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  • Title: The proteasome inhibitor CEP-18770 enhances the anti-myeloma activity of bortezomib and melphalan.
    Author: Sanchez E, Li M, Steinberg JA, Wang C, Shen J, Bonavida B, Li ZW, Chen H, Berenson JR.
    Journal: Br J Haematol; 2010 Feb; 148(4):569-81. PubMed ID: 19958357.
    Abstract:
    The anti-multiple myeloma (MM) efficacy of bortezomib has led to the development of other proteasome inhibitors (PI), including CEP-18770 which has shown anti-MM effects in preclinical studies. However, the efficacy of orally (PO) or intravenously (IV) administered CEP-18770 in multiple MM models and in combination with conventional anti-MM therapies has not been evaluated. Herein, we show that CEP-18770 combined with melphalan or bortezomib induces synergistic inhibition of MM cell viability in vitro. In MM xenograft models, the addition of CEP-18770 IV to melphalan completely prevented the growth of both melphalan-sensitive and melphalan-resistant tumours. The combination of CEP-18770 IV and bortezomib induced complete regression of bortezomib-sensitive tumours and markedly delayed progression of bortezomib-resistant tumours compared to treatment with either agent alone. Single agent CEP-18770 PO also showed marked anti-MM effects in these xenograft models. These studies provide strong preclinical rationale for further development of this novel PI in the treatment of MM as a monotherapy as well as combined with either melphalan or bortezomib.
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