Department of Haematology, School of Medicine, Cardiff University, Cardiff, UK.
Leuk Res. 2011 May;35(5):677-81. doi: 10.1016/j.leukres.2010.10.030. Epub 2010 Dec 9.
Aminopeptidase enzyme inhibition is thought to deplete the free intracellular amino acids needed by malignant cells for growth and development, resulting in profound anti-proliferative and apoptotic effects. In this study, we investigated the effects of the metalloenzyme-inhibitor CHR-2797 (tosedostat), in primary acute myeloid leukemia (AML) cells. CHR-2797 demonstrated marked in vitro cytotoxicity in AML samples and strong synergy with Cytarabine (Ara-C), but significantly less cytotoxicity to normal marrow progenitors. Furthermore mechanistic investigations revealed that CHR-2797 inhibited the intrinsic nuclear, cytoplasmic and cell surface aminopeptidase function of AML blasts in a dose-dependent manner, demonstrating a promising novel approach for AML therapy.
酶抑制剂氨肽酶被认为可以耗尽恶性细胞生长和发育所需的游离细胞内氨基酸，从而产生深远的抗增殖和凋亡作用。在这项研究中，我们研究了金属酶抑制剂 CHR-2797（托塞他定）在原发性急性髓细胞白血病（AML）细胞中的作用。CHR-2797 在 AML 样本中表现出明显的体外细胞毒性，并与阿糖胞苷（Ara-C）具有很强的协同作用，但对正常骨髓祖细胞的细胞毒性要小得多。此外，机制研究表明，CHR-2797 以剂量依赖性方式抑制 AML 白血病细胞的固有核、细胞质和细胞表面氨肽酶功能，为 AML 治疗提供了一种有前途的新方法。
