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¹ Department of Microbiology, Immunology and Molecular Genetics, ² Department of Oral Biology and Medicine, School of Dentistry, and ³ Department of Hematology and Oncology, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA

Requests for Reprints: Benjamin Bonavida, Department of Microbiology, Immunology and Molecular Genetics, UCLA School of Medicine, A2-060 CHS, 10833 Le Conte Avenue, Los Angeles, CA 90095-1747. Phone: (310) 825-2233; Fax: (310) 206-3865. E-mail: bbonavida{at}mednet.ucla.edu

The anti-CD20 monoclonal antibody rituximab (Rituxan, IDEC-C2B8) has shown promising results in the clinical treatment of a subset of patients with low grade or follicular non-Hodgkin's lymphoma (NHL). However, chemotherapy- and rituximab-refractory NHL patients may benefit from a regimen in which rituximab acts as a sensitizing agent. This study examined the apoptotic signaling mediated by rituximab on rituximab- and paclitaxel-resistant CD20⁺ NHL B cell lines (Ramos, Raji, Daudi, and 2F7). Treatment with either rituximab (20 µg/ml) or paclitaxel (0.1–1000 nM) inhibited viable cell recovery of NHL lines. Neither rituximab nor paclitaxel induced significant apoptosis, although the combination treatment resulted in synergy in apoptosis. Rituximab selectively down-regulated Bcl-xL and induced apoptosis protease activating factor 1 (Apaf-1) expressions in Ramos cells. Paclitaxel down-regulated the expression of Bcl-xL and inhibitor of apoptosis proteins (c-IAP-1) and up-regulated the expression of Bad and Apaf-1. The combination treatment resulted in the formation of truncated Bid, cytosolic accumulation of cytochrome c and second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low PI, activation of caspase-9, caspase-7, caspase-3, and cleavage of poly(ADP-ribose) polymerase. The findings identify two potential novel intracellular targets of rituximab-mediated signaling in Ramos NHL cells (i.e., Bcl-xL and Apaf-1). Further, the findings show that both rituximab and paclitaxel selectively modify the expression pattern of proteins involved in the apoptosis signal transduction pathway and, through functional complementation, the combination results in synergy in apoptosis. The potential therapeutic significance of these findings is discussed.

Grant support: Supported in part by the Boiron Research Foundation and a grant from the Department of Defense (U.S. Army DAMD 170210023). Ali Jazirehi was supported in part by a fellowship from the School of Dentistry and the Jonsson Comprehensive Cancer Center at UCLA.

Received 5/15/03; revised 7/23/03; accepted 8/24/03.

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