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Blood, 1 May 2004, Vol. 103, No. 9, pp. 3516-3520.
Prepublished online as a Blood First Edition Paper on December 24, 2003; DOI 10.1182/blood-2003-08-2795.
Submitted August 19, 2003
Accepted December 16, 2003
Fenretinide enhances Rituximab-induced cytotoxicity against B cell lymphoma xenografts via a caspase-dependent mechanism
Ajay K Gopal*, John M Pagel, Nathan Hedin, and Oliver W Press
Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, USA; Department of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
* Corresponding author; email: agopal{at}u.washington.edu.
The anti-CD20 monoclonal antibody Rituximab induces remissions in 40-60% of patients with indolent B-cell lymphomas, but virtually all will relapse. We evaluated the efficacy of concurrent administration of another biological agent, N-(4-hydroxyphenyl) retinamide (4HPR, fenretinide) with Rituximab against a variety of human B-cell lymphoma cell lines (Ramos, DHL-4 and FL-18) in vivo. Concurrent 4HPR and Rituximab administration prevented tumor progression of lymphoma-bearing mice in a minimal disease model (Rituximab + 4HPR, 100% progression-free; Rituximab alone-37.5%, p=0.01; 4HPR alone 12.5%, p<0.01; Controls 0%, p<0.01). 4HPR + Rituximab combinations exceeded the predicted 50% additive rate of disease control from each agent alone (p=0.038). Furthermore, administration of 4HPR and Rituximab to mice with established tumors induced complete responses (CRs) in 80% of animals, compared to 20-40% CRs using either agent alone (p=0.07) and resulted in significantly improved survival. Tumors harvested from 4HPR + Rituximab treated mice displayed elevated caspase activation compared to untreated controls (p=0.02). Furthermore, addition of a broad-spectrum caspase inhibitor in vivo fully abrogated the anti-tumor effects of 4HPR + Rituximab (p=0.05). These results establish the efficacy of 4HPR-Rituximab combinations, confirm the caspase-mediated mechanism of action, and offer the potential for disease control with minimal toxicity for patients with B-cell malignancies.
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