针对端粒酶的肿瘤治疗研究进展

目的 分析针对端粒酶肿瘤治疗研究的进展。方法 对近年来端粒及端粒酶的研究进行调查分析。结果 端粒及端粒酶与肿瘤发生和异常增殖密切相关，近年来，端粒及端粒酶的研究已成为生物学热点，也是人类抗肿瘤药物研究的重要“靶点”，随着人们对端粒及端粒酶结构和功能认识的加深，针对端粒酶的抗肿瘤治疗研究也不断深入。结论 针对端粒酶的肿瘤治疗研究有多种途径和方法，但是单一的端粒酶抑制是否可以作为一种主要的治疗手段来治疗肿瘤还有待临床试验来检验。     

端粒酶活性检测及检测方法的研究进展

研究发现大多数恶性肿瘤存在端粒酶活性 ,而人正常体细胞几乎未检出端粒酶活性。表明肿瘤发生与端粒酶活化密切相关 ,使端粒酶有希望成为新的恶性肿瘤标记。但仍有部分肿瘤未检出端粒酶活性 ,个别组织的肿瘤端粒酶活性检出率较低 ,使对端粒酶的肿瘤检测作用产生怀疑。本文就近年来检测端粒酶活性作为肿瘤诊断标志物的研究新进展概述如下     

肺部疾病患者痰液中脱落细胞端粒酶活性的检测

端粒酶是一种特殊的逆转录酶 ,以端粒末端富含鸟嘌呤单链为引物 ,自身 RNA组分为模板合成端粒序列。大量研究表明 :端粒酶激活与肿瘤的发生密切相关 ,因此 ,端粒酶活性可作为诊断肿瘤的参考指标。我们对肺癌与肺部良性疾病患者痰液中脱落细胞进行了端粒酶活性比较。材料和方法一、检测对象和样本采集　肺癌患者 (均经病理检查确诊 ) ,45例 ,男 33例 ,女 1 2例 ,平均年龄59.4( 31～ 78岁 )。非肺癌患者 (肺部良性疾病组 ) 2 6例 ,男 1 7例 ,女 9例 ,平均年龄 59岁 ( 2 5～ 85岁 )。分别取患者痰液 1 ml,置于无菌容器内 ,- 38℃储存备用。二…     

肺部疾病患者痰液中脱落细胞端粒酶活性的检测

端粒酶是一种特殊的逆转录酶,以端粒末端富含鸟嘌呤单链为引物,自身RNA组分为模 板合 成端粒序列。大量研究表明：端粒酶激活与肿瘤的发生密切相关,因此,端粒酶活性可作为 诊断肿瘤的参考指标。我们对肺癌与肺部良性疾病患者痰液中脱落细胞进行了端粒酶活性比 较。 材料和方法 　　一、检测对象和样本采集　肺癌患者(均经病理检查确诊),45例,男33例,女12例,平均年龄59.4(31～78岁)。非肺癌患者(肺部良性疾病组)26例,男17例,女9例,平均年 龄59岁(25～85岁)。分别取患者痰液1 ml,置于无菌容器内,-38℃储存备用。 　　二、试剂和仪器　端粒酶端粒重复扩增程序-杂交-酶免疫(TRAP-Hyb-EIA)试 剂盒(华美生物工程公司)、Wescan MK-2酶标仪、HSC-20R低温冷冻离心机、Sanyo微量高 速离心机、MJ-150扩增仪。     

端粒酶活性与宫颈癌关系研究

端粒酶活性与人类肿瘤相关,近年来端粒酶与宫颈癌之间关系及致瘤机制和基因治疗进展的研究成为热点。该文从端粒和端粒酶活性、端粒酶活性和宫颈癌、端粒酶相关成分在宫颈癌中的研究、宫颈癌端粒酶和肿瘤基因表达及基因疗法的研究几个方面,对近年来端粒酶在宫颈癌组织方面的研究及相关基因疗法的研究作一综述。     

端粒、端粒酶与肿瘤诊治的研究进展

端粒酶已经成为当今最受重视的抗肿瘤治疗的新靶点之一，人们对于端粒及端粒酶的认识也在不断加深,端粒酶可作为肿瘤诊断和预后的一个重要生物标志，抑制端粒酶可能成为一种有发展前途的抗肿瘤措施。本文综述了端粒和端粒酶的构成和功能，“端粒-端粒酶”假说，端粒酶与肿瘤的关系。     

端粒及端粒酶在恶性血液病中的研究进展

端粒和端粒酶是近来生命科学研究的热点之一。本文就有关端粒及端粒酶与恶性血液病关系的最新进展作一简述,讨论了端粒长度和端粒酶活性在疾病发生发展中的意义。端粒酶作为肿瘤标记物和治疗靶子日益受到重视。     

端粒酶活性检测及检测方法的研究进展

研究发现大多数恶性肿瘤存在端粒酶活性,而人正常体细胞几乎未检出端粒酶活性。表明肿瘤发生与端粒酶活化密切相关,使端粒酶有希望成为新的恶性肿瘤标记。但仍有部分肿瘤未检出端粒酶活性,个别组织的肿瘤端粒酶活性检出率较低,使对端粒酶的肿瘤检测作用产生怀疑。本文就近扯为检测端粒酶活性作为肿瘤诊断标志物的研究新进展概述如下。     

端粒酶活性调节的研究进展

端粒是真核细胞线性染色体末端6bp重复序列及相关蛋白质组成的特殊结构,端粒酶是合成端粒DNA重复序列的逆转录酶。普遍认为端粒酶在肿瘤的发生发展中具有重要作用。端粒酶在体内是如何被调节的,目前还知之甚少。对端粒酶活性调节的研究包括激活与抑制两个方面,抑制端粒酶以治疗肿瘤,激活端粒酶以延缓衰老。     

端粒酶hTERT基因转录调节的研究进展

端粒酶是维持端粒长度的一种逆转录酶,对细胞增殖和癌变起重要作用。端粒的磨耗限制大多数体细胞的复制,肿瘤细胞主要通过转录上调端粒酶限制成分———催化亚基端粒酶逆转录酶(hTERT)维持端粒长度。进一步认识端粒酶hTERT基因表达的调节机制,对肿瘤的诊断、防治有着重要意义。现就近几年来E-box结合蛋白、核激素、肿瘤相关病毒蛋白和RNAi抑制hTERTmR-NA表达及其他因素调节端粒酶hTERT基因表达作一综述。     

Telomerase targeted therapy in cancer and cancer stem cells

Telomerase plays a key role in cell fate: loss of telomerase in normal differentiated cells heralds senescence and limits cell division, whereas reactivation of telomerase sustains proliferation and potentiates mutagenesis and transformation. Given this pivotal role, telomerase has been the subject of intense investigation in the field of developmental cancer therapeutics. To date, a broad spectrum of therapeutic strategies has been developed, ranging from direct targeting or reprogramming of the enzyme, to immune or virus-mediated targeting of cells expressing telomerase, to strategies focusing on the telomeres themselves. The recent discovery and growing interest in cancer stem cells has thrust telomerase therapy into new relief as an approach that may be uniquely suited to neutralizing this treatment-resistant subpopulation of cancer cells. Here we will review the mechanistic rationale and preclinical and clinical state of development of the various telomerase-based therapeutic approaches, with emphasis on the role of telomerase in cancer stem cell biology and its implications for therapeutic efforts.     

PinX1 the tail on the chromosome

The PinX1 protein inhibits telomerase, an enzyme that lengthens telomeres - the structures that protect the ends of chromosomes. Loss of PinX1 leads to increased telomere length along with defects in chromosome dynamics. In this issue of the JCI, Zhou et al. present novel evidence from human tumors and mouse models indicating that PinX1 is a clinically significant tumor suppressor. Importantly, the genome-destabilizing effects of PinX1 loss appear to depend on telomerase activity, raising new models and questions for how telomeres and telomerase contribute to the development of cancer.     

Telomerase as a novel and potentially selective target for cancer chemotherapy

Telomeres are the structures that protect eukaryotic chromosomes from recognition by DNA damage surveillance mechanisms and are maintained in the germ line of multicellular animals by telomerase. In most human somatic cells telomerase is silenced during development and after extensive cell division telomeres shorten to trigger growth arrest. Around 80% of human cancers escape from this growth arrest by re‐activating telomerase but at diagnosis many cancers still have very short telomeres making them very vulnerable to the inhibition of telomerase. As normal cells have a considerable telomere reserve, even in elderly humans, this makes telomerase an attractive and potentially selective anti‐cancer drug target. Proof‐of‐principle experiments are reviewed which show that this optimism may be justified at least for the subset of human cancers with short telomeres. I also address many of the commonly raised concerns that surround telomerase as a target for anti‐cancer drug design.     

Telomerase flies the coop: the telomerase RNA component as a viral-encoded oncogene

Telomerase, the enzyme that elongates our telomeres, is crucial for cancer development based on extensive analyses of human cells, human cancers, and mouse models. New data now suggest that a viral telomerase RNA gene encoded by Marek's disease virus (MDV), an oncogenic herpesvirus of chickens, promotes tumor formation. These findings highlight the importance of telomerase in cancer and raise new questions regarding the mechanisms by which the telomerase RNA component supports tumorigenesis.     

Telomeres and telomerase in leukaemia and lymphoma.

Telomeres are DNA structures which serve to stabilize chromosomes. In human cells telomeres progressively shorten with each cell division leading to eventual chromosome instability and cell death. Telomerase is a DNA polymerase which is required for the maintenance of telomeres. Therefore, telomeres and telomerase play a role in the regulation of the life span of the cell. Human cells express low levels of telomerase, however when telomere length reaches a critical level abnormal activation of telomerase can lead to immortalization and uncontrolled proliferation. This process has been associated with the development of many leukaemias and lymphomas. Understanding these processes in normal and malignant cells could lead to therapies which target the telomere/telomerase complex.     

Telomerase--a potential molecular marker of lung and cervical cancer.

Telomerase, a ribonucleoprotein enzyme that adds hexameric TTAGGG nucleotide repeats onto telomeres is reactivated in most malignancies. Lung cancer is a common malignant disease worldwide as well as in India. Most patients present in advanced stages. As noninvasive diagnostic techniques are preferred, we assayed the telomerase activity in pre-bronchoscopy sputum and compared it with that of bronchial washings and bronchoscopic biopsies by telomeric repeat amplification protocol (TRAP) in 53 cases of lung cancer. These were corroborated with cytopathological/histopathological examinations. Telomerase activity was detected in 58.5% of sputum samples, 70% of bronchial washings and 74% of bronchoscopic biopsies thereby making it a good noninvasive diagnostic marker of lung cancer. Cervical cancer is the 7th most common cancer worldwide, with 100,000 new cases being reported annually in India. It is routinely screened by Papanicolaou's (Pap) smear. Human papilloma virus (HPV) is one of its etiological agents. We have assayed telomerase activity in relation to HPV-16/18 in cervical samples from 93 subjects ranging from normal to precancerous to frank cancers in tissue biopsies and cervical scrapings. HPV infection was detected by polymerase chain reaction (PCR) in 81% of tumor samples, in 6% of control hysterectomy samples and in 2% of cervical scrapings of normal healthy controls with HPV-16 being the predominant type. Telomerase activity was detected in 96.5% of cervical tumor samples, in 68.7% of premalignant cervical scrapings but was not detected in control hysterectomy samples, or in cervical scrapings of normal healthy controls. There was 71% correlation between telomerase activity and HPV-16/18 infection.     

Telomerase activation, cellular immortalization and cancer

The maintenance of specialized nucleoprotein structures termed telomeres is essential for chromosome stability. Without new synthesis of telomeres at chromosome ends the chromosomes shorten with progressive cell division, eventually triggering either replicative senescence or apoptosis when telomere length becomes critically short. The regulation of telomerase activity in human cells plays a significant role in the development of cancer. Telomerase is tightly repressed in the vast majority of normal human somatic cells but becomes activated during cellular immortalization and in cancers. While the mechanisms for telomerase activation in cancers have not been fully defined, they include telomerase catalytic subunit gene (hTERT) amplification and trans-activation of the hTERT promoter by the myc oncogene product. Ectopic expression of hTERT is sufficient to restore telomerase activity in cells that lack the enzyme and can immortalize many cell types. Understanding telomerase biology will eventually lead to several clinically relevant telomerase-based therapies. These applications include inhibiting or targeting telomerase as a novel antineoplastic strategy and using cells immortalized by telomerase for therapeutic applications.