升麻鳖甲汤加减方合节拍式化疗维持治疗老年急性髓系白血病的研究

There is no standardized regimen for post-induction therapy of old patients with acute myeloid leukemia (AML). A secure cost effective and effective maintenance treatment can improve the patient’s quality of life and prolong their survival, which is worthy of development. According the AML theory in Chinese Medicine, our research group pointed out that invasion of marrow by hidden heat of the toxic was the major pathogenesis of old patients with AML, and initiated heat dispelling, toxicity dissolving and static blood dissipating strategies to treat AML patients. We previously tried to treat aged AML with Cimicifugae and Carapacis Trionycis modified formula and found its therapeutic efficacy in a group of relapsed and refractory AML patients. AML patients treated with Cimicifugae and Carapacis Trionycis modified formula showed increased respond rates with or without conjugated chemotherapy and improved blood transfusion dependency and survival quality. Our research team then investigated via ex vivo experiments and demonstrated that the formula presented anti-leukemic effects. We are interested in the involved mechanism of the formula and will also investigate the multiple pathways and targets by serial ex vivo and in vivo experiments, which corresponds to the idea of metronomic chemotherapy. Meanwhile, metronomic chemotherapy plus Cimicifugae and Carapacis Trionycis modified formula will be used to treat old patients with AML in the real word study, and effectiveness, safety and economy will be determined. We anticipate the study has important meaning of theory for further enrichment Chinese Medicine’s standing of etiology and pathogenesis of AML, and meaning of reality for improvement in clinical outcome and social resources' saving.

老年急性髓系白血病（AML）缓解后治疗无“金标准”。安全、经济、有效的巩固与维持方案可提高患者生活质量，延长生存，值得开发。课题组根据老年AML温热毒邪蕴伏骨髓的关键病机，提出清热解毒散瘀治法，前期以升麻鳖甲汤加减方辅助治疗老年AML，患者耐受性良好且能显著缓解临床症状；体内外实验研究证实该复方可抑制白血病细胞生长。为进一步探讨其作用于白血病细胞、肿瘤血管新生和免疫调节等方面的机制，能够与节拍式化疗的理念相契合，本研究拟通过体内外实验探讨该方是否具有多个靶点、多种途径的作用特点。同时，结合节拍式化疗持续低剂量给药的方式，采用真实世界研究的新方法，将节拍化疗和中医药联合的新型模式应用于老年AML的维持治疗中，观察该方案对老年AML的有效性、安全性和经济性。该研究产生的新型个体化治疗方法对丰富现代中医对白血病病因病机的认识具有重要理论价值；对改善老年AML的预后、节约社会资源具有重要现实意义

背景：急性髓系白血病（acute myeloid leukemia, AML）好发于老年人群，该患病群体具有年龄大、基础疾病多、体力状态低下、核型复杂等临床及遗传特点，导致治疗相关获益低下。中医药在肿瘤的防治中有多靶点的特点以及增效减毒的作用，课题组前期临床研究证实升麻鳖甲汤加减方（Modified Shengma Biejia decoction, SMBJD）可在临床增加 AML 患者的疗效，减轻化疗相关不良反应的发生，在本项目的研究中着重探讨了 SMBJD对 AML 治疗作用的具体生物学作用及分子学机制。研究内容：细胞实验部分：1.研究 SMBJD 对 AML 细胞增殖、周期以及凋亡的影响；2.探究 SMBJD 诱导 AML 细胞凋亡的分子学机制和信号途径；3.SMBJD与Ara-C的体外协同作用验证；4.观察 SMBJD 对 AML 诱导的 HUVEC 血管新生的影响；5.探讨 SMBJD 影响 AML 相关血管新生的潜在分子学机制；6.对SMBJD的进行了高效液相质谱分析，粗测该方剂的有效作用成分。动物实验部分：1.构建裸鼠皮下荷 AML 细胞异种移植瘤模型；2.观察 SMBJD 干预后模型鼠一般生存状态的变化；3.观察 SMBJD 干预后裸鼠荷瘤体积的变化；4.观察 SMBJD 在体内对 AML细胞凋亡的影响；5.观察 SMBJD在体内对AML异种移植瘤相关血管新生的影响。临床观察部分：观察SMBJD对患者临床表现及生存治疗的影响。重要结果及关键数据：1.SMBJD可在体内外抑制AML细胞增殖并诱导细胞凋亡；2.SMBJD可与Ara-C产生协同作用；3.SMBJD诱导AML细胞凋亡的机制涉及MAPK信号通路的调控；4.SMBJD可对AML诱导的HUVEC血管新生产生抑制影响；5.SMBJD抑制AML相关血管新生的机制可能涉及VEGF/VEGFR2信号通路的调控；6.SMBJD有利于改善患者临床症状及预后。科学意义：本研究对明晰SMBJD治疗AML的具体生物学作用及分子学机制有积极作用，同时对拓展中医学对AML的认识有一定的促进作用。