养胃抗瘤冲剂对中晚期胃癌预后的影响及诱导细胞凋亡的分子机制
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摘要
胃癌(Gastric carcinoma)是严重危害人类健康的最常见恶性肿瘤之一,由于术后复发、转移是临床大多数患者的致死主因,故人们一直在寻求手术以外治疗胃癌的方法,尽量延长患者的生存期。导师孙桂芝教授四十余年来从事中西医结合治疗恶性肿瘤,疗效显著,尤其在治疗以胃癌为主的消化道肿瘤方面经验尤为丰富。养胃抗瘤冲剂(YWKL)是导师研制的治疗中晚期胃癌的中药复方,以益气养胃、健脾补肾、活血化瘀、解毒抗癌为治则,临床应用二十余年,具有防止肿瘤复发、转移,延长患者生存期的作用。本论文在既往研究的基础上对导师治疗胃癌的理、法、方、药四个方面进行系统总结,探讨中医药治疗提高临床疗效的物质基础,并用现代科技手段进行实验研究,以615小鼠前胃癌术后复发转移模型和人胃癌细胞系MGC803、BGC823抗失巢凋亡及多细胞球体模型为载体,采用免疫组化(IHC)、RealtimeRT-PCR、AV-PI、流式细胞术、TUNEL、MTT等技术,从整体-细胞-基因-信号传导等层次,深入探讨了YWKL改善胃癌总体预后的分子机制,从一个侧面揭示了扶正祛邪并重的治疗原则延长中晚期胃癌生存期的科学内涵。
1理论研究
在既往研究的基础上,从理、法、方、药四个方面系统总结导师孙桂芝教授治疗胃癌的经验,探讨了中医药治疗提高临床疗效的物质基础。
1.1胃癌病因病机的认识
祖国医学虽无“胃癌”病名之记载,但对胃的证候及症状描述有很多与胃癌相似。分析胃癌临床证候特点,当属中医“胃脘痛”、“噎膈”、“心下痞”、“胃反”等范畴。导师通过总结古人相关论述及当代医家对胃癌病因、病机的认识,更结合自己40余年临床经验,认为脾胃虚损为胃癌发病最重要环节,各种原因引起的脾胃虚损,可进一步导致脾失健运、胃失和降,进而中焦壅滞,食积不化、气滞血瘀,蕴积生毒,最终发展成为胃癌。
1.2治则治法
导师在长期临床中通过辨证与辨病结合,强调以人为本,以脾肾为中心,兼调身心,协调内外；扶正驱邪,坚持守方,以“持久战”对抗胃癌及其复发转移。常用治法包括：健脾升清、和胃消食、祛瘀生新、抗癌解毒四法连用,在抑制肿瘤的复发及转移,稳定和缩小瘤体,有效提高生活质量和延长生存期方面取得了良好的效果。
1.3常用“小范方”
导师喜用经验方,经验方又多由数个“小范方”组成,如藤虎汤,组成：藤梨根、虎杖；蒲黄白芷蜂房汤,组成：生蒲黄、白芷、露蜂房、血余炭；金麦代赭汤,组成：鸡内金、生麦芽、代赭石等。
2临床研究
养胃抗瘤冲剂(YWKL)是导师孙桂芝教授研制的治疗中晚期胃癌的中药复方,以益气养胃、健脾补肾、活血化瘀、解毒抗癌为治疗原则。目的：通过对258例中晚期胃癌的非随机同期对照研究,·评价以YWKL复方加减辨证治疗对中晚期胃癌患者生存期及生存质量的影响。方法：采用回顾性同期对照研究方法,共纳入中晚期胃癌患者258例(中西医结合组147例,单纯化疗组111例),两组均采用化疗(入组后接受以氟尿嘧啶类为基础的方案化疗,并依据细胞病理学类型、体能状况等情况可联合运用铂类、葸环类或紫杉类药物,一般治疗3-6周期)等西医治疗；中西医结合组在此基础上加用YWKL。每两周辨证一次,在基本处方基础上修正中药处方,记录服药持续的时间。进行长期随访,数据的管理采用EPidata3.1软件建立数据库,采用Kaplan-Meier法估算中位生存时间,采用SPSS17.0统计软件进行统计分析。结果：比较一年、三年、五年生存率,中西医结合组分别是：98.6%、84.4%、68.7%,单纯化疗组分别是：72.1%、12.6%、5.4%。比较中位生存时间,中西医结合组：72.69个月,单纯化疗组：21.94个月,经统计分析均有统计意义(P＜0.05)。比较治疗前后KPS评分变化,中西医结合组分别是：62.6%提高,32.6%稳定,4.7%下降,单纯化疗组分别是：27.9%提高,59.4%稳定,12.6%下降。比较治疗前后体重变化评价,中西医结合组分别是：53.1%提高,39.5%稳定,7.5%下降,单纯化疗组分别是：提高44.1%提高,25.2%稳定,30.6%下降。治疗前后KPS评分变化及体重变化评价比较差异有统计学意义(P<0.05)。结论：以YWKL为基础辨证治疗中晚期胃癌延长了患者生存期,提高了患者的生活质量。中医药治疗在改善胃癌总体预后方面的作用值得进一步作随机对照研究评价。
3实验研究
本课题在实验研究方面以615小鼠前胃癌术后复发转移模型和人胃癌细胞系MGC803.BGC823抗失巢凋亡及多细胞球体模型为载体,采用流式细胞技术FCM、TUNEL、AV-PI、Realtime RT-PCR、MTT、免疫组化等多种实验技术方法,从整体-细胞-基因-信号传导等层次,深入探讨了YWKL改善胃癌总体预后的分子机制,从一个侧面揭示了扶正祛邪并重的治疗原则延长中晚期胃癌生存期的科学内涵。
3.1动物实验部分
3.1.1成功建立和临床术后复发转移相类似的615小鼠前胃癌术后复发转移动物模型,为动态观察术后复发转移,研究复发转移的作用机制奠定了基础。
3.1.2中药复方YWKL对于615小鼠前胃癌术后局部复发和远处肺转移有一定的抑制作用(复发瘤抑制率为68.07%和肺转移抑制率为33.33%),能明显控制肿瘤复发转移的程度,提高生存质量,延长生存期(生命延长率为100%)。
3.1.3应用不同检测凋亡的方法,证实改变胃癌细胞的凋亡敏感性是YWKL防治复发转移的重要作用机制。
3.1.4中药复方YWKL可以抑制端粒酶的增殖能力,通过促进线粒体释放Cytc,激活Caspase级联反应,从而提高促凋亡蛋白Smac、Apaf-1蛋白的表达,降低凋亡抑制蛋白XIAP表达。通过对端粒酶的增殖和凋亡两方面的检测可以探讨端粒酶对肿瘤细胞凋亡的影响,为应用中医药防治肿瘤复发转移提供新的思路和科学理论依据。
3.2细胞实验部分
3.2.1成功复制人胃癌细胞系MGC803、BGC823抗失巢凋亡及多细胞球体模型,很好的拟合体内肿瘤转移时的细胞状态,为验证YWKL复方抗转移的作用机理提供了可靠的技术平台。
3.2.2采用血清药理学的方法应用正交设计制备了YWKL的含药血清,并通过MTT法动态观察和筛选出含药血清的最佳采血时间和有效浓度。
3.2.3细胞凋亡信号传导紊乱是肿瘤发生复发转移的重要机制之一,中药复方YWKL的含药血清可以通过调控线粒体途径,提高人胃癌细胞系MGC803、BGC823的凋亡敏感性,最终激活凋亡效应型Caspase-3引起肿瘤细胞凋亡。
4本研究主要创新之处
本研究的创新之处主要有以下几点：
4.1理论研究中,对导师孙桂芝教授治疗胃癌的理、法、方、药四个方面进行系统总结,探讨了中医药治疗提高临床疗效的物质基础,揭示了扶正祛邪并重的治疗原则延长中晚期胃癌生存期的科学内涵。
4.2本论文对YWKL提高中晚期胃癌患者生存期、生存质量进行了较大样本分析,在临床取得明显疗效的基础上,以615小鼠前胃癌术后复发转移模型和人胃癌细胞系MGC803、BGC823抗失巢凋亡及肿瘤多细胞球体模型为载体,·从端粒酶增殖和线粒体凋亡转导通路相关调控因子活性与表达深入探讨了YWKL提高晚期胃癌预后总体效应的分子机制,研究从一个侧面揭示了扶正祛邪并重治疗晚期肿瘤的理论内涵,为深层次挖掘名老中医经验提供了新思路。
4.3本研究引入人胃癌细胞系MGC803和BGC823抗失巢凋亡及多细胞球体培养模型,更好的模拟了肿瘤转移过程中细胞状态,进行失巢凋亡及中药复方研究,国内外未见报道,属方法创新。
Gastric carcinoma is one kind of common malignant tumor that can do serious harm to human health. As the postoperative recurrence and metastasis are major cause of death in most clinical patients, so people have been seeking treatment other than surgical method of gastric cancer to extend survival of patients. Professor Sun Gui-zhi has engaged in treating some kind of malignant tumors with methods of Integrative Medicine for 40 years. She has rich experience of treating gastrointestinal cancers, especially gastric cancer, and gets a significant effect. Yang Wei Granules (YWKL) was developed by Professor Sun Gui-zhi for treating advanced gastric cancer. Its rule is increasing Qi and providing nutrition for stomach, spleen and kidney, and promoting blood circulation, detoxify and anti-cancer. Clinically applied for 20 years, it has been proved playing a role of preventing of tumor recurrence, metastasis and prolonging survival in patients with gastric carcinoma. This thesis summarized Professor Sun Gui-zhi's experience of treating gastric carcinomas from theory, method, prescription and drugs on the basis of research in the past several years. We use modern technology to conduct experimental research and want to explore the active ingredients of those Chinese medicines to improve the clinical efficacy. The carcinoma model is 615 mice of recurrence and metastasis after surgical method of treating gastric cancer. The molecular mechanisms of inducing apoptosis and the role of improving symptoms and prolonging life of YWKL are researched by methods of immunohistochemistry (IHC), Realtime RT-PCR, AV-PI, flow cytometry, TUNEL and other techniques from the whole-cell-gene-signal transduction level. And the scientific contents of rational Fuzheng and Quxie are revealed from those sides.
1 Theory research
Based on the research in the past, I summarized the experience of Professor Sun Guizhi's treating gastic cancer from four sides, such as the principles, methods, prescriptions, and chinese traditional medicines, to explore the material basis of the clinical effect.
1.1 Understanding of the pathogenesis of gastric cancer
No records of gastric cancer that we can find in traditional Chinese medicine theory. But we can see some descriptions of stomach syndrome and symptoms those are similar with gastric cancer, such as "stomachache", "Ye Ge", "Epigastric Distension", "wei fan". Professor Sun Guizhi summarized the relevant ancient and contemporary medical practices on cancer etiology, pathogenesis of knowledge, blent with her clinical experiences for more than 40 years, indicated that the spleen deficiency as the most important aspect of gastric cancer, and that a variety of causes can damage spleen's and stomach's physical function, then the focus Yong Zhi, food product, so, qi stagnation, Yongzhi of heat stored up health drugs, eventually developed into gastric cancer.
1.2 therapeutical principle
For her long-term clinical expierince, Professor Sun Gui-zhi has summarized some important principles, such as combinating people's symptoms with pathology report as the basis of diagnose, paying more attention to the role of human' body itself, considering spleen and kidney as the center of human' health, and the role of physical and mental adjust, the role of coordinating internal and external factors, righting evil spirits, insist on defending side to "protracted war" against cancer and its recurrence and metastasis. Common treatment methods include that adjusting spleen and stomach' function and promoting digestion, removing the damaged inssue and promoting the new inssue growwing, and anti-cancer detoxification. Those methods used together in the inhibition of tumor recurrence and metastasis, stability, and shrinking the tumor, improving quality of life and prolonging survival to achieve impressive results.
1.3 commonly used formula
Professor Sun Gui-zhi usually use some experienced prescriptions which we called "Little Standard prescriptions", such as "Tenghu soup" which consists of Actinidia arguta and Polygonum, "Puhuang-Baizhi-Fengfang soup" which consists of Typhae, Angelica, Lucy hives, and Hair Carbon, "Jin-Mai-Daizhe soup" which consists of Gallus gallus, the Health and malt, Ruddle.
2 clinical research
YWKL is an exprimental prescription for Professor Sun Gui-zhi treating advanced gastric cancer which was developed by the principles of adjusting Qi and Stomach, spleen and kidney, promoting blood circulation and detoxification.
Objective:Explore the role of YWKL Modified Differential Treatment in affecting patients' survival and quality of life with advanced gastric cancer by non-randomized concurrent control studies on 258 cases of advanced gastric cancer. Methods:A retrospective control study period, included a total of 258 cases of advanced gastric cancer (147 cases of Integrated Traditional and Western group, chemotherapy group 111 cases), chemotherapy in both groups (post-entry group to fluorouracil-based programs chemotherapy, and according to type of cell pathology, physical condition, etc. can be combined use of platinum, anthracycline or taxol, the general treatment of 3-6 cycles) and other medical therapy; Integrative Medicine Group at this based on the use YWKL. Differentiations are be took on once every two weeks, and the basic prescriptions are amended correspondingly. And we record the duration of medication. For a long term we follow up those patiants. And the final data are managed by software EPidata3.1 to estimate the median survival time using Kaplan-Meier method. Finally we use SPSS 17.0 statistical software for statistical analysis. Results:Comparison of one, three, five-year survival rate, those of Integrative Medicine Group are 98.6%,84.4% and 68.7%, respectively the chemotherapy group are 72.1%,12.6%,5.4%. Median survival time of Integrative Group is 72.69 months, and in chemotherapy group it's 21.94 months, they have statistically significant by statistical analysis (P<0.05). KPS score changes before and after treatment, Integrative Medicine Group are increasing 62.6%, stably 32.6%, declining 4.7%, those of chemotherapy group are increasing 27.9%, stably 59.4%, declining 12.6% respectively. Evaluation of weight changes before and after treatment, Integrative Medicine Group are increasing 53.1%, stably 39.5%, declining 7.5%, and those of chemotherapy group are increasing 44.1%, stably 25.2%, declining 30.6%. Changes of KPS score and weight before and after treatment were significant statistically (P<0.05). Conclusion:YWKL-based differentiation in treatment of advanced gastric cancer patients prolonged their survival, improved the quality of life of patients. The role of TCM treatment in improving the overall prognosis of gastric cancer deserves more randomized controlled studies to explore.
3 exprimental research
Using 615 mouse models with gastric cancer recurrence and metastasis and human cancer cell lines MGC803, BGC823 Anoikis and multicellular spheroid model as the carrier, using flow cytometry FCM, TUNEL, AV-PI, Realtime RT-PCR, MTT, immunohistochemistry and other methods of experimental techniques, from the whole-cell-gene-the signal transduction level, we deply improve the molecular mechanism of the YWKL against tumor and promoting the overall prognosis of gastric cancer, and reveal the scientific content of the principle of attaching equal balance to extend the treatment of advanced gastric cancer survival.
3.1 animal experiments
3.1.1 Successfully established mouse 615 models which are similar to clinical metastasis and recurrence of gastric cancer for dynamic observation of recurrence and metastasis. It is a foundation foe us to research the mechanism of recurrence and metastasis of the action of gastric cancer.
3.1.2 Chinese compound herb YWKL has some inhibitory effects on carcinoma in 615 mice for the postoperative local recurrence and distant metastasis (inhibition rate of tumor recurrence and lung metastasis are 68.07% and 33.33%), and decreases the degree of tumor recurrence and metastasis, and improve the quality of life and prolong survival (100% extension of life).
3.1.3 Using different methods to detect apoptosis of gastric cancer cell and confirming that the change of apoptosis sensitivity of gastric cancer cell is an important control mechanism of YWKL for recurrence and metastasis.
3.1.4 Chinese compound herbal YWKL can inhibit telomerase proliferation by promoting mitochondrial to release Cytc and activate Caspase cascade and enhance the expression of pro-apoptotic protein Smac and Apaf-1 protein, and reduce the expression of apoptosis inhibitory protein XIAP. By detecting both proliferation and apoptosis of telomerase in tumor cells, we dissus the telomerase's effect on apoptosis, to provide new ideas and scientific theory for rational application of Traditional Chinese Medicine for decreasing recurrence and metastasis.
3.2 cell experiment
3.2.1 Successful replicate human gastric cancer cell line MGC803, BGC823 Anoikis, and multicellular spheroid model, which are fit for imitating those gastric tumor cells with metastasis in vivo state, in order to provide a reliable technology platform to verify the YWKL's role and the mechanism of anti-metastasisr.
3.2.2 Using the method of serum pharmacology prepared containing YWKL serum by orthogonal design, and observing the best time of serum screening and the effective blood concentration by MTT method.
3.2.3 Disorder of apoptosis signal transduction is one important mechanisms of tumor recurrence and metastasis. Serum of Chinese compound herbal YWKL can enhance the apoptosis sensitivity of human gastric cancer cell line MGC803, BGC823 and activate Caspase-3 to induce apoptosis of tumor cells by regulating mitochondrial pathway.
1理论研究
在既往研究的基础上,从理、法、方、药四个方面系统总结导师孙桂芝教授治疗胃癌的经验,探讨了中医药治疗提高临床疗效的物质基础。
1.1胃癌病因病机的认识
祖国医学虽无“胃癌”病名之记载,但对胃的证候及症状描述有很多与胃癌相似。分析胃癌临床证候特点,当属中医“胃脘痛”、“噎膈”、“心下痞”、“胃反”等范畴。导师通过总结古人相关论述及当代医家对胃癌病因、病机的认识,更结合自己40余年临床经验,认为脾胃虚损为胃癌发病最重要环节,各种原因引起的脾胃虚损,可进一步导致脾失健运、胃失和降,进而中焦壅滞,食积不化、气滞血瘀,蕴积生毒,最终发展成为胃癌。
1.2治则治法
导师在长期临床中通过辨证与辨病结合,强调以人为本,以脾肾为中心,兼调身心,协调内外；扶正驱邪,坚持守方,以“持久战”对抗胃癌及其复发转移。常用治法包括：健脾升清、和胃消食、祛瘀生新、抗癌解毒四法连用,在抑制肿瘤的复发及转移,稳定和缩小瘤体,有效提高生活质量和延长生存期方面取得了良好的效果。
1.3常用“小范方”
导师喜用经验方,经验方又多由数个“小范方”组成,如藤虎汤,组成：藤梨根、虎杖；蒲黄白芷蜂房汤,组成：生蒲黄、白芷、露蜂房、血余炭；金麦代赭汤,组成：鸡内金、生麦芽、代赭石等。
2临床研究
养胃抗瘤冲剂(YWKL)是导师孙桂芝教授研制的治疗中晚期胃癌的中药复方,以益气养胃、健脾补肾、活血化瘀、解毒抗癌为治疗原则。目的：通过对258例中晚期胃癌的非随机同期对照研究,·评价以YWKL复方加减辨证治疗对中晚期胃癌患者生存期及生存质量的影响。方法：采用回顾性同期对照研究方法,共纳入中晚期胃癌患者258例(中西医结合组147例,单纯化疗组111例),两组均采用化疗(入组后接受以氟尿嘧啶类为基础的方案化疗,并依据细胞病理学类型、体能状况等情况可联合运用铂类、葸环类或紫杉类药物,一般治疗3-6周期)等西医治疗；中西医结合组在此基础上加用YWKL。每两周辨证一次,在基本处方基础上修正中药处方,记录服药持续的时间。进行长期随访,数据的管理采用EPidata3.1软件建立数据库,采用Kaplan-Meier法估算中位生存时间,采用SPSS17.0统计软件进行统计分析。结果：比较一年、三年、五年生存率,中西医结合组分别是：98.6%、84.4%、68.7%,单纯化疗组分别是：72.1%、12.6%、5.4%。比较中位生存时间,中西医结合组：72.69个月,单纯化疗组：21.94个月,经统计分析均有统计意义(P＜0.05)。比较治疗前后KPS评分变化,中西医结合组分别是：62.6%提高,32.6%稳定,4.7%下降,单纯化疗组分别是：27.9%提高,59.4%稳定,12.6%下降。比较治疗前后体重变化评价,中西医结合组分别是：53.1%提高,39.5%稳定,7.5%下降,单纯化疗组分别是：提高44.1%提高,25.2%稳定,30.6%下降。治疗前后KPS评分变化及体重变化评价比较差异有统计学意义(P<0.05)。结论：以YWKL为基础辨证治疗中晚期胃癌延长了患者生存期,提高了患者的生活质量。中医药治疗在改善胃癌总体预后方面的作用值得进一步作随机对照研究评价。
3实验研究
本课题在实验研究方面以615小鼠前胃癌术后复发转移模型和人胃癌细胞系MGC803.BGC823抗失巢凋亡及多细胞球体模型为载体,采用流式细胞技术FCM、TUNEL、AV-PI、Realtime RT-PCR、MTT、免疫组化等多种实验技术方法,从整体-细胞-基因-信号传导等层次,深入探讨了YWKL改善胃癌总体预后的分子机制,从一个侧面揭示了扶正祛邪并重的治疗原则延长中晚期胃癌生存期的科学内涵。
3.1动物实验部分
3.1.1成功建立和临床术后复发转移相类似的615小鼠前胃癌术后复发转移动物模型,为动态观察术后复发转移,研究复发转移的作用机制奠定了基础。
3.1.2中药复方YWKL对于615小鼠前胃癌术后局部复发和远处肺转移有一定的抑制作用(复发瘤抑制率为68.07%和肺转移抑制率为33.33%),能明显控制肿瘤复发转移的程度,提高生存质量,延长生存期(生命延长率为100%)。
3.1.3应用不同检测凋亡的方法,证实改变胃癌细胞的凋亡敏感性是YWKL防治复发转移的重要作用机制。
3.1.4中药复方YWKL可以抑制端粒酶的增殖能力,通过促进线粒体释放Cytc,激活Caspase级联反应,从而提高促凋亡蛋白Smac、Apaf-1蛋白的表达,降低凋亡抑制蛋白XIAP表达。通过对端粒酶的增殖和凋亡两方面的检测可以探讨端粒酶对肿瘤细胞凋亡的影响,为应用中医药防治肿瘤复发转移提供新的思路和科学理论依据。
3.2细胞实验部分
3.2.1成功复制人胃癌细胞系MGC803、BGC823抗失巢凋亡及多细胞球体模型,很好的拟合体内肿瘤转移时的细胞状态,为验证YWKL复方抗转移的作用机理提供了可靠的技术平台。
3.2.2采用血清药理学的方法应用正交设计制备了YWKL的含药血清,并通过MTT法动态观察和筛选出含药血清的最佳采血时间和有效浓度。
3.2.3细胞凋亡信号传导紊乱是肿瘤发生复发转移的重要机制之一,中药复方YWKL的含药血清可以通过调控线粒体途径,提高人胃癌细胞系MGC803、BGC823的凋亡敏感性,最终激活凋亡效应型Caspase-3引起肿瘤细胞凋亡。
4本研究主要创新之处
本研究的创新之处主要有以下几点：
4.1理论研究中,对导师孙桂芝教授治疗胃癌的理、法、方、药四个方面进行系统总结,探讨了中医药治疗提高临床疗效的物质基础,揭示了扶正祛邪并重的治疗原则延长中晚期胃癌生存期的科学内涵。
4.2本论文对YWKL提高中晚期胃癌患者生存期、生存质量进行了较大样本分析,在临床取得明显疗效的基础上,以615小鼠前胃癌术后复发转移模型和人胃癌细胞系MGC803、BGC823抗失巢凋亡及肿瘤多细胞球体模型为载体,·从端粒酶增殖和线粒体凋亡转导通路相关调控因子活性与表达深入探讨了YWKL提高晚期胃癌预后总体效应的分子机制,研究从一个侧面揭示了扶正祛邪并重治疗晚期肿瘤的理论内涵,为深层次挖掘名老中医经验提供了新思路。
4.3本研究引入人胃癌细胞系MGC803和BGC823抗失巢凋亡及多细胞球体培养模型,更好的模拟了肿瘤转移过程中细胞状态,进行失巢凋亡及中药复方研究,国内外未见报道,属方法创新。
Gastric carcinoma is one kind of common malignant tumor that can do serious harm to human health. As the postoperative recurrence and metastasis are major cause of death in most clinical patients, so people have been seeking treatment other than surgical method of gastric cancer to extend survival of patients. Professor Sun Gui-zhi has engaged in treating some kind of malignant tumors with methods of Integrative Medicine for 40 years. She has rich experience of treating gastrointestinal cancers, especially gastric cancer, and gets a significant effect. Yang Wei Granules (YWKL) was developed by Professor Sun Gui-zhi for treating advanced gastric cancer. Its rule is increasing Qi and providing nutrition for stomach, spleen and kidney, and promoting blood circulation, detoxify and anti-cancer. Clinically applied for 20 years, it has been proved playing a role of preventing of tumor recurrence, metastasis and prolonging survival in patients with gastric carcinoma. This thesis summarized Professor Sun Gui-zhi's experience of treating gastric carcinomas from theory, method, prescription and drugs on the basis of research in the past several years. We use modern technology to conduct experimental research and want to explore the active ingredients of those Chinese medicines to improve the clinical efficacy. The carcinoma model is 615 mice of recurrence and metastasis after surgical method of treating gastric cancer. The molecular mechanisms of inducing apoptosis and the role of improving symptoms and prolonging life of YWKL are researched by methods of immunohistochemistry (IHC), Realtime RT-PCR, AV-PI, flow cytometry, TUNEL and other techniques from the whole-cell-gene-signal transduction level. And the scientific contents of rational Fuzheng and Quxie are revealed from those sides.
1 Theory research
Based on the research in the past, I summarized the experience of Professor Sun Guizhi's treating gastic cancer from four sides, such as the principles, methods, prescriptions, and chinese traditional medicines, to explore the material basis of the clinical effect.
1.1 Understanding of the pathogenesis of gastric cancer
No records of gastric cancer that we can find in traditional Chinese medicine theory. But we can see some descriptions of stomach syndrome and symptoms those are similar with gastric cancer, such as "stomachache", "Ye Ge", "Epigastric Distension", "wei fan". Professor Sun Guizhi summarized the relevant ancient and contemporary medical practices on cancer etiology, pathogenesis of knowledge, blent with her clinical experiences for more than 40 years, indicated that the spleen deficiency as the most important aspect of gastric cancer, and that a variety of causes can damage spleen's and stomach's physical function, then the focus Yong Zhi, food product, so, qi stagnation, Yongzhi of heat stored up health drugs, eventually developed into gastric cancer.
1.2 therapeutical principle
For her long-term clinical expierince, Professor Sun Gui-zhi has summarized some important principles, such as combinating people's symptoms with pathology report as the basis of diagnose, paying more attention to the role of human' body itself, considering spleen and kidney as the center of human' health, and the role of physical and mental adjust, the role of coordinating internal and external factors, righting evil spirits, insist on defending side to "protracted war" against cancer and its recurrence and metastasis. Common treatment methods include that adjusting spleen and stomach' function and promoting digestion, removing the damaged inssue and promoting the new inssue growwing, and anti-cancer detoxification. Those methods used together in the inhibition of tumor recurrence and metastasis, stability, and shrinking the tumor, improving quality of life and prolonging survival to achieve impressive results.
1.3 commonly used formula
Professor Sun Gui-zhi usually use some experienced prescriptions which we called "Little Standard prescriptions", such as "Tenghu soup" which consists of Actinidia arguta and Polygonum, "Puhuang-Baizhi-Fengfang soup" which consists of Typhae, Angelica, Lucy hives, and Hair Carbon, "Jin-Mai-Daizhe soup" which consists of Gallus gallus, the Health and malt, Ruddle.
2 clinical research
YWKL is an exprimental prescription for Professor Sun Gui-zhi treating advanced gastric cancer which was developed by the principles of adjusting Qi and Stomach, spleen and kidney, promoting blood circulation and detoxification.
Objective:Explore the role of YWKL Modified Differential Treatment in affecting patients' survival and quality of life with advanced gastric cancer by non-randomized concurrent control studies on 258 cases of advanced gastric cancer. Methods:A retrospective control study period, included a total of 258 cases of advanced gastric cancer (147 cases of Integrated Traditional and Western group, chemotherapy group 111 cases), chemotherapy in both groups (post-entry group to fluorouracil-based programs chemotherapy, and according to type of cell pathology, physical condition, etc. can be combined use of platinum, anthracycline or taxol, the general treatment of 3-6 cycles) and other medical therapy; Integrative Medicine Group at this based on the use YWKL. Differentiations are be took on once every two weeks, and the basic prescriptions are amended correspondingly. And we record the duration of medication. For a long term we follow up those patiants. And the final data are managed by software EPidata3.1 to estimate the median survival time using Kaplan-Meier method. Finally we use SPSS 17.0 statistical software for statistical analysis. Results:Comparison of one, three, five-year survival rate, those of Integrative Medicine Group are 98.6%,84.4% and 68.7%, respectively the chemotherapy group are 72.1%,12.6%,5.4%. Median survival time of Integrative Group is 72.69 months, and in chemotherapy group it's 21.94 months, they have statistically significant by statistical analysis (P<0.05). KPS score changes before and after treatment, Integrative Medicine Group are increasing 62.6%, stably 32.6%, declining 4.7%, those of chemotherapy group are increasing 27.9%, stably 59.4%, declining 12.6% respectively. Evaluation of weight changes before and after treatment, Integrative Medicine Group are increasing 53.1%, stably 39.5%, declining 7.5%, and those of chemotherapy group are increasing 44.1%, stably 25.2%, declining 30.6%. Changes of KPS score and weight before and after treatment were significant statistically (P<0.05). Conclusion:YWKL-based differentiation in treatment of advanced gastric cancer patients prolonged their survival, improved the quality of life of patients. The role of TCM treatment in improving the overall prognosis of gastric cancer deserves more randomized controlled studies to explore.
3 exprimental research
Using 615 mouse models with gastric cancer recurrence and metastasis and human cancer cell lines MGC803, BGC823 Anoikis and multicellular spheroid model as the carrier, using flow cytometry FCM, TUNEL, AV-PI, Realtime RT-PCR, MTT, immunohistochemistry and other methods of experimental techniques, from the whole-cell-gene-the signal transduction level, we deply improve the molecular mechanism of the YWKL against tumor and promoting the overall prognosis of gastric cancer, and reveal the scientific content of the principle of attaching equal balance to extend the treatment of advanced gastric cancer survival.
3.1 animal experiments
3.1.1 Successfully established mouse 615 models which are similar to clinical metastasis and recurrence of gastric cancer for dynamic observation of recurrence and metastasis. It is a foundation foe us to research the mechanism of recurrence and metastasis of the action of gastric cancer.
3.1.2 Chinese compound herb YWKL has some inhibitory effects on carcinoma in 615 mice for the postoperative local recurrence and distant metastasis (inhibition rate of tumor recurrence and lung metastasis are 68.07% and 33.33%), and decreases the degree of tumor recurrence and metastasis, and improve the quality of life and prolong survival (100% extension of life).
3.1.3 Using different methods to detect apoptosis of gastric cancer cell and confirming that the change of apoptosis sensitivity of gastric cancer cell is an important control mechanism of YWKL for recurrence and metastasis.
3.1.4 Chinese compound herbal YWKL can inhibit telomerase proliferation by promoting mitochondrial to release Cytc and activate Caspase cascade and enhance the expression of pro-apoptotic protein Smac and Apaf-1 protein, and reduce the expression of apoptosis inhibitory protein XIAP. By detecting both proliferation and apoptosis of telomerase in tumor cells, we dissus the telomerase's effect on apoptosis, to provide new ideas and scientific theory for rational application of Traditional Chinese Medicine for decreasing recurrence and metastasis.
3.2 cell experiment
3.2.1 Successful replicate human gastric cancer cell line MGC803, BGC823 Anoikis, and multicellular spheroid model, which are fit for imitating those gastric tumor cells with metastasis in vivo state, in order to provide a reliable technology platform to verify the YWKL's role and the mechanism of anti-metastasisr.
3.2.2 Using the method of serum pharmacology prepared containing YWKL serum by orthogonal design, and observing the best time of serum screening and the effective blood concentration by MTT method.
3.2.3 Disorder of apoptosis signal transduction is one important mechanisms of tumor recurrence and metastasis. Serum of Chinese compound herbal YWKL can enhance the apoptosis sensitivity of human gastric cancer cell line MGC803, BGC823 and activate Caspase-3 to induce apoptosis of tumor cells by regulating mitochondrial pathway.
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