[Targeting Bcl-2 family members with the BH3 mimetic AT-101 markedly enhances the therapeutic effects of chemotherapeutic agents in in vitro and in vivo models of B-cell lymphoma]
>>Blood. 2008 Feb 21 [Epub ahead of print]
Targeting Bcl-2 family members with the BH3 mimetic AT-101 markedly enhances the therapeutic effects of chemotherapeutic agents in in vitro and in vivo models of B-cell lymphoma.
Paoluzzi L, Gonen M, Gardner JR, Mastrella J, Yang D, Holmlund J, Sorensen M, Leopold L, Manova K, Marcucci G, Heaney ML, O' Connor OA.
Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY.
Over-expression of anti-apoptotic members of the Bcl-2 family are observed in approximately 80% of B-cell lymphomas, contributing to intrinsic and acquired drug resistance. Nullifying anti-apoptotic function can potentially overcome this intrinsic and acquired drug resistance. AT-101 is a BH3 mimetic known to be a potent inhibitor of anti-apoptotic Bcl-2 family members including Bcl-2, Bcl- XL and Mcl-1. In vitro, AT-101 exhibits concentration and time dependent cytotoxicity against lymphoma and multiple myeloma cell lines, enhancing the activity of cytotoxic agents. The IC50 for AT-101 is between 1 and 10 microM for a diverse panel of B-cell lymphomas. AT-101 was synergistic with carfilzomib (C), etoposide (E), doxorubicin (D) and 4-hydroxycyclophosphamide (4-HC) in mantle cell lymphoma (MCL) lines. In a transformed large B-cell lymphoma line (RL), AT-101 was synergistic when sequentially combined with 4-HC, but not when both drugs were added simultaneously. AT-101 also induced potent mitochondrial membrane depolarization (DeltaPsim) and apoptosis when combined with carfilzomib, but not with bortezomib in MCL. In SCID beige mouse models of drug resistant B-cell lymphoma, 35 mg/kg/day of AT-101 was safe and efficacious. The addition of AT-101 to cyclophosphamide (Cy) and rituximab (R) in a schedule-dependent manner enhanced the efficacy of the conventional therapy.<<
So, finally something that not only does not synergize with bortezomib, but does synergize with a competing proteasome inhibitor.
Cheers, Tuck |
