抑瘤宁对S180小鼠的抗癌作用及其对细胞生长周期的影响
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摘要
目的：
恶性肿瘤已成现今危害人类健康的常见病、多发病,在对恶性肿瘤的治疗方面我们经历了漫长的探索过程,西方医学从外科手术遵循“整块”广泛的根治术原则,认为切除越广,根治越彻底,疗效也越好,到现今的向组织及功能保存的转化,于是发展了手术方案个体化、微创外科、移植修复外科、预防性手术。内科也从自氮芥问世以来,研究开发的大量相对非特异的细胞毒药物,和对于细胞周期不同阶段的癌细胞轮番加以杀伤,转向了靶向性治疗,有单克隆抗体、肿瘤疫苗、抗血管生成药物、抗氧乏细胞毒药物、诱导肿瘤细胞分化凋亡、抗信号传导治疗、基因治疗等。放射治疗也无例外地从应用单一的电离辐射造成多细胞损伤转向联合性治疗,使其适应性增加、疗效提高而对正常的组织损伤减小。作为中国的传统医学在恶性肿瘤的治疗方面,也从扶正的观点即改善预后向祛邪的方向发展即抑制肿瘤细胞生长和诱导其凋亡。中药材的价格低廉、毒副作用小也是不可忽视的因素,抑瘤宁就是在此基础上研制的。它对消化系统肿瘤的治疗有令人瞩目的效果,尤其是食管癌、贲门.胃底癌、肝癌、胰腺癌等。疗效确切,长期服用无明显肝、肾、心毒性及骨髓抑制。与化疗联合应用具有增效,减轻机体毒副反应等优点。
抑瘤宁是由冬凌草、刺五加、龙葵和蛇莓组成,体外实验表明：能明显地抑制人食管癌Eca-109细胞、人胃癌SGC-7901细胞、人胰腺癌BBxpc-3细胞和人肝癌Bel-7402细胞、人乳腺癌MDA-MB-231细胞、人肺癌NCI-H520细胞、人肺癌A549细胞、人宫颈癌Hela细胞的生长。体内实验表明：能抑制小鼠S180实体瘤的生长、延长S180腹水瘤小鼠的生存期,抑瘤机制可能与下调TOPO-Ⅱ(拓扑异构酶—Ⅱ)的表达有关。同时对荷EC-9706裸鼠有明显的抑瘤作用,通过改变肿瘤细胞cox-2(内环氧合酶-2)及ki-67(细胞核相关抗原)的表达,抑制肿瘤血管生成,从而抑制肿瘤生长。
本课题进行了抑瘤宁的急性毒性实验,并通过对小鼠S180实体瘤及腹水瘤的实验及其对细胞生长周期影响的研究,为临床应用提供实验依据。
方法：
急性毒性试验：预实验：给小鼠经口灌胃,按照500g生药/kg(最小全不致死量)、250g生药/kg、167g生药/kg、125g生药/kg、100g生药/kg(最大全存活量)的梯度给药,各剂量组动物均为6只,雌雄各半,直至全部存活,观察药物的毒性反应2周。正式实验：根据预试验的结果100g生药/kg,再对20只雌雄各半的小鼠经口灌胃给药,观察药物的毒性反应2周。
药效学试验：建立昆明小鼠S180实体瘤及腹水瘤模型,将雄性小鼠随机分成5组,每组8只：空白对照组(等容量无菌生理盐水,ig，1次/d)；阳性对照组(实体瘤用环磷酰胺20mg/kg, ig,1次/d；腹水瘤用丝裂霉素0.2mg/kg, ip,1次/d)；抑瘤宁低、中、高剂量组(提取物分别为7.47g生药/kg,14.94g生药/kg,22.41g生药/kg,ig,1次/d)。实体瘤实验组均连续灌胃10d,观察各组小鼠的瘤重变化及一般情况。实体瘤各组第11天处死动物,取出瘤体称重,计算抑瘤率。腹水瘤各组均连续灌胃10天,其后观察各动物的死亡时间,计算生命延长率。
机理探讨：将瘤体制作细胞悬液,流式细胞仪分折DNA含量分布,multicycle软件分析G1、S、G2各期细胞比例。
结果：
抑瘤宁的急性毒性试验结果为100g生药/kg(体重),相当于临床用药量的120.5倍。
阳性对照组及抑瘤宁低、中、高剂量组的抑瘤率分别为64.15%、33.49%、35.38%、39.62%,与空白对照组比较均有统计学意义(P<0.05)；抑瘤宁三个剂量组间随着剂量的增大抑瘤效果越来越明显,呈量效关系；各组动物实验结束时体重都高于初始体重。抑瘤宁高剂量组的生命延长率为23.53%,与空白对照组比较,虽有差异但无实际意义。抑瘤宁低、中剂量组的生命延长率分别是6.86%、14.71%,与空白对照组比较,差异均无显著性(P>0.05)。抑瘤宁低、中、高剂量组S期比例分别为52.226%、58.206%、59.004%,与模型对照组比较,差异均有显著性(P<0.05)。
结论：
(1)给动物灌服100g生药/kg的抑瘤宁,在观察期内动物无一死亡,短期内未发现急性毒性反应；
(2)抑瘤宁各剂量组对S180荷瘤小鼠的瘤体有明显的抑制作用,呈量效关系；
(3)抑瘤宁高剂量组与空白对照组相比虽能延长生存期,但无实际意义；
(4)抑瘤宁对S180荷瘤小鼠的抑瘤作用主要是阻滞细胞在S期。
Purpose:
Nowadays malignant tumour has become common disease and frequently-occurring disease threatening human health. We have gone through a long process to explore the therapy of malignant tumour. Previously, people believed that surgical operation should follow monoblock and widely radical operation principle in Western medicine, considering that the wider it was excised, the more thorough it was cured. At present, people's attitudes toward oncotherapy turns to preserve tissues and functions. Consequently,multiple treatment options get developed,such as individual operation regimen,minimally invasive surgery,transplant repair surgery and preventive surgery.Medicine also transforms from researching and developing kinds of relatively non-specific cytotoxic agents used for taking turns killing and wounding cancer cells of different cell cycle phases since nitroqen mustard came out to targeted therapy,including monoclonal antibody,tumor vaccine,Antiangiogenic drugs,Antioxidant cytotoxic drugs,Inducing tumor cell differentiation apoptosis,Resistance to signal transduction treatment,gene therapy etc. Radiotherapy is no exception, shifts from applying single ionizing radiation causing multicellular damage to combined therapy which makes its adaptability increase, curative effect improve and meanwhile reduces the damage to the normal tissues. The traditional Chinese medicine also converts from the view of strengthening the body resistance, that is improving prognosis, to the direction of eliminating pathogens by inhibiting tumor cells growth and inducing them apoptosis in the treatment of malignant tumor. Chinese herbal medicines has inneglectable advantages such as low cost and small toxicity etc. Yiliuning is deemed as a kind of antineoplastic prescription on that basis.There are spectacular results in the therapy of digestive system neoplasms applying Chinese herbal medicines,especially esophageal cancinoma, gastrocardiac carcinoma,liver cancer, pancreatic cancer etc. Meanwhile, they have definite curative effect and neither obvious toxicity of liver, kidney and heart nor bone marrow inhibition for a long-term use. Combined with chemotherapy, they can add curative efficacy, reduce side effects and so on.
Yiliuning is composed of Rab,Aca, Duc and Sol.The experiment in vitro indicated that it could obviously inhibit the growth of diversified tumor cells,including esophageal cancer Eca-109 cells,gastric cancer SGC-7901 cells,pancreatic cancer BBxpc-3 cells,and liver cancer Bel-7402 cells,breast cancer MDA-MB-231 cells,lung cancer NCI-H520,lung cancer A549 cells,cervical cancer Hela cells. The experiments in vivo demonstrated that it had an anti-growth effect on S180 solid tumor mice and prolonged survival of mice with S180 ascites tumor.The anti-tumor mechanism might be TOPO-Ⅱ(the down-regulation of topology isomerase-Ⅱ) expression.It had an evident anti-tumor effect on tumor-bearing Ec-9706 nude mice.Influencing the expression of within an enzyme called cox-2 (cyclooxygenase-2) and ki-67 (the nucleus related antigen) in cancer cells,it could inhibit tumor angiogenesis and tumor growth.
We observed the acute toxicity of Yiliuning and the test on S180 solid tumor mice and ascites tumor mice, then analyzed the influence of the cell growth cycle, which provided experiment evidence for clinic.
Methods:
Acute Toxicity Test:Infuse liquid medicine into mice's stomach by 500g/kg(the minimum no lethal dose)、250g/kg、167g/kg、125g/k、100g/kg(the most live dose)until all survive,each dose group of animals is 6 (bisexual each half),and then observe drug toxicity two weeks. Official Test:According to the result (100g/kg)of the previous experiment, observe drug toxicity two weeks after twenty mice(bisexual each half) are perfused.
The pharmacodynamics Test:Establish the model of solid tumor and ascitic tumor male mice S180,and then random separate into five groups, eight each group: Negative control group(the same volume of physiological saline); Positive control group (solid tumor:20mg/kg.d of the cyclophosphamide,ig;ascitic tumor:0.2mg/kg.d of the mitomycin,ip);low,moderate,high three dosage groups of Yiliuning(7.47g/kg.d, 14.94 g/kg.d,22.41g/kg.d of Yiliuning'extracts, respectively,ig). The administration route is gavage through mouth in all the groups. After giving drugs for ten days continuously,observe the changes of tumors'weight and generally of mice in each group. On the 11th day, execute all the mice of solid tumor groups, take out the neoplasms to weigh, calculate the tumor-suppressing rates To ascitic tumor,After giving drugs for ten days continuously,observe the groups of mice survival time.and calculate the life-prolonging rate.
The experimental mechanism:Making cell suspension to the tumour. Then analyse the content distribution of DNA using FCM and the propotion of cells of G1, G2,S phases via multicycle software.
Results:
T Acute toxicity results of Yiliuning is 100 g/kg. which is as much as 120.5 times of clinical medication.
The tumor-suppressing rates in positive control group and experimental groups (low,moderate, high three dosage-groups of Yiliuning) are respectivly 64.15%, 33.49%,35.38%,39.62%.Compared with negative control group,the difference of all groups are statistically significant(P<0.05).As the dosage increases,the effect of anti-tumor is more and more obvious among the Yiliuning groups,which shows a quantity-efficiency relation. When the experiments are over,the weight of the mice in the positive group and Yiliuning group are higher than that of the negative control group. Yiliuning group with high dosage is 23.53%. Compared with the negative control group,the datas have statistically significant difference,but have no practical significance. The life-prolonging rate of the Yiliuning group with low, moderate dosage are respectively 6.86% and 14.71%,and there are no statistically significant difference(P>0.05) compared with the negative control group. The S phase rates in experimental groups (low,moderate, high three dosage-groups of Yiliuning) are respectivly 52.226%、58.206%、59.004%.Compared with negative control group,the difference of all groups are statistically significant(P<0.05).
Conclusion:
1.During observation period,there are no death animals and do not find toxic effects in short-term after giving 100g/kg of Yiliuning;
2.The compound preparation of Yiliuning can obviously restrain the growth of solid tumor Kunming mice S180, which shows a quantity-efficiency relation;
3. Compared with control group, the high dose group, which have statistically significant difference,but have no practical significance.
4.The anti-tumor mechanism of the compound preparation of Yiliuning may be inducing tumor cells apoptosis, and blocking tumor cells in S phase.
恶性肿瘤已成现今危害人类健康的常见病、多发病,在对恶性肿瘤的治疗方面我们经历了漫长的探索过程,西方医学从外科手术遵循“整块”广泛的根治术原则,认为切除越广,根治越彻底,疗效也越好,到现今的向组织及功能保存的转化,于是发展了手术方案个体化、微创外科、移植修复外科、预防性手术。内科也从自氮芥问世以来,研究开发的大量相对非特异的细胞毒药物,和对于细胞周期不同阶段的癌细胞轮番加以杀伤,转向了靶向性治疗,有单克隆抗体、肿瘤疫苗、抗血管生成药物、抗氧乏细胞毒药物、诱导肿瘤细胞分化凋亡、抗信号传导治疗、基因治疗等。放射治疗也无例外地从应用单一的电离辐射造成多细胞损伤转向联合性治疗,使其适应性增加、疗效提高而对正常的组织损伤减小。作为中国的传统医学在恶性肿瘤的治疗方面,也从扶正的观点即改善预后向祛邪的方向发展即抑制肿瘤细胞生长和诱导其凋亡。中药材的价格低廉、毒副作用小也是不可忽视的因素,抑瘤宁就是在此基础上研制的。它对消化系统肿瘤的治疗有令人瞩目的效果,尤其是食管癌、贲门.胃底癌、肝癌、胰腺癌等。疗效确切,长期服用无明显肝、肾、心毒性及骨髓抑制。与化疗联合应用具有增效,减轻机体毒副反应等优点。
抑瘤宁是由冬凌草、刺五加、龙葵和蛇莓组成,体外实验表明：能明显地抑制人食管癌Eca-109细胞、人胃癌SGC-7901细胞、人胰腺癌BBxpc-3细胞和人肝癌Bel-7402细胞、人乳腺癌MDA-MB-231细胞、人肺癌NCI-H520细胞、人肺癌A549细胞、人宫颈癌Hela细胞的生长。体内实验表明：能抑制小鼠S180实体瘤的生长、延长S180腹水瘤小鼠的生存期,抑瘤机制可能与下调TOPO-Ⅱ(拓扑异构酶—Ⅱ)的表达有关。同时对荷EC-9706裸鼠有明显的抑瘤作用,通过改变肿瘤细胞cox-2(内环氧合酶-2)及ki-67(细胞核相关抗原)的表达,抑制肿瘤血管生成,从而抑制肿瘤生长。
本课题进行了抑瘤宁的急性毒性实验,并通过对小鼠S180实体瘤及腹水瘤的实验及其对细胞生长周期影响的研究,为临床应用提供实验依据。
方法：
急性毒性试验：预实验：给小鼠经口灌胃,按照500g生药/kg(最小全不致死量)、250g生药/kg、167g生药/kg、125g生药/kg、100g生药/kg(最大全存活量)的梯度给药,各剂量组动物均为6只,雌雄各半,直至全部存活,观察药物的毒性反应2周。正式实验：根据预试验的结果100g生药/kg,再对20只雌雄各半的小鼠经口灌胃给药,观察药物的毒性反应2周。
药效学试验：建立昆明小鼠S180实体瘤及腹水瘤模型,将雄性小鼠随机分成5组,每组8只：空白对照组(等容量无菌生理盐水,ig，1次/d)；阳性对照组(实体瘤用环磷酰胺20mg/kg, ig,1次/d；腹水瘤用丝裂霉素0.2mg/kg, ip,1次/d)；抑瘤宁低、中、高剂量组(提取物分别为7.47g生药/kg,14.94g生药/kg,22.41g生药/kg,ig,1次/d)。实体瘤实验组均连续灌胃10d,观察各组小鼠的瘤重变化及一般情况。实体瘤各组第11天处死动物,取出瘤体称重,计算抑瘤率。腹水瘤各组均连续灌胃10天,其后观察各动物的死亡时间,计算生命延长率。
机理探讨：将瘤体制作细胞悬液,流式细胞仪分折DNA含量分布,multicycle软件分析G1、S、G2各期细胞比例。
结果：
抑瘤宁的急性毒性试验结果为100g生药/kg(体重),相当于临床用药量的120.5倍。
阳性对照组及抑瘤宁低、中、高剂量组的抑瘤率分别为64.15%、33.49%、35.38%、39.62%,与空白对照组比较均有统计学意义(P<0.05)；抑瘤宁三个剂量组间随着剂量的增大抑瘤效果越来越明显,呈量效关系；各组动物实验结束时体重都高于初始体重。抑瘤宁高剂量组的生命延长率为23.53%,与空白对照组比较,虽有差异但无实际意义。抑瘤宁低、中剂量组的生命延长率分别是6.86%、14.71%,与空白对照组比较,差异均无显著性(P>0.05)。抑瘤宁低、中、高剂量组S期比例分别为52.226%、58.206%、59.004%,与模型对照组比较,差异均有显著性(P<0.05)。
结论：
(1)给动物灌服100g生药/kg的抑瘤宁,在观察期内动物无一死亡,短期内未发现急性毒性反应；
(2)抑瘤宁各剂量组对S180荷瘤小鼠的瘤体有明显的抑制作用,呈量效关系；
(3)抑瘤宁高剂量组与空白对照组相比虽能延长生存期,但无实际意义；
(4)抑瘤宁对S180荷瘤小鼠的抑瘤作用主要是阻滞细胞在S期。
Purpose:
Nowadays malignant tumour has become common disease and frequently-occurring disease threatening human health. We have gone through a long process to explore the therapy of malignant tumour. Previously, people believed that surgical operation should follow monoblock and widely radical operation principle in Western medicine, considering that the wider it was excised, the more thorough it was cured. At present, people's attitudes toward oncotherapy turns to preserve tissues and functions. Consequently,multiple treatment options get developed,such as individual operation regimen,minimally invasive surgery,transplant repair surgery and preventive surgery.Medicine also transforms from researching and developing kinds of relatively non-specific cytotoxic agents used for taking turns killing and wounding cancer cells of different cell cycle phases since nitroqen mustard came out to targeted therapy,including monoclonal antibody,tumor vaccine,Antiangiogenic drugs,Antioxidant cytotoxic drugs,Inducing tumor cell differentiation apoptosis,Resistance to signal transduction treatment,gene therapy etc. Radiotherapy is no exception, shifts from applying single ionizing radiation causing multicellular damage to combined therapy which makes its adaptability increase, curative effect improve and meanwhile reduces the damage to the normal tissues. The traditional Chinese medicine also converts from the view of strengthening the body resistance, that is improving prognosis, to the direction of eliminating pathogens by inhibiting tumor cells growth and inducing them apoptosis in the treatment of malignant tumor. Chinese herbal medicines has inneglectable advantages such as low cost and small toxicity etc. Yiliuning is deemed as a kind of antineoplastic prescription on that basis.There are spectacular results in the therapy of digestive system neoplasms applying Chinese herbal medicines,especially esophageal cancinoma, gastrocardiac carcinoma,liver cancer, pancreatic cancer etc. Meanwhile, they have definite curative effect and neither obvious toxicity of liver, kidney and heart nor bone marrow inhibition for a long-term use. Combined with chemotherapy, they can add curative efficacy, reduce side effects and so on.
Yiliuning is composed of Rab,Aca, Duc and Sol.The experiment in vitro indicated that it could obviously inhibit the growth of diversified tumor cells,including esophageal cancer Eca-109 cells,gastric cancer SGC-7901 cells,pancreatic cancer BBxpc-3 cells,and liver cancer Bel-7402 cells,breast cancer MDA-MB-231 cells,lung cancer NCI-H520,lung cancer A549 cells,cervical cancer Hela cells. The experiments in vivo demonstrated that it had an anti-growth effect on S180 solid tumor mice and prolonged survival of mice with S180 ascites tumor.The anti-tumor mechanism might be TOPO-Ⅱ(the down-regulation of topology isomerase-Ⅱ) expression.It had an evident anti-tumor effect on tumor-bearing Ec-9706 nude mice.Influencing the expression of within an enzyme called cox-2 (cyclooxygenase-2) and ki-67 (the nucleus related antigen) in cancer cells,it could inhibit tumor angiogenesis and tumor growth.
We observed the acute toxicity of Yiliuning and the test on S180 solid tumor mice and ascites tumor mice, then analyzed the influence of the cell growth cycle, which provided experiment evidence for clinic.
Methods:
Acute Toxicity Test:Infuse liquid medicine into mice's stomach by 500g/kg(the minimum no lethal dose)、250g/kg、167g/kg、125g/k、100g/kg(the most live dose)until all survive,each dose group of animals is 6 (bisexual each half),and then observe drug toxicity two weeks. Official Test:According to the result (100g/kg)of the previous experiment, observe drug toxicity two weeks after twenty mice(bisexual each half) are perfused.
The pharmacodynamics Test:Establish the model of solid tumor and ascitic tumor male mice S180,and then random separate into five groups, eight each group: Negative control group(the same volume of physiological saline); Positive control group (solid tumor:20mg/kg.d of the cyclophosphamide,ig;ascitic tumor:0.2mg/kg.d of the mitomycin,ip);low,moderate,high three dosage groups of Yiliuning(7.47g/kg.d, 14.94 g/kg.d,22.41g/kg.d of Yiliuning'extracts, respectively,ig). The administration route is gavage through mouth in all the groups. After giving drugs for ten days continuously,observe the changes of tumors'weight and generally of mice in each group. On the 11th day, execute all the mice of solid tumor groups, take out the neoplasms to weigh, calculate the tumor-suppressing rates To ascitic tumor,After giving drugs for ten days continuously,observe the groups of mice survival time.and calculate the life-prolonging rate.
The experimental mechanism:Making cell suspension to the tumour. Then analyse the content distribution of DNA using FCM and the propotion of cells of G1, G2,S phases via multicycle software.
Results:
T Acute toxicity results of Yiliuning is 100 g/kg. which is as much as 120.5 times of clinical medication.
The tumor-suppressing rates in positive control group and experimental groups (low,moderate, high three dosage-groups of Yiliuning) are respectivly 64.15%, 33.49%,35.38%,39.62%.Compared with negative control group,the difference of all groups are statistically significant(P<0.05).As the dosage increases,the effect of anti-tumor is more and more obvious among the Yiliuning groups,which shows a quantity-efficiency relation. When the experiments are over,the weight of the mice in the positive group and Yiliuning group are higher than that of the negative control group. Yiliuning group with high dosage is 23.53%. Compared with the negative control group,the datas have statistically significant difference,but have no practical significance. The life-prolonging rate of the Yiliuning group with low, moderate dosage are respectively 6.86% and 14.71%,and there are no statistically significant difference(P>0.05) compared with the negative control group. The S phase rates in experimental groups (low,moderate, high three dosage-groups of Yiliuning) are respectivly 52.226%、58.206%、59.004%.Compared with negative control group,the difference of all groups are statistically significant(P<0.05).
Conclusion:
1.During observation period,there are no death animals and do not find toxic effects in short-term after giving 100g/kg of Yiliuning;
2.The compound preparation of Yiliuning can obviously restrain the growth of solid tumor Kunming mice S180, which shows a quantity-efficiency relation;
3. Compared with control group, the high dose group, which have statistically significant difference,but have no practical significance.
4.The anti-tumor mechanism of the compound preparation of Yiliuning may be inducing tumor cells apoptosis, and blocking tumor cells in S phase.
引文
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