Glucocorticoids and rituximab in vitro: synergistic direct antiproliferative and apoptotic effects.
Rituximab, a chimeric human immunoglobulin G(1) (IgG(1)) anti-CD20 monoclonal antibody has been shown to mediate cytotoxicity in malignant B cells via several mechanisms in vitro. These include direct antiproliferative and apoptotic effects, complement-dependent cytotoxicity (CDC), and antibody-dependent cell-mediated cytotoxicity (ADCC). Glucocorticoids (GCs) are often administered in conjunction with rituximab in chemotherapeutic regimens or as premedication to reduce infusion-related symptoms. The effects of GCs on CDC and ADCC, and the direct apoptotic and antiproliferative effects of rituximab are unknown. Therefore, we evaluated these mechanisms in 9 B-cell non-Hodgkin lymphoma (B-NHL) cell lines using rituximab and GCs. Rituximab and dexamethasone induced synergistic growth inhibition in 6 B-NHL cell lines. Dexamethasone and rituximab induced significant G(1) arrest in 9 of 9 cell lines. The combination of rituximab and dexamethasone resulted in supra-additive increases in phosphatidylserine exposure and hypodiploid DNA content in 5 and 3 B-NHL cell lines, respectively. CDC and ADCC were neither impaired nor enhanced when dexamethasone and rituximab were administered concurrently. However, preincubation of both effector and tumor cells with dexamethasone reduced specific lysis in ADCC assays in 4 B-NHL cell lines. Preincubation of tumor cell lines with dexamethasone significantly increased cell sensitivity to CDC in 3 B-NHL cell lines. We conclude that the addition of dexamethasone to rituximab results in supra-additive cytotoxicity with respect to its direct antiproliferative and apoptotic effects, induces a cell-dependent increased sensitivity to rituximab-induced CDC, and has minimal negative impact on ADCC when used simultaneously with rituximab.
Rose
Andrea L
AL
Fred Hutchinson Cancer Research Center, Seattle, WA, USA. arose@fhcrc.org
Smith
Barbara E
BE
Maloney
David G
DG
D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003167:Complement Activation; D003907:Dexamethasone / Q000494:pharmacology* / Q000627:therapeutic use; D004357:Drug Synergism; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000473:pathology; D000069283:Rituximab; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000069283:Rituximab; D003907:Dexamethasone