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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.
NEOPLASIA 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 lymphoma1 Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY; Departments of 2 Epidemiology & Biostatistics and 3 Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY; 4 Ascenta Therapeutics, Malvern, PA; 5 Molecular Cytology Core Facility, Memorial Sloan-Kettering Cancer Center, New York, NY; 6 Division of Hematology/Oncology, The Ohio State University, Columbus; and 7 College of Physician and Surgeons, The New York Presbyterian Hospital, Columbia University, New York, NY
Overexpression of antiapoptotic members of the Bcl-2 family are observed in approximately 80% of B-cell lymphomas, contributing to intrinsic and acquired drug resistance. Nullifying antiapoptotic function can potentially overcome this in-trinsic and acquired drug resistance. AT-101 is a BH3 mimetic known to be a potent inhibitor of antiapoptotic 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 (
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| Copyright © 2008 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
m) and apoptosis when combined with carfilzomib, but not with bortezomib in MCL. In severe combined immunodeficient (SCID) beige mouse models of drug-resistant B-cell lymphoma, 35 mg/kg per 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. 
