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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.
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NEOPLASIA
Fenretinide enhances rituximab-induced cytotoxicity against B-cell lymphoma xenografts through a caspase-dependent mechanism
Ajay K. Gopal,
John M. Pagel,
Nathan Hedin, and
Oliver W. Press
From the Seattle Cancer Care Alliance, University of Washington, Seattle, and the Fred Hutchinson Cancer Research Center, Seattle, WA.
The anti-CD20 monoclonal antibody rituximab induces remission in 40% to 60% of patients with indolent B-cell lymphoma, but virtually all patients have relapses. We evaluated the efficacy of concurrent administration of another biologic 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% progression free, P = .01; 4HPR alone, 12.5% progression free, P < .01; controls, 0% progression free, P < .01). Combinations of 4HPR + rituximab exceeded the predicted 50% additive rate of disease control from each agent alone (P = .038). Administering 4HPR and rituximab to mice with established tumors induced complete responses (CRs) in 80% of animals compared with 20% to 40% CRs using either agent alone (P = .07), resulting in significantly improved survival. Tumors harvested from 4HPR + rituximab-treated mice displayed elevated caspase activation compared with untreated controls (P = .02). Adding a broad-spectrum caspase inhibitor in vivo fully abrogated the antitumor effects of 4HPR + rituximab (P = .05). These results establish the efficacy of 4HPR/rituximab combinations, confirm their caspase-mediated mechanism of action, and offer the potential for disease control with minimal toxicity for patients with B-cell malignancies. (Blood. 2004;103:3516-3520)
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