title: Fenretinide enhances rituximab-induced cytotoxicity against B-cell lymphoma xenografts through a caspase-dependent mechanism.
abstract: 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.
authors.affiliation: Seattle Cancer Care Alliance, Mailstop G6-800, Rm 6802, University of Washington, 825 Eastlake Ave E, Seattle, 98109, USA. agopal@u.washington.edu
authors.forename: Ajay K
authors.initials: AK
authors.lastname: Gopal
authors.forename: John M
authors.initials: JM
authors.lastname: Pagel
authors.forename: Nathan
authors.initials: N
authors.lastname: Hedin
authors.forename: Oliver W
authors.initials: OW
authors.lastname: Press
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005260:Female; D017313:Fenretinide / Q000494:pharmacology*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D018365:Neoplasm, Residual / Q000188:drug therapy; D012074:Remission Induction / Q000379:methods; D000069283:Rituximab; D015996:Survival Rate; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D017313:Fenretinide; D000069283:Rituximab; D020169:Caspases