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Effectiveness of Ecteinascidin-743 against Drug-sensitive and -resistant Bone Tumor Cells¹

Laboratorio di Ricerca Oncologica, Istituti Ortopedici Rizzoli, 40136 Bologna, Italy [K. S., S. P., M. C. M., M. S., S. B., V. C., R. S., G. R-B., P. P.]; Dipartimento di Scienze Anatomiche Umane, Sezione di Fisiopatologia dell’Apparato Locomotore, Università degli Studi di Bologna, Bologna, Italy [M. M.]; Pharma Mar US, Cambridge, MA [G. F.]; and Dipartimento di Oncologia, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy [M. D.]

Purpose: The identification of new drugs is strongly needed for bone tumors.Ecteinascidin-743 (ET-743), a highly promising antitumor agent isolated from the marine tunicate Ecteinascidia turbinata, is currently under Phase II clinical investigation in Europe and the United States for treatment of soft tissue sarcoma. In this study, we analyzed the preclinical effectiveness of this drug in osteosarcoma and Ewing’s sarcoma.

Experimental Design: The effects of ET-743 were evaluated against a panel of human osteosarcoma and Ewing’s sarcoma cell lines characterized by different drug responsiveness and compared with the effects of standard anticancer agents. In addition, combination treatments with ET-743 and the other standard chemotherapy agents for sarcoma were analyzed to highlight the best drug-to-drug interaction

Results: A potent activity of ET-743 was clearly observed against both drug-sensitive and drug-resistant (multidrug-resistant, methotrexate- and cisplatin-resistant) bone tumor cells at concentrations that are easily achievable in patients (pM to nM range). Ewing’s sarcoma cells appeared to be particularly sensitive to the effects of this drug. The analysis of the effects of ET-743 on cell cycle, apoptosis, and differentiation indicated that both osteosarcoma and Ewing’s sarcoma cells had a slower progression through the different phases of the cell cycle after treatment with ET-743. However, the drug was able to induce a massive apoptosis in Ewing’s sarcoma but not in osteosarcoma cells. In the latter neoplasm, ET-743 showed a differential effect, as indicated by the significant increase in the expression and activity of alkaline phosphatase, a marker of osteoblastic differentiation. Concurrent exposure of cells to ET-743 and other chemotherapeutic agents resulted in greater than additive interactions when doxorubicin and cisplatin were used, whereas subadditive effects were observed with methotrexate, vincristine, and actinomycin D.

Conclusions: Overall, these results encourage the inclusion of this drug in the treatment of patients with bone tumors, although a careful design of new regimens is required to identify the best therapeutic conditions.

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