参桃软肝煎治疗中晚期肝癌的临床和实验研究
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摘要
研究目的:临床研究部分主要观察参桃软肝丸对中晚期肝癌患者的临床疗效,特别是对肝功能有较好的保护作用,按照常见中药不良反应的表现,主要观察对患者消化系统、对肾功能和心血管系统的影响,评价参桃软肝治疗中晚期肝癌的临床疗效以及安全性。实验研究部分:通过实验研究初步探讨参桃软肝丸对人肝癌细胞HepG2的抑瘤率、细胞凋亡及相关调控基因表达的影响,进一步验证其可能的作用机理。
方法:临床研究部分:将符合纳入标准的40例患者,采用随机单盲分组法,分为参桃软肝丸治疗组和槐耳颗粒对照组。两组患者均采用相同的对症支持疗法。参桃软肝丸治疗组除对症支持治疗外加服参桃软肝丸,每日一剂,连续服药40天。对照组在对症支持治疗的基础上加服槐耳颗粒,每次一包,每日三次,连用40天。主要观察每组病人的临床治疗效果(包括临床症状、体征、生活质量、肝肾功能、凝血功能、瘤体大小等)以及每组的不良反应,评价参桃软肝丸治疗中晚期肝癌的临床疗效以及安全性。实验研究部分:将雄性新西兰家兔分为3组,每组3只,参桃软肝丸组以成人口服剂量的10倍给雄性新西兰家兔灌胃。空白血清组以等量生理盐水灌胃,阳性药物对照组(5-氟尿嘧啶组),给予药液41.67mg/kg/day灌胃。连续给药3日,每日分两次给药,第3日给药2小时后同剂量追加给药1次,于最后1次灌药后1小时(灌药前禁食不禁水12小时),乙醚麻醉,75%乙醇消毒,心脏采血,无菌分离血清,同组家兔药物血清混匀,水浴灭活处理后,置-20℃冰箱保存备用。人肝癌细胞株HepG2细胞接种于含10%新生牛血清、抗生素(100U/ml青霉素和链霉素)的RPMI 1640培养液中。培养环境为5%CO2,37℃及饱和湿度。细胞培养为3～5天,以0.25%胰蛋白酶消化适当后1:3传代。MTT显色法测定含药血清的抑瘤率,流式细胞仪观察参桃软肝丸对人肝癌HepG2细胞凋亡及周期的影响,用ELISA法检测参桃软肝丸对bcl-2、p53基因表达的调控影响,进一步验证其可能的作用机理。
结果:参桃软肝丸具有健脾养肝,清热解毒,凉血祛瘀之功效,临床试验表明,参桃软肝丸在稳定瘤体、提高患者的卡氏评分,改善患者的症状,特别是对改善患者肝区疼痛、腹胀、纳呆、乏力等4个方面的主症有较好疗效,此作用可能与防止ALB、PA下降的有关,通过药物不良反应监测,发现极少数患者会出现Ⅰ-Ⅱ度恶心和暂时性呕吐,但无需处理,可自行缓解,未发现心血管系统和其他系统的不良反应,说明服用该药物是安全的。实验表明,参桃软肝丸对人肝癌细胞株HepG2的生长有抑制作用,且随剂量的增加而增强。其中,高浓度组抑瘤率最高可达43.2%,与无含药血清相比有统计学意义(P＜0.01),且其抑瘤率随着剂量及作用时间的增加而逐渐提高,48小时时达高峰,与空白组比较有显著性差异(P＜0.01)。参桃软肝丸组含药血清高、中、低浓度均对突变型P53、bcl-2有不同程度的抑制作用,其中三个浓度对突变型P53的抑制与阳性组和空白组比较有统计学意义,P值分别小于0.01和0.05,对bcl-2的抑制与阳性组和空白组比较无统计学意义,但数值有下降趋势,三者中以中浓度即20%浓度抑制效果较好。参桃软肝丸对人肝癌细胞HepG-2有较好的诱导凋亡作用,凋亡率可达15.6%,且阻滞细胞增殖于G0/G1期。说明参桃软肝丸对突变型P53、bcl-2的抑制作用及诱导肿瘤细胞凋亡可能是其抗肿瘤作用机制之一。
结论:参桃软肝丸具有健脾养肝,清热解毒,凉血祛瘀之功效,参桃软肝丸在稳定瘤体、提高患者的卡氏评分,改善患者的症状,特别是对改善患者肝区疼痛、腹胀、纳呆、乏力等4个方面的主症有较好疗效,此作用可能与防止ALB、PA下降的有关,通过药物不良反应监测,发现极少数患者会出现Ⅰ-Ⅱ度恶心和暂时性呕吐,但无需处理,可自行缓解,未发现心血管系统和其他系统的不良反应,说明服用该药物是安全的。参桃软肝丸对人肝癌细胞株HepG2的生长有抑制作用,且其抑瘤率随着剂量及作用时间的增加而逐渐提高,含药血清高、中、低浓度均对突变型P53、bcl-2有不同程度的抑制作用,参桃软肝丸对人肝癌细胞HepG-2有较好的诱导凋亡作用,且阻滞细胞增殖于G0/G1期。本实验通过观察参桃软肝丸对人肝癌细胞HepG-2的抑瘤作用、对突变型P53、bcl-2的抑制作用、诱导肿瘤细胞凋亡等方面的影响,初步探讨该方药的作用机理,为该方在原发性肝癌的临床运用提供理论依据。
Objective:The purpose of clinical research is to observe the therapeutic efficacy of STRG on medium and late stage primary liver cancer,to prove if it can protect the hepatic function,According to the common traditional Chinese medicine adverse effect,mainly observe the effect of digestive system,renal function and cardiovascular system,then estimate it clinical effect and safety.The purpose of experimental research is to observe the pharmaceutical serum effect the inhibitory rate, cell cycle and the apoptosis genetic expression on hepatoma carcinoma cell(HCC)cell line,then discuss the possible mechanism.
Methods:Clinical research:Collected 60 eligible patients with stageⅢ-Ⅳliver cancer were divided randomly into two group,as STRG treated group and Huaier Drop control group,each group has twenty patients.The two groups accepted the same supporting treatment.Meanwhile,the treated group were treated with STRG,one dose per day,last 40 days,the control group were treated with Huaier Drop,one pack every time,three times one day,last 40 days.The therapeutic efficiency and adverse effect of the two groups were evaluated after curing 40 days,then estimate it clinical effect and safety.Experimental research:9 New-Zealand male rabbit were randomly divided into three groups,treated group,blank serum group and positive group,three in each group.The treated group fed with STRG more than 10 times adult oral dose by gavages.The blank serum group fed with the partes aequlaes normal sodium by gavages.The positive group fed with 5-FU by gavages,the dose was 41.67mg/kg/day. All the groups fed three days,twice every day.Three groups boosted the same dose after two hours in the third day,etherization after one hour.75%alcohol sterilizes, from the heart cull blood,asepsis bolter blood serum,all the same groups blood serum were mixed uniformity.Afer waterbath inactivate disposal,put them in the refrigerator below zero 20.HCC cell line was had an inoculation RPMI 1640 culture fluid that contained 10%new-born calf serum and some antibiotics.The cultivation environment was 5%CO2,37℃and saturation humidity.The cell was cultivated three or five days,then passaged after trypsin digestion adequacy.The inhibiting rate of cells observed by MTT,the cell apoptosis and period were measured by Flow Cytometry(FCM),bcl-2 and p53 gene expression were measured by ELISA,in order to discuss STRG the possible mechanism.
Results:STRG has the function of invigorate the spleen and support the liver, heat-clearing and detoxicating,cool the blood and removing blood stasis,Clinical research shows STRG has stabilized the tumor,improved KPS score and the patients symptoms,especially improve hepatic region pain,abdominal distention, anorexia,hypodynamia better.This effect could have concerned with prevent ALB and PA from descending.By drug adverse reaction,a few patients had some nausea and temporary vomiting,but no need treatment,they all could relieve,not found cardiovascular system and other systems adverse reaction.It proved STRG was safety. Experimental research shows that STRG has the inhibitory on HCC cell line growth, and the dose increasing more,the function enhancement more,the inhibitory rate on tumor growth of the high density pharmaceutical serum group was significant than the no pharmaceutical serum group,which inhibitory rate reached 43.2%,and the inhibitory rate on tumor was enhanced following the dose and time increasing,48 hour reached the peak,more significant than the blank group(P＜0.01).The high, middle and low density pharmaceutical serum of STRG had inhibited to mutant P53 and bcl-2.Compared with the positive group and the blank group,three density had more significant(P＜0.01 and 0.05).There were no significant between the pharmaceutical serum and the positive group or the blank group to bcl-2,but the pharmaceutical serum figure had lower tendency,the middle density had better effect. STRG could induce apoptosis,apoptosis rate reached 15.6%,and hold cell proliferation up G0/G1 stage.It proved that STRG could induce apoptosis,inhibit mutant P53 and bcl-2,which had anticancer function by this possible mechanism possibly.
Conclusion:STRG has the function of invigorate the spleen and support the liver, heat-clearing and detoxicating,cool the blood and removing blood stasis,STRG has stabilized the tumor,improved KPS score and the patients symptoms,especially improve hepatic region pain,abdominal distention,anorexia,hypodynamia better. This effect could have concerned with prevent ALB and PA from descending.By drug adverse reaction,a few patients had some nausea and temporary vomiting,but no need treatment,they all could relieve,not found cardiovascular system and other systems adverse reaction.It proved STRG was safety.STRG has the inhibitory on HCC cell line growth,and the inhibitory rate on tumor was enhanced following the dose and time increasing,The high,middle and low density pharmaceutical serum of STRG had inhibited to mutant P53 and bcl-2.STRG could induce apoptosis,and hold cell proliferation up G0/G1 stage.The results of experimental research showed that STRG had the effect of inhibitory rate on tumor,inhibited to mutant P53 and bcl-2, induce apoptosis,which would be the partial mechanism of STRG in fighting the PLC and offered the theory foundation to clinical applying.
方法:临床研究部分:将符合纳入标准的40例患者,采用随机单盲分组法,分为参桃软肝丸治疗组和槐耳颗粒对照组。两组患者均采用相同的对症支持疗法。参桃软肝丸治疗组除对症支持治疗外加服参桃软肝丸,每日一剂,连续服药40天。对照组在对症支持治疗的基础上加服槐耳颗粒,每次一包,每日三次,连用40天。主要观察每组病人的临床治疗效果(包括临床症状、体征、生活质量、肝肾功能、凝血功能、瘤体大小等)以及每组的不良反应,评价参桃软肝丸治疗中晚期肝癌的临床疗效以及安全性。实验研究部分:将雄性新西兰家兔分为3组,每组3只,参桃软肝丸组以成人口服剂量的10倍给雄性新西兰家兔灌胃。空白血清组以等量生理盐水灌胃,阳性药物对照组(5-氟尿嘧啶组),给予药液41.67mg/kg/day灌胃。连续给药3日,每日分两次给药,第3日给药2小时后同剂量追加给药1次,于最后1次灌药后1小时(灌药前禁食不禁水12小时),乙醚麻醉,75%乙醇消毒,心脏采血,无菌分离血清,同组家兔药物血清混匀,水浴灭活处理后,置-20℃冰箱保存备用。人肝癌细胞株HepG2细胞接种于含10%新生牛血清、抗生素(100U/ml青霉素和链霉素)的RPMI 1640培养液中。培养环境为5%CO2,37℃及饱和湿度。细胞培养为3～5天,以0.25%胰蛋白酶消化适当后1:3传代。MTT显色法测定含药血清的抑瘤率,流式细胞仪观察参桃软肝丸对人肝癌HepG2细胞凋亡及周期的影响,用ELISA法检测参桃软肝丸对bcl-2、p53基因表达的调控影响,进一步验证其可能的作用机理。
结果:参桃软肝丸具有健脾养肝,清热解毒,凉血祛瘀之功效,临床试验表明,参桃软肝丸在稳定瘤体、提高患者的卡氏评分,改善患者的症状,特别是对改善患者肝区疼痛、腹胀、纳呆、乏力等4个方面的主症有较好疗效,此作用可能与防止ALB、PA下降的有关,通过药物不良反应监测,发现极少数患者会出现Ⅰ-Ⅱ度恶心和暂时性呕吐,但无需处理,可自行缓解,未发现心血管系统和其他系统的不良反应,说明服用该药物是安全的。实验表明,参桃软肝丸对人肝癌细胞株HepG2的生长有抑制作用,且随剂量的增加而增强。其中,高浓度组抑瘤率最高可达43.2%,与无含药血清相比有统计学意义(P＜0.01),且其抑瘤率随着剂量及作用时间的增加而逐渐提高,48小时时达高峰,与空白组比较有显著性差异(P＜0.01)。参桃软肝丸组含药血清高、中、低浓度均对突变型P53、bcl-2有不同程度的抑制作用,其中三个浓度对突变型P53的抑制与阳性组和空白组比较有统计学意义,P值分别小于0.01和0.05,对bcl-2的抑制与阳性组和空白组比较无统计学意义,但数值有下降趋势,三者中以中浓度即20%浓度抑制效果较好。参桃软肝丸对人肝癌细胞HepG-2有较好的诱导凋亡作用,凋亡率可达15.6%,且阻滞细胞增殖于G0/G1期。说明参桃软肝丸对突变型P53、bcl-2的抑制作用及诱导肿瘤细胞凋亡可能是其抗肿瘤作用机制之一。
结论:参桃软肝丸具有健脾养肝,清热解毒,凉血祛瘀之功效,参桃软肝丸在稳定瘤体、提高患者的卡氏评分,改善患者的症状,特别是对改善患者肝区疼痛、腹胀、纳呆、乏力等4个方面的主症有较好疗效,此作用可能与防止ALB、PA下降的有关,通过药物不良反应监测,发现极少数患者会出现Ⅰ-Ⅱ度恶心和暂时性呕吐,但无需处理,可自行缓解,未发现心血管系统和其他系统的不良反应,说明服用该药物是安全的。参桃软肝丸对人肝癌细胞株HepG2的生长有抑制作用,且其抑瘤率随着剂量及作用时间的增加而逐渐提高,含药血清高、中、低浓度均对突变型P53、bcl-2有不同程度的抑制作用,参桃软肝丸对人肝癌细胞HepG-2有较好的诱导凋亡作用,且阻滞细胞增殖于G0/G1期。本实验通过观察参桃软肝丸对人肝癌细胞HepG-2的抑瘤作用、对突变型P53、bcl-2的抑制作用、诱导肿瘤细胞凋亡等方面的影响,初步探讨该方药的作用机理,为该方在原发性肝癌的临床运用提供理论依据。
Objective:The purpose of clinical research is to observe the therapeutic efficacy of STRG on medium and late stage primary liver cancer,to prove if it can protect the hepatic function,According to the common traditional Chinese medicine adverse effect,mainly observe the effect of digestive system,renal function and cardiovascular system,then estimate it clinical effect and safety.The purpose of experimental research is to observe the pharmaceutical serum effect the inhibitory rate, cell cycle and the apoptosis genetic expression on hepatoma carcinoma cell(HCC)cell line,then discuss the possible mechanism.
Methods:Clinical research:Collected 60 eligible patients with stageⅢ-Ⅳliver cancer were divided randomly into two group,as STRG treated group and Huaier Drop control group,each group has twenty patients.The two groups accepted the same supporting treatment.Meanwhile,the treated group were treated with STRG,one dose per day,last 40 days,the control group were treated with Huaier Drop,one pack every time,three times one day,last 40 days.The therapeutic efficiency and adverse effect of the two groups were evaluated after curing 40 days,then estimate it clinical effect and safety.Experimental research:9 New-Zealand male rabbit were randomly divided into three groups,treated group,blank serum group and positive group,three in each group.The treated group fed with STRG more than 10 times adult oral dose by gavages.The blank serum group fed with the partes aequlaes normal sodium by gavages.The positive group fed with 5-FU by gavages,the dose was 41.67mg/kg/day. All the groups fed three days,twice every day.Three groups boosted the same dose after two hours in the third day,etherization after one hour.75%alcohol sterilizes, from the heart cull blood,asepsis bolter blood serum,all the same groups blood serum were mixed uniformity.Afer waterbath inactivate disposal,put them in the refrigerator below zero 20.HCC cell line was had an inoculation RPMI 1640 culture fluid that contained 10%new-born calf serum and some antibiotics.The cultivation environment was 5%CO2,37℃and saturation humidity.The cell was cultivated three or five days,then passaged after trypsin digestion adequacy.The inhibiting rate of cells observed by MTT,the cell apoptosis and period were measured by Flow Cytometry(FCM),bcl-2 and p53 gene expression were measured by ELISA,in order to discuss STRG the possible mechanism.
Results:STRG has the function of invigorate the spleen and support the liver, heat-clearing and detoxicating,cool the blood and removing blood stasis,Clinical research shows STRG has stabilized the tumor,improved KPS score and the patients symptoms,especially improve hepatic region pain,abdominal distention, anorexia,hypodynamia better.This effect could have concerned with prevent ALB and PA from descending.By drug adverse reaction,a few patients had some nausea and temporary vomiting,but no need treatment,they all could relieve,not found cardiovascular system and other systems adverse reaction.It proved STRG was safety. Experimental research shows that STRG has the inhibitory on HCC cell line growth, and the dose increasing more,the function enhancement more,the inhibitory rate on tumor growth of the high density pharmaceutical serum group was significant than the no pharmaceutical serum group,which inhibitory rate reached 43.2%,and the inhibitory rate on tumor was enhanced following the dose and time increasing,48 hour reached the peak,more significant than the blank group(P＜0.01).The high, middle and low density pharmaceutical serum of STRG had inhibited to mutant P53 and bcl-2.Compared with the positive group and the blank group,three density had more significant(P＜0.01 and 0.05).There were no significant between the pharmaceutical serum and the positive group or the blank group to bcl-2,but the pharmaceutical serum figure had lower tendency,the middle density had better effect. STRG could induce apoptosis,apoptosis rate reached 15.6%,and hold cell proliferation up G0/G1 stage.It proved that STRG could induce apoptosis,inhibit mutant P53 and bcl-2,which had anticancer function by this possible mechanism possibly.
Conclusion:STRG has the function of invigorate the spleen and support the liver, heat-clearing and detoxicating,cool the blood and removing blood stasis,STRG has stabilized the tumor,improved KPS score and the patients symptoms,especially improve hepatic region pain,abdominal distention,anorexia,hypodynamia better. This effect could have concerned with prevent ALB and PA from descending.By drug adverse reaction,a few patients had some nausea and temporary vomiting,but no need treatment,they all could relieve,not found cardiovascular system and other systems adverse reaction.It proved STRG was safety.STRG has the inhibitory on HCC cell line growth,and the inhibitory rate on tumor was enhanced following the dose and time increasing,The high,middle and low density pharmaceutical serum of STRG had inhibited to mutant P53 and bcl-2.STRG could induce apoptosis,and hold cell proliferation up G0/G1 stage.The results of experimental research showed that STRG had the effect of inhibitory rate on tumor,inhibited to mutant P53 and bcl-2, induce apoptosis,which would be the partial mechanism of STRG in fighting the PLC and offered the theory foundation to clinical applying.
引文
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