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Blood, 1 September 2002, Vol. 100, No. 5, pp. 1765-1773
IMMUNOBIOLOGY
Glucocorticoids and rituximab in vitro: synergistic
direct antiproliferative and apoptotic effects
Andrea L. Rose,
Barbara E. Smith, and
David G. Maloney
From the Fred Hutchinson Cancer Research Center,
Seattle, WA.
Rituximab, a chimeric human immunoglobulin G1
(IgG1) 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
G1 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.
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