Arginine deprivation using pegylated arginine deiminase has activity against primary acute myeloid leukemia cells in vivo
Arginine deprivation using pegylated arginine deiminase has activity against primary acute myeloid leukemia cells in vivo
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DOI：
10.1182/blood-2014-10-608133
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发表时间：
2015-06-25
期刊：
影响因子：
20.3
通讯作者：
Taussig, David C.
中科院分区：
文献类型：
--
作者：
Miraki-Moud, Farideh;Ghazaly, Essam;Taussig, David C.
酶降解氨基酸以剥夺恶性细胞的重要营养物质的策略是急性淋巴细胞白血病诱导治疗的既定组成部分。在这里，我们表明，急性髓性白血病（AML）细胞从大多数患者的AML是缺乏精氨酸合成所需的关键酶，乙酰氨基琥珀酸合成酶-1（ASS 1）。因此，这些ASS 1缺陷型AML细胞依赖于输入细胞外精氨酸。因此，我们在异种移植模型和体外研究了使用聚乙二醇化精氨酸脱亚胺酶（ADI-PEG 20）去除血浆精氨酸对原发性AML的影响。ADI-PEG 20单独在体外38个AML中的19个和体内6个AML中的3个中诱导应答，导致敏感AML中的半胱天冬酶活化。ADI-PEG 20耐药AML的ASS 1相对表达量高于敏感AML。这表明耐药AML通过该代谢途径产生精氨酸而存活，并且ASS 1表达可用作反应的生物标志物。敏感的AML表现出更积极的摄取精氨酸从细胞外环境与他们的精氨酸营养缺陷型一致。ADI-PEG 20和阿糖胞苷化疗的组合比单独治疗更有效，导致体内测试的6/6个AML中的6个应答。我们的数据表明，精氨酸剥夺是AML的合理策略，为临床试验铺平了道路。
The strategy of enzymatic degradation of amino acids to deprive malignant cells of important nutrients is an established component of induction therapy of acute lymphoblastic leukemia. Here we show that acute myeloid leukemia (AML) cells from most patients with AML are deficient in a critical enzyme required for arginine synthesis, argininosuccinate synthetase-1 (ASS1). Thus, these ASS1-deficient AML cells are dependent on importing extracellular arginine. We therefore investigated the effect of plasma arginine deprivation using pegylated arginine deiminase (ADI-PEG 20) against primary AMLs in a xenograft model and in vitro. ADI-PEG20 alone induced responses in 19 of 38 AMLs in vitro and 3 of 6 AMLs in vivo, leading to caspase activation in sensitive AMLs. ADI-PEG20-resistant AMLs showed higher relative expression of ASS1 than sensitive AMLs. This suggests that the resistant AMLs survive by producing arginine through this metabolic pathway and ASS1 expression could be used as a biomarker for response. Sensitive AMLs showed more avid uptake of arginine from the extracellular environment consistent with their auxotrophy for arginine. The combination of ADI-PEG 20 and cytarabine chemotherapy was more effective than either treatment alone resulting in responses in 6 of 6 AMLs tested in vivo. Our data show that arginine deprivation is a reasonable strategy in AML that paves the way for clinical trials.