谷胱甘肽转移酶与克服肿瘤多药耐药药物的研究进展

肿瘤多药耐药是一个多因素的现象.许多研究表明,外排转运蛋白和Ⅱ相结合酶在肿瘤细胞中的协同表达与肿瘤的多药耐药相关.特别是谷胱甘肽-S-转移酶(GST)和肿瘤外排泵过度表达可能降低肿瘤细胞对抗癌药物的反应性.近年来很多证据表明谷胱甘肽-S-转移酶通过抑制JNK信号通路参与调控细胞凋亡.     

谷胱甘肽-S-转移酶π研究进展

从谷胱甘肽-S-转移酶π(GSTπ)的结构及其介导的肿瘤细胞耐药性、GSTπ抑制剂、GSTπ活化前药、GSTπ与化学预防等方面介绍GSTπ的最新研究进展,指出GSTπ的过量表达与肿瘤细胞的耐药性紧密相关,特异性抑制GSTπ的活性,是消除GSTπ介导的肿瘤药物耐药性的有效途径.     

肿瘤多药耐药机制及其逆转剂研究进展

肿瘤细胞多药耐药性（multidrug resistance,MDR）的产生是导致肿瘤化疗失败的主要原因之一。MDR是指肿瘤细胞对一种抗肿瘤药物产生耐药性的同时,对结构和作用机制完全不同的其他抗肿瘤药物产生交叉耐药性的现象。因此,研究MDR产生的机制、寻求有效的耐药逆转剂及逆转措施,克服MDR现象已成为国内外的研究热点。本文就MDR产生的机制、目前国内外逆转耐药的研究进展做一综述。     

肿瘤多药耐药及其逆转研究现状

所谓多药耐药是指肿瘤细胞接触一种化疗药物后 ,不但对该药产生耐药性 ,而且对其他结构和作用机制不同的多种药物产生耐药性 ,即有交叉耐药性。多药耐药主要有两种类型 :(1)内在性多药耐药 :是指肿瘤细胞固有的对化疗药物不敏感 ;(2)获得性多药耐药 :是指肿瘤开始对化疗药物敏感 ,但经过几个疗程化疗后 ,肿瘤细胞不仅对该药产生耐药 ,而且对结构和作用机理不同的药物也产生耐药。1肿瘤的多药耐药机制1.1转运蛋白的过度表达 :(1)P-糖蛋白 (Permeability- glyco protein,P- gp,P170)是由MDR-1基因编码的 ,分子量为170KD的跨膜糖蛋白 (故又…     

消化道恶性肿瘤多药耐药的临床研究

目的 研究消化道恶性肿瘤化疗耐药与多药耐药基因MDR（p-gP）、谷胱甘肽转移酶（GST）、拓扑异构酶（TOPOⅡ）之间关系。方法 用免疫组化单克隆技术，定量分析P-gp、GST、TOPOⅡ在肿瘤组织中的阳性及阴性表达。结果 P-gp在恶性肿瘤中阳性表达率为39．6％，化疗耐药中占55．9％；GST在恶性肿瘤中阳性表达率为64．0％，化疗耐药中占76．5％；TOPOⅡ在恶性肿瘤中阳性表达率为54．0％，化疗耐药中占35．3％。结论 P-gp、GST、TOPOⅡ参与肿瘤耐药机制的形成。     

多药耐药机制的探究

肿瘤细胞的耐药性可分为原发性耐药(intrinsic resistance)和获得性耐药(acquired resistance)。前者在化疗前就存在于肿瘤细胞中,与药物的使用无关,后者是由化疗药物诱导产生的,即在药物使用前对药物敏感,而在药物应用后产生耐药。获得性耐药根据耐药谱不同可分为原药耐药(primary drugresis-tance,PDR)和多药耐药(multi-drugs resistance,MDR)。PDR只对     

膀胱肿瘤多药耐药性的逆转

膀胱肿瘤的治疗基本上是以手术结合腔内灌注化疗为主。然而化疗后的复发率很高,其中一个重要的原因是由于化疗过程中肿瘤细胞多药耐药(MDR)的产生。MDR是指肿瘤细胞接触一种化疗药物后,不仅对该药产生耐受性,而且对其他结构及作用机制不同的药物也产生交叉耐受。交叉耐药的产生     

乳腺癌患者血浆多药耐药基因谷胱甘肽巯基转移酶活性分析及其临床应用

目的：通过对乳腺癌患者血浆样本中多药耐药基因谷胱甘肽巯基转移酶（GST）活性检测，掌握治疗过程中耐药信息的变化，为临床治疗提供参考依据。方法：采用生化反应方法，将血浆样本与化学试剂加在一起混匀，根据反应前后透光率的不同，计算每个样本GST活性。结果：治疗前GST活性平均为（842±606）nmol·min^-1·mL^-1，化疗3个周期后GST活性平均为（796±587）nmol·min^-1·mL^-1。有淋巴结转移与无淋巴结转移者相比较，治疗前GST活性差异有统计学意义（P〈0．05）。结论：乳腺癌患者血浆GST活性测定，对乳腺癌化疗用药选择及预后具有参考价值。     

脂质体逆转肿瘤多药耐药研究进展

本文就肿瘤细胞多药耐药机理、脂质体的一般特点、脂质体逆转肿瘤细胞多药耐药的机理以及近年来脂质体应用于逆转肿瘤细胞多药耐药的研究进行综述。     

Glutathione S-transferase and P-glycoprotein in multidrug resistant Chinese hamster cells

Glutathione S-transferases (GSTs) have been reported to be elevated in some forms of hepatic carcinogenesis, in multidrug resistant (MDR) cells exhibiting elevated P-glycoprotein, and in cells resistant to alkylating agents independent of the MDR phenotype. The reported elevation of GST in association with the MDR phenotype and the overexpression of P-glycoprotein along with induction of GST in hepatic carcinogenesis suggest a correlation in the two mechanisms of cellular detoxification. To evaluate this hypothesis we examined the expression of GSTs in an MDR Chinese hamster fibroblast cell line overexpressing P-glycoprotein. We were unable to demonstrate concordant elevation of GST in these MDR cells. We conclude that GST expression is independent of P-glycoprotein expression in MDR Chinese hamster fibroblasts. The overexpression of GSTs in certain cells may provide an alternative mechanism for the development of drug resistance, either in association with or independent of P-glycoprotein overexpression, but is not essential for the MDR phenotype.     

Glutathione S-transferase M1 and multidrug resistance protein 1 act in synergy to protect melanoma cells from vincristine effects

Previous studies have shown that glutathione S-transferases (GSTs) can operate in synergy with efflux transporters, multi-drug resistance proteins (MRPs), to confer resistance to several carcinogens, mutagens and anticancer drugs. To address the poorly documented role of the GSTM1 in cancer chemoresistance, we used CAL1 human melanoma cells expressing no endogenous GSTM1 and a high level of MRP1. Cells were transfected with an expression vector containing the GSTM1 cDNA, and different clones were selected expressing different levels of GSTM1 (RT-PCR, Western blot, and enzyme activity). Cells overexpressing GSTM1 displayed a 3- to 4-fold increase in resistance to anticancer drugs vincristine (VCR) and chlorambucil (CHB) in proliferation, cytotoxic, and clonogenic survival assays. Inhibitors of MRP1 (sulfinpyrazone, verapamil) and GST (dicumarol, curcumin) completely reversed the GSTM1-associated resistance to VCR, indicating that a MRP efflux function is necessary to potentiate GSTM1-mediated resistance to VCR. Conversely, MRP1 inhibitors had no effect on the sensitivity to CHB. Using immunofluorescence assay, GSTM1 was also shown to protect microtubule network integrity from VCR-induced inhibition of microtubule polymerization. In conclusion, these results show that GSTM1 alone is involved in melanoma resistance to CHB, whereas it can act in synergy with MRP1 to protect cells from toxic effects of VCR.     

谷胱甘肽及其相关酶系统与肿瘤多药耐药的关系

临床化疗失败的重要原因是肿瘤细胞对化疗药物产生多药耐药(MDR)。经典的P糖蛋白、多药耐药相关蛋白等耐药机制已基本明确。因此，进一步了解非经典的耐药途径对于完善多药耐药机制有重要意义。本文综述了谷胱甘肽及其相关酶系统在肿瘤多药耐药中的作用，介导多药耐药的可能机制以及谷胱甘肽类似物结构与转运活性的关系。     

Glutathione S-transferase activity in human placenta

Glutathione S-transferase activity has been identified in human placenta cytosol. The soluble protein fraction subjected to isoelectric focusing was resolved into a single peak of activity towards 1-chloro-2,4-dinitrobenzene centred at pH 4.65. Gel filtration experiments indicated that the protein had a molecular weight of 60,000. There was no apparent binding of sulphobromophthalein to this protein. The placental glutathione S-transferase system was inhibited by some non-substrate anions but apparently not by bilirubin. Glutathione S-transferase activity was located in the cytosol of the chorial villi and to a lesser extent in the amnion; it appears in the early stages of pregnancy. This activity was not detected in the amniotic fluid.     

Glutathione S-transferase polymorphisms and susceptibility to neuroblastoma

There is evidence to suggest that polymorphic variations in the glutathione S-transferase (GSTs) are associated with cancer susceptibility. The GST supergene family includes several genes with well characterized polymorphisms. Approximately 50% of the Caucasian population is homozygous for deletions in GSTM1 and approximately 20% are homozygous for deletions in GSTT1. Deletions lead to an absence of the protein, thus resulting in conjugation deficiency of mutagenic electrophiles to glutathione. The GSTP1 gene displays a polymorphism at codon 105 resulting in an Ile to Val substitution, which alters the enzymatic activity of the protein, and this has been suggested as a putative high-risk genotype in various cancers. In the present study, we investigated the relationship between GSTs polymorphism and the susceptibility to neuroblastoma, comparing GSTs genotypes of 256 children with neuroblastoma with those of 392 normal control subjects. No significant differences of allele frequencies were found between patients and controls. Within the neuroblastoma group, we further investigated whether any particular GSTs genotype was correlated with clinical and biological characteristics at diagnosis, but no association was detected. Our data do not support an important effect of GSTs genotype on neuroblastoma susceptibility.     

Glutathione S-transferase polymorphisms and their biological consequences

Two supergene families encode proteins with glutathione S-transferase (GST) activity: the family of soluble enzymes comprises at least 16 genes; the separate family of microsomal enzymes comprises at least 6 genes. These two GST families are believed to exert a critical role in cellular protection against oxidative stress and toxic foreign chemicals. They detoxify a variety of electrophilic compounds, including oxidized lipid, DNA and catechol products generated by reactive oxygen species-induced damage to intracellular molecules. An increasing number of GST genes are being recognized as polymorphic. Certain alleles, particularly those that confer impaired catalytic activity (e.g. GSTM1(*)0, GSTT1(*)0), may be associated with increased sensitivity to toxic compounds. GST polymorphisms may be disease modifying; for example, in subgroups of patients with basal cell carcinoma or bronchial hyper-responsiveness, certain GST appear to exert a statistically significant and biologically relevant impact on disease susceptibility.     

Glutathione S-transferase (GST) inhibitors

The glutathione S-transferases (GSTs; EC 2.5.1.18) comprise a family of widely distributed Phase II detoxication enzymes that catalyse the conjugation of a broad variety of reactive electrophiles to the nucleophilic sulfur atom of the major intracellular thiol, the tripeptide glutathione. The diverse functions, including catalytic GSH conjugation, passive ligandin-type binding and modulation of signal transduction, may be selectively targeted by different inhibitors. GST inhibitors are emerging as promising therapeautic agents for managing the development of resistance amongst anticancer agents. In diagnostic medicine, as well as in antiparasitic drug development, GST inhibitors are important lead molecules. In this review, the important molecules known for their GST inhibition together with potential therapeutic uses are summarised.     

Glutathione S-transferase in humans: development and tissue distribution

Glutathione S-transferase (GST) was investigated with benzo(a)pyrene-4,5-oxide (BPO) as substrate in tissue specimens from 26 fetal and 27 adult livers and 27 placentas. The average (±SEM) of GST activity in the cytosol was 1.80±0.18 (fetal liver), 3.05 ± 0.30 (adult liver) and 1.18 ±0.07 (placenta) nmol/min/mg. GST was also investigated in human fetal and adult lungs, kidneys and gut. In these tissues the average (±SEM) GST activity ranged between 0.71±0.12 (adult intestine) and 2.11±0.18 (fetal lungs) nmol/min/mg. Whereas in the fetal liver the conjugation of BPO was catalyzed at a rate of about two-thirds of the adult rate, similar or higher GST activities were found in the fetal non-hepatic tissues as compared to the adult organs. No correlation was found between the activity of the GST in fetal liver and placenta and the gestational age (11–25 weeks). GST develops before the 11th week of gestation and it does not undergo changes during the mid-gestation. No correlation was found between GST activity in adult liver and age (32–70 years).     

Glutathione S-transferase activities in placentas from smoking and non-smoking women

1. Microsomal mono-oxygenase activity toward 7-ethoxyresoryfin, and cytosolic glutathione S-transferase activity toward 1-chloro-2, 4-dinitrobenzene were determined in 53 placentas obtained at delivery from smoking and non-smoking women.

2. Whereas mono-oxygenase activity was clearly stimulated in placentas from women who smoked, no parallel enhancement of glutathione S-transferase activity was evident.

3. This disparity in response could result in imbalance among placental detoxication systems following exposure to certain compounds.     

Glutathione and glutathione S-transferase activities of mammalian cells in culture

Continuous cell cultures derived from various tissues of rat, mouse, hamster and man were assayed for their glutathione (GSH) content and glutathione S-transferase activities. GSH S-transferase activities were monitored toward the substrates 1-chloro-2,4-dinitro-benzene (CDNB), 1,2-dichloro-4-nitrobenzene (DCNB) and 1,2-epoxy-3-(p-nitrophenoxy)propane (PO). All cell lines tested contained appreciable amounts of GSH ranging from 10 to 65 mol/mg cellular protein. Likewise, all cell lines expressed GSH S-transferase activities. However, the various cell lines differed considerably in their relative transferase activities exhibiting some degree of species-specificity.