
Ecteinascidin-743 (ET-743) is a tetrahydroisoquinoline alkaloid isolated from Ecteinascidia turbinata, a tunicate growing in mangrove roots in Caribbean, which exhibits potent antitumor activity.  [Future supplies of ecteinascidins will probably be available from synthesis or aquaculture.]  [3, 6]

It binds to the minor groove of DNA, distorting the shape of the molecule by bending the DNA toward the major groove. [10]  The binding of ET-743 to DNA was abolished when guanines were substituted with inosines.  This suggests that ecteinascidin 743 is a novel DNA minor groove, guanine-specific alkylating agent. [8]
It might also prevent DNA copying and reproduction in other ways.  A mode of action of ET-743 might be related to its ability to modify the interaction between some DNA binding proteins and DNA. [6].  Ecteinascidin 743 disorganizes the microtubule network as well.[7] Previous studies [in vitro and phase I] suggest potent cytotoxic activity of ET-743 in some mesenchymal tumors.  Because of this, phase II clinical trials have been instigated to look at the effectiveness of ET-743 against sarcomas. [4]

"6 of 10 evaluable pts (60%) in the upfront study have exhibited stable disease or minor response after 2 cycles of therapy, as have 4 of 12 evaluable pts (33%) with prior CT. Preliminary evidence of clinical activity has been observed in liposarcoma, leiomyosarcoma, and synovial sarcoma. ... We conclude from these ongoing trials that ET-743 represents an extremely promising agent for the management of several histologic subtypes of STS."[4] 

The EORTC phase trial with ET 743 treated GIST patients and advanced sarcoma patients.  
There were no responses in the GIST arm.  
There was an overall response rate of 11% in the 2nd line sarcoma arm The median time to progression was 3 months, and median survival 7 months.  This compares favorably with other drugs tested as second line chemotherapy agents. [2]

" We report the results of an ongoing multicenter Phase II study assessing activity and safety of ET-743 in [Pretreated ] STS pts, given at 1500 mcg/mē by [24 hour intravenous continuous infusion every] 3 weeks.  ["The pharmacology of ET-743 supports its use as a 3-h IV infusion, and that study is now active in STS."] [5, 9]

Since 2/98, 50 PSTS pts have been enrolled. ... Twenty-two pts (44%) had leiomyosarcoma (10 uterine origin) and 3 pts (6%) GIST. Thirteen pts (26%) had bulky disease (at least 1 mass greater than 10cm) and 14 pts (28%) had liver metastasis.   All but one had previously received anthracyclines (A).  20 pts (40%) were considered refractory to anthracycline treatment (A-R) (PD as best response under last A regimen). Median number of prior chemotherapies: 2 (2-5)."  [5] 

48 pts were evaluable for response.  6% had a partial response, 12% had a minor response [tumor reduction between 25 and 50%, and 34% had stable disease, all were clinically significant.
Median duration of Partial Response was 7.6 months.
Median duration of Minor Response was 3.8 months.
Median duration of Stable Disease was 5.1 months.
Responses were seen in liver, bulky tumors and anthracycline resistant tumors, as well.
52% of this group had some degree of nonprogression of the disease.
Median overall time to progression was 2.6 months and median overall survival was 10.7 months.

Progression free survival rate was 18% and overall survival rates at 1 year were 49% for the first-line study, and 11% and 55% for the prior chemotherapy study. The conclusion was that "ET-743 yields durable disease control and objective responses in a subset of pts with a variety of STS histologies."  [9]  "... a randomized study is planned to assess the survival benefit associated with ET-743 therapy." [9]

 
<b>Side effects</b>: [1, 2, 4, 5, 9]
No hair loss, and no severe GI toxicity.  Nausea has been essentially eliminated by incorporating dexamethasone into a prophylactic antiemetic regimen. 
Liver transaminases enzymes had a grade 3 to 4 temporary elevation in 32% of subjects
Low white count with fever in <5% of subjects
Low white count grade 3 to 4  in  45% of subjects
Low platelet count grade 3 to 4   in 27% of subjects
Nausea grade 2-3 in 17%
Vomiting grade 2-3 in 11%
Fatigue grade 2-3 in 32%
Toxic Deaths of 4 subjects, possibly related to low level cholangitis [gall bladder inflammation].
