Lenalidomide (CC-5013) is a 4-amino-glutamyl analog of thalidomide, with greater potency and without the sedative and neuropathic side effects associated with thalidomide. Lenalidomide is an immunomodulator, affecting both the cellular and humoral arms of the immune system, and has demonstrated activity in clinical trials for cancer, including anti-angiogenic, anti-proliferative, and pro-erythropoietic activities. Lenalidomide acts as a molecular glue that binds to the CRBN-CRL4 E3 ubiquitin ligase complex, promoting ubiquitination of Ikaros family zinc finger 1 (IKZF1) and IKZF3 and thereby inhibiting proliferation of multiple myeloma cells. Lenalidomide is approved in the United States for a subset of Myelodysplastic Syndromes (MDS) patients and for treatment of patients with multiple myeloma when used in combination with dexamethasone[1][2].
In vitro, Lenalidomide (0.1-10μM; 72h) dose-dependently inhibited proliferation of CFSE-labeled OPM1 cells, regardless of co-culture with HS-5 BMSCs, significantly reduced the percentage of side population (SP) cells, and increased the proportions of CD138−/low+ and CFSE+/7-AAD+ cells[3]. Lenalidomide (10μM; 6h) inhibited the suppression of IL-2–induced NK cell cytotoxicity and IFN-γ secretion mediated by IL-6 and TGF-β1 in neuroblastoma/monocyte-conditioned media[4].
In vivo, in female NOD/SCID mice injected with CHLA-255-Fluc neuroblastoma cells and PBMCs, treatment with Lenalidomide (50mg/kg/d; 9+5d; i.p.) in combination with ch14.18 improved survival[4]. Lenalidomide (50mg/kg/d; 21d; i.p.) inhibited tumor growth and spread in xenograft mouse models of Mantle cell lymphoma (MCL)[5].
References:
[1] Krönke J, Hurst SN, Ebert BL. Lenalidomide induces degradation of IKZF1 and IKZF3. Oncoimmunology. 2014;3(7):e941742.
[2] Kotla V, Goel S, Nischal S, et al. Mechanism of action of lenalidomide in hematological malignancies. J Hematol Oncol. 2009;2:36.
[3] Jakubikova J, Adamia S, Kost-Alimova M, et al. Lenalidomide targets clonogenic side population in multiple myeloma: pathophysiologic and clinical implications. Blood. 2011;117(17):4409-4419.
[4] Xu Y, Sun J, Sheard MA, et al. Lenalidomide overcomes suppression of human natural killer cell anti-tumor functions by neuroblastoma microenvironment-associated IL-6 and TGFβ1. Cancer Immunol Immunother. 2013;62(10):1637-1648.
[5] Agliano, Alice et al. “Therapeutic effect of lenalidomide in a novel xenograft mouse model of human blastic NK cell lymphoma/blastic plasmacytoid dendritic cell neoplasm.” Clinical cancer research : an official journal of the American Association for Cancer Research vol. 17,19 (2011): 6163-73.
Lenalidomide (CC-5013)是thalidomide的4-氨基-谷氨酰类似物，具有更强的效力，且不具有thalidomide相关的镇静和神经病变等神经系统副作用。Lenalidomide是一种免疫调节剂，影响免疫系统的细胞和体液分支，并在癌症的临床试验中显示出活性，包括抗血管生成、抗增殖和促红细胞生成活性。Lenalidomide作为一种分子胶，结合于CRBN-CRL4 E3泛素连接酶复合体，促进Ikaros锌指家族蛋白1（IKZF1）和IKZF3的泛素化，从而抑制多发性骨髓瘤细胞的增殖。Lenalidomide已在美国获批用于部分骨髓增生异常综合征（MDS）患者以及与地塞米松联合使用治疗多发性骨髓瘤患者[1][2]。
体外实验中，Lenalidomide（0.1–10μM；72h）以剂量依赖方式抑制了CFSE标记的OPM1细胞的增殖（无论是否与HS-5 BMSCs共培养），显著降低了侧群（SP）细胞的比例，并增加了CD138−/low+细胞和CFSE+/7-AAD+细胞的比例[3]。Lenalidomide（10μM；6h）可抑制神经母细胞瘤/单核细胞条件培养基中IL-6和TGF-β1对IL-2诱导的NK细胞细胞毒性和IFN-γ分泌的抑制作用[4]。
体内实验中，在注射了CHLA-255-Fluc神经母细胞瘤细胞和PBMC的雌性NOD/SCID小鼠中，Lenalidomide（50mg/kg/天；9+5天；腹腔注射）联合ch14.18治疗可提高小鼠生存率[4]。Lenalidomide（50mg/kg/天；21天；腹腔注射）抑制了套细胞淋巴瘤（MCL）异种移植小鼠模型中的肿瘤生长和扩散[5]。