2006 Jul;18
ET-743: a novel agent with activity in soft-tissue sarcomas.
Fayette J, Coquard IR, Alberti L, Boyle H, Meeus P, Decouvelaere AV, Thiesse P, Sunyach MP, Ranchere D, Blay JY.
aHopital Edouard Herriot, Service d'oncologie medicale, France bCentre Leon Berard, France cINSERM U590, Centre Leon Berard, Lyon, France.
PURPOSE OF REVIEW: ET-743 (ecteinascidin-743, trabectedin, Yondelis) is a natural marine product that has shown clinical activity in sarcoma. This paper reviews the current knowledge on this compound. RECENT FINDINGS: ET-743 interferes with several transcription factors, traps protein from the nucleotide-excision repair system, thus resulting in DNA damage, modulates gene expression, and blocks cells in the G2-M phase. In the clinical setting, after failure of standard treatment, ET-743 at 1.5 mg/m in 24 h continuous infusion every 21 days yielded an overall response rate close to 8% and stabilization rates of 30-40%, some lasting beyond 3 years. Leiomyosarcomas, liposarcomas, and synovial sarcomas may be the more sensitive histotypes. The major toxicities of ET-743 are hepatic - through biliary duct destruction - and hematologic. They are not cumulative and a significant number of patients may receive 12 courses or more. In a randomized Phase II study testing weekly ET-743 with treatment every 3 weeks, an improved progression-free survival rate was observed in the 3-weekly arm; the results of the follow-up Phase III trial should be available at the American Society of Clinical Oncology meeting of 2006. Phase I combination studies are in currently progress. SUMMARY: ET-743 is a novel active drug for sarcoma which yields prolonged disease-free survival in subsets of patients.
.Maki del Memorial sloan Cancer lo explica mejor que yo http://www.mskcc.org/mskcc/html/62455.cfm :
Early trials found that the response rate to ET-743 is low, with only about ten percent of tumors showing significant shrinkage. "But in two of the most common types of sarcoma, the drug occasionally works brilliantly," Dr. Maki said. These types are leiomyosarcoma (tumors of smooth muscle) and liposarcoma (tumors that originate in fat cells). The drug works by binding to the minor groove of DNA, thus changing the DNA's configuration and altering gene transcription.
"This drug really stands out as a novel agent for the treatment of sarcoma because it is a natural product," Dr. Maki said, explaining that most other sarcoma drugs currently in development are tyrosine-kinase targeted therapies. ET-743 is currently in trials designed to determine the best way to administer the drug as a single agent, and investigators have begun evaluating it in combination with other drugs -- including the natural products paclitaxel and doxorubicin (Adriamycin®).