Synergistic Effects of the Fenretinide (4-HPR) and Anti-CD20 Monoclonal Antibodies on Apoptosis Induction of Malignant Human B Cells

• Published in: Clinical cancer research 2001-08, Vol.7 (8), p.2490-2495
• Main Authors: Shan, D, Gopal, A K, Press, O W
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal - pharmacology; Antigens, CD20 - immunology; Antineoplastic agents; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Caspases - drug effects; Caspases - metabolism; Cell Division - drug effects; Chemotherapy; Dose-Response Relationship, Drug; Drug Synergism; Fenretinide - pharmacology; Humans; Lymphoma, B-Cell - drug therapy; Lymphoma, B-Cell - pathology; Medical sciences; Pharmacology. Drug treatments; Signal Transduction - drug effects; Tretinoin - pharmacology; Tumor Cells, Cultured
• ISSN: 1078-0432; 1557-3265

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 μ m . 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 μ m 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.