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The Oncologist, Vol. 10, No. 10, 827-832, November 2005; doi:10.1634/theoncologist.10-10-827
© 2005 AlphaMed Press

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ET-743: A Novel Agent with Activity in Soft Tissue Sarcomas

Jérôme Fayettea,b, Isabelle Ray Coquarda, Laurent Albertia, Dominique Ranchèrea, Helen Boylea, Jean-Yves Blaya,b

a Hôpital Edouard Herriot, Medical Oncology Department, Lyon, France; b INSERM U590, Centre Léon Bérard, Lyon, France

Key Words. Sarcoma • Ecteinascidin-743 • Cytotoxic • First-line treatment

Correspondence: Jean-Yves Blay, M.D., Ph.D., Hôpital Edouard Herriot, Service d’oncologie médicale, Pavillon E, 5 place d’Arsonval, 69003 LYON, France. Telephone: 33-4-72-11-73-98; Fax: 33-4-72-11-73-28; e-mail: blay{at}lyon.fnclcc.fr

Ecteinascidin-743 (ET-743) is a natural product derived from the marine tunicate Ectenascidia turbinate. ET-743 binds in the minor groove of DNA, blocks transcription factors activity, and traps protein from the nucleotide excision repair system, thus blocking cells in G2-M phase. ET-743 demonstrated cytotoxic activity at very low concentrations against sarcoma cell lines in pre-clinical studies. In several phase II clinical studies in patients with advanced sarcoma failing conventional doxorubicin- and ifosfamide-based chemotherapy, ET-743 delivered by continuous intravenous 24-hour infusion at a dose of 1,500 µg/m2 every 21 days yielded 8% overall response and 30%–40% stabilization rates for a clinical benefit rate close to 40%. Interestingly, long-term stabilizations over more than 3 years have been described. In vivo, ET-743 has a specific toxicity profile, the major toxicity of this product being hepatic, through biliary duct destruction, and hematologic. ET-743 has also been evaluated in first-line treatment for these patients. Finally, due to its original mode of action and the lack of cross-resistance with other chemotherapy agents, ET-743 was tested in a preclinical model in combination with other drugs. Synergy was reported in vitro with doxorubicin and cisplatin; phase I combination studies are in progress.




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 Proc. Natl. Acad. Sci. USAHome page
D. G. Soares, A. E. Escargueil, V. Poindessous, A. Sarasin, A. de Gramont, D. Bonatto, J. A. P. Henriques, and A. K. Larsen
From the Cover: Replication and homologous recombination repair regulate DNA double-strand break formation by the antitumor alkylator ecteinascidin 743
PNAS, August 7, 2007; 104(32): 13062 - 13067.
[Abstract] [Full Text] [PDF]


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