A Review of Trabectedin (ET-743): A Unique Mechanism of Action

Abstract

Trabectedin (ET-743) is a marine alkaloid isolated from the Caribbean tunicate Ecteinascidia turbinata, with a chemical structure characterized by three fused tetrahydroisoquinoline rings. Two of these rings (subunits A and B) provide the framework for covalent interaction with the minor groove of the DNA double helix, whereas the third ring (subunit C) protrudes from the DNA duplex, apparently allowing interactions with adjacent nuclear proteins. The compound's chemical interactions trigger a cascade of events that interfere with several transcription factors, DNA binding proteins, and DNA repair pathways, likely to be different from other DNA-interacting agents. Trabectedin also causes modulation of the production of cytokines and chemokines by tumor and normal cells, suggesting that the antitumor activity could also be ascribed to changes in the tumor microenvironment. The promising data on the combination of trabectedin with other anticancer agents, observed in preclinical systems, have prompted several clinical studies that are currently ongoing. One of these combinations (trabectedin-pegylated liposomal doxorubicin) was recently authorized by the European Commission for the treatment of patients with relapsed platinum-sensitive ovarian cancer.

Antiangiogenic activity of trabectedin in myxoid liposarcoma: Involvement of host TIMP‐1 and TIMP‐2 and tumor thrombospondin‐1

“…1 It has been approved in Europe for the treatment of advanced or metastatic soft tissue sarcoma and relapsed ovarian cancer, and is currently undergoing phase II trials for several other tumors.…”

“…It binds to N2 of guanine in the minor groove of DNA and interacts with DNA-binding proteins such as DNA repair proteins and transcription factors. 1 It affects transcription regulation in a gene-and promoter-dependent fashion in both cancer and normal cells (i.e., macrophages). [1][2][3][4] As a result trabectedin has a dual antineoplastic effect.…”

Trabectedin – the DNA minor groove binder

“…Трабектедин блокирует транскрипционную активность экспресси-руемого химерным геном белка EWS-FLI1, который регулирует более 70 генов. Клетки других соедини-тельнотканных опухолей -остеосарком, рабдомио-сарком и синовиальных сарком, не имеющие этой аномалии, значительно более резистентны к трабек-тедину [5,24]. Среди эпителиальных опухолей сочета-ние низкой активности гомологичной рекомбинации с сохранением TC-NER имеют некоторые формы рака молочной железы (РМЖ) и яичников.…”

“…Высокий уровень экспрессии CUL4A в клетках сарком с нарушенной системой гомологичной рекомбинации коррелирует с положительным прогнозом при их лечении трабек-тедином [5,42,43].…”

“…Преимущественными сайтами связывания являются триплеты TGG, CGG, AGC и GGC, но не CGA (рис. 2) [5]. Анализ аддуктов тра-бектедина на ДНК показал, что в триплетах он связы-вается с тем же гуанином, что и цинковый палец транскрипционных факторов типа EGR1, активиру-ющих экспрессию пропролиферативных и провоспа-лительных генов [6].…”