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

AuthorsDavid-Cordonnier, Marie-Hélène; Gajate, Consuelo; Iglesia-Vicente, Janis de la; Mollinedo, Faustino
Issue Date2005
CitationChemistry and Biology 12(11): 1201-1210 (2005)
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.
Identifiersdoi: 10.1016/j.chembiol.2005.08.009
issn: 1074-5521
Appears in Collections:(IBMCC) Artículos
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