| Literature DB >> 16298299 |
Marie-Hélène David-Cordonnier1, Consuelo Gajate, Osvaldo Olmea, William Laine, Janis de la Iglesia-Vicente, Carlos Perez, Carmen Cuevas, Gabriel Otero, Ignacio Manzanares, Christian Bailly, Faustino Mollinedo.
Abstract
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 approximately ET-594 > ET-637-OBu >> 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.Entities:
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Year: 2005 PMID： 16298299 DOI： 10.1016/j.chembiol.2005.08.009
Source DB: PubMed Journal: Chem Biol ISSN： 1074-5521