Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
Anticancer Res. 2012 Aug;32(8):3125-36.
BACKGROUND/AIM: For chronic lymphocytic leukemia (CLL) patients with poor-prognostic genomic aberrations the therapeutic options are limited. We used the Spectrum Collection library to identify compounds with anti-leukemia activity in high-risk CLL.
We identified substances with equal high cytotoxic activity in vitro in samples from poor-prognostic CLL (11q-/17p-, n=3) as compared to those from favourable-prognostic CLL (13q-, n=3). Cell survival was measured by fluorometric microculture cytotoxicity assay.
Out of 2,000 compounds, 65 had a similar effect in both prognostic groups. Fifteen compounds were selected for dose-response experiments in 16 additional CLL samples. Of these compounds, 12 continued to have similar cytotoxicity between prognostic subgroups. Additional experiments demonstrated that in CLL cells with 11q or 17p deletion, 5-azacytidine induced apoptosis in a dose-dependent manner and lipoprotein lipase expression was reduced following orlistat treatment.
Using primary cultures of cells from high-risk CLL patients for compound screening is a feasible approach and that 5-azacytidine and orlistat exemplify substances that exhibit cytotoxicity in poor-risk CLL.
背景/目的：对于具有不良预后基因组异常的慢性淋巴细胞白血病 (CLL) 患者，治疗选择有限。我们使用 Spectrum 文库来鉴定对高危 CLL 具有抗白血病活性的化合物。
我们在来自预后不良的 CLL（11q-/17p-，n=3）的样本中鉴定出体外细胞毒性活性相等的物质，与来自预后良好的 CLL（13q-，n=3）的样本相比。通过荧光微培养细胞毒性测定法测量细胞存活率。
在 2000 种化合物中，有 65 种在两个预后组中具有相似的作用。选择了 15 种化合物用于在另外 16 个 CLL 样本中进行剂量反应实验。其中 12 种化合物在预后亚组之间继续具有相似的细胞毒性。进一步的实验表明，在具有 11q 或 17p 缺失的 CLL 细胞中，5-氮杂胞苷以剂量依赖的方式诱导细胞凋亡，而奥利司他治疗后脂蛋白脂肪酶的表达减少。
使用高危 CLL 患者的原代细胞进行化合物筛选是一种可行的方法，5-氮杂胞苷和奥利司他是在低危 CLL 中表现出细胞毒性的物质的范例。
