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dc.contributor.authorDavid-Cordonnier, Marie-Hélène-
dc.contributor.authorGajate, Consuelo-
dc.contributor.authorIglesia-Vicente, Janis de la-
dc.contributor.authorMollinedo, Faustino-
dc.identifierdoi: 10.1016/j.chembiol.2005.08.009-
dc.identifierissn: 1074-5521-
dc.identifier.citationChemistry and Biology 12(11): 1201-1210 (2005)-
dc.description.abstractWe 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-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. ©2005 Elsevier Ltd All rights reserved.-
dc.description.sponsorshipThis work was supported by grants from Fondo de Investigación Sanitaria and European Commission (FIS04/0843, FIS02/1199), Fundación de Investigación Médica Mutua Madrileña (FMM), Fundación ‘‘la Caixa’’ (BM05-30-0), Junta de Castilla y León (CSI04A05) (to F.M.) C.G. was supported by the Ramón y Cajal Program from the Ministerio de Educación y Ciencia of Spain. -
dc.titleDNA and non-DNA targets in the mechanism of action of the antitumor drug trabectedin-
dc.description.versionPeer Reviewed-
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