艾迪注射液和阿霉素的协同作用及其机制研究

Aidi injection (AD) often combined with doxorubicin (DOX) to treat hepatocellular carcinoma (HCC). However, there is few report on the pharmacological effects and mechanisms of their combination. The risk of these two drugs combined is increasing year by yea. Previous research of our group found that AD can significantly improved the liver function of HCC rats, reduced liver CYP450s, GSTs activities or expressions, significantly increased the blood concentration of DOX in HCC rats (AUC increased by 4 times). It indicate that the combination of AD and DOX can significantly alter the PK process of DOX, and also manifest it may increase the cardiotoxicity of DOX. Based on previous studies, this study aims to investigate the effects of two drugs combination on the in vivo processes of DOX, and to explore the changes of metabolic enzymes and transporters of each treatment groups, to clarify the molecular mechanism of pharmacokinetic changes. Meanwhile, we are going to study the effect of two drugs combination on tumor suppressive strength and related mechanisms to study the effect of AD on DOX-induced myocardial toxicity from the mitochondrial function, cell membrane damage, apoptosis mechanism. At last, we will get a theoretical basis for the clinical rationality and scientific connotation of AD combined with DOX.

艾迪注射液（AD）常联合阿霉素（DOX）治疗肝癌，但临床合并用药的药理作用及其机制研究少有报道，临床合并用药的风险逐年增加。课题组前期研究发现AD能显著改善HCC大鼠肝功能，降低肝脏CYP450s，GSTs活性或表达，显著提高HCC大鼠体内DOX的血药浓度（AUC增大4倍），表明AD与DOX联用能显著改变DOX的体内过程，同时也提示可能增加DOX的心脏毒性作用。本课题在前期研究基础上，拟从大鼠、小鼠、细胞，多水平、多角度开展两药合用对DOX体内过程的影响，探讨联合用药对病理状态下各药物代谢酶和转运体的变化，明确药动学改变的分子机制；同时研究两药联用对肿瘤抑制强度的影响以及相关机制，从线粒体功能、细胞膜损伤、细胞凋亡机制研究AD对DOX导致的心脏毒性的影响，为阐明AD与DOX联合应用的临床合理性和科学内涵提供理论依据。

艾迪注射液（AD）是由斑蝥、人参、黄芪、刺五加四味药组成的中药注射液，具有清热解毒、消瘀散结功能，常用于各种恶性肿瘤的治疗，已成为临床抗肿瘤中药的常用药物。在治疗肝癌时，AD通常与阿霉素（DOX）、表阿霉素和吡喃阿霉素等蒽环类药物联合使用，可增强肿瘤对化疗药的敏感度、增强免疫力、降低毒副作用，具有显著的协同作用。然而，有关AD对化疗药物的协同作用多为临床使用疗效观察，缺乏基础研究，其在体内如何发挥协同作用的机制并未见报道。本课题执行期间从体内外、多模型、多角度解释了AD与化疗药阿霉素（DOX）联用具有增强抗肿瘤作用和降低DOX心脏毒性的作用，并阐明了相关作用机制。实验表明AD可通过改变多种药物代谢酶活性或表达，增加DOX血药浓度和肿瘤内DOX浓度，发挥“增效作用”；通过降低H9c2心肌细胞中CBR1的表达，从而降低心脏组织和H9c2心肌细胞中阿霉素毒性代谢产物阿霉素醇的浓度，发挥“减毒作用”。实验还证明了AD通过促进肿瘤细胞凋亡（线粒体途径）、抑制血管生成和抑制肿瘤细胞增殖来增强DOX的抗肿瘤作用。体外细胞代谢组学实验表明ADI增强DOX的抗肿瘤作用，可能通过平衡氨基酸和能量相关物质的代谢发挥协同抗肿瘤作用。通过本课题的实施，阐明了AD与DOX联合应用的临床合理性和为二者联用的科学内涵提供了理论依据。