ECTEINASCIDIN 743 (Yondelis®, ET-743)

Molecular Weight: 761.84 g/mol
Molecular Formula: C39H43N30O11S

Source: The tunicate Ecteinascidia turbinata (CHORDATA)
Activity: Anti-cancer agent via apoptosis induction
Status: Phase II Clinical Trials, European Orphan Drug Designation against soft tissue sarcoma (see below).


Ecteinascidin 743 (ET-743; Etrabectedin) was isolated from the Caribbean sea squirt (Ascidia) Ecteinascidia turbinata, a common component of the intertidal/subtidal mangrove prop root community. It is classified as a tetrahydroisoquinoline alkaloid.

Preclinical trials showed ET-743 was active against a range of tumor types in standard animal models. Subsequent human trials showed efficacy against advanced soft tissue sarcoma, osteosarcoma and metastatic breast cancers. In Phase I human clinical trials the drug showed effectiveness against advanced-stage breast, colon, ovarian and lung cancers, melanoma, mesothelioma and several types of sarcoma. Phase II studies with ET-743 are currently being conducted in the United States and four other countries.

Research into the mode of action of ET-743 has revealed that binding of the drug to target cell DNA inhibits cell division and leads to apoptosis of cancer cells. Setting the drug apart from others that trigger 'cell suicide' mechanisms is the fact that ET-743 induces apoptosis only during active gene transcription. This makes actively dividing cancer cells more vulnerable to drug toxicity than normal cells because they exhibit greatly accelerated transcription and translation rates.

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 Ortho Biotech. 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.


NCBI PubChem compound summary page - [ LINK ]

NCBI PubMed biomedical literature citations and abstracts - [ LINK ]


References

Kijjoa A and P Sawangwong. 2004. Drugs and cosmetics from the sea (review paper). Mar. Drugs 2004:73-82.

Bonetta, L. 2001. Anticancer squirt. Nature Medicine 7: 891.

Takebayashi, Y., Pourquier, P., Zimonjic, D.B., Nakayama, K., Emmert, S., Ueda, T., Urasaki, Y., Kanzaki, A., Akiyama, S., Popescu, N., Kraemer, K. H., and Y. Pommier. 2001. Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair. Nature Medicine 7:961-966.