Glucocorticoids and rituximab in vitro: synergistic direct antiproliferative and apoptotic effects.
Glucocorticoids and rituximab in vitro: synergistic direct antiproliferative and apoptotic effects.
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DOI：
10.1182/blood.v100.5.1765.h81702001765_1765_1773
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发表时间：
2002-09
期刊：
影响因子：
20.3
通讯作者：
Andrea L. Rose;Barbara E. Smith;D. Maloney
中科院分区：
文献类型：
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作者：
Andrea L. Rose;Barbara E. Smith;D. Maloney
利妥昔单抗是一种嵌合人免疫球蛋白G（1）（IgG（1））抗CD 20单克隆抗体，已被证明在体外通过多种机制介导恶性B细胞的细胞毒性。这些包括直接抗增殖和凋亡作用、补体依赖性细胞毒性（CDC）和抗体依赖性细胞介导的细胞毒性（ADCC）。糖皮质激素（GC）通常在化疗方案中与利妥昔单抗联合给药，或作为术前用药，以减少输注相关症状。GC对CDC和ADCC的影响以及利妥昔单抗的直接凋亡和抗增殖作用尚不清楚。因此，我们在9个B细胞非霍奇金淋巴瘤（B-NHL）细胞系使用利妥昔单抗和GC评估这些机制。利妥昔单抗和地塞米松在6个B-NHL细胞系中诱导协同生长抑制。地塞米松和利妥昔单抗在9个细胞系中诱导了显著的G（1）阻滞。利妥昔单抗和地塞米松的组合分别导致5和3个B-NHL细胞系中磷脂酰丝氨酸暴露和亚二倍体DNA含量的超累加增加。当地塞米松和利妥昔单抗同时给药时，CDC和ADCC既没有受损也没有增强。然而，预孵育的效应和肿瘤细胞与地塞米松减少特异性溶解在ADCC测定4 B-NHL细胞系。地塞米松预孵育的肿瘤细胞系显着增加细胞对CDC在3 B-NHL细胞系的敏感性。我们的结论是，除了地塞米松利妥昔单抗的结果在超累加的细胞毒性方面，其直接的抗增殖和凋亡的影响，诱导细胞依赖性增加利妥昔单抗诱导的CDC的敏感性，并有最小的负面影响ADCC同时使用时，与利妥昔单抗。
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.