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Cancer Chemotherapy and Pharmacology

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14.12.2015 | Review Article

Unique features of trabectedin mechanism of action

verfasst von: Annette K. Larsen, Carlos M. Galmarini, Maurizio D’Incalci

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 4/2016

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Abstract

Trabectedin (Yondelis^®, ET-743) is a marine-derived natural product that was initially isolated from the marine ascidian Ecteinascidia turbinata and is currently prepared synthetically. Trabectedin is used as a single agent for the treatment of patients with soft tissue sarcoma after failure of doxorubicin or ifosfamide or who are unsuited to receive these agents, and in patients with relapsed, platinum-sensitive ovarian cancer in combination with pegylated liposomal doxorubicin. Trabectedin presents a complex mechanism of action affecting key cell biology processes in tumor cells as well as in the tumor microenvironment. The inhibition of trans-activated transcription and the interaction with DNA repair proteins appear as a hallmark of the antiproliferative activity of trabectedin. Inhibition of active transcription is achieved by an initial direct mechanism that involves interaction with RNA polymerase II, thereby inducing its ubiquitination and degradation by the proteasome. This subsequently modulates the production of cytokines and chemokines by tumor and tumor-associated macrophages. Another interesting effect on activated transcription is mediated by the displacement of oncogenic transcription factors from their target promoters, thereby affecting oncogenic signaling addiction. In addition, it is well established that DNA repair systems including transcription-coupled nucleotide excision repair and homologous recombination play a role in the antitumor activity of trabectedin. Ongoing studies are currently addressing how to exploit these unique mechanistic features of trabectedin to combine this agent either with immunological or microenvironmental modulators or with classical chemotherapeutic agents in a more rational manner.

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Titel: Unique features of trabectedin mechanism of action
verfasst von: Annette K. Larsen
Carlos M. Galmarini
Maurizio D’Incalci
Publikationsdatum: 14.12.2015
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 4/2016
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-015-2918-1

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Springer Medizin

Unique features of trabectedin mechanism of action

Abstract

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