活性，并在I期临床试验中得到令人鼓舞的结果。ET-743作用1h后，SW 620和LoVo细胞S期进程明显减慢，并在G（2）M期聚集。G（1）期同步化细胞对ET-743的敏感性明显高于S期同步化细胞，甚至高于G（2）M期同步化细胞。通过碱性洗脱技术评估，高达IC 50值4倍的ET-743浓度未导致可检测的DNA断裂或DNA-蛋白质交联。ET-743在表达野生型（wt）（p53）的细胞系中诱导p53水平显著增加。然而，通过比较p53（-/-）或（+/+）小鼠胚胎成纤维细胞和A2780卵巢癌细胞或用显性阴性突变体TP 53转染的A2780/CX 3亚系中的药物敏感性，证明p53状态似乎与ET-743细胞毒性活性无关。ET-743的细胞毒性效力在核苷酸切除修复（NER）熟练或缺乏的CHO细胞系中进行了比较评估，并且发现ET-743在ERCC 3/XPB和ERCC 1缺陷细胞中的活性比对照细胞低约7-8倍。G（1）期细胞对ET-743敏感，而NER缺陷细胞对ET-743耐药，这表明ET-743的作用方式是独特的，不同于其他DNA相互作用药物。(C)2001年由Elsevier Science Ltd.出版
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 G(2)M phase. The sensitivity to ET-743 of G(1) synchronised cells was much higher than that of cells synchronised in S phase and even higher than that of cells synchronised in G(2)M. ET-743 concentrations up to Four times higher than the IC50 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 nas found that ET-743 was approximately 7-8 times less active in ERCC3/XPB and ERCC1-deficient cells than control cells. The findings that G(1) 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. (C) 2001 Published by Elsevier Science Ltd.