Zalypsis (PM00104) is a potent inducer of gamma-H2AX foci and reveals the importance of the C ring of trabectedin for transcription-coupled repair inhibition.
Zalypsis (PM00104) is a potent inducer of gamma-H2AX foci and reveals the importance of the C ring of trabectedin for transcription-coupled repair inhibition.
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DOI：
10.1158/1535-7163.mct-09-0336
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发表时间：
2009-07
影响因子：
5.7
通讯作者：
Pommier Y
中科院分区：
文献类型：
--
作者：
Guirouilh-Barbat J;Antony S;Pommier Y
Zepiensis ®（PM 00104）是一种与trabectedin（Ecteinascidin 743; Et 743）相关的新型四氢异喹啉生物碱。Et 743和PM 00104具有相似的A环和B环，但它们的C环不同。本研究表明，Et 743和PM 00104至少在两个方面不同：在它们的DNA结合特性和细胞靶向的NER依赖性。DNA酶I足迹法显示，这两种药物结合DNA的差异。我们还发现，与Et 743相比，PM 00104的抗增殖活性不依赖于转录偶联的核苷酸切除修复（NER）。因此，PM 00104在NER缺陷或活性细胞中以相同的效率诱导γ-H2 AX灶。此外，对于PM 00104，γ-H2 AX焦点的形成是复制依赖性的，而在Et 743的情况下，它是转录和复制依赖性的。这些发现证明了四氢异喹啉海鞘素衍生物的C环结构对于NER靶向的重要性。最后，PM 00104在纳摩尔浓度下发挥抗增殖活性，并在两种尤文肉瘤细胞系中诱导γ-H2 AX应答，表明γ-H2 AX可作为PM 00104临床开发的药效学生物标志物。
Zalypsis® (PM00104) is a novel tetrahydroisoquinoline alkaloid related to trabectedin (Ecteinascidin 743; Et743). Et743 and PM00104 have similar A- and B-rings but differ in their C-rings. The present study demonstrates that Et743 and PM00104 differ in at least two ways: in their DNA binding properties and NER dependency for cellular targeting. DNase I footprinting shows that the two drugs bind DNA differentially. We also found that, in contrast to Et743, the antiproliferative activity of PM00104 does not depend on transcription-coupled nucleotide excision repair (NER). Accordingly, PM00104 induces γ-H2AX foci with the same efficiency in NER-deficient or proficient cells. Moreover, the formation of γ-H2AX foci is replication-dependent for PM00104 whereas it is both transcription- and replication-dependent in the case of Et743. These findings demonstrate the importance of the C-ring structure of tetrahydroisoquinoline ecteinascidin derivatives for NER targeting. Finally, PM00104 exerts antiproliferative activity at nanomolar concentrations and induces γ-H2AX response in two Ewing sarcoma cell lines, suggesting that γ-H2AX could serve as a pharmacodynamic biomarker for the clinical development of PM00104.