Nature's Lessons to Design an Effective, Rational and Selective Drug for Soft Tissue Sarcoma Treatment: The Ecteinascidins

Soft tissue sarcomas (STSs) belong to a rare, heterogeneous family of malignancies of mesenchymal origin. Inoperable or metastatic sarcomas typically show low responsiveness to conventional chemotherapy probably due to overexpression of several genes related to cell cycle control, cell maintenance, and DNA repair. The ecteinascidins (ETs) are potent and selective antitumor agents isolated from marine tunicades from the Caribbean, Ecteinascidia turbinate. Of the numerous ETs that have been isolated, ET-743 (Yondelis™, Trabectedin™) is the most promising compound for treatment of STSs. ET-743 is an alkaloid composed of three fused tetrahydroisoquinoline rings (A, B and C subunits) and is structurally related to the DNA-reactive saframycins. While the A and B subunits of ET-743 provide the scaffold for DNA recognition and binding, the C subunit makes only limited contacts with DNA. It has been proposed that ET-743 can also bind to the major endonucleases involved in base (BER) and nucleotide (NER) excision DNA repair, resulting in cytotoxic DNA-ET-743-protein ternary complexes. Interestingly, absence of the C subunit in the ET molecule results in distinct pharmacological activities when compared to ET-743 and could lead to the design of more potent and selective ET-derived drugs for STSs treatment.