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Blood, 1 June 2008, Vol. 111, No. 11, pp. 5350-5358.
Prepublished online as a Blood First Edition Paper on February 21, 2008; DOI 10.1182/blood-2007-12-129833.
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Submitted December 27, 2007
Accepted February 13, 2008
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
Luca Paoluzzi, Mithat Gonen, Jeffrey R Gardner, Jill Mastrella, Dajun Yang, Jon Holmlund, Mel Sorensen, Lance Leopold, Katia Manova, Guido Marcucci, Mark L Heaney, and Owen A O' Connor*
Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY
Department of Epidemiology & Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY
Ascenta Therapeutics, Malvern, CA
Molecular Cytology Core Facility, Memorial Sloan-Kettering Cancer Center, New York, NY
Division of Hematology/Oncology, Ohio State University, Columbus, OH
College of Physician and Surgeons, Columbia University, New York, NY
* Corresponding author; email: oo2130{at}columbia.edu.
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 µM 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 (  m) 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.
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