基于“蜘蛛网”模式辨析艾迪注射液抗肿瘤和心脏毒性保护作用的质量标志物研究

Discrimination of anti-tumor and cardioprotective effect quality markers from Aidi Injection based on"spider web"mode

在肿瘤治疗中,中药制剂发挥减毒和抗肿瘤作用的地位同等重要。国内外尚无综合“辨识”多种治疗作用中药制剂质量标志物(Q-marker)的报道。因此笔者以艾迪注射液(Aidi Injection,AD)为例,基于“蜘蛛网”模式综合辨识AD抗肿瘤作用和心脏保护作用的质量标志物。首先基于可测性原则,对方中化学成分进行定性分析,再对方中含量较高且可定量测定的成分进行定量分析,作为可测性评价指标;基于稳定性原则,考察光照和温度因素对AD各成分含量的影响,作为稳定性的评价指标;基于配伍原则,依据其原药材在复方中的君、臣、佐、使配伍规律归属化合物;基于有效性原则,评价候选质量标志物的抗肿瘤、抗血管生成活性及其分别协同阿霉素(doxorubicin,DOX)抗肿瘤、抗血管生成和降低心肌毒性的活性,作为有效性的评价指标。建立“配伍-含量-稳定性-抗肿瘤细胞活性-协同DOX抗肿瘤活性-抗血管生成活性-协同DOX抗血管生成活性”七维度蜘蛛网和“配伍-含量-稳定性-降低DOX心脏毒性作用”四维度蜘蛛网,综合辨析AD抗肿瘤和心脏毒性保护作用的质量标志物。结果筛选出12个成分作为AD的质量标志物,其中斑蝥素、人参皂苷Re、人参皂苷Rb_(1)、黄芪皂苷Ⅱ、隐绿原酸和人参皂苷Rg_(2)为AD抗肿瘤的质量标志物,人参皂苷Rd、异嗪皮啶、紫丁香苷、刺五加苷E、毛蕊异黄酮葡萄糖苷、王二酸作为AD心脏毒性保护作用的质量标志物。综合辨识出的12个质量标志物可覆盖全方4味药材,兼顾抗肿瘤和心脏毒性保护作用。这为AD的质量控制提供了科学依据,为辨识2种重要作用的中药制剂全面合理的质量标志物提供了有效方法。

Chinese medicinal preparations play an equally important role in reducing toxicity and treating tumors.Few studies discriminate the quality markers(Q-markers)conferring different therapeutic effects of traditional Chinese medicine preparations.Therefore,we take Aidi Injection(AD)as an example to comprehensively identify the Q-markers of anti-tumor and cardioprotective effects based on the"spider web"mode.Firstly,based on the principle of measurability,the chemical components in the prescription were qualitatively analyzed,and then the components with high content and capable to be measured were quantitatively analyzed as measurable evaluation indexes.Based on the principle of stability,the effects of light and temperature on the content of each component of AD were investigated as indicators of stability.Based on the principle of compatibility,the compounds were classified according to the law of compatibility of sovereign,minister,assistant,and guide medicinal materials in the prescription.Based on the principle of efficacy,the anti-tumor and antiangiogenic activities of the Q-markers were evaluated,and their synergistic effects with doxorubicin(DOX)in inhibiting tumorigenesis and angiogenesis and lowering cardiotoxicity were evaluated as the evaluation indexes of effectiveness.The seven-dimensional spider web of"compatibility-content-stability-antitumor activity-synergistic anti-tumor activity with DOX-antiangiogenic activity-synergistic anti-angiogenic activity with DOX"and the four-dimensional spider web of"compatibilitycontent-stability-protective effects against DOX-induced myocardial toxicity"were established,on the basis of which the Q-markers of anti-tumor and cardioprotective effects of AD were comprehensively analyzed.The results showed that 12 components were selected as the Q-markers of AD,among which cantharidin,ginsenoside Re,ginsenoside Rb_(1),astragalosideⅡ,cryptochlorogenic acid,and ginsenoside Rg_(2) were the anti-tumor Q-markers of AD.Ginsenoside Rd,isofraxidin,syringin,eleutheroside E,calycosin-7-O-β-Dglucoside,and azelaic acid were the cardioprotective Q-markers of AD.Taking into account both the anti-tumor and cardioprotective effects,these Q-markers could cover the four herbs constituting the prescription.The findings provides a scientific basis for the quality control of AD and an effective method for identifying comprehensive and reasonable Q-markers for the two effects of Chinese medicinal preparations.