ET-743

Ecteinascidin-743 of ET-743, ook gekend als trabectedine is een tetrahydroisoquinoline alkaloïde gevonden in de mangrove zakpijp [Ecteinascidia turbinate ] afkomstig uit de Caribische en Middellandse zee. Het geneesmiddel is op de markt verkrijgbaar onder de naam Yondelis®), en werd ontwikkeld door het Spaanse marine pharmaceutica bedrijf PharmaMar in samenwerking Centocor Ortho Biotech Inc. Het is een uniek kankerbestrijdend middel dat interageert met de DNA synthese van tumors en toont zijn beste resultaten in de bestrijding van darm, borst, long, hersen en eierstok kanker.

Werking

It was found that ET-743 prevents the formation of P-glycoprotein, a protein associated with multidrug-resistant tumours [10]. P-glycoprotein is a membrane protein that transports toxins such as chemotherapy agents out of the cancer cells, preventing the chemotherapy drugs from destroying the tumour. By interfering with that process, ET-743 may keep the tumour cells vulnerable to chemotherapy. Even if ET-743 is not proven effective on its own, it may become a key ingredient in chemotherapy “cocktails” to prevent tumours from developing resistance to drugs currently used.

The MOA of this potent antitumor compound is based on its ability to mediate the interaction between cellular DNA and various transcription factors and other proteins. ET-743 is also affective as an inhibitor of DNA synthesis, capable of arresting the cell cycle and inducing p53-independent apoptosis in target cells. The compound also exhibits tubulin interactive bioactivity. Preclinical in vitro screens indicated ET-743 was most active against cancers in colon, breast, lung, brain, and ovarian cell lines.

Ecteinascidin 743 also may hold promise in keeping tumors from becoming resistant to chemotherapy. Ecteinascidin 743 interferes with the gene that produces P-glycoprotein, a membrane protein that confers drug resistance on cancer cells by actively transporting toxic compounds (like drug therapies) out of the cells. Such activity suggests that ET-743 may become important as a key ingredient in multi-drug 'cocktails' if it can prevent target cells from developing resistance to the other drug therapies ET-743 has been co-developed under the trade name Yondelis® by the Spanish marine pharmaceutical company PharmaMar and Johnson & Johnson subsidiary Centocor Ortho Biotech Inc.. The drug is well along in Phase II clinical trials. The company reports that Yondelis is the first new drug in 20 years that is effective against soft tissue sarcoma (STS) a rare but pernicious form of cancer. In 2001, Yondelis obtained Orphan Drug Designation for the treatment of STS in Europe.

Yondelis® (Trabectedin, ET-743), is a unique anticancer agent that binds the minor groove of DNA. Extracts of E. turbinata were shown to have antitumour effects in 1969, but isolation of the active compound was not achieved until 1990. Phase I and II clinical trials were carried out using material derived from aquaculture, but this was not deemed feasible for the larger phase III trials. For this reason, an economically viable semisynthetic process was developed starting with the natural product safracin B isolated from the microorganism Pseudomonas fluorescens. Pharmamar received approval to market Yondelis® in Europe in September 2007 for the treatment of soft tissue sarcoma and this was the first drug to be approved for this condition for more than 25 years.

Figuur 1: Chemische structuur van ET-743

Oorsprong & Ontwikkeling

De ecteinascidines zijn een family van alkaloide stoffen die geisoleerd worden uit de de mangrove zakpijp [Ecteinascidia turbinate ]. ET-743 in het bijzonder toonde zowel sterke bioactiviteit als hoge concentraties in het organisme in vergelijking met andere ecteinascidines, wat een extra motivatie was voor verder onderzoek van deze stof. Reeds in 1969 werd aangetoont dat extracten uit [Ecteinascidia turbinate ] anti-tumor (zie: antineoplastisch) wekingen hadden, maar identificatie en extractie van de stof (ET-743) liet op zich wachten tot 1990. Vroeg onderzoek gebeurde op basis van ET-743 bekomen uit aquacultuur van [Ecteinascidia turbinate ], maar om voldoende voorraad te hebben voor verder onderzoek moest eerst een semi syntetisch alternatief opgesteld worden. Kunstmatige synthese van ET-743 gebeurt nu vertrekkend van safracine B, een stof geisoleerd uit een eenvoudig te kweken microorganisme (Pseudomonas fluorescens). Phase I and II clinical trials were carried out using material derived from aquaculture, but this was not deemed feasible for the larger phase III trials. For this reason, an economically viable semisynthetic process was developed starting with the natural product safracin B isolated from the microorganism Pseudomonas fluorescens. ET-743 kwam in 2007 op de Europese markt als behandeling tegen weke delen sarcoma onder de naam Yondelis®.

Figuur 2: De mangrove zakpijp ( Ecteinascidia turbinata )