Cytotoxic agent - ecteinascidin 743
The natural world is a rich source of drug lead compounds, and highly potent anticancer agents in particular are commonly extracted from nature. One such compound, being developed by Pharma Mar and licensed to the Johnson & Johnson company Ortho Biotech, is ecteinascidin 743, or ET-743. Isolated from the marine invertebrate Caribbean tunicate Ecteinascidia turbinata, the tetrahydroquinoline alkaloid shows promise against a range of tumour types, including lung, breast and ovarian cancer, and melanoma.
Its mechanism of action is thought to be by DNA minor groove alkylation, which induces topoisomerase I mediated protein linked DNA strand breakage. Its cytotoxic effects have been compared with methotrexate, doxorubicin, etoposide and paclitaxel in eight different human soft tissue sarcoma cell lines.1 ET-743 was shown to be more potent than any of these commonly used agents in all of the cell lines tested. In a Phase I study in 40 patients with solid tumours, ET-743 was administered by infusion every 21 days at nine dose levels from 50-1100 µg/m2. Thrombocytopoenia and fatigue were the dose limiting toxicities.
A Phase II trial has been carried out on 26 patients with advanced or metastatic breast cancer. They were given a median of three treatment cycles of the drug, with 1,500µg/m2 being administered by 24 hour continuous infusion. Seven of the 24 evaluable patients showed a partial response, and 11 patients had their disease stabilised for between two and 11 months.2 A further Phase II trial in 47 patients with advanced soft tissue sarcoma has been carried out, using a similar dosing regime. Of the 29 patients evaluated, three had a partial response, two a minor response, nine no change and 12 progressive disease. Toxicity problems were observed, but these were reduced by reducing the dose to 1,200µg/m2.3 Phase II/III trials are now under way, with the drug being administered as a single infusion every 21 days. Because of the associated side-effects, a further trial is being carried out, with patients being given doses of between 300 and 650µg/m2 ET-743 as a 3 hour i.v. infusion every week for three weeks out of four in patients with advanced cancer. Initial results indicate that this dosing regime may have an improved therapeutic effect.4 The novel antineoplastic DNA binding agent has been awarded orphan drug status by EMEA for the treatment of soft tissue sarcoma.