DNA and non-DNA targets in the mechanism of action of the antitumor drug trabectedin

被引：57

作者：

David-Cordonnier, MH

Gajate, C

Olmea, O

Laine, W

de la Igiesia-Vicente, J

Perez, C

Cuevas, C

Otero, G

Manzanares, I

Bailly, C

Mollinedo, F

机构：

[1] Univ Salamanca, Ctr Invest Canc, Inst Biol Mol & Celular Canc, CSIC, E-37007 Salamanca, Spain

[2] INSERM, U 524, F-59045 Lille, France

[3] IRCL, Lab Pharmacol Antitumorale, F-59045 Lille, France

[4] IRCL, Ctr Oscar Lambret, F-59045 Lille, France

[5] Hosp Univ Salamanca, Unidad Invest, E-37007 Salamanca, Spain

[6] PharmaMar, E-28770 Madrid, Spain

来源：

CHEMISTRY & BIOLOGY | 2005年 / 12卷 / 11期

关键词：

D O I：

10.1016/j.chembiol.2005.08.009

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

We have analyzed the DNA binding properties of the antitumor agent trabectedin (ET-743, Yondelis) and different analogs, namely, ET-745, lacking the C21-hydroxyl group, and ET-637, ET-594, ET-637-OBu, with modifications at the trabectedin C domain, versus their effects on cell cycle, apoptosis, and gene expression. ET-745 failed to bind DNA, highlighting the importance of the C21-hydroxyl group for DNA binding. Analogs ranked trabectedin >> ET-637 ET-594 > ET-637-013u >> ET-745 for their DNA binding capacity; ET-637 and ET-594 display very different biological activities. Drugs were clustered in three major groups showing high (trabectedin, ET-637), intermediate (ET-637-OBu), and low (ET-594, ET-745) cytotoxic activity and similar transcriptional profiling responses. C21-hydroxyl-deficient analogs of the above-mentioned compounds showed a dramatic decrease in biological activity. Our data suggest that trabectedin interacts with an additional non-DNA target to raise an effective antitumor response, and that this interaction is favored through trabectedin-DNA complexes.

引用

页码：1201 / 1210

页数：10

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