Division of Hematology and Oncology, Department of Internal Medicine, Karmanos Cancer Institute, Wayne State University School of Medicine, 732 HWCRC, 4100 John R Street, Detroit, Michigan 48201, USA.
Mol Cancer. 2009 Dec 3;8:115. doi: 10.1186/1476-4598-8-115.
MI-319 is a synthetic small molecule designed to target the MDM2-P53 interaction. It is closely related to MDM2 antagonists MI-219 and Nutlin-3 in terms of the expected working mechanisms. The purpose of this study was to evaluate anti-lymphoma activity of MI-319 in WSU-FSCCL, a B-cell follicular lymphoma line. For comparison purpose, MI-319, MI-219 and Nutlin-3 were assessed side by side against FSCCL and three other B-cell hematological tumor cell lines in growth inhibition and gene expression profiling experiments.
MI-319 was shown to bind to MDM2 protein with an affinity slightly higher than that of MI-219 and Nutlin-3. Nevertheless, cell growth inhibition and gene expression profiling experiments revealed that the three compounds have quite similar potency against the tumor cell lines tested in this study. In vitro, MI-319 exhibited the strongest anti-proliferation activity against FSCCL and four patient cells, which all have wild-type p53. Data obtained from Western blotting, cell cycle and apoptosis analysis experiments indicated that FSCCL exhibited strong cell cycle arrest and significant apoptotic cell death; cells with mutant p53 did not show significant apoptotic cell death with drug concentrations up to 10 muM, but displayed weaker and differential cell cycle responses. In our systemic mouse model for FSCCL, MI-319 was tolerated well by the animals, displayed effectiveness against FSCCL-lymphoma cells in blood, brain and bone marrow, and achieved significant therapeutic impact (p < 0.0001) by conferring the treatment group a > 28% (%ILS, 14.4 days) increase in median survival days.
Overall, MI-319 probably has an anti-lymphoma potency equal to that of MI-219 and Nutlin-3. It is a potent agent against FSCCL in vitro and in vivo and holds the promises to be developed further for the treatment of follicular lymphoma that retains wild-type p53.
MI-319 是一种合成小分子，旨在针对 MDM2-P53 相互作用。就预期的工作机制而言，它与 MDM2 拮抗剂 MI-219 和 Nutlin-3 密切相关。本研究的目的是评估 MI-319 在 WSU-FSCCL（B 细胞滤泡性淋巴瘤系）中的抗淋巴瘤活性。为了进行比较，MI-319、MI-219 和 Nutlin-3 被评估为在生长抑制和基因表达谱实验中对 FSCCL 和其他三种 B 细胞血液肿瘤细胞系的作用。
MI-319 被证明与 MDM2 蛋白具有亲和力，其亲和力略高于 MI-219 和 Nutlin-3。然而，细胞生长抑制和基因表达谱实验表明，这三种化合物对本研究中测试的肿瘤细胞系具有相当相似的效力。在体外，MI-319 对 FSCCL 和四个具有野生型 p53 的患者细胞表现出最强的抗增殖活性。来自 Western blotting、细胞周期和凋亡分析实验的数据表明，FSCCL 表现出强烈的细胞周期停滞和显著的细胞凋亡；在药物浓度高达 10 μM 时，具有突变型 p53 的细胞不会显示出明显的细胞凋亡，但表现出较弱和不同的细胞周期反应。在我们用于 FSCCL 的系统性小鼠模型中，MI-319 被动物很好地耐受，对血液、大脑和骨髓中的 FSCCL 淋巴瘤细胞有效，并通过使治疗组的中位生存天数增加 28%（ILS，14.4 天）来实现显著的治疗效果（p < 0.0001）。
总体而言，MI-319 可能具有与 MI-219 和 Nutlin-3 相当的抗淋巴瘤效力。它是体外和体内 FSCCL 的有效药物，有望进一步开发用于治疗保留野生型 p53 的滤泡性淋巴瘤。
