健脾解毒方治疗原发性肝癌的临床和机理研究
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摘要
原发性肝癌(PLC)是临床最常见的恶性肿瘤之一,是我国第2位恶性肿瘤致死原因。主要治疗方法有手术、介入和中医药等。因大部分PLC患者确诊时,已属中晚期,失去手术机会,故目前治疗采用经皮肝动脉栓塞化疗术(TACE)为主。尽管TACE术可以一定程度地缩小瘤体、改善PLC预后,但对患者生存期和生活质量方面的疗效并不理想。而中医药具有独特优势,从整体进行辨证论治,扶正祛邪,标本兼顾,是治疗肝癌的有效方法。
健脾解毒方(JJP)是导师刘沈林教授基于对肝癌中医发病机制的总结,结合多年临床实践得出的经验方。由太子参、茯苓、炒白术、薏苡仁、半枝莲、莪术、地鳖虫、白花蛇舌草、山慈菇、炙甘草组成,具有健脾益气,解毒散结之功效,临床疗效确切。本研究临床部分为探索肝癌中西医优化治疗方案,实验部分为求进一步探讨该方抗肝癌的机理。
临床研究部分
目的观察JJP联合介入治疗PLC的疗效及对生存期、生活质量的改善情况
方法按照随机平行对照的方法,将66例肝癌患者随机分为对照组和治疗组2组,每组33人。对照组采用TACE治疗为主,治疗组采用TACE+健脾解毒方,疗程为3个月。疗程结束后,观察症状、证候、瘤体、血常规、肝功能等指标以及Child-pugh分级、KPS积分、安全性评价,以及随访6月和12月观察生存率。数据采用统计学处理。
结果
1.2组患者治疗前年龄、性别、病情、基线症状无统计学差别,P>0.05,具有可比性。
2. TACE术联合JJP治疗可以明显改善肝癌患者的症状、证候、血细胞水平及肝
功能,与对照组比较,P<0.01或P<0.05,有显著差异。3.联合治疗组在Child-pugh分级、KPS积分、生存期方面均有显著改善,与对
照组比较,P<0.05,有明显差异。
4.2组患者在瘤体缩小方面的比较,P>0.05,差异无统计学意义。
5.联合治疗组显示出良好的安全性。
结论TACE术联合JJP治疗PLC,可减毒增效,提高生存质量,延长生存时间,从而改善肝癌患者的预后。发挥中医药优势,弥补TACE治疗远期疗效不佳的缺点,为中西医结合治疗PLC提供了一定的依据。
实验研究部分
目的探讨JJP体外抗肝癌的效应和作用机制。
方法用血清药理学方法,按低、中、高3种浓度制备JJP含药血清,分别作用于人肝癌细胞HepG2和SMMC-7721细胞,并以生理盐水血清为阴性对照组,5-FU血清为阳性对照组,用光学显微镜、透射电镜观察JJP血清作用后,2种肝癌细胞形态和超微结构的变化；用MTT法检测JJP血清对2种肝癌细胞增殖的抑制率；流式细胞仪、AnnexinV/PI染色法、荧光显微镜检测JJP血清对2种肝癌细胞的凋亡作用；Transwell法检测JJP血清对2种肝癌细胞迁移、侵袭能力的影响；用RT-PCR法,在mRNA水平检测JJP血清对HepG2和SMMC-7721细胞中CD44和VEGF基因表达的影响。
结果
1.光镜下,经不同浓度JJP含药血清作用,HepG2和SMMC-7721细胞形态均出现死亡或凋亡改变,增殖程度受到明显抑制,与阴性对照组相比,(P<0.01),并具有浓度和时间依赖性。电镜下的超微结构显示,JJP血清作用后,肝癌细胞出现典型的凋亡表现,其中高剂量组表现更加明显。
2.JJP血清对HepG2细胞增殖的抑制率：(按低、中、高浓度排列)24h分别为20.52%,46.47%,59.45%；48h为26.47%,57.97%,67.84%,与阴性对照组相比有明显差异(P<0.01),JJP血清对SMMC-7721细胞的抑制率：24h为41.7%,59.42%,70.15%；48h为49.29%,69.04%,73.04%。与阴性对照组相比有明显差异(P<0.01)。其中JJP血清作用48h后,对SMMC-7721细胞的抑制率与阳性对照组5-FU血清抑制率接近。
3.JJP血清对HepG2细胞的凋亡率分别达到9.23±0.51%,19.67±2.48%,40.6±1.77%；对SMMC-7721的凋亡率分别为：9.27±0.71%,14.77±1.62%,25.67±2.37%,与阴性对照组相比有明显差异(P<0.01)。荧光显微镜下,经AnnexinV/PI染色,随着JJP血清作用时间的延长渐出现早期、晚期凋亡细胞和坏死细胞的荧光染色表现。
4.JJP血清对HepG2细胞的迁移抑制率为：36.63%,42.57%,64.35%。与阴性对照组相比均(P<0.01)；对SMMC-7721细胞的迁移抑制率为32.46%,49.12%,58.77%,与阴性对照组相比均有明显差异(P<0.01或P<0.05)。JJP血清对HepG2细胞的侵袭抑制率为：23.07%,46.15%,69.23%,与阴性对照组相比有明显差异(P<0.01)。JJP血清对SMMC-7721细胞的侵袭抑制率为31.25%,52.08%,64.58%,与阴性对照组相比有明显差异(P<0.01或P<0.05)
5.JJP血清对HepG2细胞CD44的相对光密度比值为1.68±0.15,1.63±0.27,1.39±0.53,与阴性对照组比较有明显差异(P<0.01或P<0.05),高剂量JJP组比值超过阳性对照组(P<0.05)。JJP血清对HepG2细胞VEGF相对光密度比值为0.92±0.02,0.89±0.26,0.72±0.03,中、高剂量组与阴性对照组相比有明显差异(P<0.01或P<0.05)。JJP血清对SMMC-7721细胞CD44的相对光密度比值为1.81±0.06,1.78±0.04,1.69±0.38,中、高剂量组与阴性对照组相比有明显差异(P<0.01或P<0.05),JJP血清对SMMC-7721细胞VEGF的光密度比值为0.99±0.06,0.94±0.18,0.89±0.07,与阴性对照组相比有明显差异(P<0.05或P<0.01)。
结论JJP含药血清体外可以抑制肝癌细胞增殖,并诱导其凋亡,抑制肝癌细胞侵袭迁移能力。JJP含药血清抗肝癌的效应,可能与通过下调CD44和VEGF基因的表达,从而达到抑制肝癌侵袭转移及血管生成有关。
Primary liver cancer(PLC)is one of the most common magligant turmor in clinic, which is ranked the second palce on the cause of magligant tumor.The main treat methods include surgery, transcather and Chinese Medicine.The most PLC patients had entered later stage and lost the chance of surgery when the diagnosis was made clear. So Transcatheter Arterial Chemoembolization (TACE) has become main treat methods at present. The TACE curative effect of the quality of life and survivial rate is not satisfied, howeve, it can lessen the size of tumor and improve the prognosis.While Chinese Medicine has unique advantages.It is effective that deffentiate PLC patients in whole and threat with strengthing the vital and expelling the toxic, treating both symptoms and radical.
JianPiJieDu Prescription(JJP)is an empirical presciption from the director, Professor Liu Shenlin who summary mechanization of PLC with the theory of Traditional Chinese Medicine.It is effected by many years of practises and consisted of Pseudostellaria heterophylla, Poria cocos, Atractylodes macrocephala, Coix lacryma-jobi, Portulaca grandiflore Curcuma phaeocaulis, Eupolyphaga seu, Oldenlandia diffusa, Cremastra appendiculate and Glycyrrhiza uralensis.The presription provided the effects of strengthening the spleen, invigorating Qi, expelling toxin and removing blood stasis have demonstrated the exact efficacy in clinical application. The clinical research part of our study was investigation of combination optimized treatment of Chinese and Western medicine for PLC. The experimental research part was the investigation of the mechanism of anti-hepatoma by JJP.
Clinical research component
Objective Observation of the curative effect and improvement of the survival rate and quality of life in treat with combination of TACE and JJP.
Methods Following the experimental principle of randomization and paralled control, the 66 cases of PLC patients were divided into 2 groups.The control group was treated with TACE only. The treatment group is treated with TACE and JJP modified. The course of treatment is 3 months. When the course was end, we evaluated the results of the symptoms, TCM syndromes, size of tumor, blood regular test, liver function, level of Child-pugh class, KPS value and time of survival and evaluation of security. All clinical results were processed by statistical analysis software.
Results
1. The variety of sex, age, stage of illness and symptoms base line had no statistical defference in 2 groups, P>0.05
2. The combination of two treatments improved the symptoms, TCM syndromes, blood cell level and value of liver function obviously. By test, the deference is distinct, vs control group, P<0.01 or P<0.05.
3. The combination group had significant improvement on the class of Child-pugh, value of KPS and time of survival, vs control group, P<0.05.
4. The variety of lessen of value of tumor had no difference in 2 groups, P> 0.05
5. The combination group had clinical safety.
Conclusion The combinated treatment of TACE and JianPiJieDu Prescription can reduce toxicity and enhance curative effect, improve the quality of life and extend the time of survival. TCM can make up the shortage of TACE.
Experimental reaserch component
Objective To investigate the mechanism of the anti-hepatoma cancer of JianPiJieDu Prescription.
Methods With the method of pharmacological serum,3 consistencies of serum were made.And serum was manipulated into human hepatoma cells of HepG2 and SMMC-7721.With the constract of negtive and positive serum of NS and 5-FU.Observate the change of shape and size of human hepatoma cells with miscroscope and TEM. Detect the growth inhibiting rate with MTT Method, Probe the apoptosis of cell with FCM and immuno fluorscent. Assess the migration and invasion of human hepatoma cells by transwell technique.Expression levels of CD44 and VEGF mRNA in HepG2 and SMMC-7721 cell were determined by reverse transcription-polymerase-chain-reaction (RT-PCR).
Results With the function of pharmacological serum,the human hepatoma cells of HepG2 and SMMC-7721 took out view of death and apoptosis. The growth of cells were significantly inhibited than in the negative control group, P<0.01.The number of migration and invasion was significantly lower in pharmacological serum group than in he negative control group,P<0.01.The inhibiting rate of high dose group of pharmacological serum is mild higher than the rate of positive group. A significant down-regulation of expression of CD44 and VEGF gene mRNA were observed in HepG2 and SMMC-7721 cells.
Conclusion Pharmacological serum of JianPiJieDu Prescription has the function of anti-cancer in vitro.It is able to inhibit the growth of human hepatoma cell, induce apoptosis of cell and inhibit the invasion and metastasis of cells.It was reckon that inhibiting capable of veil liver metastasis of PLC possibly related by down regulation of CD44 and VEGF gene expression.
健脾解毒方(JJP)是导师刘沈林教授基于对肝癌中医发病机制的总结,结合多年临床实践得出的经验方。由太子参、茯苓、炒白术、薏苡仁、半枝莲、莪术、地鳖虫、白花蛇舌草、山慈菇、炙甘草组成,具有健脾益气,解毒散结之功效,临床疗效确切。本研究临床部分为探索肝癌中西医优化治疗方案,实验部分为求进一步探讨该方抗肝癌的机理。
临床研究部分
目的观察JJP联合介入治疗PLC的疗效及对生存期、生活质量的改善情况
方法按照随机平行对照的方法,将66例肝癌患者随机分为对照组和治疗组2组,每组33人。对照组采用TACE治疗为主,治疗组采用TACE+健脾解毒方,疗程为3个月。疗程结束后,观察症状、证候、瘤体、血常规、肝功能等指标以及Child-pugh分级、KPS积分、安全性评价,以及随访6月和12月观察生存率。数据采用统计学处理。
结果
1.2组患者治疗前年龄、性别、病情、基线症状无统计学差别,P>0.05,具有可比性。
2. TACE术联合JJP治疗可以明显改善肝癌患者的症状、证候、血细胞水平及肝
功能,与对照组比较,P<0.01或P<0.05,有显著差异。3.联合治疗组在Child-pugh分级、KPS积分、生存期方面均有显著改善,与对
照组比较,P<0.05,有明显差异。
4.2组患者在瘤体缩小方面的比较,P>0.05,差异无统计学意义。
5.联合治疗组显示出良好的安全性。
结论TACE术联合JJP治疗PLC,可减毒增效,提高生存质量,延长生存时间,从而改善肝癌患者的预后。发挥中医药优势,弥补TACE治疗远期疗效不佳的缺点,为中西医结合治疗PLC提供了一定的依据。
实验研究部分
目的探讨JJP体外抗肝癌的效应和作用机制。
方法用血清药理学方法,按低、中、高3种浓度制备JJP含药血清,分别作用于人肝癌细胞HepG2和SMMC-7721细胞,并以生理盐水血清为阴性对照组,5-FU血清为阳性对照组,用光学显微镜、透射电镜观察JJP血清作用后,2种肝癌细胞形态和超微结构的变化；用MTT法检测JJP血清对2种肝癌细胞增殖的抑制率；流式细胞仪、AnnexinV/PI染色法、荧光显微镜检测JJP血清对2种肝癌细胞的凋亡作用；Transwell法检测JJP血清对2种肝癌细胞迁移、侵袭能力的影响；用RT-PCR法,在mRNA水平检测JJP血清对HepG2和SMMC-7721细胞中CD44和VEGF基因表达的影响。
结果
1.光镜下,经不同浓度JJP含药血清作用,HepG2和SMMC-7721细胞形态均出现死亡或凋亡改变,增殖程度受到明显抑制,与阴性对照组相比,(P<0.01),并具有浓度和时间依赖性。电镜下的超微结构显示,JJP血清作用后,肝癌细胞出现典型的凋亡表现,其中高剂量组表现更加明显。
2.JJP血清对HepG2细胞增殖的抑制率：(按低、中、高浓度排列)24h分别为20.52%,46.47%,59.45%；48h为26.47%,57.97%,67.84%,与阴性对照组相比有明显差异(P<0.01),JJP血清对SMMC-7721细胞的抑制率：24h为41.7%,59.42%,70.15%；48h为49.29%,69.04%,73.04%。与阴性对照组相比有明显差异(P<0.01)。其中JJP血清作用48h后,对SMMC-7721细胞的抑制率与阳性对照组5-FU血清抑制率接近。
3.JJP血清对HepG2细胞的凋亡率分别达到9.23±0.51%,19.67±2.48%,40.6±1.77%；对SMMC-7721的凋亡率分别为：9.27±0.71%,14.77±1.62%,25.67±2.37%,与阴性对照组相比有明显差异(P<0.01)。荧光显微镜下,经AnnexinV/PI染色,随着JJP血清作用时间的延长渐出现早期、晚期凋亡细胞和坏死细胞的荧光染色表现。
4.JJP血清对HepG2细胞的迁移抑制率为：36.63%,42.57%,64.35%。与阴性对照组相比均(P<0.01)；对SMMC-7721细胞的迁移抑制率为32.46%,49.12%,58.77%,与阴性对照组相比均有明显差异(P<0.01或P<0.05)。JJP血清对HepG2细胞的侵袭抑制率为：23.07%,46.15%,69.23%,与阴性对照组相比有明显差异(P<0.01)。JJP血清对SMMC-7721细胞的侵袭抑制率为31.25%,52.08%,64.58%,与阴性对照组相比有明显差异(P<0.01或P<0.05)
5.JJP血清对HepG2细胞CD44的相对光密度比值为1.68±0.15,1.63±0.27,1.39±0.53,与阴性对照组比较有明显差异(P<0.01或P<0.05),高剂量JJP组比值超过阳性对照组(P<0.05)。JJP血清对HepG2细胞VEGF相对光密度比值为0.92±0.02,0.89±0.26,0.72±0.03,中、高剂量组与阴性对照组相比有明显差异(P<0.01或P<0.05)。JJP血清对SMMC-7721细胞CD44的相对光密度比值为1.81±0.06,1.78±0.04,1.69±0.38,中、高剂量组与阴性对照组相比有明显差异(P<0.01或P<0.05),JJP血清对SMMC-7721细胞VEGF的光密度比值为0.99±0.06,0.94±0.18,0.89±0.07,与阴性对照组相比有明显差异(P<0.05或P<0.01)。
结论JJP含药血清体外可以抑制肝癌细胞增殖,并诱导其凋亡,抑制肝癌细胞侵袭迁移能力。JJP含药血清抗肝癌的效应,可能与通过下调CD44和VEGF基因的表达,从而达到抑制肝癌侵袭转移及血管生成有关。
Primary liver cancer(PLC)is one of the most common magligant turmor in clinic, which is ranked the second palce on the cause of magligant tumor.The main treat methods include surgery, transcather and Chinese Medicine.The most PLC patients had entered later stage and lost the chance of surgery when the diagnosis was made clear. So Transcatheter Arterial Chemoembolization (TACE) has become main treat methods at present. The TACE curative effect of the quality of life and survivial rate is not satisfied, howeve, it can lessen the size of tumor and improve the prognosis.While Chinese Medicine has unique advantages.It is effective that deffentiate PLC patients in whole and threat with strengthing the vital and expelling the toxic, treating both symptoms and radical.
JianPiJieDu Prescription(JJP)is an empirical presciption from the director, Professor Liu Shenlin who summary mechanization of PLC with the theory of Traditional Chinese Medicine.It is effected by many years of practises and consisted of Pseudostellaria heterophylla, Poria cocos, Atractylodes macrocephala, Coix lacryma-jobi, Portulaca grandiflore Curcuma phaeocaulis, Eupolyphaga seu, Oldenlandia diffusa, Cremastra appendiculate and Glycyrrhiza uralensis.The presription provided the effects of strengthening the spleen, invigorating Qi, expelling toxin and removing blood stasis have demonstrated the exact efficacy in clinical application. The clinical research part of our study was investigation of combination optimized treatment of Chinese and Western medicine for PLC. The experimental research part was the investigation of the mechanism of anti-hepatoma by JJP.
Clinical research component
Objective Observation of the curative effect and improvement of the survival rate and quality of life in treat with combination of TACE and JJP.
Methods Following the experimental principle of randomization and paralled control, the 66 cases of PLC patients were divided into 2 groups.The control group was treated with TACE only. The treatment group is treated with TACE and JJP modified. The course of treatment is 3 months. When the course was end, we evaluated the results of the symptoms, TCM syndromes, size of tumor, blood regular test, liver function, level of Child-pugh class, KPS value and time of survival and evaluation of security. All clinical results were processed by statistical analysis software.
Results
1. The variety of sex, age, stage of illness and symptoms base line had no statistical defference in 2 groups, P>0.05
2. The combination of two treatments improved the symptoms, TCM syndromes, blood cell level and value of liver function obviously. By test, the deference is distinct, vs control group, P<0.01 or P<0.05.
3. The combination group had significant improvement on the class of Child-pugh, value of KPS and time of survival, vs control group, P<0.05.
4. The variety of lessen of value of tumor had no difference in 2 groups, P> 0.05
5. The combination group had clinical safety.
Conclusion The combinated treatment of TACE and JianPiJieDu Prescription can reduce toxicity and enhance curative effect, improve the quality of life and extend the time of survival. TCM can make up the shortage of TACE.
Experimental reaserch component
Objective To investigate the mechanism of the anti-hepatoma cancer of JianPiJieDu Prescription.
Methods With the method of pharmacological serum,3 consistencies of serum were made.And serum was manipulated into human hepatoma cells of HepG2 and SMMC-7721.With the constract of negtive and positive serum of NS and 5-FU.Observate the change of shape and size of human hepatoma cells with miscroscope and TEM. Detect the growth inhibiting rate with MTT Method, Probe the apoptosis of cell with FCM and immuno fluorscent. Assess the migration and invasion of human hepatoma cells by transwell technique.Expression levels of CD44 and VEGF mRNA in HepG2 and SMMC-7721 cell were determined by reverse transcription-polymerase-chain-reaction (RT-PCR).
Results With the function of pharmacological serum,the human hepatoma cells of HepG2 and SMMC-7721 took out view of death and apoptosis. The growth of cells were significantly inhibited than in the negative control group, P<0.01.The number of migration and invasion was significantly lower in pharmacological serum group than in he negative control group,P<0.01.The inhibiting rate of high dose group of pharmacological serum is mild higher than the rate of positive group. A significant down-regulation of expression of CD44 and VEGF gene mRNA were observed in HepG2 and SMMC-7721 cells.
Conclusion Pharmacological serum of JianPiJieDu Prescription has the function of anti-cancer in vitro.It is able to inhibit the growth of human hepatoma cell, induce apoptosis of cell and inhibit the invasion and metastasis of cells.It was reckon that inhibiting capable of veil liver metastasis of PLC possibly related by down regulation of CD44 and VEGF gene expression.
引文
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