Synergistic effects of the fenretinide (4-HPR) and anti-CD20 monoclonal antibodies on apoptosis induction of malignant human B cells.
Retinoids have been shown to be clinically useful in the biological therapy of certain myeloid and T-cell malignancies, whereas CD20 has proven to be an effective target in B-cell lymphoma immunotherapy. Both retinoic acid derivatives and anti-CD20 monoclonal antibodies have also been shown to induce apoptosis of malignant cells in vitro. Retinoid-induced apoptosis is thought to be mediated by nuclear retinoid receptor binding and transcriptional activation, whereas CD20 ligation appears to initiate transmembrane Ca(2+) influx with resultant programmed cell death. In this report, we evaluate the in vitro effects of N-(4-hydroxyphenyl) retinamide (4-HPR) with and without anti-CD20 antibodies in B-cell lymphoma lines. We demonstrate that 4-HPR inhibits the growth of malignant B-cells beyond that of all-trans-retinoic acid and 13-cis-retinoic acid. We also show that this 4-HPR-mediated growth inhibition is attributable to apoptosis, is consistent across a variety of malignant B-cell lines (Ramos, Ramos AW, SU-DHL4, and Raji), peaks at 96 to 144 h, and is attainable with concentrations as low as 2 microM. As with CD20-mediated apoptosis, we show that the final common pathway includes caspase activation that can be blocked by 2-val-Ala-Asp-fluoromethyl ketone (z-VAD), a specific inhibitor of caspase function. Coincubation of a 2 microM concentration of 4-HPR and the anti-CD20 antibodies rituximab and tositumomab exhibited a supra-additive increase in levels of apoptosis induction of 24% (P = 0.009) and 42% (P = 0.0019) relative to expected additive levels of these same agents. These in vitro findings suggest that the potential in vivo synergy of these well-tolerated drugs may augment the previously demonstrated clinical activity of anti-CD20 monoclonal antibodies in the treatment of B-cell malignancies.
Shan
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Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA 98195, USA.
Gopal
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Press
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D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D018951:Antigens, CD20 / Q000276:immunology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D017313:Fenretinide / Q000494:pharmacology*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D017313:Fenretinide; D014212:Tretinoin; D020169:Caspases