砒霜为中药砒石升华所得精制品，在临床上用于治疗急性早幼粒细胞白血病的效果已被国际认可。但目前对砒霜治疗白血病的机理研究，大多数研究者都集中在单一As2O3对细胞影响作用机理研究上，而忽略了砷在体内代谢过程中所产生的活性代谢产物对治疗的白血病的贡献及作用。研究发现砷在人体内在砷甲基转移酶催化下，可迅速代谢为不同形态的有机代谢产物，如活性极高的三价一甲基（MMAIII）和二甲基亚砷酸（DMAIII）等。因此，砒霜的中间代谢产物很可能发挥着更强的诱导白血病细胞分化或凋亡作用，或与As2O3有协同治疗作用。本实验采用流式细胞术、免疫印迹、免疫荧光共聚焦等技术重点研究砷的活性中间代谢产物对白血病细胞NB4的作用，探讨其机制，阐明砷的中间代谢产物对降解PML-RARa融合蛋白、诱导细胞分化以及凋亡等方面的异同点。通过上述实验，拟优化砷化合物在APL治疗上的效果，延长急性早幼粒细胞白血病患者的生存周期。

In traditional chinese medicine, arsenic trioxide (As2O3) is being widely used in the treatment of acute promyelocytic leukemia (APL), because it has been demonstrated that As2O3 is able to bound to PML-RARα fusion proteins, which resulted in initiating PML/RARα oncoprotein degradation, promoting its APL cells differentiation and clinical remission of APL patients. On the other hand, As2O3 can be transformed metabolically into most toxic methylated metabolites such as trivalent monomethylarsonous acid (MMAIII) and dimethylarsinous acid (DMAIII) in the body, and the final metabolites that are excreted in the urine are mostly mono- and dimethylated pentavalent species. However, it is unknown regarding he anticancer effect of its active intermediate metabolites (i.e., MMAIII and DMAIII) in clinical remission of APL pateints. Thereby, the mechanism underlying the effects of arsenic compound should be clearly identified. In the present study, we used human APL cell line NB4 cells, and focused on the effects of As2O3 and its intermediates (i.e., MMAIII and DMAIII) on cell survival, induction of apoptosis and differentiation as well as degradation of PML-RARa fusion proteins. In our preliminary experiment, we found the intermediate metabolites have strong effects on the induction of apoptosis, and mechanism of intermediates action is unlikely to be similar to that of precursors, As2O3. Moreover, only As2O3 but not other two species induce the attachment of the ubiquitin-like SUMO-1 molecule to the PML moiety of PML-RARa. From above observations, we propose that the methylated MMAIII and DMAIII may have a beneficial therapeutic effect (e.g., induction of apoptosis) on APL patients.