对白血病化疗药物左旋天冬酰胺酶II的热稳定性改造以及微小残留白血病DNA疫苗的构建、纯化和免疫效果研究
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摘要
在治疗急性淋巴细胞白血病的临床实践中有两个长期困扰人们的难题:一个是化疗药物的副作用问题;另一个是导致白血病完全缓解后又不断复发的肿瘤细胞微小残留问题。本课题针对这两个问题进行了初步的探索。
在急性淋巴细胞白血病的化疗方案中,左旋大肠杆菌天冬酰胺酶Ⅱ是重要的药物组成部分。但是该酶具有较大的副作用,同时由于其相对较短的半衰期和热不稳定性,使得该药在实际治疗中需要进行频繁地注射,结果使病人产生了更大的痛苦。因此在本研究课题中对如何提高该酶的热稳定性以便进一步提高其半衰期进行了初步研究:通过生物信息学分析手段确定了天冬酰胺酶蛋白质二级结构中一个与热稳定性关系密切的β-转角,并用定点突变的方法将该转角上的第178位的天冬氨酸突变为脯氨酸。实验结果显示:与野生型酶相比,突变体酶在不同温度条件下的热稳定性得到了提高;从能量角度上看,改造后的酶在保持动力学性质(K_m和K_(cat))基本不变的同时活化能得到了增加。这说明笔者对左旋天冬酰胺酶的改造在不影响酶活性的前提下提高了其热稳定性。
对于化疗和骨髓移植不能彻底解决的白血病细胞微小残留问题,本课题对相应的免疫学解决方案进行了探索。虽然肿瘤细胞疫苗在目前来说是一种较有前景的免疫治疗形式,但出于对其安全性方面考虑,笔者决定尝试用另外一种相对安全的免疫形式——DNA疫苗,来治疗微小残留白血病,并对其免疫效果进行了初步研究。本课题采用双质粒系统,其中一个质粒表达经过改造灭活的肿瘤细胞特异性超表达抗原生存素(survivin)和能特异性引起Th1细胞免疫反应的发夹状单链RNA(ssRNA);另一个质粒表达细胞因子GM-CSF和共刺激分子CD80。结果证明用该DNA疫苗系统免疫BalB/C小鼠能引起较强的细胞免疫应答,诱导较强的T细胞增殖和对肿瘤细胞的CTL杀伤活力。这些结果为进一步研究DNA疫苗对微小残留白血病的实际治疗提供了前期实验室数据基础。
DNA疫苗大规模纯化技术的研发是DNA疫苗走向实际临床应用和工业化生产的必不可少的环节。本课题重点对利用排阻层析纯化质粒的技术进行了研究。笔者对不同种类及不同浓度盐缓冲液存在时,各种核酸分子排阻层析行为的变化进行了观察比较。结果显示:在高浓度中性盐存在情况下,不仅是RNA,其它的核酸分子包括宿主基因组DNA和各种质粒同分异构体的层析分辨率都得到了较大提高。进一步探讨深层机制,笔者认为在这一高盐排阻层析纯化过程中同时存在两种分离模式:1、超螺旋质粒DNA主要受到压缩效应的影响以排阻模式被洗脱;2、RNA和宿主基因组DNA则主要受疏水效应的影响从而以相互作用模式被洗脱。我们的实验结果证明使用高浓度(2 M)的中性盐(硫酸铵)将提高排阻层析纯化DNA疫苗的效率。
In the treatments of acute lymphoblastic leukaemia, there are two problems puzzling people all alone: One is the side-effects caused by chemotherapy; and another is the minimal residual leukaemia which leads to the relapse of cured patient. The present study has dong some researches to try to solve these problems.
L-Asparaginase II of E. coli is a kind of effective drug in the treatment of acute lymphoblastic leukaemia. However, during asparaginase therapy, repeated using of the drug is commonly needed because of the enzyme's relatively short half-life and instability in the processes of production and treatment. This leads to more serious toxic effects on patients. In order to stabilize the enzyme, a higher thermostable mutant L-asparaginase II was created in the present study by replacing Aspl78 with proline in a hydrogen-bonded turn (178-180DGR) which is contribute to the thermostability of the enzyme. The results displayed that values of K_m and K_(cat) for the mutant enzyme are not affected although the energy of activation is increased comparing to the wild-type enzyme. These data suggest that such alteration for L-asparaginase II enhances the thermostability of the enzyme without changing the enzyme's activity and thus the therapeutical use of L-asparaginase II might be benefit from these results.
In present study, the immune-therapy method has been explored when it comes to the problem of minimal residual leukemia (MRL). Immunized with the DNA vaccine is a potential way to treat MRL for its better safety comparing to the tumor cells vaccines. In present study, a two-plasmid vaccine system which is used to express a tumor-special antigen (Survivin) has been constructed and immunized with mice. Furthermore, a barrette-like ssRNA, GM-CSF and a co-stimulating factor CD80 have also been co-expressed in the same system. The results displayed that strong T cell immune response and CTL activity were induced by the DNA vaccine. It demonstrated that DNA vaccine is a promising immune-therapy method to fight against MRL.
Techniques for large-scale preparation of clinical-grade plasmid DNA serve as an important base for clinical trials and industrialization of DNA vaccines. In the present study, we compared the performances of size-exclusion chromatography for the purification of plasmid DNA when different concentrations (0.5 M, 1M, 2 M, respectively) of two types of salt (NaCl and (NH_4)_2SO_4) are present in running buffers. Our experiment results displayed that it is not only the resolution of RNA but also those of supercoiled plasmid DNA and host's genomic DNA were increased greatly in the presence of high concentration of water-structure salt. We deduce that two separation modes may be involved in the process: The supercoiled plasmid DNA is influenced mainly by compaction effect and eluted in the size-exclusion mode; whereas, RNA and genomic DNA are influenced mainly by hydrophobic effect due to their stretched and loose structures and eluted in the interaction mode. This method led to an improved efficiency of size-exclusion chromatography.
在急性淋巴细胞白血病的化疗方案中,左旋大肠杆菌天冬酰胺酶Ⅱ是重要的药物组成部分。但是该酶具有较大的副作用,同时由于其相对较短的半衰期和热不稳定性,使得该药在实际治疗中需要进行频繁地注射,结果使病人产生了更大的痛苦。因此在本研究课题中对如何提高该酶的热稳定性以便进一步提高其半衰期进行了初步研究:通过生物信息学分析手段确定了天冬酰胺酶蛋白质二级结构中一个与热稳定性关系密切的β-转角,并用定点突变的方法将该转角上的第178位的天冬氨酸突变为脯氨酸。实验结果显示:与野生型酶相比,突变体酶在不同温度条件下的热稳定性得到了提高;从能量角度上看,改造后的酶在保持动力学性质(K_m和K_(cat))基本不变的同时活化能得到了增加。这说明笔者对左旋天冬酰胺酶的改造在不影响酶活性的前提下提高了其热稳定性。
对于化疗和骨髓移植不能彻底解决的白血病细胞微小残留问题,本课题对相应的免疫学解决方案进行了探索。虽然肿瘤细胞疫苗在目前来说是一种较有前景的免疫治疗形式,但出于对其安全性方面考虑,笔者决定尝试用另外一种相对安全的免疫形式——DNA疫苗,来治疗微小残留白血病,并对其免疫效果进行了初步研究。本课题采用双质粒系统,其中一个质粒表达经过改造灭活的肿瘤细胞特异性超表达抗原生存素(survivin)和能特异性引起Th1细胞免疫反应的发夹状单链RNA(ssRNA);另一个质粒表达细胞因子GM-CSF和共刺激分子CD80。结果证明用该DNA疫苗系统免疫BalB/C小鼠能引起较强的细胞免疫应答,诱导较强的T细胞增殖和对肿瘤细胞的CTL杀伤活力。这些结果为进一步研究DNA疫苗对微小残留白血病的实际治疗提供了前期实验室数据基础。
DNA疫苗大规模纯化技术的研发是DNA疫苗走向实际临床应用和工业化生产的必不可少的环节。本课题重点对利用排阻层析纯化质粒的技术进行了研究。笔者对不同种类及不同浓度盐缓冲液存在时,各种核酸分子排阻层析行为的变化进行了观察比较。结果显示:在高浓度中性盐存在情况下,不仅是RNA,其它的核酸分子包括宿主基因组DNA和各种质粒同分异构体的层析分辨率都得到了较大提高。进一步探讨深层机制,笔者认为在这一高盐排阻层析纯化过程中同时存在两种分离模式:1、超螺旋质粒DNA主要受到压缩效应的影响以排阻模式被洗脱;2、RNA和宿主基因组DNA则主要受疏水效应的影响从而以相互作用模式被洗脱。我们的实验结果证明使用高浓度(2 M)的中性盐(硫酸铵)将提高排阻层析纯化DNA疫苗的效率。
In the treatments of acute lymphoblastic leukaemia, there are two problems puzzling people all alone: One is the side-effects caused by chemotherapy; and another is the minimal residual leukaemia which leads to the relapse of cured patient. The present study has dong some researches to try to solve these problems.
L-Asparaginase II of E. coli is a kind of effective drug in the treatment of acute lymphoblastic leukaemia. However, during asparaginase therapy, repeated using of the drug is commonly needed because of the enzyme's relatively short half-life and instability in the processes of production and treatment. This leads to more serious toxic effects on patients. In order to stabilize the enzyme, a higher thermostable mutant L-asparaginase II was created in the present study by replacing Aspl78 with proline in a hydrogen-bonded turn (178-180DGR) which is contribute to the thermostability of the enzyme. The results displayed that values of K_m and K_(cat) for the mutant enzyme are not affected although the energy of activation is increased comparing to the wild-type enzyme. These data suggest that such alteration for L-asparaginase II enhances the thermostability of the enzyme without changing the enzyme's activity and thus the therapeutical use of L-asparaginase II might be benefit from these results.
In present study, the immune-therapy method has been explored when it comes to the problem of minimal residual leukemia (MRL). Immunized with the DNA vaccine is a potential way to treat MRL for its better safety comparing to the tumor cells vaccines. In present study, a two-plasmid vaccine system which is used to express a tumor-special antigen (Survivin) has been constructed and immunized with mice. Furthermore, a barrette-like ssRNA, GM-CSF and a co-stimulating factor CD80 have also been co-expressed in the same system. The results displayed that strong T cell immune response and CTL activity were induced by the DNA vaccine. It demonstrated that DNA vaccine is a promising immune-therapy method to fight against MRL.
Techniques for large-scale preparation of clinical-grade plasmid DNA serve as an important base for clinical trials and industrialization of DNA vaccines. In the present study, we compared the performances of size-exclusion chromatography for the purification of plasmid DNA when different concentrations (0.5 M, 1M, 2 M, respectively) of two types of salt (NaCl and (NH_4)_2SO_4) are present in running buffers. Our experiment results displayed that it is not only the resolution of RNA but also those of supercoiled plasmid DNA and host's genomic DNA were increased greatly in the presence of high concentration of water-structure salt. We deduce that two separation modes may be involved in the process: The supercoiled plasmid DNA is influenced mainly by compaction effect and eluted in the size-exclusion mode; whereas, RNA and genomic DNA are influenced mainly by hydrophobic effect due to their stretched and loose structures and eluted in the interaction mode. This method led to an improved efficiency of size-exclusion chromatography.
引文
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[Rev1]郭霞,李强.急性白血病发病机制研究进展.实用儿科临床杂志,2005,20(7):690-693
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[Rev4]郑胡镛.儿童急性淋巴细胞白血病治疗进展.实用儿科临床杂志 2007 22(3) 167-169.
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