基于移植性S-180和EAC肿瘤模型的异常黑胆质成熟剂体内抗肿瘤机制研究
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摘要
目的：
肿瘤是严重威胁人类健康的一类复杂性、疑难性疾病。寻找有效的抗肿瘤药物以及方法，彻底攻克肿瘤等复杂性疾病是全世界医学界的重要研究课题。肿瘤的治疗强调综合治疗，中医药、维医药的应用可使患者症状显著改善并保持全身状态好转，延缓病情发展，亦可使肿瘤缩小或带瘤而长期生存，故其在中晚期肿瘤的综合治疗中占有重要地位。肿瘤在化疗的过程中出现多药耐药（Multidrug resistanceMDR）是化疗失败的主要原因之一。当今抗肿瘤药物发展战略之一是从天然药物中寻找其活性成分，而新疆有丰富的中维药资源以及数千年的中维药理论与实践经验，对中维药抗肿瘤作用的研究与开发前景良好。目前已筛选出一些具有抗肿瘤作用的天然中药及单体，如苦参碱、苦杏仁甘、紫杉醇等，其中一些已广泛地应用于临床，显示出良好的效果。同样，天然药物中寻找逆转肿瘤耐药性及增效化疗药物的作用的有效低毒的逆转剂，长期以来一直是全世界医学界关注的的热点。
维吾尔医学认为，异常黑胆质作为胆液质、血液质、粘液质、黑胆质被“燃烧”，继而“沉淀”最终形成病理产物或表现形式，经常导致肿瘤、哮喘等难治性疾病。临床决大部分肿瘤患者表现为异常黑胆质性。新疆维吾尔自治区名老维吾尔医巴黑玉素甫和吐尔逊托乎提阿吉等多年来根据维医理论和临床治疗原则将维医异常黑胆质成熟剂应用于癌症以及哮喘患者的治疗，取得良好的疗效，被患者誉为“神医”。
异常黑胆质成熟剂（国家发明专利№：C082130082.8），又称异黑成熟颗粒，是维吾尔医复方制剂。由破布木（Cordia dichotoma Forst.）、红枣（Ziziphus jujubaMill.）、甘草（Glycyrrhiza uralensis Fisch.）、牛舌草（Anchusa italica Retz.）、小茴香（Foeniculum vulgare Mill.）、地锦草（Euphorbia humifusa Willd.）等药材组成，临床应用于由异常黑胆质所导致的肿瘤、糖尿病和心血管疾病等复杂性疾病。以哈木拉提.吾甫尔教授为首的课题组在以往的研究表明，异常黑胆质成熟剂可清除自由基，保护羟自由基引发的DNA氧化损伤和线粒体氧化损伤等，具有较强的抑制HepG2细胞体外生长、抑制HepG2细胞DNA、RNA和蛋白质生物合成；异常黑胆质成熟剂具有体外逆转肿瘤细胞多药耐药性之功效；对结肠癌细胞（Caco-2）体外抗癌作用；有抑制DMH诱发的大鼠结肠ACF形成的作用；肝癌耐药细胞（Bel/Fu）具有逆转多药耐药MDR的作用；异常黑胆质成熟剂总酚与顺铂、多西他赛联用对体外培养的人宫颈癌HeLa细胞增殖和凋亡的影响等研究。
本研究目的在于研究异常黑胆质成熟剂对两种移植性肿瘤（S-180和EAC）的抑制作用，对化疗药物（阿霉素和5-氟尿嘧啶）致毒副作用的拮抗作用，对氟尿嘧啶的增效减毒作用以及通过耐缺氧和爬杆实验，进一步确定异常黑胆质成熟剂的体内抗癌作用和抗疲劳、耐缺氧和抗氧化作用。
方法：
1．建立移植性S-180肿瘤模型：180只小鼠，随机分为6组，正常对照组、肿瘤模型组、异黑高剂量组、异黑中剂量组、异黑低剂量组、环磷酰胺（CY）对照组。分批测指标，观察小鼠抑瘤率、脾指数、胸腺指数和肝脏指数，小鼠血清中的TNF-α，IL-1β，IL-2，IFN-γ、NK、LPO含量变化以及用HE染色法检查小鼠肿瘤、脾脏等脏器的情况，用MTT法测定小鼠脾脏淋巴细胞增殖情况，小鼠全血中的淋巴细胞亚群CD_3~+、CD_4~+、CD_8~+、CD_4~+/CD_8~+含量变化。
2．建立移植性S-180肿瘤模型：60只小鼠，随机分为6组，正常对照组，肿瘤模型组、5-氟尿嘧啶（5-FU）对照组、5-FU联合异黑高剂量组、5-FU联合异黑中剂量组、5-FU联合异黑低剂量组。观察小鼠抑瘤率、脾指数、胸腺指数和肝脏指数，小鼠血清中的SOD、MDA、GSH-PX的含量变化。
3．建立移植性EAC肿瘤模型：180只小鼠，随机分为6组，正常对照组、肿瘤模型组、异黑高剂量组、异黑中剂量组、异黑低剂量组、环磷酰胺（CY）对照组。分批测指标，观察小鼠抑瘤率、脾指数、胸腺指数和肝脏指数，小鼠血清中的TNF-α，IL-1β，IL-2，IFN-γ、NK、LPO含量变化以及用HE染色法检查小鼠肿瘤、脾脏等脏器的情况，用MTT法测定小鼠脾脏淋巴细胞增殖情况，小鼠全血中的淋巴细胞亚群CD_3~+、CD_4~+、CD_8~+、CD_4~+/CD_8~+含量变化。
4．建立移植性EAC肿瘤模型：60只小鼠，随机分为6组，正常对照组，肿瘤模型组、5-氟尿嘧啶（5-Fu）对照组、5-FU联合异黑高剂量组、5-FU联合异黑中剂量组、5-FU联合异黑低剂量组。观察小鼠抑瘤率、脾指数、胸腺指数和肝脏指数，小鼠血清中的SOD、MDA、GSH-PX的含量变化。
5．建立化疗药（阿霉素和5-氟尿嘧啶）毒副作用模型：50只小鼠，随机分为5组，正常对照组、AF（阿霉素和5-氟尿嘧啶）模型对照组、AF~+异黑高剂量组、AF~+异黑中剂量组、AF~+异黑低剂量组。观察小鼠脾指数、胸腺指数和肝脏指数，小鼠血清中的ALT、AST、TP含量变化和小鼠心脏中SOD、MDA、GSH-PX的含量变化以及用HE染色法检查小鼠心脏、肝脏等脏器的情况。
6．分别建立移植性S-180肿瘤模型和建立移植性EAC肿瘤模型：研究异常黑胆质成熟剂对小鼠血清的SOD、MDA、GSH-PX指标的影响，以及对小鼠的抑瘤率、脾指数、胸腺指数和肝脏指数的影响；异常黑胆质成熟剂对小鼠常压耐缺氧试验和爬竿试验的影响。
结果：
1．异常黑胆质成熟剂各组与环磷酰胺组比较：异常黑胆质成熟剂高剂量组、异常黑胆质成熟剂中剂量组、异常黑胆质成熟剂低剂量组的脾脏/体重比值均明显升高，差异均有显著性（P＜0.05）。异常黑胆质成熟剂高剂量组、异常黑胆质成熟剂中剂量组、异常黑胆质成熟剂低剂量组和环磷酰胺组的抑瘤率分别为49.05%、64.26%，43.43%和50.88%具有明显的抑瘤作用，但环磷酰胺组和异黑高剂量组间的差别不明显。与肿瘤模型组血清中IL-1β含量相比，异黑各剂量组有显著变化，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组IL-1β含量最高。与肿瘤模型组、阳性对照组血清中IL-2含量相比，异常黑胆质成熟剂各剂量组相对上升，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组最高。血清中TNF-α的含量，异常黑胆质成熟剂各剂量组均高于肿瘤模型组、环磷酰胺组，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组最高。与肿瘤模型组血清中IFN-γ含量相比，异常黑胆质成熟剂各剂量组有显著变化，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组IFN-γ含量最高。与肿瘤模型组、环磷酰胺组血清中IFN-γ含量相比，异常黑胆质成熟剂各剂量组相对上升，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组最高。血清中LPO的含量，异常黑胆质成熟剂各剂量组均低于肿瘤模型组、环磷酰胺组，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组最低。与肿瘤模型组血清中NK含量相比，异常黑胆质成熟剂各剂量组有显著变化，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组NK含量最高。异常黑胆质成熟剂高剂量组CD_3~+、CD_8~+和CD_4~+明显降低，CD_4~+/CD_8~+比值升高，其中CD_4~+/CD_8~+比值已经接近正常对照值（与肿瘤模型组比较差异有显著性，与正常对照组比较差异无显著性）。异常黑胆质成熟剂中剂量组CD_8~+降低，CD_3~+、CD_4~+明显升高，CD_4~+/CD_8~+比值升高，其中CD_4~+/CD_8~+比值已经接近正常对照组值，异常黑胆质成熟剂低剂量组各指标均无显著性改善。正常对照组与肿瘤模型组小鼠肝脏中SOD，GSH-PX，MDA含量相比，差异有显著性（P＜0.05）。与肿瘤模型组小鼠肝脏中SOD，GSH-PX含量相比，异常黑胆质成熟剂各剂量组相对上升，差异均有显著性（P＜0.05），其中异黑颗粒中剂量组最高。小鼠肝脏中的MDA含量，异常黑胆质成熟剂各剂量组均低于肿瘤模型组及环磷酰胺组，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组最低。通过HE染色法检查，小鼠肝脏、脾脏、胸腺等脏器正常，小鼠S-180肿瘤坏死及液化。
2．5-FU联合异常黑胆质成熟剂高剂量组、5-FU联合异常黑胆质成熟剂中剂量组、5-FU联合异常黑胆质成熟剂低剂量组和氟尿嘧啶对照组的抑瘤率分别为52.26%、66.41%，44.87%和48.02%。正常对照组与肿瘤模型组小鼠胸腺/体重比值、脾脏/体重比值和肝脏/体重比值相比，差异有显著性（P＜0.05）。与肿瘤模型组比较，5-FU联合异常黑胆质成熟剂中剂量组、5-FU联合异常黑胆质成熟剂低剂量组的胸腺/体重比值均明显降低；与氟尿嘧啶对照组比较，5-FU联合异常黑胆质成熟剂高剂量组、5-FU联合异常黑胆质成熟剂中剂量组、5-FU联合异常黑胆质成熟剂低剂量组的脾脏/体重比值均明显升高，差异均有显著性（P＜0.05）。与肿瘤模型组比较，5-FU联合异常黑胆质成熟剂高剂量组、5-FU联合异常黑胆质成熟剂低剂量组的肝脏/体重比值变化明显，差异均有显著性（P＜0.05）。正常对照组与肿瘤模型组小鼠肝脏中SOD，GSH-PX，MDA含量相比，差异有显著性（P＜0.05）。与肿瘤模型组血清中SOD、GSH-PX含量比较，异常黑胆质成熟剂高低剂量组有显著升高，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组最高已接近正常值。与5-Fu对照组血清中SOD、GSH-PX含量比较，异常黑胆质成熟剂各剂量组有显著升高，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组SOD、GSH-PX含量最高已接近正常值。MDA值中异常黑胆质成熟剂中剂量组最低，与5-Fu对照组比较有显著降低，差异均有显著性（P＜0.05）。
3．异常黑胆质成熟剂各组与环磷酰胺组比较，异常黑胆质成熟剂高剂量组、异常黑胆质成熟剂中剂量组、异常黑胆质成熟剂低剂量组的脾脏/体重比值均明显升高，差异均有显著性（P＜0.05）。异常黑胆质成熟剂高剂量组、异常黑胆质成熟剂中剂量组、异常黑胆质成熟剂低剂量组和环磷酰胺组的抑瘤率分别为46.84%、59.53%，40.05%和49.71%。异常黑胆质成熟剂中剂量具有明显的抑瘤作用，但环磷酰胺组和异常黑胆质成熟剂高剂量组间的差别不明显。与肿瘤模型组血清中IL-1β含量相比，异常黑胆质成熟剂各剂量组有显著变化，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组IL-1β含量最高。与肿瘤模型组、环磷酰胺组血清中IL-2含量相比，异常黑胆质成熟剂各剂量组明显上升，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组最高。血清中TNF-α的含量，异常黑胆质成熟剂各剂量组均高于肿瘤模型组、环磷酰胺组，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组最高。与肿瘤模型组血清中IFN-γ含量相比，异常黑胆质成熟剂各剂量组有显著变化，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组IFN-γ含量最高。与肿瘤模型组、环磷酰胺组血清中IFN-γ含量相比，异常黑胆质成熟剂各剂量组相对上升，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组最高。血清中LPO的含量，异常黑胆质成熟剂各剂量组均低于肿瘤模型组、环磷酰胺组，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组最低。与肿瘤模型组血清中NK含量相比，异常黑胆质成熟剂各剂量组有显著变化，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组NK含量最高。肿瘤模型组与正常对照组相比，CD_8~+升高，CD3~+、CD4~+降低，CD4~+/CD_8~+比值降低。与肿瘤模型组比较，异常黑胆质成熟剂高剂量组CD4~+明显升高，CD4~+/CD_8~+比值升高，其中CD4~+/CD_8~+比值已经接近正常对照值。与肿瘤模型组比较，异常黑胆质成熟剂中剂量组CD3~+、CD4~+升高，CD4~+降低，CD4~+/CD_8~+比值升高，其中CD4~+/CD_8~+比值已经接近正常对照组值，异常黑胆质成熟剂低剂量组各指标均无显著性改善。正常对照组与肿瘤模型组小鼠肝脏中SOD，GSH-PX，MDA含量相比，差异有显著性（P＜0.05）。与肿瘤模型组小鼠肝脏中SOD，GSH-PX含量相比，异常黑胆质成熟剂各剂量组相对上升，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组最高。小鼠肝脏中的MDA含量，异常黑胆质成熟剂各剂量组均低于肿瘤模型组、环磷酰胺组，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组最低。通过HE染色法检查，小鼠肝脏、脾脏、胸腺等脏器正常，小鼠EAC肿瘤坏死及液化。
4．5-FU联合异常黑胆质成熟剂高剂量组、5-FU联合异常黑胆质成熟剂中剂量组、5-FU联合异常黑胆质成熟剂低剂量组和氟尿嘧啶对照组的抑瘤率分别为42.41%、58.09%，41.58%和50.83%。正常对照组与肿瘤模型组小鼠胸腺/体重比值、脾脏/体重比值和肝脏/体重比值相比，差异有显著性（P＜0.05）。与肿瘤模型组比较，5-FU联合异常黑胆质成熟剂中剂量组、5-FU联合异常黑胆质成熟剂低剂量组的胸腺/体重比值均明显降低；与氟尿嘧啶对照组比较，5-FU联合异常黑胆质成熟剂高剂量组、5-FU联合异常黑胆质成熟剂中剂量组、5-FU联合异常黑胆质成熟剂低剂量组的脾脏/体重比值均明显升高，差异均有显著性（P＜0.05）。与肿瘤模型组比较，5-FU联合异常黑胆质成熟剂高剂量组、5-FU联合异常黑胆质成熟剂低剂量组的肝脏/体重比值变化明显，差异均有显著性（P＜0.05）。正常对照组与肿瘤模型组小鼠血清中SOD，GSH-PX，MDA含量相比，差异有显著性（P＜0.05）。与肿瘤模型组血清中SOD、GSH-PX含量比较，5-FU联合异黑高低剂量组有显著升高，差异均有显著性（P＜0.05），其中5-FU联合异黑中剂量组最高，已接近正常值。与5-FU对照组血清中SOD、GSH-PX含量比较，5-FU联合异常黑胆质成熟剂各剂量组有显著升高，差异均有显著性（P＜0.05），其中5-FU联合异常黑胆质成熟剂中剂量组SOD、GSH-PX含量最高已接近正常值。MDA值5-FU联合异常黑胆质成熟剂中剂量最低，与肿瘤模型组比较有显著降低，差异均有显著性（P＜0.05）。
5．正常对照组与AF模型对照组小鼠血清中ALT，AST，TP含量相比，差异有显著性（P＜0.05）。与AF模型对照组血清中ALT，AST含量比较，异常黑胆质成熟剂各剂量组有显著降低，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组ALT，AST含量最低已接近正常值。TP值异常黑胆质成熟剂中剂量组最高，与AF模型对照组比较有显著升高，差异均有显著性（P＜0.05）。与正常对照组血清中ALT，AST含量比较，异常黑胆质成熟剂各剂量组有显著降低，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组最低。正常对照组与AF模型对照组心脏中SOD，GSH-PX，MDA含量相比，差异有显著性（P＜0.05）。与AF模型对照组心脏中SOD、GSH-PX含量比较，异常黑胆质成熟剂各剂量组有显著升高，差异均有显著性（P＜0.05），其中异黑中剂量组SOD、GSH-PX含量最高已接近正常值。异常黑胆质成熟剂中剂量组MDA值最低，与AF模型对照组比较有显著降低，差异均有显著性（P＜0.05）。
6．建立移植性肿瘤S-180小鼠模型进行爬竿、耐缺氧实验：异常黑胆质成熟剂各剂量与环磷酰胺组比较，异常黑胆质成熟剂高剂量组、异常黑胆质成熟剂中剂量组、异常黑胆质成熟剂低剂量组的脾脏/体重比值均明显升高，差异均有显著性（P＜0.05）。与肿瘤模型组比较，异常黑胆质成熟剂中剂量组和异常黑胆质成熟剂低剂量组的肝脏/体重比值变化明显，差异均有显著性（P＜0.05）。与环磷酰胺组血清中SOD、GSH-PX含量比较，异常黑胆质成熟剂各剂量组有升高，其中异常黑胆质成熟剂中剂量组SOD、GSH-PX含量已接近正常值，与环磷酰胺组比较有显著上升，差异均有显著性（P＜0.05）。MDA值异常黑胆质成熟剂中剂量最低，与肿瘤模型组比较有显著降低，差异均有显著性（P＜0.05）。肿瘤模型组与正常对照组相比，爬竿时间降低有显著性差异（P＜0.05）。与环磷酰胺组相比，异常黑胆质成熟剂各剂量组都能提高小鼠爬竿时间，尤以异常黑胆质成熟剂中剂量效果最为显著（P＜0.05）。与肿瘤模型组比较，异常黑胆质成熟剂各剂量组都能提高小鼠耐缺氧时间，差异均有显著性（P＜0.05）。与正常对照组相比，异常黑胆质成熟剂各剂量组都能提高小鼠耐缺氧时间，尤以异常黑胆质成熟剂中剂量效果最为显著。
7．建立移植性肿瘤EAC小鼠模型进行爬竿、耐缺氧实验：异常黑胆质成熟剂各剂量与环磷酰胺组比较，异常黑胆质成熟剂高剂量组、异常黑胆质成熟剂中剂量组、异常黑胆质成熟剂低剂量组的脾脏/体重比值均明显升高，差异均有显著性（P＜0.05）。与肿瘤模型组比较，异常黑胆质成熟剂中剂量组和异常黑胆质成熟剂低剂量组的肝脏/体重比值变化明显，差异均有显著性（P＜0.05）。肿瘤模型组与正常对照组相比，爬竿时间降低有显著性差异（P＜0.05）。与环磷酰胺组相比，异常黑胆质成熟剂各剂量组都能提高小鼠爬竿时间，尤以异常黑胆质成熟剂中剂量效果最为显著（P＜0.05）。与环磷酰胺组血清中SOD、GSH-PX含量比较，异常黑胆质成熟剂各剂量组有升高，其中异黑中剂量组SOD、GSH-PX含量已接近正常值，与环磷酰胺组比较有显著上升，差异均有显著性（P＜0.05）。MDA值异黑中剂量最低，与肿瘤模型组比较有降低。与正常对照组相比，异常黑胆质成熟剂各剂量组都能提高小鼠耐缺氧时间，尤以异常黑胆质成熟剂中剂量效果最好。与肿瘤模型组相比，异常黑胆质成熟剂各剂量组均有上升，差异均有显著性（P＜0.05）。与维拉帕米组相比，异常黑胆质成熟剂高低剂量组均有下降，差异均有显著性（P＜0.05）。
结论：
1．肿瘤是一种免疫缺陷性疾病，免疫机制的紊乱和相关抗肿瘤因子活性的降低、功能缺失是肿瘤发生、发展的重要内因。激活人体自主抗肿瘤免疫机制，增强细胞因子活性是治疗肿瘤的重要方面。本研究发现异常黑胆质成熟剂通过机体免疫功能的改善，免疫器官中抗氧化酶活性的提升、淋巴细胞亚群含量的调节、细胞因子的调控达到抑制肿瘤的作用。表现在移植性S-180和EAC肿瘤模型小鼠的肿瘤肿块体积减小、质量减轻、发生坏死和液化。
2．发现异常黑胆质成熟剂对化疗药AF致毒副作用具有良好的拮抗作用，能保护肝脏和心脏，能减少化疗药物对肝脏和心脏的损伤。能降低血清中的ALT，AST含量，提高TP的水平，同时提高模型小鼠心脏组织中SOD, GSH-PX的含量，降低MDA的水平。与模型组比较异常黑胆质成熟剂各剂量组没有心肌损伤，心肌细胞排列整齐，细胞没有空泡样变性，肌间隙没有变宽，心肌肌原纤维没有断裂，也没有点状坏死;肝细胞索排列整齐，细胞间隙正常，肝细胞没有肿胀，无水样变性或气球样变性，没有点状或灶状坏死。还发现异常黑胆质成熟剂能提高5-FU增效减毒模型小鼠血清中SOD, GSH-PX的含量，降低MDA的水平。
3．异常黑胆质成熟剂具有良好的抗氧化、耐缺氧和抗疲劳作用。与其他对照组比较异常黑胆质成熟剂可明显提高肿瘤模型小鼠一般生存状况，小鼠活动状态良好，皮毛基本光泽，体重没有明显降低。
4．与异常黑胆质成熟剂高剂量和低剂量组比较，在抑制移植性S-180和EAC肿瘤、对化疗药AF致毒副作用的拮抗作用、对5-FU增效减毒、对移植性肿瘤小鼠抗氧化、耐缺氧和抗疲劳等方面，异常黑胆质成熟剂中剂量组效果良好，差异显著。
Objective:
A number of anti-tumor agents including alkyl-ting agents, anti-tumor antibiotics,anti-metabolites and various other agents such as platinum derivatives, procarbazine andemetine have been administered alone or in a variety of combinations by different routesto treat carcinoma, but the predictable response rate is no more than20%. Additionally,adverse drug reactions are frequent. Some current trials have been investigating the use ofplant derivatives and much attention has been paid to Chinese herb since it has littletoxicity comparatively and is not susceptible to drug resistance and it plays the role ofanti-tumor by multiple means. Multi-drug resistance (MDR) is the protection of tumorcell population against numerous drugs which differ in structure and in actingmechanisms on the tumor cells. MDR is also one of the major causes of failure ofchemotherapy of human malignancies, which is related to many active mechanisms.Often several different mechanisms are switched on in the cells, but usually one majormechanism would operate. The active mechanisms are summarized as follows:1)activation of trans-membrane proteins refluxing different chemical substances from thecells (P-glycoprotein is the most known efflux pump);2) activation of the enzymes ofglutathione detoxification system; alteration of the genes and the proteins involved intothe control of apoptosis (especially P53and Bcl-2); changes of activity and quantity oftopoisomerases. Study on multi-drug resistance of tumor cell and to look forchemotherapy drug with effectiveness and little toxic have long been an interesting topicof research.
It is believed in Traditional Uighur medicine (TUM) that Abnormal Savda is apathological production resulted from the combustion of different body fluids known as Savda, Sapra, Belghem and Kan, which is believed to be the leading cause of cancers,and about90%of cancers are attributed to Abnormal Savda in clinical reports by TUM.Bahki Yusup and Tursun Tohti Haji, two of the most famous Uighur physicians, haveapplied the ASMq-TF in treatment of cancers based on the traditional therapy, whichdemonstrated remarkable clinical results, there by they gain the honor of “highly skilledphysician” by the local people.
Abnormal savda munziq (ASMq)(National Invention Patent No: C082130082.8) isan Uighur medical compound preparation，which consists of Cordia dichotoma, Ziziphusjujuba Mill, Glycyrrhiza uralensis Fisch, Anchusa italica Retz, Foeniculum vulgare Mill,Euphorbia humifusa Willd and other herbs, which are used to treat tumor, diabetes andcardiovascular disease caused by abnormal ASMq. Recent studies have shown that ASMqcan scavenge free radicals and protect DNA oxidative damage and mitochondrialoxidative damage from Hydroxyl free radical, resulting in inhibiting the growth ofHepG2in-vitro and its synthesis of protein, DNA and RNA significantly.
This study aims to explore the inhibitive effect of abnormal savda munziq on twokinds of transplanted tumor, protective effect of abnormal savda munziq onchemotherapy by reducing toxicity, synergistic attenuation of abnormal savda munziq onfluorouracil and further identify anticancer effect, the anti-fatigue and hypoxia resistanceeffect of abnormal savda munziq in vivo by hypoxia and pole climbing experiment.
Methods:
1．Establishment of transplanted S-180tumor model：180mice were randomized to6groups: normal control group, tumor control group, high-dose group of ASMq, middledose group of ASMq, low dose group of ASMq, cyclophosphamide (CY) control group.Indexes are measured in batch. Mouse tumor inhibition rate, spleen index, thymus indexand the index of liver are measured. Variation of mouse serum TNF-α, IL-1β, IL-2, IFN-γ,NK, LPO are observed. Pathological conditions of Tumor in mice spleen and other organsare examined by HE staining. By the MTT method, the proliferation of spleenlymphocytes in mice and variation of serum lymphocyte subsets such as CD_3~+, CD_4~+,CD_8~+, CD_4~+/CD_8~+are identified.
2．Establishment of transplanted S-180tumor model:60mice were randomlydivided into6groups: normal control group, tumor control group,5-fluorouracil (5-FU)group, high dose of5-FU ASMq group, middle dose of5-FU ASMq group, and low doseof5-FU ASMq group. Variations of mouse tumor inhibition rate, indexes of thymus, spleen and liver, mouse serum SOD, MDA, GSH-PX are observed.
3．Establishment of transplanted EAC tumor model:180mice were randomlydivided into six groups, normal control group, tumor control group, high-dose group ofASMq, middle dose group of ASMq, low dose group of ASMq, cyclophosphamide (CY)control group. Observation the mouse tumor inhibition rate, spleen index thymus index,and the index of liver, mouse TNF-α, IL-1β, IL-2, IFN-γ, NK, LPO content in serum andHE staining examination of tumor in mice spleen and other organs pathologicalconditions. Determination of the proliferation of murine spleen lymphocytes by MTTmethod and mouse serum lymphocyte subsets in CD_3~+, CD_4~+, CD_8~+, CD_4~+/CD_8~+.
4．Establishment of the transplanted EAC tumor model:60mice were randomlydivided into6groups: normal control group, tumor control group,5-fluorouracil (5-FU)group, high dose of5-FU ASMq group, middle dose of5-FU ASMq group, and low doseof5-FU ASMq group. Variations of mouse tumor inhibition rate, index of spleen, thymus,and liver, mouse serum SOD, MDA, GSH-PX are observed.
5．Establishment of chemotherapy drug toxicity model:50mice were randomlydivided into5groups: normal control group, tumor control group，AF（amycin and5-fluorouracil (5-Fu) group, AF~+ASMq high dose group, AF~+ASMq middle dose group,and AF~+ASMq low dose group. Spleen, liver and thymus index，mouse serum ALT, AST,TP content, SOD in mouse heart, MDA, GSH-PX content are observed and pathologicconditions of mouse heart, liver and other viscera are examined by HE staining methods.
6．Establishment of transplanted S-180tumor model and EAC tumor modelrespectively: ASMq effect on mice serum SOD, MDA, GSH-PX indexes, as well as onmouse tumor inhibition rate, spleen index, thymus index and liver index are evaluated;ASMq effect on mice under normal pressure hypoxia tolerance test and polele test areevaluated.
Results:
1．Comparison between each dose group of ASMq and cyclophosphamide: Thespleen/weight ratio increased significantly in each dose group of ASMq (P＜0.05). Theinhibition rate of each dose group of ASMq and cyclophosphamide were49.5%、64.26%、43.43%and50.88%respectively, in which inhibitory effect was observed. But there wereno significant differences between the cyclophosphamide and ASMq high does group.Compared with tumor model group, serum IL-1β level varied in ASMq every dose groupsignificantly (P＜0.05), the content of IL-1β was the highest in ASMq middle dose group. Compared to the group of tumor model and positive control, Serum IL-2contentincreased in every dose group of ASMq significantly (P＜0.05), and ASMq middle dosegroup was the highest. The serum TNF-α content was higher in every dose group ofASMq than in the tumor model group and in cyclophosphamide, there was significantdifference (P＜0.05), which was the highest in ASMq middle dose group. Compared withtumor model group, serum IFN-γ content varied in every dose group of ASMqsignificantly (P＜0.05), the content of IL-1β was the highest in ASMq middle dose group.Compared to tumor model group and cyclophosphamide, Serum IFN-γ content increasesin every dose group of ASMq, there was significant difference (P＜0.05), Serum IFN-γwas the highesin in ASMq middle dose group. The serum LPO content in every dosegroup of ASMq were all lower than tumor model group and cyclophosphamide, there wassignificant difference (P＜0.05), and serum LPO was the lowest in ASMq middle dosegroup. Compared with tumor model group, the serum NK content varied significantly inevery dose group of ASMq, there was significant difference (P＜0.05), the content of NKwas the highest in ASMq middle dose group. In ASMq high dose group, CD_3~+, CD_8~+andCD_4~+was reduced apparently, the CD_4~+/CD_8~+ratio increased and The CD_4~+/CD_8~+ratiowas close to the normal value. In ASMq middle dose group, CD_8~+decreased, CD_3~+, CD_4~+CD_8~+and CD_4~+was reduced apparently, the CD_4~+/CD_8~+ratio increased. The CD_4~+/CD_8~+ratio was close to the normal value. There was no significant improvement in the ASMqlow dose group. Comparison between normal control and tumor model group, the SOD，GSH-PX, MDA content in the liver of both ASMq and tumor groups were significantlydifferent. The difference was significant (P＜0.05). The SOD，GSH-PX content in theliver of ASMq every dose group increased, there was significant difference (P＜0.05),ASMq middle dose group was the highest. The MDA content in mouse liver, of everydose group of ASMq were all lower than tumor model group and cyclophosphamidegroup, there was significant difference (P＜0.05). ASMq middle dose group was thelowest. After examinations of mouse liver, spleen, thymus and other organs by HEstaining methods, Pathological conditions are all shown normal, necrosis and liquefactionof transplanted S-180tumor mouse tumor was observed.
2．The inhibition rates of5-Fu-ASMq high dose group,5-Fu-ASMq middle dosegroup, low dose group of5-Fu~+ASMq And5-fluorouracil group were52.26%,66.41%,44.87%and48.02%. There was significant difference between normal control group and5-Fu group in SOD, GSH-PX content in serum(P＜0.05), SOD, GSH-PX contentdecreased significantly in every dose group of ASMq, In ASMq middle dose group, the highest content of SOD GSH-PX was close to the normal value. The MDA value ofwhich was lowest there was significantly reduced comparing with the5-Fu control group,the difference was significant (P＜0.05). Compared to tumor model group with, serumSOD, GSH-PX content in the model group, both ASMq high and low dose groups weresignificantly lower. The difference was significant (P＜0.05), in which the ASMq middledose group maximum has been close to or exceed the normal values.
3． Compared with the spleen/weight ratio each group of ASMq andcyclophosphamide, ASMq every dose group significantly increased, there was significantdifference (P＜0.05), in which ASMq middle dose group. The inhibition rate of eachdose ASMq and cyclophosphamide were49.5%、64.26%、43.43%and50.88%respectively, which inhibitory effect was observed, but there has no difference betweenthe groups of cyclophosphamide and ASMq. Compared with the serum IL-1βcontent,ASMq every dose group significantly changed, there was significant difference (P＜0.05),the content of IL-1βwas the highest in which ASMq middle dose group Compared withthe serum IL-1βcontent between the group of tumor model and positive control, ASMqevery dose group significantly increased, there was significant difference (P＜0.05), inwhich ASMq middle dose group was the highest, The serum TNF-αcontent in ASMqevery dose group were all higher than tumor model group and cyclophosphamide, therewas significant difference (P＜0.05),. in which ASMq middle dose group was the highest,Compared with the serum IFN-γ content, ASMq every dose group significantly changed,there was significant difference (P＜0.05), the content of IL-1βwas the highest in whichASMq middle dose group. Compared with the serum IFN-γ content in tumor modelgroup and cyclophosphamide, ASMq every dose group of relative to rise, there wassignificant difference (P＜0.05), in which ASMq middle dose group was the highest, Theserum LPO content in ASMq every dose group were all lower than tumor model groupand cyclophosphamide, there was significant difference (P＜0.05), in which ASMqmiddle dose group was the lowest, Compared with the serum NK content, ASMq everydose group significantly changed, there was significant difference (P＜0.05), the contentof NK was the highest in which ASMq middle dose group ASMq high dose group, CD_3~+、CD_8~+and CD_4~+was reduced apparently, the CD_4~+/CD_8~+ratio increased, and TheCD_4~+/CD_8~+ratio was close to the normal value. ASMq middle dose group, CD_8~+decreased, CD_3~+、CD_4~+CD_8~+and CD_4~+was reduced apparently, the CD_4~+/CD_8~+ratioincreased, elevated CD_4~+/CD_8~+ratio increased, and this ratio was close to the normalvalue. There was no significant improvement with the ASMq low dose group. Compared with, the SOD, GSH-PX, MDA content in the liver of both ASMq and tumor groups weresignificantly difference. The difference was significant (P＜0.05).Compared with theSOD，GSH-PX content in the liver of tumor model group, ASMq every dose group ofrelative to rise, there was significant difference (P＜0.05), in which ASMq middle dosegroup was the highest, Compared with the MDA content in mouse liver, ASMq everydose group were all lower than tumor model group and cyclophosphamide, there wassignificant difference (P＜0.05), in which ASMq middle dose group was the lowest, HEstaining methods of mouse liver, spleen, thymus and other organs Pathological conditionsare all normally, transplanted S-180tumor mouse tumor necrosis and liquefaction.
4．In the5-FU high-dose ASMq group,5-FU medium-dose ASMq group,5-FUlow-dose ASMq group and5-FU group, the values of tumor inhibition rate were42.41%、58.09%,41.58%and50.83%, respectively, showing that tumor function had beenweakened. Compared with the model group, the thymus/body weight ratio was clearlyreduced in the5-FU medium-dose ASMq group and5-FU low-dose ASMq group.Compared with the5-FU group, the spleen/body weight ratio was clearly increased in the5-FU high-dose ASMq group,5-FU medium-dose ASMq group, and5-FU low-doseASMq group, and the difference was significant (P＜0.05). The5-FU ASMq dose groupshad reduced levels of SOD and GSH-PX compared with the5-FU control group, and thedifference was significant (P＜0.05). In the5-FU medium-dose ASMq group, SOD andGSH-PX levels were high. With respect to MDA values, the5-FU medium-dose ASMqgroup had the lowest values and in comparison with the model control group, thedifference was significant (P＜0.05). With respect to SOD and GSH-PX levels, comparedwith the model group, the5-FU high dose ASMq group had lower levels, and thedifference was significant (P＜0.05).
5．Compared with the AF model group,serum ALT, AST content, in every dosegroup of ASMq significantly decreased, there was significant difference (P＜0.05), whichwas the lowest in ASMq middle dose group, ALT, AST content were close to the normalvalue. The TP value of ASMq middle dose group is the highest, compared to the AFmodel control group, which had significantly increased, the difference was significant (P＜0.05). Compared with the normal control group, serum ALT, AST content in abnormalsavda munziq every dose group significantly decreased, there was significant difference(P＜0.05), TP value of which in the ASMq middle dose group was the highest. Comparedwith the AF model group, SOD, GSH-PX content in the heart, significantly increased inASMq every dose group. The difference was significant (P＜0.05), in which ASMq middle dose group had the highest content of SOD, GSH-PX and which were close to thenormal values. Compared with the AF model group, MDA value of ASMq with middledoses was significantly lower; the difference was significant (P＜0.05). Compared withthe normal control group SOD, GSH-PX content in the heart, ASMq high and low dosegroups were significantly lower. The difference was significant (P＜0.05), in which theASMq middle dose group maximum has been close to or exceed the normal values.ASMq cannot only improve the spleen index, but also reduce the serum levels of ALT,AST content and improve the mouse heart SOD, GSH-PX content, and protect the heartand liver in preventing necrosis.
6．Experiments of transplanted tumor S-180mice model for climbing, hypoxiatolerance: Compared with cyclophosphamide group, ASMq high dose group, mediumdose group, low dose group showed significantly higher spleen/body weight ratio; thedifferences were significant (P＜0.05). Compared with tumor model group, the abnormalsavda munziq middle dose group and low dose group have obvious liver/body weightratio changes, the difference was significant (P＜0.05). Compared with cyclophos-phamide group, in terms of the content of SOD, GSH-PX in serum, every dose group ofabnormal Savda Munziq is increased significantly, and is close to the normal level; thedifference was significant (P＜0.05). The dose of MDA in abnormal savda munziq is thelowest, compared with tumor model group; the difference was significant (P＜0.05).Compared tumor model group with normal controls, the time of climbing was decreasedsignificantly (P＜0.05). Compared with cyclophosphamide, every dose group ofabnormal savda munziq can improve the time of mice climbing, particularly in abnormalsavda munziq dose for which the effect is significant (P＜0.05). Compared with tumormodel group, every dose group of abnormal savda munziq can enhance the time of micehypoxia tolerance, and there is significant difference (P＜0.05). Compared with thenormal control group, every dose group of abnormal savda munziq can enhance the timeof hypoxia tolerance; especially for the dose of abnormal savda munziq the effect is mostremarkable.
7．Experiments of transplanted EAC tumor mice model for climbing, hypoxiatolerance test: Compared with cyclophosphamide group, the abnormal savda munziq highdose group, middle dose group, and low dose group have increased spleen/body weightratio, the difference was significant (P＜0.05). Compared with tumor model group, theabnormal savda munziq middle dose group and the low dose group have obviousliver/body weight ratio changes; the difference was significant (P＜0.05). Compared the model group tumor with normal control group, the climbing time was decreasedsignificantly (P＜0.05). Compared with cyclophosphamide group, every dose group ofabnormal savda munziq can improve the mice climbing time, particularly for the dose ofabnormal savda munziq the effect is significant (P＜0.05). Compared the content of SOD,GSH-PX in serum of cyclophosphamide group, every dose group of abnormal savdamunziq was increased, in which the content of SOD, GSH-PX of middle dose group isclose to the normal value, and cyclophosphamide group was increased significantly, thedifference was significant (P＜0.05). The MDA value of abnormal savda munziq is lowerthan tumor model group. Compared with the normal control group, every dose ofabnormal savda munziq group can enhance hypoxia tolerance in mice; especially themiddle dose abnormal savda munziq is the best. Compared with tumor model, every dosegroup of abnormal savda munziq was increased; the difference was significant (P＜0.05).Compared with verapamil, the abnormal savda munziq high and low dose groups weredecreased, and the difference was significant (P＜0.05).
Conclusion:
1．Tumor is an immunodeficiency disease, which is mainly caused by immunesystem disorders, decreased anti-tumor activity factor and loss of function. Activating thebody independent anti-tumor immune mechanisms and strengthening the activity ofcytokines are important aspects of cancer treatment. This study found that ASMq canimprove immune system function, enhance antioxidant enzyme activity in immuneorgans, and regulate the lymphocyte subsets levels and cytokines to reach the purpose oftumor suppression. Performance of experiments in transplanted S-180and EAC tumormodels in mice showed decreased mass volume, decreased weight, and necrosis andliquefaction in the tumor, by thus the anti-tumor rate increased.
2． The ASMq has a good antagonism on the toxicity side effects of thechemotherapy drug doxorubicin and5-fluorouracil (AF), it can protect the liver and heartand reduce the damage of chemotherapeutic drugs on the liver and heart. It can reduceserumin ALT, AST content and improve the level of TP. It increases the content of themouse model of heart tissue SOD and GSH-PX, and reduces the level of MDA.Abnormal black Munziq can improve the content of serum SOD and GSH-PX in5-fluorouracil Reducing Toxicity Model and reduce the level of MDA.
3．The ASMq has a function of anti-oxidation, hypoxia and anti-fatigue effect invivo. Compared with the other control group, ASMq can significantly improve the general living conditions of the tumor model mice, active state and mouse fur luster,while weight is not significantly reduced.
4．It was found that compared to ASMq high dose group and low dose group, interms of suppressing the transplanted S-180and EAC tumor, the protective effect of toxicside effects induced by the chemotherapy drug doxorubicin and5-fluorouracil (AF),5-fluorouracil efficiency attenuation, anti-oxidation, hypoxia and anti-fatigue effect inclimbing the pole and hypoxia experiment, ASMq middle dose group shows better effect
肿瘤是严重威胁人类健康的一类复杂性、疑难性疾病。寻找有效的抗肿瘤药物以及方法，彻底攻克肿瘤等复杂性疾病是全世界医学界的重要研究课题。肿瘤的治疗强调综合治疗，中医药、维医药的应用可使患者症状显著改善并保持全身状态好转，延缓病情发展，亦可使肿瘤缩小或带瘤而长期生存，故其在中晚期肿瘤的综合治疗中占有重要地位。肿瘤在化疗的过程中出现多药耐药（Multidrug resistanceMDR）是化疗失败的主要原因之一。当今抗肿瘤药物发展战略之一是从天然药物中寻找其活性成分，而新疆有丰富的中维药资源以及数千年的中维药理论与实践经验，对中维药抗肿瘤作用的研究与开发前景良好。目前已筛选出一些具有抗肿瘤作用的天然中药及单体，如苦参碱、苦杏仁甘、紫杉醇等，其中一些已广泛地应用于临床，显示出良好的效果。同样，天然药物中寻找逆转肿瘤耐药性及增效化疗药物的作用的有效低毒的逆转剂，长期以来一直是全世界医学界关注的的热点。
维吾尔医学认为，异常黑胆质作为胆液质、血液质、粘液质、黑胆质被“燃烧”，继而“沉淀”最终形成病理产物或表现形式，经常导致肿瘤、哮喘等难治性疾病。临床决大部分肿瘤患者表现为异常黑胆质性。新疆维吾尔自治区名老维吾尔医巴黑玉素甫和吐尔逊托乎提阿吉等多年来根据维医理论和临床治疗原则将维医异常黑胆质成熟剂应用于癌症以及哮喘患者的治疗，取得良好的疗效，被患者誉为“神医”。
异常黑胆质成熟剂（国家发明专利№：C082130082.8），又称异黑成熟颗粒，是维吾尔医复方制剂。由破布木（Cordia dichotoma Forst.）、红枣（Ziziphus jujubaMill.）、甘草（Glycyrrhiza uralensis Fisch.）、牛舌草（Anchusa italica Retz.）、小茴香（Foeniculum vulgare Mill.）、地锦草（Euphorbia humifusa Willd.）等药材组成，临床应用于由异常黑胆质所导致的肿瘤、糖尿病和心血管疾病等复杂性疾病。以哈木拉提.吾甫尔教授为首的课题组在以往的研究表明，异常黑胆质成熟剂可清除自由基，保护羟自由基引发的DNA氧化损伤和线粒体氧化损伤等，具有较强的抑制HepG2细胞体外生长、抑制HepG2细胞DNA、RNA和蛋白质生物合成；异常黑胆质成熟剂具有体外逆转肿瘤细胞多药耐药性之功效；对结肠癌细胞（Caco-2）体外抗癌作用；有抑制DMH诱发的大鼠结肠ACF形成的作用；肝癌耐药细胞（Bel/Fu）具有逆转多药耐药MDR的作用；异常黑胆质成熟剂总酚与顺铂、多西他赛联用对体外培养的人宫颈癌HeLa细胞增殖和凋亡的影响等研究。
本研究目的在于研究异常黑胆质成熟剂对两种移植性肿瘤（S-180和EAC）的抑制作用，对化疗药物（阿霉素和5-氟尿嘧啶）致毒副作用的拮抗作用，对氟尿嘧啶的增效减毒作用以及通过耐缺氧和爬杆实验，进一步确定异常黑胆质成熟剂的体内抗癌作用和抗疲劳、耐缺氧和抗氧化作用。
方法：
1．建立移植性S-180肿瘤模型：180只小鼠，随机分为6组，正常对照组、肿瘤模型组、异黑高剂量组、异黑中剂量组、异黑低剂量组、环磷酰胺（CY）对照组。分批测指标，观察小鼠抑瘤率、脾指数、胸腺指数和肝脏指数，小鼠血清中的TNF-α，IL-1β，IL-2，IFN-γ、NK、LPO含量变化以及用HE染色法检查小鼠肿瘤、脾脏等脏器的情况，用MTT法测定小鼠脾脏淋巴细胞增殖情况，小鼠全血中的淋巴细胞亚群CD_3~+、CD_4~+、CD_8~+、CD_4~+/CD_8~+含量变化。
2．建立移植性S-180肿瘤模型：60只小鼠，随机分为6组，正常对照组，肿瘤模型组、5-氟尿嘧啶（5-FU）对照组、5-FU联合异黑高剂量组、5-FU联合异黑中剂量组、5-FU联合异黑低剂量组。观察小鼠抑瘤率、脾指数、胸腺指数和肝脏指数，小鼠血清中的SOD、MDA、GSH-PX的含量变化。
3．建立移植性EAC肿瘤模型：180只小鼠，随机分为6组，正常对照组、肿瘤模型组、异黑高剂量组、异黑中剂量组、异黑低剂量组、环磷酰胺（CY）对照组。分批测指标，观察小鼠抑瘤率、脾指数、胸腺指数和肝脏指数，小鼠血清中的TNF-α，IL-1β，IL-2，IFN-γ、NK、LPO含量变化以及用HE染色法检查小鼠肿瘤、脾脏等脏器的情况，用MTT法测定小鼠脾脏淋巴细胞增殖情况，小鼠全血中的淋巴细胞亚群CD_3~+、CD_4~+、CD_8~+、CD_4~+/CD_8~+含量变化。
4．建立移植性EAC肿瘤模型：60只小鼠，随机分为6组，正常对照组，肿瘤模型组、5-氟尿嘧啶（5-Fu）对照组、5-FU联合异黑高剂量组、5-FU联合异黑中剂量组、5-FU联合异黑低剂量组。观察小鼠抑瘤率、脾指数、胸腺指数和肝脏指数，小鼠血清中的SOD、MDA、GSH-PX的含量变化。
5．建立化疗药（阿霉素和5-氟尿嘧啶）毒副作用模型：50只小鼠，随机分为5组，正常对照组、AF（阿霉素和5-氟尿嘧啶）模型对照组、AF~+异黑高剂量组、AF~+异黑中剂量组、AF~+异黑低剂量组。观察小鼠脾指数、胸腺指数和肝脏指数，小鼠血清中的ALT、AST、TP含量变化和小鼠心脏中SOD、MDA、GSH-PX的含量变化以及用HE染色法检查小鼠心脏、肝脏等脏器的情况。
6．分别建立移植性S-180肿瘤模型和建立移植性EAC肿瘤模型：研究异常黑胆质成熟剂对小鼠血清的SOD、MDA、GSH-PX指标的影响，以及对小鼠的抑瘤率、脾指数、胸腺指数和肝脏指数的影响；异常黑胆质成熟剂对小鼠常压耐缺氧试验和爬竿试验的影响。
结果：
1．异常黑胆质成熟剂各组与环磷酰胺组比较：异常黑胆质成熟剂高剂量组、异常黑胆质成熟剂中剂量组、异常黑胆质成熟剂低剂量组的脾脏/体重比值均明显升高，差异均有显著性（P＜0.05）。异常黑胆质成熟剂高剂量组、异常黑胆质成熟剂中剂量组、异常黑胆质成熟剂低剂量组和环磷酰胺组的抑瘤率分别为49.05%、64.26%，43.43%和50.88%具有明显的抑瘤作用，但环磷酰胺组和异黑高剂量组间的差别不明显。与肿瘤模型组血清中IL-1β含量相比，异黑各剂量组有显著变化，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组IL-1β含量最高。与肿瘤模型组、阳性对照组血清中IL-2含量相比，异常黑胆质成熟剂各剂量组相对上升，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组最高。血清中TNF-α的含量，异常黑胆质成熟剂各剂量组均高于肿瘤模型组、环磷酰胺组，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组最高。与肿瘤模型组血清中IFN-γ含量相比，异常黑胆质成熟剂各剂量组有显著变化，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组IFN-γ含量最高。与肿瘤模型组、环磷酰胺组血清中IFN-γ含量相比，异常黑胆质成熟剂各剂量组相对上升，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组最高。血清中LPO的含量，异常黑胆质成熟剂各剂量组均低于肿瘤模型组、环磷酰胺组，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组最低。与肿瘤模型组血清中NK含量相比，异常黑胆质成熟剂各剂量组有显著变化，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组NK含量最高。异常黑胆质成熟剂高剂量组CD_3~+、CD_8~+和CD_4~+明显降低，CD_4~+/CD_8~+比值升高，其中CD_4~+/CD_8~+比值已经接近正常对照值（与肿瘤模型组比较差异有显著性，与正常对照组比较差异无显著性）。异常黑胆质成熟剂中剂量组CD_8~+降低，CD_3~+、CD_4~+明显升高，CD_4~+/CD_8~+比值升高，其中CD_4~+/CD_8~+比值已经接近正常对照组值，异常黑胆质成熟剂低剂量组各指标均无显著性改善。正常对照组与肿瘤模型组小鼠肝脏中SOD，GSH-PX，MDA含量相比，差异有显著性（P＜0.05）。与肿瘤模型组小鼠肝脏中SOD，GSH-PX含量相比，异常黑胆质成熟剂各剂量组相对上升，差异均有显著性（P＜0.05），其中异黑颗粒中剂量组最高。小鼠肝脏中的MDA含量，异常黑胆质成熟剂各剂量组均低于肿瘤模型组及环磷酰胺组，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组最低。通过HE染色法检查，小鼠肝脏、脾脏、胸腺等脏器正常，小鼠S-180肿瘤坏死及液化。
2．5-FU联合异常黑胆质成熟剂高剂量组、5-FU联合异常黑胆质成熟剂中剂量组、5-FU联合异常黑胆质成熟剂低剂量组和氟尿嘧啶对照组的抑瘤率分别为52.26%、66.41%，44.87%和48.02%。正常对照组与肿瘤模型组小鼠胸腺/体重比值、脾脏/体重比值和肝脏/体重比值相比，差异有显著性（P＜0.05）。与肿瘤模型组比较，5-FU联合异常黑胆质成熟剂中剂量组、5-FU联合异常黑胆质成熟剂低剂量组的胸腺/体重比值均明显降低；与氟尿嘧啶对照组比较，5-FU联合异常黑胆质成熟剂高剂量组、5-FU联合异常黑胆质成熟剂中剂量组、5-FU联合异常黑胆质成熟剂低剂量组的脾脏/体重比值均明显升高，差异均有显著性（P＜0.05）。与肿瘤模型组比较，5-FU联合异常黑胆质成熟剂高剂量组、5-FU联合异常黑胆质成熟剂低剂量组的肝脏/体重比值变化明显，差异均有显著性（P＜0.05）。正常对照组与肿瘤模型组小鼠肝脏中SOD，GSH-PX，MDA含量相比，差异有显著性（P＜0.05）。与肿瘤模型组血清中SOD、GSH-PX含量比较，异常黑胆质成熟剂高低剂量组有显著升高，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组最高已接近正常值。与5-Fu对照组血清中SOD、GSH-PX含量比较，异常黑胆质成熟剂各剂量组有显著升高，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组SOD、GSH-PX含量最高已接近正常值。MDA值中异常黑胆质成熟剂中剂量组最低，与5-Fu对照组比较有显著降低，差异均有显著性（P＜0.05）。
3．异常黑胆质成熟剂各组与环磷酰胺组比较，异常黑胆质成熟剂高剂量组、异常黑胆质成熟剂中剂量组、异常黑胆质成熟剂低剂量组的脾脏/体重比值均明显升高，差异均有显著性（P＜0.05）。异常黑胆质成熟剂高剂量组、异常黑胆质成熟剂中剂量组、异常黑胆质成熟剂低剂量组和环磷酰胺组的抑瘤率分别为46.84%、59.53%，40.05%和49.71%。异常黑胆质成熟剂中剂量具有明显的抑瘤作用，但环磷酰胺组和异常黑胆质成熟剂高剂量组间的差别不明显。与肿瘤模型组血清中IL-1β含量相比，异常黑胆质成熟剂各剂量组有显著变化，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组IL-1β含量最高。与肿瘤模型组、环磷酰胺组血清中IL-2含量相比，异常黑胆质成熟剂各剂量组明显上升，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组最高。血清中TNF-α的含量，异常黑胆质成熟剂各剂量组均高于肿瘤模型组、环磷酰胺组，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组最高。与肿瘤模型组血清中IFN-γ含量相比，异常黑胆质成熟剂各剂量组有显著变化，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组IFN-γ含量最高。与肿瘤模型组、环磷酰胺组血清中IFN-γ含量相比，异常黑胆质成熟剂各剂量组相对上升，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组最高。血清中LPO的含量，异常黑胆质成熟剂各剂量组均低于肿瘤模型组、环磷酰胺组，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组最低。与肿瘤模型组血清中NK含量相比，异常黑胆质成熟剂各剂量组有显著变化，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组NK含量最高。肿瘤模型组与正常对照组相比，CD_8~+升高，CD3~+、CD4~+降低，CD4~+/CD_8~+比值降低。与肿瘤模型组比较，异常黑胆质成熟剂高剂量组CD4~+明显升高，CD4~+/CD_8~+比值升高，其中CD4~+/CD_8~+比值已经接近正常对照值。与肿瘤模型组比较，异常黑胆质成熟剂中剂量组CD3~+、CD4~+升高，CD4~+降低，CD4~+/CD_8~+比值升高，其中CD4~+/CD_8~+比值已经接近正常对照组值，异常黑胆质成熟剂低剂量组各指标均无显著性改善。正常对照组与肿瘤模型组小鼠肝脏中SOD，GSH-PX，MDA含量相比，差异有显著性（P＜0.05）。与肿瘤模型组小鼠肝脏中SOD，GSH-PX含量相比，异常黑胆质成熟剂各剂量组相对上升，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组最高。小鼠肝脏中的MDA含量，异常黑胆质成熟剂各剂量组均低于肿瘤模型组、环磷酰胺组，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组最低。通过HE染色法检查，小鼠肝脏、脾脏、胸腺等脏器正常，小鼠EAC肿瘤坏死及液化。
4．5-FU联合异常黑胆质成熟剂高剂量组、5-FU联合异常黑胆质成熟剂中剂量组、5-FU联合异常黑胆质成熟剂低剂量组和氟尿嘧啶对照组的抑瘤率分别为42.41%、58.09%，41.58%和50.83%。正常对照组与肿瘤模型组小鼠胸腺/体重比值、脾脏/体重比值和肝脏/体重比值相比，差异有显著性（P＜0.05）。与肿瘤模型组比较，5-FU联合异常黑胆质成熟剂中剂量组、5-FU联合异常黑胆质成熟剂低剂量组的胸腺/体重比值均明显降低；与氟尿嘧啶对照组比较，5-FU联合异常黑胆质成熟剂高剂量组、5-FU联合异常黑胆质成熟剂中剂量组、5-FU联合异常黑胆质成熟剂低剂量组的脾脏/体重比值均明显升高，差异均有显著性（P＜0.05）。与肿瘤模型组比较，5-FU联合异常黑胆质成熟剂高剂量组、5-FU联合异常黑胆质成熟剂低剂量组的肝脏/体重比值变化明显，差异均有显著性（P＜0.05）。正常对照组与肿瘤模型组小鼠血清中SOD，GSH-PX，MDA含量相比，差异有显著性（P＜0.05）。与肿瘤模型组血清中SOD、GSH-PX含量比较，5-FU联合异黑高低剂量组有显著升高，差异均有显著性（P＜0.05），其中5-FU联合异黑中剂量组最高，已接近正常值。与5-FU对照组血清中SOD、GSH-PX含量比较，5-FU联合异常黑胆质成熟剂各剂量组有显著升高，差异均有显著性（P＜0.05），其中5-FU联合异常黑胆质成熟剂中剂量组SOD、GSH-PX含量最高已接近正常值。MDA值5-FU联合异常黑胆质成熟剂中剂量最低，与肿瘤模型组比较有显著降低，差异均有显著性（P＜0.05）。
5．正常对照组与AF模型对照组小鼠血清中ALT，AST，TP含量相比，差异有显著性（P＜0.05）。与AF模型对照组血清中ALT，AST含量比较，异常黑胆质成熟剂各剂量组有显著降低，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组ALT，AST含量最低已接近正常值。TP值异常黑胆质成熟剂中剂量组最高，与AF模型对照组比较有显著升高，差异均有显著性（P＜0.05）。与正常对照组血清中ALT，AST含量比较，异常黑胆质成熟剂各剂量组有显著降低，差异均有显著性（P＜0.05），其中异常黑胆质成熟剂中剂量组最低。正常对照组与AF模型对照组心脏中SOD，GSH-PX，MDA含量相比，差异有显著性（P＜0.05）。与AF模型对照组心脏中SOD、GSH-PX含量比较，异常黑胆质成熟剂各剂量组有显著升高，差异均有显著性（P＜0.05），其中异黑中剂量组SOD、GSH-PX含量最高已接近正常值。异常黑胆质成熟剂中剂量组MDA值最低，与AF模型对照组比较有显著降低，差异均有显著性（P＜0.05）。
6．建立移植性肿瘤S-180小鼠模型进行爬竿、耐缺氧实验：异常黑胆质成熟剂各剂量与环磷酰胺组比较，异常黑胆质成熟剂高剂量组、异常黑胆质成熟剂中剂量组、异常黑胆质成熟剂低剂量组的脾脏/体重比值均明显升高，差异均有显著性（P＜0.05）。与肿瘤模型组比较，异常黑胆质成熟剂中剂量组和异常黑胆质成熟剂低剂量组的肝脏/体重比值变化明显，差异均有显著性（P＜0.05）。与环磷酰胺组血清中SOD、GSH-PX含量比较，异常黑胆质成熟剂各剂量组有升高，其中异常黑胆质成熟剂中剂量组SOD、GSH-PX含量已接近正常值，与环磷酰胺组比较有显著上升，差异均有显著性（P＜0.05）。MDA值异常黑胆质成熟剂中剂量最低，与肿瘤模型组比较有显著降低，差异均有显著性（P＜0.05）。肿瘤模型组与正常对照组相比，爬竿时间降低有显著性差异（P＜0.05）。与环磷酰胺组相比，异常黑胆质成熟剂各剂量组都能提高小鼠爬竿时间，尤以异常黑胆质成熟剂中剂量效果最为显著（P＜0.05）。与肿瘤模型组比较，异常黑胆质成熟剂各剂量组都能提高小鼠耐缺氧时间，差异均有显著性（P＜0.05）。与正常对照组相比，异常黑胆质成熟剂各剂量组都能提高小鼠耐缺氧时间，尤以异常黑胆质成熟剂中剂量效果最为显著。
7．建立移植性肿瘤EAC小鼠模型进行爬竿、耐缺氧实验：异常黑胆质成熟剂各剂量与环磷酰胺组比较，异常黑胆质成熟剂高剂量组、异常黑胆质成熟剂中剂量组、异常黑胆质成熟剂低剂量组的脾脏/体重比值均明显升高，差异均有显著性（P＜0.05）。与肿瘤模型组比较，异常黑胆质成熟剂中剂量组和异常黑胆质成熟剂低剂量组的肝脏/体重比值变化明显，差异均有显著性（P＜0.05）。肿瘤模型组与正常对照组相比，爬竿时间降低有显著性差异（P＜0.05）。与环磷酰胺组相比，异常黑胆质成熟剂各剂量组都能提高小鼠爬竿时间，尤以异常黑胆质成熟剂中剂量效果最为显著（P＜0.05）。与环磷酰胺组血清中SOD、GSH-PX含量比较，异常黑胆质成熟剂各剂量组有升高，其中异黑中剂量组SOD、GSH-PX含量已接近正常值，与环磷酰胺组比较有显著上升，差异均有显著性（P＜0.05）。MDA值异黑中剂量最低，与肿瘤模型组比较有降低。与正常对照组相比，异常黑胆质成熟剂各剂量组都能提高小鼠耐缺氧时间，尤以异常黑胆质成熟剂中剂量效果最好。与肿瘤模型组相比，异常黑胆质成熟剂各剂量组均有上升，差异均有显著性（P＜0.05）。与维拉帕米组相比，异常黑胆质成熟剂高低剂量组均有下降，差异均有显著性（P＜0.05）。
结论：
1．肿瘤是一种免疫缺陷性疾病，免疫机制的紊乱和相关抗肿瘤因子活性的降低、功能缺失是肿瘤发生、发展的重要内因。激活人体自主抗肿瘤免疫机制，增强细胞因子活性是治疗肿瘤的重要方面。本研究发现异常黑胆质成熟剂通过机体免疫功能的改善，免疫器官中抗氧化酶活性的提升、淋巴细胞亚群含量的调节、细胞因子的调控达到抑制肿瘤的作用。表现在移植性S-180和EAC肿瘤模型小鼠的肿瘤肿块体积减小、质量减轻、发生坏死和液化。
2．发现异常黑胆质成熟剂对化疗药AF致毒副作用具有良好的拮抗作用，能保护肝脏和心脏，能减少化疗药物对肝脏和心脏的损伤。能降低血清中的ALT，AST含量，提高TP的水平，同时提高模型小鼠心脏组织中SOD, GSH-PX的含量，降低MDA的水平。与模型组比较异常黑胆质成熟剂各剂量组没有心肌损伤，心肌细胞排列整齐，细胞没有空泡样变性，肌间隙没有变宽，心肌肌原纤维没有断裂，也没有点状坏死;肝细胞索排列整齐，细胞间隙正常，肝细胞没有肿胀，无水样变性或气球样变性，没有点状或灶状坏死。还发现异常黑胆质成熟剂能提高5-FU增效减毒模型小鼠血清中SOD, GSH-PX的含量，降低MDA的水平。
3．异常黑胆质成熟剂具有良好的抗氧化、耐缺氧和抗疲劳作用。与其他对照组比较异常黑胆质成熟剂可明显提高肿瘤模型小鼠一般生存状况，小鼠活动状态良好，皮毛基本光泽，体重没有明显降低。
4．与异常黑胆质成熟剂高剂量和低剂量组比较，在抑制移植性S-180和EAC肿瘤、对化疗药AF致毒副作用的拮抗作用、对5-FU增效减毒、对移植性肿瘤小鼠抗氧化、耐缺氧和抗疲劳等方面，异常黑胆质成熟剂中剂量组效果良好，差异显著。
Objective:
A number of anti-tumor agents including alkyl-ting agents, anti-tumor antibiotics,anti-metabolites and various other agents such as platinum derivatives, procarbazine andemetine have been administered alone or in a variety of combinations by different routesto treat carcinoma, but the predictable response rate is no more than20%. Additionally,adverse drug reactions are frequent. Some current trials have been investigating the use ofplant derivatives and much attention has been paid to Chinese herb since it has littletoxicity comparatively and is not susceptible to drug resistance and it plays the role ofanti-tumor by multiple means. Multi-drug resistance (MDR) is the protection of tumorcell population against numerous drugs which differ in structure and in actingmechanisms on the tumor cells. MDR is also one of the major causes of failure ofchemotherapy of human malignancies, which is related to many active mechanisms.Often several different mechanisms are switched on in the cells, but usually one majormechanism would operate. The active mechanisms are summarized as follows:1)activation of trans-membrane proteins refluxing different chemical substances from thecells (P-glycoprotein is the most known efflux pump);2) activation of the enzymes ofglutathione detoxification system; alteration of the genes and the proteins involved intothe control of apoptosis (especially P53and Bcl-2); changes of activity and quantity oftopoisomerases. Study on multi-drug resistance of tumor cell and to look forchemotherapy drug with effectiveness and little toxic have long been an interesting topicof research.
It is believed in Traditional Uighur medicine (TUM) that Abnormal Savda is apathological production resulted from the combustion of different body fluids known as Savda, Sapra, Belghem and Kan, which is believed to be the leading cause of cancers,and about90%of cancers are attributed to Abnormal Savda in clinical reports by TUM.Bahki Yusup and Tursun Tohti Haji, two of the most famous Uighur physicians, haveapplied the ASMq-TF in treatment of cancers based on the traditional therapy, whichdemonstrated remarkable clinical results, there by they gain the honor of “highly skilledphysician” by the local people.
Abnormal savda munziq (ASMq)(National Invention Patent No: C082130082.8) isan Uighur medical compound preparation，which consists of Cordia dichotoma, Ziziphusjujuba Mill, Glycyrrhiza uralensis Fisch, Anchusa italica Retz, Foeniculum vulgare Mill,Euphorbia humifusa Willd and other herbs, which are used to treat tumor, diabetes andcardiovascular disease caused by abnormal ASMq. Recent studies have shown that ASMqcan scavenge free radicals and protect DNA oxidative damage and mitochondrialoxidative damage from Hydroxyl free radical, resulting in inhibiting the growth ofHepG2in-vitro and its synthesis of protein, DNA and RNA significantly.
This study aims to explore the inhibitive effect of abnormal savda munziq on twokinds of transplanted tumor, protective effect of abnormal savda munziq onchemotherapy by reducing toxicity, synergistic attenuation of abnormal savda munziq onfluorouracil and further identify anticancer effect, the anti-fatigue and hypoxia resistanceeffect of abnormal savda munziq in vivo by hypoxia and pole climbing experiment.
Methods:
1．Establishment of transplanted S-180tumor model：180mice were randomized to6groups: normal control group, tumor control group, high-dose group of ASMq, middledose group of ASMq, low dose group of ASMq, cyclophosphamide (CY) control group.Indexes are measured in batch. Mouse tumor inhibition rate, spleen index, thymus indexand the index of liver are measured. Variation of mouse serum TNF-α, IL-1β, IL-2, IFN-γ,NK, LPO are observed. Pathological conditions of Tumor in mice spleen and other organsare examined by HE staining. By the MTT method, the proliferation of spleenlymphocytes in mice and variation of serum lymphocyte subsets such as CD_3~+, CD_4~+,CD_8~+, CD_4~+/CD_8~+are identified.
2．Establishment of transplanted S-180tumor model:60mice were randomlydivided into6groups: normal control group, tumor control group,5-fluorouracil (5-FU)group, high dose of5-FU ASMq group, middle dose of5-FU ASMq group, and low doseof5-FU ASMq group. Variations of mouse tumor inhibition rate, indexes of thymus, spleen and liver, mouse serum SOD, MDA, GSH-PX are observed.
3．Establishment of transplanted EAC tumor model:180mice were randomlydivided into six groups, normal control group, tumor control group, high-dose group ofASMq, middle dose group of ASMq, low dose group of ASMq, cyclophosphamide (CY)control group. Observation the mouse tumor inhibition rate, spleen index thymus index,and the index of liver, mouse TNF-α, IL-1β, IL-2, IFN-γ, NK, LPO content in serum andHE staining examination of tumor in mice spleen and other organs pathologicalconditions. Determination of the proliferation of murine spleen lymphocytes by MTTmethod and mouse serum lymphocyte subsets in CD_3~+, CD_4~+, CD_8~+, CD_4~+/CD_8~+.
4．Establishment of the transplanted EAC tumor model:60mice were randomlydivided into6groups: normal control group, tumor control group,5-fluorouracil (5-FU)group, high dose of5-FU ASMq group, middle dose of5-FU ASMq group, and low doseof5-FU ASMq group. Variations of mouse tumor inhibition rate, index of spleen, thymus,and liver, mouse serum SOD, MDA, GSH-PX are observed.
5．Establishment of chemotherapy drug toxicity model:50mice were randomlydivided into5groups: normal control group, tumor control group，AF（amycin and5-fluorouracil (5-Fu) group, AF~+ASMq high dose group, AF~+ASMq middle dose group,and AF~+ASMq low dose group. Spleen, liver and thymus index，mouse serum ALT, AST,TP content, SOD in mouse heart, MDA, GSH-PX content are observed and pathologicconditions of mouse heart, liver and other viscera are examined by HE staining methods.
6．Establishment of transplanted S-180tumor model and EAC tumor modelrespectively: ASMq effect on mice serum SOD, MDA, GSH-PX indexes, as well as onmouse tumor inhibition rate, spleen index, thymus index and liver index are evaluated;ASMq effect on mice under normal pressure hypoxia tolerance test and polele test areevaluated.
Results:
1．Comparison between each dose group of ASMq and cyclophosphamide: Thespleen/weight ratio increased significantly in each dose group of ASMq (P＜0.05). Theinhibition rate of each dose group of ASMq and cyclophosphamide were49.5%、64.26%、43.43%and50.88%respectively, in which inhibitory effect was observed. But there wereno significant differences between the cyclophosphamide and ASMq high does group.Compared with tumor model group, serum IL-1β level varied in ASMq every dose groupsignificantly (P＜0.05), the content of IL-1β was the highest in ASMq middle dose group. Compared to the group of tumor model and positive control, Serum IL-2contentincreased in every dose group of ASMq significantly (P＜0.05), and ASMq middle dosegroup was the highest. The serum TNF-α content was higher in every dose group ofASMq than in the tumor model group and in cyclophosphamide, there was significantdifference (P＜0.05), which was the highest in ASMq middle dose group. Compared withtumor model group, serum IFN-γ content varied in every dose group of ASMqsignificantly (P＜0.05), the content of IL-1β was the highest in ASMq middle dose group.Compared to tumor model group and cyclophosphamide, Serum IFN-γ content increasesin every dose group of ASMq, there was significant difference (P＜0.05), Serum IFN-γwas the highesin in ASMq middle dose group. The serum LPO content in every dosegroup of ASMq were all lower than tumor model group and cyclophosphamide, there wassignificant difference (P＜0.05), and serum LPO was the lowest in ASMq middle dosegroup. Compared with tumor model group, the serum NK content varied significantly inevery dose group of ASMq, there was significant difference (P＜0.05), the content of NKwas the highest in ASMq middle dose group. In ASMq high dose group, CD_3~+, CD_8~+andCD_4~+was reduced apparently, the CD_4~+/CD_8~+ratio increased and The CD_4~+/CD_8~+ratiowas close to the normal value. In ASMq middle dose group, CD_8~+decreased, CD_3~+, CD_4~+CD_8~+and CD_4~+was reduced apparently, the CD_4~+/CD_8~+ratio increased. The CD_4~+/CD_8~+ratio was close to the normal value. There was no significant improvement in the ASMqlow dose group. Comparison between normal control and tumor model group, the SOD，GSH-PX, MDA content in the liver of both ASMq and tumor groups were significantlydifferent. The difference was significant (P＜0.05). The SOD，GSH-PX content in theliver of ASMq every dose group increased, there was significant difference (P＜0.05),ASMq middle dose group was the highest. The MDA content in mouse liver, of everydose group of ASMq were all lower than tumor model group and cyclophosphamidegroup, there was significant difference (P＜0.05). ASMq middle dose group was thelowest. After examinations of mouse liver, spleen, thymus and other organs by HEstaining methods, Pathological conditions are all shown normal, necrosis and liquefactionof transplanted S-180tumor mouse tumor was observed.
2．The inhibition rates of5-Fu-ASMq high dose group,5-Fu-ASMq middle dosegroup, low dose group of5-Fu~+ASMq And5-fluorouracil group were52.26%,66.41%,44.87%and48.02%. There was significant difference between normal control group and5-Fu group in SOD, GSH-PX content in serum(P＜0.05), SOD, GSH-PX contentdecreased significantly in every dose group of ASMq, In ASMq middle dose group, the highest content of SOD GSH-PX was close to the normal value. The MDA value ofwhich was lowest there was significantly reduced comparing with the5-Fu control group,the difference was significant (P＜0.05). Compared to tumor model group with, serumSOD, GSH-PX content in the model group, both ASMq high and low dose groups weresignificantly lower. The difference was significant (P＜0.05), in which the ASMq middledose group maximum has been close to or exceed the normal values.
3． Compared with the spleen/weight ratio each group of ASMq andcyclophosphamide, ASMq every dose group significantly increased, there was significantdifference (P＜0.05), in which ASMq middle dose group. The inhibition rate of eachdose ASMq and cyclophosphamide were49.5%、64.26%、43.43%and50.88%respectively, which inhibitory effect was observed, but there has no difference betweenthe groups of cyclophosphamide and ASMq. Compared with the serum IL-1βcontent,ASMq every dose group significantly changed, there was significant difference (P＜0.05),the content of IL-1βwas the highest in which ASMq middle dose group Compared withthe serum IL-1βcontent between the group of tumor model and positive control, ASMqevery dose group significantly increased, there was significant difference (P＜0.05), inwhich ASMq middle dose group was the highest, The serum TNF-αcontent in ASMqevery dose group were all higher than tumor model group and cyclophosphamide, therewas significant difference (P＜0.05),. in which ASMq middle dose group was the highest,Compared with the serum IFN-γ content, ASMq every dose group significantly changed,there was significant difference (P＜0.05), the content of IL-1βwas the highest in whichASMq middle dose group. Compared with the serum IFN-γ content in tumor modelgroup and cyclophosphamide, ASMq every dose group of relative to rise, there wassignificant difference (P＜0.05), in which ASMq middle dose group was the highest, Theserum LPO content in ASMq every dose group were all lower than tumor model groupand cyclophosphamide, there was significant difference (P＜0.05), in which ASMqmiddle dose group was the lowest, Compared with the serum NK content, ASMq everydose group significantly changed, there was significant difference (P＜0.05), the contentof NK was the highest in which ASMq middle dose group ASMq high dose group, CD_3~+、CD_8~+and CD_4~+was reduced apparently, the CD_4~+/CD_8~+ratio increased, and TheCD_4~+/CD_8~+ratio was close to the normal value. ASMq middle dose group, CD_8~+decreased, CD_3~+、CD_4~+CD_8~+and CD_4~+was reduced apparently, the CD_4~+/CD_8~+ratioincreased, elevated CD_4~+/CD_8~+ratio increased, and this ratio was close to the normalvalue. There was no significant improvement with the ASMq low dose group. Compared with, the SOD, GSH-PX, MDA content in the liver of both ASMq and tumor groups weresignificantly difference. The difference was significant (P＜0.05).Compared with theSOD，GSH-PX content in the liver of tumor model group, ASMq every dose group ofrelative to rise, there was significant difference (P＜0.05), in which ASMq middle dosegroup was the highest, Compared with the MDA content in mouse liver, ASMq everydose group were all lower than tumor model group and cyclophosphamide, there wassignificant difference (P＜0.05), in which ASMq middle dose group was the lowest, HEstaining methods of mouse liver, spleen, thymus and other organs Pathological conditionsare all normally, transplanted S-180tumor mouse tumor necrosis and liquefaction.
4．In the5-FU high-dose ASMq group,5-FU medium-dose ASMq group,5-FUlow-dose ASMq group and5-FU group, the values of tumor inhibition rate were42.41%、58.09%,41.58%and50.83%, respectively, showing that tumor function had beenweakened. Compared with the model group, the thymus/body weight ratio was clearlyreduced in the5-FU medium-dose ASMq group and5-FU low-dose ASMq group.Compared with the5-FU group, the spleen/body weight ratio was clearly increased in the5-FU high-dose ASMq group,5-FU medium-dose ASMq group, and5-FU low-doseASMq group, and the difference was significant (P＜0.05). The5-FU ASMq dose groupshad reduced levels of SOD and GSH-PX compared with the5-FU control group, and thedifference was significant (P＜0.05). In the5-FU medium-dose ASMq group, SOD andGSH-PX levels were high. With respect to MDA values, the5-FU medium-dose ASMqgroup had the lowest values and in comparison with the model control group, thedifference was significant (P＜0.05). With respect to SOD and GSH-PX levels, comparedwith the model group, the5-FU high dose ASMq group had lower levels, and thedifference was significant (P＜0.05).
5．Compared with the AF model group,serum ALT, AST content, in every dosegroup of ASMq significantly decreased, there was significant difference (P＜0.05), whichwas the lowest in ASMq middle dose group, ALT, AST content were close to the normalvalue. The TP value of ASMq middle dose group is the highest, compared to the AFmodel control group, which had significantly increased, the difference was significant (P＜0.05). Compared with the normal control group, serum ALT, AST content in abnormalsavda munziq every dose group significantly decreased, there was significant difference(P＜0.05), TP value of which in the ASMq middle dose group was the highest. Comparedwith the AF model group, SOD, GSH-PX content in the heart, significantly increased inASMq every dose group. The difference was significant (P＜0.05), in which ASMq middle dose group had the highest content of SOD, GSH-PX and which were close to thenormal values. Compared with the AF model group, MDA value of ASMq with middledoses was significantly lower; the difference was significant (P＜0.05). Compared withthe normal control group SOD, GSH-PX content in the heart, ASMq high and low dosegroups were significantly lower. The difference was significant (P＜0.05), in which theASMq middle dose group maximum has been close to or exceed the normal values.ASMq cannot only improve the spleen index, but also reduce the serum levels of ALT,AST content and improve the mouse heart SOD, GSH-PX content, and protect the heartand liver in preventing necrosis.
6．Experiments of transplanted tumor S-180mice model for climbing, hypoxiatolerance: Compared with cyclophosphamide group, ASMq high dose group, mediumdose group, low dose group showed significantly higher spleen/body weight ratio; thedifferences were significant (P＜0.05). Compared with tumor model group, the abnormalsavda munziq middle dose group and low dose group have obvious liver/body weightratio changes, the difference was significant (P＜0.05). Compared with cyclophos-phamide group, in terms of the content of SOD, GSH-PX in serum, every dose group ofabnormal Savda Munziq is increased significantly, and is close to the normal level; thedifference was significant (P＜0.05). The dose of MDA in abnormal savda munziq is thelowest, compared with tumor model group; the difference was significant (P＜0.05).Compared tumor model group with normal controls, the time of climbing was decreasedsignificantly (P＜0.05). Compared with cyclophosphamide, every dose group ofabnormal savda munziq can improve the time of mice climbing, particularly in abnormalsavda munziq dose for which the effect is significant (P＜0.05). Compared with tumormodel group, every dose group of abnormal savda munziq can enhance the time of micehypoxia tolerance, and there is significant difference (P＜0.05). Compared with thenormal control group, every dose group of abnormal savda munziq can enhance the timeof hypoxia tolerance; especially for the dose of abnormal savda munziq the effect is mostremarkable.
7．Experiments of transplanted EAC tumor mice model for climbing, hypoxiatolerance test: Compared with cyclophosphamide group, the abnormal savda munziq highdose group, middle dose group, and low dose group have increased spleen/body weightratio, the difference was significant (P＜0.05). Compared with tumor model group, theabnormal savda munziq middle dose group and the low dose group have obviousliver/body weight ratio changes; the difference was significant (P＜0.05). Compared the model group tumor with normal control group, the climbing time was decreasedsignificantly (P＜0.05). Compared with cyclophosphamide group, every dose group ofabnormal savda munziq can improve the mice climbing time, particularly for the dose ofabnormal savda munziq the effect is significant (P＜0.05). Compared the content of SOD,GSH-PX in serum of cyclophosphamide group, every dose group of abnormal savdamunziq was increased, in which the content of SOD, GSH-PX of middle dose group isclose to the normal value, and cyclophosphamide group was increased significantly, thedifference was significant (P＜0.05). The MDA value of abnormal savda munziq is lowerthan tumor model group. Compared with the normal control group, every dose ofabnormal savda munziq group can enhance hypoxia tolerance in mice; especially themiddle dose abnormal savda munziq is the best. Compared with tumor model, every dosegroup of abnormal savda munziq was increased; the difference was significant (P＜0.05).Compared with verapamil, the abnormal savda munziq high and low dose groups weredecreased, and the difference was significant (P＜0.05).
Conclusion:
1．Tumor is an immunodeficiency disease, which is mainly caused by immunesystem disorders, decreased anti-tumor activity factor and loss of function. Activating thebody independent anti-tumor immune mechanisms and strengthening the activity ofcytokines are important aspects of cancer treatment. This study found that ASMq canimprove immune system function, enhance antioxidant enzyme activity in immuneorgans, and regulate the lymphocyte subsets levels and cytokines to reach the purpose oftumor suppression. Performance of experiments in transplanted S-180and EAC tumormodels in mice showed decreased mass volume, decreased weight, and necrosis andliquefaction in the tumor, by thus the anti-tumor rate increased.
2． The ASMq has a good antagonism on the toxicity side effects of thechemotherapy drug doxorubicin and5-fluorouracil (AF), it can protect the liver and heartand reduce the damage of chemotherapeutic drugs on the liver and heart. It can reduceserumin ALT, AST content and improve the level of TP. It increases the content of themouse model of heart tissue SOD and GSH-PX, and reduces the level of MDA.Abnormal black Munziq can improve the content of serum SOD and GSH-PX in5-fluorouracil Reducing Toxicity Model and reduce the level of MDA.
3．The ASMq has a function of anti-oxidation, hypoxia and anti-fatigue effect invivo. Compared with the other control group, ASMq can significantly improve the general living conditions of the tumor model mice, active state and mouse fur luster,while weight is not significantly reduced.
4．It was found that compared to ASMq high dose group and low dose group, interms of suppressing the transplanted S-180and EAC tumor, the protective effect of toxicside effects induced by the chemotherapy drug doxorubicin and5-fluorouracil (AF),5-fluorouracil efficiency attenuation, anti-oxidation, hypoxia and anti-fatigue effect inclimbing the pole and hypoxia experiment, ASMq middle dose group shows better effect
引文
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