清毒饮（片）和养正片联合化疗治疗急性白血病疗效及其分子机制的研究
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摘要
急性白血病(AL)是严重危害人类健康和生命的重大疾病。上个世纪70年代以后,随着化疗策略逐渐完善,抗白血病新药的应用,造血干细胞移植技术的发展,免疫和基因疗法的使用,白血病的治疗有了巨大的进步。但是,欲真正明了其病因和发病机理,探求安全、高效而经济可行的防治方法,则仍然任重而道远。从祖国医药宝库里探求抗AL新药,仍具有重要的学术价值与经济价值。
据此,我院血证研究室从1991年至今,进行了中医药治疗白血病的临床和实验研究,本人作为主要研究人员之一,参与其中。在国家中医药管理局和广东省科委科研基金等的资助下,在自拟抗白血病中药Ⅰ、Ⅱ、Ⅲ号方治疗白血病取得较好疗效的基础上,我们制订了清毒饮和养正片两个中药复方,辨证用于AL化疗的不同阶段,取得良好效果;我们又进而利用AL动物模型和细胞株,开展了该二方抗AL疗效机理的研究,取得了一系列成果。但受限于病床数等原因,既往的观察病例数偏少;自2002年以后,我们在先前研究的基础上,为了便于患者服用和携带,进一步改良了清毒饮,并将其改为素片,即成为清毒片;并增加了观察样本,继续与养正片一道辨证应用于化疗的不同阶段,并取得了较满意的疗效。
研究目的 本研究旨在进一步观察中医药联合化疗治疗人类AL的增效减毒方案,并探讨其对人类白血病疗效的分子机制,为临床治疗AL提供安全、有效、廉价的更佳方案,并为将来开发抗AL中药新药打下基础。
研究方法与内容 本研究包括文献研究、临床研究与实验研究,在先前系列观察的基础上,进一步扩大临床观察样本,以观察中药清毒饮(片)和养正片联合化疗治疗AL近、中、远期增效减毒作用,并直接观察服用该二方后AL病人体内药物作用的分子机制。
文献研究:总结分析了近年来,特别是近5年来国内外AL中西医研究领域的一系列进展,并提出存在问题和可能的解决方案。
临床研究:1994年2月-2005年12月选取137例AL患者,随机分为中西医联合治疗组和单纯化疗组。中西医联合治疗组92例,再按中医辨证分为两组,治以辨证分期、序贯服用清毒饮(片)和养正片并联合化疗;与单纯化疗组45例作组间和自身前后比较,从临床疗效、提高生存质量、降低症候积分等进行分析;并比较了清毒片和清毒饮、中西医联合疗法对AL不同亚型的疗效差异。
实验研究:选取AL患者作为研究对象,采用自身前后对照,抽取化疗前患者用清毒饮和养正片治疗前、后的骨髓液,运用免疫细胞化学染色和原位杂交法检测观察了中药对其Bcl-2、p~(53)、Fas及其mRNA表达影响。
Acute leukemia (AL) is a serious danger to the mankind. Since 1970s, along with the chemotherapy strategy gradually perfect, application of new medicine of anti-leukemia, the development of technique of hematopoietic stem cell transplantation, immunotherapy and gene therapy, the therapy for leukemia had made greatly gain. However, it is a long way to go to set our hope on the perspicuity of what it is the pathogen and the pathogenesis, and to search for the therapeutics of safety, availability and economy. Investigating the new medicine of anti-leukemia from TCM still has important value on both scholarship and economy.Therefore, our laboratory has been making a series of disquisitions on TCM to treat leukemia in clinic and experiment, and I am the main member of the team, working with my colleague researchers since the year 1991. Funded by SATCM of PRC and DS&T of Guangdong Province, we developed two new TCM compounds of Qingdu decoction and Yangzheng tablet to treat acute leukemia according to differential diagnosis in the three successive phases of chemotherapy based on our self-made anti-leukemia compounds number I , II and III. We farther applied mouse models and leukemia cell lines to study the curative effects and mechanism of the two compounds. We made some progress on them. Yet, Being limited by the sickbed number, the observed cases were still lack in number. After 2002, we amended Qingdu decoction and changed it to be Qingdu tablet. And tablet is convenient to carry and easy to take. Qingdu tablets have been combined with Yangzheng tablets to treat leukemia. The observed cases have been increasing with
Objectives:The purposes of this study are, firstly, to observe Chinese Herbal Medicine, Qingdu decoction/Qingdu tablet and Yangzheng tablet matching with the chemotherapy to cure human acute leukemia by promoting the effects and inhibiting the toxicity;secondly, the purposes are to probe into the possible molecular mechanism of them;thirdly, to offer better precept that is safer, cheaper and more efficacious for acute leukemia;and finally, to lay the foundations for manufacturing some new drugs for leukemia.Methods and Contents:These studies include: Literature study, clinical study and experimental study. These studies are to observe the effect promoting and toxicity reducing actions of Qingdu decoction/Qingdu tablet and Yangzheng tablet matching with the chemotherapy during the near and middle and further stages of treatment with expanded cases of acute leukemia based on former studies that we had done. Also to directly observe the in vivo molecular pharmaceutical mechanism of the two compounds in the leukemia patients.Literature study: The Chinese and international literatures of TCM and western medicine on acute leukemia in recent years, especially in the last 5 years, were analyzed and summarized to bring up some existent problems in these domains and their possible solutions.Clinical study: About 137 cases of acute leukemia patients from 1994. 2 to 2005.12 were selected and randomly grouped into group A of 92 cases and group B of 45 cases. Group A was separated into group Al (with hyperactivity of virulent heat-evil) and group A2 (with deficiency of both vital energy and blood) according to differential diagnosis. And both groups were treated with different doses of Qingdu decoction/Qingdu tablet and Yangzheng tablet in the three successive phases of chemotherapy. Meanwhile the group B is just treated by chemotherapy. The group Al, group A2 and Group B were compared on the curative effects of treatments, life quality and scores of symptoms and signs in the patients.Experimental study: The AL patients were selected as research objects.
The method of self-control before and after treatments was adopted. The patients' bone marrow fluid was taken before and after administration of Qingdu decoction/Qingdu tablet and Yangzheng tablet. The methods of immunocytochemistry and TUNEL were applied to observe drug' s influence on the gene expression of Bcl-2, P53, Fas and their mRNA.Results:Literature study:The modern western medicine for acute leukemia including chemotherapy, hematopoietic stem cells transplantation, immunotherapy and gene therapy have gained great advance, however, they still have many disadvantages including a high recurrence rate, multiple drug resistance, lack of marrow donors, high risk in treatment, low security and heavy costs so on. So investigation for new methods and medicine with high validity, low toxicity and low price are still urgent and formidable. On the other hand, most national and international anti-leukemia studies are clinical ones on small samples or of short-terms or experimental ones on animal models or leukemia cell lines. It is necessary for us to make further study, because there is a big difference between the truly clinical reality and the experimental studies of human acute leukemia.Clinical research:1. The group A treated by traditional Chinese combed with Western medicine and group B treated only by western medicine were compared, the variances of the tow groups were homogenous (P>0. 05).2. Although the CR rates of group Al and group A2 are in some sort higher than that of group B, but the differences between the three groups were not significant (P>0. 05).3. The marrow blast decline index (MBDI) is an index designed to measure the curative effect in acute leukemia. MBDI>60 score can be evaluated as good. In this study, MBDI>60 score rate after treatment in group A are 73/92 cases (39/53) cases in group Al and 34/39 cases in group A2 and totally 79. 35%. but the MBDI>60 score rate in group B is only 27/45 cases (60. 00%) , it is obvious that the curative effect in group A is better than that in group B. The group A2 with both deficiency of qi and blood had a better MBDL>60 score rate than group Al (P<0. 05). It is indicated that the herbal drugs can promote the curative effects of chemotherapy.
4. The life quality and the symptoms scores of every groups after treatments were analyzed by the rank-sum test. The differences between group A and group were significant (both P<0. 01), but no significant difference between group Al and group A2 (P>0. 05). The results showed that both drugs could promote the curative effects and inhibit the toxicity.5. Comparison of Qingdu decoction with Qingdu tablet: After analysis of variance and t teat (both side), the results showed that there was no significant difference between the curative effects of Qingdu decoction and Qingdu tablet (P>0. 05). It indicated that Qingdu decoction and Qingdu tablet have equal curative effects.6. Compare the effects of Qingdu decoction/tablet and Yangzheng tablet in every subtype of leukemia. The results of ridit analysis and variance analysis showed that the curative effects in every subtypes of leukemia had no significant differences (P>0.05). That is the tow compounds have no specific effects on any subtype of leukemia.Experimental study1. The expression of Bcl-2, P53 and Fas. After treatment with Qingdu decoction and Yangzheng tablet, the expression of Bcl-2 gene was down regulated and Fas gene was up regulated. Compared with before treatment, the differences were obviously significant or significant (P<0. 05 or P<0. 01). P53gene was lightly up regulated, but the difference was not significant (P>0. 05).2. The expression of raRNA of Bcl-2, P53 and Fas. After treatment with Qingdu decoction and Yangzheng tablet, the expression of Bcl-2mRNA and P53mRNA were obviously decreased, and Fas mRNA expression was greatly increased. The differences with before treatment were all obviously significant (both P<0. 01) .Conclusion:This research expended the observational sample, it showed that both the Qingdu decoction and Yangzheng tablet have anti-leukemia functions which were displayed as effect promoting and toxicity releasing actions on chemotherapy and increasing of life quality and decreasing of syndrome scores.This research observed the differences of the curative effects between Qingdu decoction and Qingdu tablet. The results showed that the
similar efficacy. So after improvement, the Qingdu tablet not only kept the original anti-leukemia function but also become convenient for carrying and easy for administration.The each subtype of acute leukemia has on significantly different curative effects, indicating that the effects of Qingdu decoction and Qangzheng tablet have no leukemia subtype specificity.The 15 cases of leukemia patients showed high levels of expression of Bcl-2 and its mRNA, and the higher the expression level is, worse is the curative effect. The 15 patients showed low levels of expression of P53 and Fas and their mRNA. In some example patients the expression were even deficient, after treatment with Qingdu decoction and Yangzheng tablet , expression of Bcl-2 and its mRNA decreased;The expression of Fas and its mRNA increased, and P53 mRNA expression decreased but P53 no obvious change. So, the mechanism could be inferred for the anti-leukemia effects of Qingdu decoction and Yangzheng tablet. Both the tow drugs can up-regulate the expression of gene Fas and down regulate the gene Bcl-2 and P53, which mediate the apoptosis of leukemia cells. The results were much consistent with our former study.This research also summarized the experiences of our laboratory and myself in the clinical treatment of acute leukemia by Chinese medicine combined with western medicine.
据此,我院血证研究室从1991年至今,进行了中医药治疗白血病的临床和实验研究,本人作为主要研究人员之一,参与其中。在国家中医药管理局和广东省科委科研基金等的资助下,在自拟抗白血病中药Ⅰ、Ⅱ、Ⅲ号方治疗白血病取得较好疗效的基础上,我们制订了清毒饮和养正片两个中药复方,辨证用于AL化疗的不同阶段,取得良好效果;我们又进而利用AL动物模型和细胞株,开展了该二方抗AL疗效机理的研究,取得了一系列成果。但受限于病床数等原因,既往的观察病例数偏少;自2002年以后,我们在先前研究的基础上,为了便于患者服用和携带,进一步改良了清毒饮,并将其改为素片,即成为清毒片;并增加了观察样本,继续与养正片一道辨证应用于化疗的不同阶段,并取得了较满意的疗效。
研究目的 本研究旨在进一步观察中医药联合化疗治疗人类AL的增效减毒方案,并探讨其对人类白血病疗效的分子机制,为临床治疗AL提供安全、有效、廉价的更佳方案,并为将来开发抗AL中药新药打下基础。
研究方法与内容 本研究包括文献研究、临床研究与实验研究,在先前系列观察的基础上,进一步扩大临床观察样本,以观察中药清毒饮(片)和养正片联合化疗治疗AL近、中、远期增效减毒作用,并直接观察服用该二方后AL病人体内药物作用的分子机制。
文献研究:总结分析了近年来,特别是近5年来国内外AL中西医研究领域的一系列进展,并提出存在问题和可能的解决方案。
临床研究:1994年2月-2005年12月选取137例AL患者,随机分为中西医联合治疗组和单纯化疗组。中西医联合治疗组92例,再按中医辨证分为两组,治以辨证分期、序贯服用清毒饮(片)和养正片并联合化疗;与单纯化疗组45例作组间和自身前后比较,从临床疗效、提高生存质量、降低症候积分等进行分析;并比较了清毒片和清毒饮、中西医联合疗法对AL不同亚型的疗效差异。
实验研究:选取AL患者作为研究对象,采用自身前后对照,抽取化疗前患者用清毒饮和养正片治疗前、后的骨髓液,运用免疫细胞化学染色和原位杂交法检测观察了中药对其Bcl-2、p~(53)、Fas及其mRNA表达影响。
Acute leukemia (AL) is a serious danger to the mankind. Since 1970s, along with the chemotherapy strategy gradually perfect, application of new medicine of anti-leukemia, the development of technique of hematopoietic stem cell transplantation, immunotherapy and gene therapy, the therapy for leukemia had made greatly gain. However, it is a long way to go to set our hope on the perspicuity of what it is the pathogen and the pathogenesis, and to search for the therapeutics of safety, availability and economy. Investigating the new medicine of anti-leukemia from TCM still has important value on both scholarship and economy.Therefore, our laboratory has been making a series of disquisitions on TCM to treat leukemia in clinic and experiment, and I am the main member of the team, working with my colleague researchers since the year 1991. Funded by SATCM of PRC and DS&T of Guangdong Province, we developed two new TCM compounds of Qingdu decoction and Yangzheng tablet to treat acute leukemia according to differential diagnosis in the three successive phases of chemotherapy based on our self-made anti-leukemia compounds number I , II and III. We farther applied mouse models and leukemia cell lines to study the curative effects and mechanism of the two compounds. We made some progress on them. Yet, Being limited by the sickbed number, the observed cases were still lack in number. After 2002, we amended Qingdu decoction and changed it to be Qingdu tablet. And tablet is convenient to carry and easy to take. Qingdu tablets have been combined with Yangzheng tablets to treat leukemia. The observed cases have been increasing with
Objectives:The purposes of this study are, firstly, to observe Chinese Herbal Medicine, Qingdu decoction/Qingdu tablet and Yangzheng tablet matching with the chemotherapy to cure human acute leukemia by promoting the effects and inhibiting the toxicity;secondly, the purposes are to probe into the possible molecular mechanism of them;thirdly, to offer better precept that is safer, cheaper and more efficacious for acute leukemia;and finally, to lay the foundations for manufacturing some new drugs for leukemia.Methods and Contents:These studies include: Literature study, clinical study and experimental study. These studies are to observe the effect promoting and toxicity reducing actions of Qingdu decoction/Qingdu tablet and Yangzheng tablet matching with the chemotherapy during the near and middle and further stages of treatment with expanded cases of acute leukemia based on former studies that we had done. Also to directly observe the in vivo molecular pharmaceutical mechanism of the two compounds in the leukemia patients.Literature study: The Chinese and international literatures of TCM and western medicine on acute leukemia in recent years, especially in the last 5 years, were analyzed and summarized to bring up some existent problems in these domains and their possible solutions.Clinical study: About 137 cases of acute leukemia patients from 1994. 2 to 2005.12 were selected and randomly grouped into group A of 92 cases and group B of 45 cases. Group A was separated into group Al (with hyperactivity of virulent heat-evil) and group A2 (with deficiency of both vital energy and blood) according to differential diagnosis. And both groups were treated with different doses of Qingdu decoction/Qingdu tablet and Yangzheng tablet in the three successive phases of chemotherapy. Meanwhile the group B is just treated by chemotherapy. The group Al, group A2 and Group B were compared on the curative effects of treatments, life quality and scores of symptoms and signs in the patients.Experimental study: The AL patients were selected as research objects.
The method of self-control before and after treatments was adopted. The patients' bone marrow fluid was taken before and after administration of Qingdu decoction/Qingdu tablet and Yangzheng tablet. The methods of immunocytochemistry and TUNEL were applied to observe drug' s influence on the gene expression of Bcl-2, P53, Fas and their mRNA.Results:Literature study:The modern western medicine for acute leukemia including chemotherapy, hematopoietic stem cells transplantation, immunotherapy and gene therapy have gained great advance, however, they still have many disadvantages including a high recurrence rate, multiple drug resistance, lack of marrow donors, high risk in treatment, low security and heavy costs so on. So investigation for new methods and medicine with high validity, low toxicity and low price are still urgent and formidable. On the other hand, most national and international anti-leukemia studies are clinical ones on small samples or of short-terms or experimental ones on animal models or leukemia cell lines. It is necessary for us to make further study, because there is a big difference between the truly clinical reality and the experimental studies of human acute leukemia.Clinical research:1. The group A treated by traditional Chinese combed with Western medicine and group B treated only by western medicine were compared, the variances of the tow groups were homogenous (P>0. 05).2. Although the CR rates of group Al and group A2 are in some sort higher than that of group B, but the differences between the three groups were not significant (P>0. 05).3. The marrow blast decline index (MBDI) is an index designed to measure the curative effect in acute leukemia. MBDI>60 score can be evaluated as good. In this study, MBDI>60 score rate after treatment in group A are 73/92 cases (39/53) cases in group Al and 34/39 cases in group A2 and totally 79. 35%. but the MBDI>60 score rate in group B is only 27/45 cases (60. 00%) , it is obvious that the curative effect in group A is better than that in group B. The group A2 with both deficiency of qi and blood had a better MBDL>60 score rate than group Al (P<0. 05). It is indicated that the herbal drugs can promote the curative effects of chemotherapy.
4. The life quality and the symptoms scores of every groups after treatments were analyzed by the rank-sum test. The differences between group A and group were significant (both P<0. 01), but no significant difference between group Al and group A2 (P>0. 05). The results showed that both drugs could promote the curative effects and inhibit the toxicity.5. Comparison of Qingdu decoction with Qingdu tablet: After analysis of variance and t teat (both side), the results showed that there was no significant difference between the curative effects of Qingdu decoction and Qingdu tablet (P>0. 05). It indicated that Qingdu decoction and Qingdu tablet have equal curative effects.6. Compare the effects of Qingdu decoction/tablet and Yangzheng tablet in every subtype of leukemia. The results of ridit analysis and variance analysis showed that the curative effects in every subtypes of leukemia had no significant differences (P>0.05). That is the tow compounds have no specific effects on any subtype of leukemia.Experimental study1. The expression of Bcl-2, P53 and Fas. After treatment with Qingdu decoction and Yangzheng tablet, the expression of Bcl-2 gene was down regulated and Fas gene was up regulated. Compared with before treatment, the differences were obviously significant or significant (P<0. 05 or P<0. 01). P53gene was lightly up regulated, but the difference was not significant (P>0. 05).2. The expression of raRNA of Bcl-2, P53 and Fas. After treatment with Qingdu decoction and Yangzheng tablet, the expression of Bcl-2mRNA and P53mRNA were obviously decreased, and Fas mRNA expression was greatly increased. The differences with before treatment were all obviously significant (both P<0. 01) .Conclusion:This research expended the observational sample, it showed that both the Qingdu decoction and Yangzheng tablet have anti-leukemia functions which were displayed as effect promoting and toxicity releasing actions on chemotherapy and increasing of life quality and decreasing of syndrome scores.This research observed the differences of the curative effects between Qingdu decoction and Qingdu tablet. The results showed that the
similar efficacy. So after improvement, the Qingdu tablet not only kept the original anti-leukemia function but also become convenient for carrying and easy for administration.The each subtype of acute leukemia has on significantly different curative effects, indicating that the effects of Qingdu decoction and Qangzheng tablet have no leukemia subtype specificity.The 15 cases of leukemia patients showed high levels of expression of Bcl-2 and its mRNA, and the higher the expression level is, worse is the curative effect. The 15 patients showed low levels of expression of P53 and Fas and their mRNA. In some example patients the expression were even deficient, after treatment with Qingdu decoction and Yangzheng tablet , expression of Bcl-2 and its mRNA decreased;The expression of Fas and its mRNA increased, and P53 mRNA expression decreased but P53 no obvious change. So, the mechanism could be inferred for the anti-leukemia effects of Qingdu decoction and Yangzheng tablet. Both the tow drugs can up-regulate the expression of gene Fas and down regulate the gene Bcl-2 and P53, which mediate the apoptosis of leukemia cells. The results were much consistent with our former study.This research also summarized the experiences of our laboratory and myself in the clinical treatment of acute leukemia by Chinese medicine combined with western medicine.
引文
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