昆参颗粒影响血管生成因子表达的实验研究及其治疗进展期胃癌的临床观察
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摘要
目的:通过回顾性调查进展期胃癌病历,从中抽提出评价进展期胃癌临床疗效的中医证候指标、疾病指标和综合调理指标;利用回顾性调查研究抽提的三类指标评价昆参颗粒治疗进展期胃癌的临床疗效;通过观察昆参颗粒对实验动物模型血管生成因子的调控作用,探讨昆参颗粒治疗进展期胃癌的作用机制。
方法:1.回顾性调查研究:查阅1999年～2009年山东省中医院住院病人中147例进展期胃癌患者的病历,以填写调查表的形式收集患者症状、肿瘤标志物、复发转移、贫血等方面的资料,并应用Microsoft Office Excel整理并处理数据,着重分析各检查项目中的主要异常元素,从中抽提证候指标、疾病指标、综合调理指标;2.临床研究:将符合纳入标准的54例进展期胃癌患者,按数字表法随机分为昆参颗粒辅助化疗组(昆参组)30例,单纯化疗组(对照组)24例,观察对中医证候指标、疾病指标、综合调理指标的影响;3.实验研究:采用“MNNG+雷尼替丁+乙醇+饥饱失调”的综合方法复制Wistar大鼠模型,按体重随机分为正常组、模型组、昆参颗粒大、中、小剂量组和参莲胶囊组,分别给予药物干预后,采用免疫组化法检测血浆及组织中VEGF、bFGF、MVD的表达;建立S180荷瘤小鼠模型,用免疫组化法检测移植性肉瘤VEGF蛋白表达。
结果:1.回顾性调查研究结果:抽提出中医证候指标,即主症:食少纳呆,上腹痛或痞,形体消瘦,体倦乏力,舌质暗或淡,舌苔厚腻或苔少,脉弦、滑或沉细;次症:腹胀、恶心呕吐、黑便、神疲懒言、烧心泛酸、大便溏结不调、进食梗阻感。疾病指标:肿瘤标志物、免疫功能指标、血管生成因子表达、基因变化等均可以作为进展期胃癌复发、转移和疗效评价的监测指标。综合调理指标:用KPS(Karnofsky)评分、QLQ-C30生活质量调查问卷、胃癌特异量表等反映胃癌患者生活质量,用生存率、生存时间、肿瘤稳定率、体重等指标评价患者整体状况。
2.临床研究结果:治疗前后病灶变化比较,昆参颗粒辅助化疗组30例有效率56.67%,病灶稳定率86.67%;对照组有效率41.67%,病灶稳定率75%,经卡方检验无显著差异(P>0.05)。昆参组患者的各项肿瘤标志物、免疫功能(CD3、CD4、CD4/CD8、NK细胞),较对照组均有明显改善(P<0.01)。两组患者体重、Karnofsky评分、QLQ-C30评分均有不同程度地改善,昆参颗粒辅助化疗组显著优于对照组(P<0.01);昆参颗粒辅助化疗组不良反应发生率明显低于对照组,尤其是白细胞下降、便秘、发热、恶心呕吐等不良反应的发生率显著下降(P<0.05)。
3.实验研究结果:①血浆VEGF:模型组大鼠VEGF血浆含量在53周后增加,参莲组则在53周达到高峰,而大、中、小剂量组在57周达到高峰,之后有不同程度的下降,以大剂量组下降最为明显;②组织VEGF:与正常组比较,造模各组大鼠VEGF表达均显著升高(P<0.01),药物干预后,昆参颗粒大、中、小剂量组VEGF表达显著下降(与模型组相比,均P<0.01),与参莲胶囊组比较无差异;③组织bFGF:正常组bFGF的表达较弱,模型组表达强烈,二组比较差异显著(P<0.01),昆参颗粒大、中、小剂量组与模型组比较有不同程度差异;④MVD:模型组的MVD与正常组比较差异显著(P<0.01),昆参颗粒大、中、小剂量组与模型组比较均有显著差异(P<0.01或P<0.05);⑤S180肉瘤VEGF表达:模型组VEGF呈强阳性表达,昆参颗粒小剂量组VEGF呈中度阳性表达,而在昆参颗粒大剂量组,VEGF呈弱阳性表达。
结论:1.回顾性调查研究:在对进展期胃癌患者进行疗效评价时,我们既要考虑近期临床症状、肿瘤标志物等指标的改善,同时也要评价对胃癌复发率、转移率、贫血发生率等情况的远期疗效,从而建立全面、有效的临床疗效评价体系。2.临床研究:通过临床随机、对照观察,昆参颗粒辅助化疗组在证候指标、疾病指标、综合调理指标方面明显优于单纯化疗组,提示中医药在改善患者整体状况、提高患者生存质量等方面具有明显优势。3.实验研究:昆参颗粒能有效抑制血管生成因子(VEGF、bFGF、MVD)的表达,这可能是其治疗进展期胃癌的关键作用机制。
Objective:By retrospective reviewing the cases of advanced gastric cancer patients, the zhenghou indexs, disease indexs and colligation regulation indexs were extracted to evaluate clinical curative effect of advanced gastric cancer. Three kinds of indexs were extrated to evaluate clinical curative effect of Kunshen granule to cure advanced gastric cancer by retrospective reviewing. By observing regulation effect to vascular growth factor of Kunshen granule on experimental animals, mechanism of action of Kunshen granule is explored to cure advanced gastric cancer.
Methods: 1.Retrospective review: We consulted the cases of 147 advanced gastric cancer patients of ShanDong Traditional Chinese Medicine Hospital from 1999 to 2009, and filled questionnaire to collect patients’datas about symptom, tumor marker recurrence, metastasis and anemia et al. And then used Microsoft Office Excel to arrange the datas, analyzed the major abnormal elements of gastric cancer, and extracted the zhenghou indexs, disease indexs and colligation regulation indexs. 2. Clinical research: 54 cases of advanced gastric cancer had been randomly divided into two groups according to numeration table. One was the treatment group of 30 cases which used chemotherapy as well as Kunshen granule. Another was the control group of 24 cases which only used chemotherapy. 3. Empirical study: Wistar rats were uesd comprehensive method of“MNNG+ Ranitidine + ethanol + disharmony of hungry and full”to make model .The rats were randomly divided into normal group, model group,Kunshen granule large, medium and small dose groups and Shenlian capsule group. The immunochemistry method was used to detect the expression of VEGF、bFGF、MVD in rats’plasma and tissue after treatment. We established S180 tumor-bearing mice model, and used the immunochemistry method to detect the expression of transplanted sarcoma’s VEGF.
Results:1. Results of retrospective review: Zhenghou indexs included main syndrome, as less eating, anorexia, upper abdominal pain, painful abdominal mass, emaciated physique and body, feeling tired, lack of power, dark tongue proper, thick and greasy fur, few fur, pulses of string, slide, menstrual stagnation and thin, and subcardinal syndrome, as abdominal distension, nausea and vomiting, dark stools, lack of power to speak, heartburn, pantothenic acid, disharmony of loose stool and obstipation, obstruction of eating. Tumor marker, immune functional parameter, expression of angiogenesis factor, and genes variation were indexs to monitor recurrence, metastasis and therapeutic effect of advanced gastric cancer. Colligation regulation indexs: Karnofsky Score, QLQ-C30 life quality questionnaire, rating scale of gastric cancer could reflex patients’life quality. Survival rate, live time, stable rate of tumor, body weight could evaluate the patients’whole conditions.
2. Result of clinical research: Comparing focus variation of prior treatment and post-treatment, the effective power of treatment group was 56.67%, stable rate of focus was 86.67%. However, the control group was 41.67% and 75%. There was no significant deviation by chi square test (P>0.05). The treatment group had more curative effects than the control group about tumor markers and immune function(CD3、CD4、CD4/CD8、NK cells)(P<0.01). The treatment group had more curative effects than the control group about body weight, Karnofsky Score and QLQ-C30 Score (P<0.01). The treatment group was obviously lower than the control group on incidence rate of untoward reaction, especially leucopenia, constipation, fever, nausea and vomiting et al. (P<0.05)
3. Result of empirical study:①Plasma VEGF:Plasma VEGF content of model group rats increased after 53 weeks. However, ShenLian capsule group achieved peak after 53 weeks. Kunshen granule large, medium and small dose groups achieved peak after 57 weeks, and descended with different degree later, especially large dose group.②Tissue VEGF: Expression of VEGF advance significantly(P<0.01). After treatment, expression of Kunshen granule large, medium and small dose groups were all significantly descended. (Compaired with model group, P<0.01)Compaired with ShenLian capsule group, there was no significant difference.③Tissue bFGF: expression of normal group were weak, however, expression of model group were intensity. There was significant difference (P<0.01). Compaired with model group and Kunshen granule large,medium and small dose groups, there was significant difference (P<0.01).④M VD:Compaired with model group and nomal group,there was significant difference (P<0.01). Compaired with model group and Kunshen granule large,medium and small dose groups,there was significant difference (P<0.01 or P<0.05).⑤expression of S180 sarcoma VEGF: The normal group was strong positive expression. Kunshen granule small dose group were mezzo positive expression, however, large dose group were weak positive expression.
Conclusion:1. Retrospective review: When evaluating curative effect of advanced gastric cancer patients, we need not noly consider improvement of clinical symptoms in the near future and tumor marker, but also evaluate prostecdtive efficacy as recurrence rate, metastasis rate and incidence of anemia an so on. So, we can establish a evaluation system of clinical curative effect which is overall and effective.2. Clinical research: By clinical observation of random and comparison, compaired with the treatment group which used chemotherapy as well as Kunshen granule and the control group which only used chemotherapy , there was significant difference about the zhenghou indexs, disease indexs and colligation regulation indexs. So, traditional Chinese medicine has obviously dominance on improving the patients’whole conditions and life quality. 3. Experimental study: Kunshen granule can restrain expression of angiogenesis factors(VEGF、bFGF、MVD)significantly. That maybe the key point of mechanism of action of Kunshen granule to cure advanced gastric cancer.
方法:1.回顾性调查研究:查阅1999年～2009年山东省中医院住院病人中147例进展期胃癌患者的病历,以填写调查表的形式收集患者症状、肿瘤标志物、复发转移、贫血等方面的资料,并应用Microsoft Office Excel整理并处理数据,着重分析各检查项目中的主要异常元素,从中抽提证候指标、疾病指标、综合调理指标;2.临床研究:将符合纳入标准的54例进展期胃癌患者,按数字表法随机分为昆参颗粒辅助化疗组(昆参组)30例,单纯化疗组(对照组)24例,观察对中医证候指标、疾病指标、综合调理指标的影响;3.实验研究:采用“MNNG+雷尼替丁+乙醇+饥饱失调”的综合方法复制Wistar大鼠模型,按体重随机分为正常组、模型组、昆参颗粒大、中、小剂量组和参莲胶囊组,分别给予药物干预后,采用免疫组化法检测血浆及组织中VEGF、bFGF、MVD的表达;建立S180荷瘤小鼠模型,用免疫组化法检测移植性肉瘤VEGF蛋白表达。
结果:1.回顾性调查研究结果:抽提出中医证候指标,即主症:食少纳呆,上腹痛或痞,形体消瘦,体倦乏力,舌质暗或淡,舌苔厚腻或苔少,脉弦、滑或沉细;次症:腹胀、恶心呕吐、黑便、神疲懒言、烧心泛酸、大便溏结不调、进食梗阻感。疾病指标:肿瘤标志物、免疫功能指标、血管生成因子表达、基因变化等均可以作为进展期胃癌复发、转移和疗效评价的监测指标。综合调理指标:用KPS(Karnofsky)评分、QLQ-C30生活质量调查问卷、胃癌特异量表等反映胃癌患者生活质量,用生存率、生存时间、肿瘤稳定率、体重等指标评价患者整体状况。
2.临床研究结果:治疗前后病灶变化比较,昆参颗粒辅助化疗组30例有效率56.67%,病灶稳定率86.67%;对照组有效率41.67%,病灶稳定率75%,经卡方检验无显著差异(P>0.05)。昆参组患者的各项肿瘤标志物、免疫功能(CD3、CD4、CD4/CD8、NK细胞),较对照组均有明显改善(P<0.01)。两组患者体重、Karnofsky评分、QLQ-C30评分均有不同程度地改善,昆参颗粒辅助化疗组显著优于对照组(P<0.01);昆参颗粒辅助化疗组不良反应发生率明显低于对照组,尤其是白细胞下降、便秘、发热、恶心呕吐等不良反应的发生率显著下降(P<0.05)。
3.实验研究结果:①血浆VEGF:模型组大鼠VEGF血浆含量在53周后增加,参莲组则在53周达到高峰,而大、中、小剂量组在57周达到高峰,之后有不同程度的下降,以大剂量组下降最为明显;②组织VEGF:与正常组比较,造模各组大鼠VEGF表达均显著升高(P<0.01),药物干预后,昆参颗粒大、中、小剂量组VEGF表达显著下降(与模型组相比,均P<0.01),与参莲胶囊组比较无差异;③组织bFGF:正常组bFGF的表达较弱,模型组表达强烈,二组比较差异显著(P<0.01),昆参颗粒大、中、小剂量组与模型组比较有不同程度差异;④MVD:模型组的MVD与正常组比较差异显著(P<0.01),昆参颗粒大、中、小剂量组与模型组比较均有显著差异(P<0.01或P<0.05);⑤S180肉瘤VEGF表达:模型组VEGF呈强阳性表达,昆参颗粒小剂量组VEGF呈中度阳性表达,而在昆参颗粒大剂量组,VEGF呈弱阳性表达。
结论:1.回顾性调查研究:在对进展期胃癌患者进行疗效评价时,我们既要考虑近期临床症状、肿瘤标志物等指标的改善,同时也要评价对胃癌复发率、转移率、贫血发生率等情况的远期疗效,从而建立全面、有效的临床疗效评价体系。2.临床研究:通过临床随机、对照观察,昆参颗粒辅助化疗组在证候指标、疾病指标、综合调理指标方面明显优于单纯化疗组,提示中医药在改善患者整体状况、提高患者生存质量等方面具有明显优势。3.实验研究:昆参颗粒能有效抑制血管生成因子(VEGF、bFGF、MVD)的表达,这可能是其治疗进展期胃癌的关键作用机制。
Objective:By retrospective reviewing the cases of advanced gastric cancer patients, the zhenghou indexs, disease indexs and colligation regulation indexs were extracted to evaluate clinical curative effect of advanced gastric cancer. Three kinds of indexs were extrated to evaluate clinical curative effect of Kunshen granule to cure advanced gastric cancer by retrospective reviewing. By observing regulation effect to vascular growth factor of Kunshen granule on experimental animals, mechanism of action of Kunshen granule is explored to cure advanced gastric cancer.
Methods: 1.Retrospective review: We consulted the cases of 147 advanced gastric cancer patients of ShanDong Traditional Chinese Medicine Hospital from 1999 to 2009, and filled questionnaire to collect patients’datas about symptom, tumor marker recurrence, metastasis and anemia et al. And then used Microsoft Office Excel to arrange the datas, analyzed the major abnormal elements of gastric cancer, and extracted the zhenghou indexs, disease indexs and colligation regulation indexs. 2. Clinical research: 54 cases of advanced gastric cancer had been randomly divided into two groups according to numeration table. One was the treatment group of 30 cases which used chemotherapy as well as Kunshen granule. Another was the control group of 24 cases which only used chemotherapy. 3. Empirical study: Wistar rats were uesd comprehensive method of“MNNG+ Ranitidine + ethanol + disharmony of hungry and full”to make model .The rats were randomly divided into normal group, model group,Kunshen granule large, medium and small dose groups and Shenlian capsule group. The immunochemistry method was used to detect the expression of VEGF、bFGF、MVD in rats’plasma and tissue after treatment. We established S180 tumor-bearing mice model, and used the immunochemistry method to detect the expression of transplanted sarcoma’s VEGF.
Results:1. Results of retrospective review: Zhenghou indexs included main syndrome, as less eating, anorexia, upper abdominal pain, painful abdominal mass, emaciated physique and body, feeling tired, lack of power, dark tongue proper, thick and greasy fur, few fur, pulses of string, slide, menstrual stagnation and thin, and subcardinal syndrome, as abdominal distension, nausea and vomiting, dark stools, lack of power to speak, heartburn, pantothenic acid, disharmony of loose stool and obstipation, obstruction of eating. Tumor marker, immune functional parameter, expression of angiogenesis factor, and genes variation were indexs to monitor recurrence, metastasis and therapeutic effect of advanced gastric cancer. Colligation regulation indexs: Karnofsky Score, QLQ-C30 life quality questionnaire, rating scale of gastric cancer could reflex patients’life quality. Survival rate, live time, stable rate of tumor, body weight could evaluate the patients’whole conditions.
2. Result of clinical research: Comparing focus variation of prior treatment and post-treatment, the effective power of treatment group was 56.67%, stable rate of focus was 86.67%. However, the control group was 41.67% and 75%. There was no significant deviation by chi square test (P>0.05). The treatment group had more curative effects than the control group about tumor markers and immune function(CD3、CD4、CD4/CD8、NK cells)(P<0.01). The treatment group had more curative effects than the control group about body weight, Karnofsky Score and QLQ-C30 Score (P<0.01). The treatment group was obviously lower than the control group on incidence rate of untoward reaction, especially leucopenia, constipation, fever, nausea and vomiting et al. (P<0.05)
3. Result of empirical study:①Plasma VEGF:Plasma VEGF content of model group rats increased after 53 weeks. However, ShenLian capsule group achieved peak after 53 weeks. Kunshen granule large, medium and small dose groups achieved peak after 57 weeks, and descended with different degree later, especially large dose group.②Tissue VEGF: Expression of VEGF advance significantly(P<0.01). After treatment, expression of Kunshen granule large, medium and small dose groups were all significantly descended. (Compaired with model group, P<0.01)Compaired with ShenLian capsule group, there was no significant difference.③Tissue bFGF: expression of normal group were weak, however, expression of model group were intensity. There was significant difference (P<0.01). Compaired with model group and Kunshen granule large,medium and small dose groups, there was significant difference (P<0.01).④M VD:Compaired with model group and nomal group,there was significant difference (P<0.01). Compaired with model group and Kunshen granule large,medium and small dose groups,there was significant difference (P<0.01 or P<0.05).⑤expression of S180 sarcoma VEGF: The normal group was strong positive expression. Kunshen granule small dose group were mezzo positive expression, however, large dose group were weak positive expression.
Conclusion:1. Retrospective review: When evaluating curative effect of advanced gastric cancer patients, we need not noly consider improvement of clinical symptoms in the near future and tumor marker, but also evaluate prostecdtive efficacy as recurrence rate, metastasis rate and incidence of anemia an so on. So, we can establish a evaluation system of clinical curative effect which is overall and effective.2. Clinical research: By clinical observation of random and comparison, compaired with the treatment group which used chemotherapy as well as Kunshen granule and the control group which only used chemotherapy , there was significant difference about the zhenghou indexs, disease indexs and colligation regulation indexs. So, traditional Chinese medicine has obviously dominance on improving the patients’whole conditions and life quality. 3. Experimental study: Kunshen granule can restrain expression of angiogenesis factors(VEGF、bFGF、MVD)significantly. That maybe the key point of mechanism of action of Kunshen granule to cure advanced gastric cancer.
引文
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