Effective combination of ET-743 and doxorubicin in sarcoma: preclinical studies

Cancer Chemotherapy and Pharmacology
Daniela MecoRiccardo Riccardi

Abstract

To investigate the cytotoxic and antitumor effects of the combination of the novel anticancer drug ET-743 and doxorubicin (Dx) and to determine whether any pharmacokinetic interaction occurs in sarcoma-bearing mice. The cytotoxicity of each drug and of their combinations was assessed in the rhabdomyosarcoma cell line TE-671 by a clonogenic assay, and isobologram analysis was performed to detect any synergistic, additive or antagonistic effects. The antitumor activities of each drug and of the combinations were also evaluated in nude mice transplanted subcutaneously with human TE-671 rhabdomyosarcoma and in C3H female mice injected intravenously with UV2237 M fibrosarcoma or with the Dx-resistant subline UV2237 M-ADM which overexpresses Pgp. Antitumor activity was evaluated by monitoring the TE-671 tumor volume over time and, in the case of the murine fibrosarcomas, by evaluation of lung deposits at autopsy quantified by determining lung weight. Pharmacokinetic studies were performed in TE-671-bearing mice. ET-743 was determined in plasma by an HPLC-MS method and Dx in plasma and tissue by an HPLC method with fluorescence detection. The combination of ET-743 and Dx was found to be additive with the average combination index slig...Continue Reading

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