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Effectiveness of Ecteinascidin-743 against drug-sensitive and -resistant bone tumor cells
Katia Scotlandi1, Stefania Perdichizzi, Maria Cristina Manara
1Laboratorio di Ricerca Oncologica, Istituti Ortopedici Rizzoli, 40136 Bologna, Italy. katia.scotlandi@ior.it
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.
Insights
Ecteinascidin-743 (ET-743) shows potent activity against drug-resistant bone tumors, particularly Ewing's sarcoma. Further research is needed to optimize its use in new treatment regimens for bone cancers.
Area of Science:
- Oncology
- Pharmacology
- Marine Biotechnology
Background:
- New drug development is crucial for treating bone tumors.
- Ecteinascidin-743 (ET-743), derived from marine tunicate Ecteinascidia turbinata, is a promising antitumor agent.
- ET-743 is currently in Phase II clinical trials for soft tissue sarcoma.
Purpose of the Study:
- To evaluate the preclinical efficacy of ET-743 against osteosarcoma and Ewing's sarcoma.
- To assess ET-743's activity in both drug-sensitive and drug-resistant bone tumor cell lines.
- To investigate potential drug-drug interactions between ET-743 and standard chemotherapy agents.
Main Methods:
- ET-743's effects were tested on human osteosarcoma and Ewing's sarcoma cell lines with varying drug responsiveness.
- Comparative analysis was performed against standard anticancer agents.
- Combination treatments of ET-743 with other chemotherapy drugs were analyzed for synergistic or antagonistic effects.
Main Results:
- ET-743 demonstrated potent activity against drug-sensitive and resistant bone tumor cells at achievable patient concentrations (pM to nM).
- Ewing's sarcoma cells were particularly sensitive. ET-743 induced cell cycle arrest and massive apoptosis in Ewing's sarcoma, but not osteosarcoma.
- In osteosarcoma, ET-743 promoted osteoblastic differentiation. Synergistic effects were observed with doxorubicin and cisplatin combinations, while methotrexate, vincristine, and actinomycin D showed subadditive interactions.
Conclusions:
- ET-743 exhibits significant preclinical efficacy against bone tumors, including drug-resistant types.
- The drug's distinct mechanisms in osteosarcoma (differentiation) and Ewing's sarcoma (apoptosis) warrant further investigation.
- These findings support the potential inclusion of ET-743 in bone tumor treatment, necessitating careful regimen design for optimal therapeutic outcomes.