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Connective Tissue Oncology Society |
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| 2001 CTOS Annual Meeting Posters— Biology IN VITRO EFFECTIVENESS
OF THE ANTINEOPLASTIC DRUG ECTEINASCIDIN-743 ON SENSITIVE AND MULTIDRUG
RESISTANT OSTEOSARCOMA CELLS OBJECTIVE: Ecteinascidin-743 (ET-743) is a highly promising antitumor agent isolated from the marine tunicate Ecteinascidia turbinate and is currently under phase II clinical investigation in Europe and the United States. Preclinical studies have shown that ET-743 is active against a variety of tumor cell lines in vitro and against several rodent tumors and human tumor xenografts in vivo at low concentrations. In this study the antitumor activity of this drug was evaluated against a panel of human osteosarcoma cell lines characterized by different drug responsiveness. METHODS: A panel of 13, P-glycoprotein negative, human osteosarcoma cell lines as well as 6 multidrug-resistant (MDR), P-glycoprotein overexpressing, variants and two methotrexate- resistant cell derivatives were analyzed in vitro to test the effectiveness of ET-743 and its mechanisms of action. The degree of sensitivity was expressed as the drug concentration resulting in 50% inhibition of growth (IC50) after 1 h or 96hr of continuous exposure to ET-743. Cell cycle analysis and Bromodeoxyuridine labeling index were obtained by flow cytometry after 24, 48 and 72 hr of drug exposure. Cell death induced by ET-743 was evaluated by Annexin-test and morphologic analysis of apoptotic nuclei. RESULTS: 12/13 osteosarcoma cell lines showed an IC50 value ranging from 0.3 to 1 nM after a long-term exposure. These concentrations are remarkably low, very well achievable in clinical conditions and indicate that osteosarcoma is particularly sensitive to ET-743. In comparable conditions, ET-743 was overall more active than doxorubicin, methotrexate and cisplatin, the three leader drugs in the treatment of osteosarcoma. Furthermore, this drug was found to be completely active against methotrexate-resistant cells and significantly overcome MDR. Cell lines showing up to 200-fold of resistance against doxorubicin, exhibit resistance levels to ET-743 lower than 10-fold. Long-term exposure produced a higher extent of inhibition than a one-hour exposure, especially on MDR cells. At IC50 doses, ET-743 appeared to have a cytostatic rather than a cytotoxic effect. Cells exposed to ET-743 progress through the cell cycle more slowly than untreated cells. No induction of apoptosis was observed at these concentrations. CONCLUSION: ET-743 appears to be very effective against osteosarcoma cell lines, both against P-glycoprotein-negative and P-glycoprotein overexpressing cells. This is particularly relevant since P-glycoprotein is a major adverse prognostic factor in this neoplasm. Therefore, ET-743 should be considered in the treatment of osteosarcoma patients.
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