表观遗传调控与肿瘤耐药

恶性肿瘤严重威胁着人类健康,抗肿瘤药物是目前治疗肿瘤最主要的方法,但肿瘤对药物不可避免的出现抗药,使其成为攻克肿瘤的最大难题之一。目前对肿瘤抗药的分子机制并不十分清楚,除了传统观点强调的基因突变,近年来越来越多的研究揭示了表观遗传调控在肿瘤耐药中的作用,本文从DNA甲基化,组蛋白修饰,非编码RNA和染色质重塑对抗肿瘤药物的治疗作用进行综述和分析,旨在为抗肿瘤药物安全有效的合理使用提供新的思路,以及为肿瘤个体化治疗提供更有效的治疗靶点。     

大肠癌化疗疗效及毒性预测分子的研究进展

大肠癌患者对化疗药物的反应和毒性具有明显的个体差异,这种差异是个体遗传多态性通过影响药物的代谢、转运和作用靶点等引起。治疗前对患者进行抗肿瘤药物疗效和（或）不良反应相关的基因检测,从而可以实现合理选择化疗药物,本文对大肠癌化疗疗效及毒性预测分子作一综述,以指导临床个体化用药。     

骨髓增生异常综合征表观遗传学治疗进展

 表观遗传改变与基因改变有一个重要的区别就是表观遗传改变是可逆的,通过使用相应的表观遗传药物可使沉默的抑癌基因重新表达。骨髓增生异常综合征（MDS）的表观遗传治疗已经取得了很大的发展,当前应用于临床的表观遗传药物主要包括DNA去甲基化药物和去乙酰化酶抑制剂。得到FDA批准上市的DNA去甲基化药物5-氮杂胞苷和地西他滨均为MDS治疗药物,可作为中高危患者尤其是不能耐受化疗的老年患者重要的治疗选择;去乙酰化酶抑制剂如丙戊酸等目前在治疗MDS中大多处于I期临床试验阶段,可能在治疗低危MDS中有一定价值,但其剂量和治疗效果尚需进一步评估;去甲基化药物和去乙酰化抑制剂二者联用治疗MDS可能具有协同作用,但目前的临床试验尚不能证实其优于去甲基化药物的单用,仍需大样本的临床病例和合理的治疗方案来验证其安全有效性。     

表观遗传修饰在肿瘤免疫治疗中的意义

肿瘤是危害人类健康最严重的疾病之一,并且我国的肿瘤死亡率呈逐年上升趋势.肿瘤免疫治疗作为手术、放疗和化疗之后第4种治疗手段被临床广泛应用.肿瘤免疫治疗通过激发或调动机体的免疫系统,增强肿瘤微环境的抗肿瘤免疫力,从而控制和杀伤肿瘤细胞,是当前肿瘤治疗领域最具前景的研究方向之一.表观遗传学是研究DNA序列未改变而基因表达发生变化的一种可遗传改变,其调节机制主要包括DNA甲基化、组蛋白修饰和非编码RNA调节等.表观遗传修饰在免疫应答及肿瘤免疫治疗中的调控作用越来越受到重视.本文综述了表观遗传修饰对机体免疫细胞的调控以及通过干预进行肿瘤免疫治疗的相关研究和应用前景.     

分子靶向抗肿瘤药物临床应用

分子靶向抗肿瘤药物有独特的靶向抗肿瘤作用,在当前临床治疗中已发挥一定作用,并显示出良好的应用前景.主要有抗信号转导药物、抗血管生成药物、肿瘤耐药逆转剂及以细胞膜分化抗原为靶点的药物等.现就这些分子靶向药物的临床应用与目前研究进展作一综述.     

分子靶向抗肿瘤药物临床应用

分子靶向抗肿瘤药物有独特的靶向抗肿瘤作用，在当前临床治疗中已发挥一定作用，并显示出良好的应用前景。主要有抗信号转导药物、抗血管生成药物、肿瘤耐药逆转剂及以细胞膜分化抗原为靶点的药物等。现就这些分子靶向药物的临床应用与目前研究进展作一综述。     

表观遗传学在抗肿瘤中的基础研究及临床转化新进展

表观遗传学近年来备受关注,它主要是指在细胞表型中不依赖于DNA序列改变所产生的可遗传改变。研究已证实,在肿瘤的发生发展中,表观遗传学改变也起到关键作用,尤其是抗癌基因的DNA甲基化、组蛋白乙酰化修饰以及部分抗癌microRNA的失调等表观遗传学改变在肿瘤演进中意义重大。在深入研究这些机制的同时,抗肿瘤治疗的转化研究也逐渐开展并取得了一定成效。本文将从DNA甲基化、组蛋白乙酰化修饰和microRNA调控等方面阐述表观遗传学在抗肿瘤研究中的具体机制,以及由此开展的转化医学研究等内容进行综述。     

肺鳞癌的分子病理学研究进展

肺鳞癌是最具代表性的多发于吸烟人群的恶性肿瘤。目前研究多集中在肺腺癌和不吸烟患者,对鳞癌分子病理学改变的认知远远落后于腺癌。未来非小细胞肺癌的研究热点将集中在鉴定不同肺癌亚型的分子改变及研发相应靶点的靶向治疗药物。近来研究已发现多个具有潜在临床指导意义的抗肿瘤靶点并即将制成鳞癌基因图谱,有望为鳞癌的基因分型提供依据。本文将对肺鳞癌分子病理学的最新研究进展作一综述。     

在抗肿瘤药物临床试验中运用替代终点的审评考量

患者的总生存时间延长是评价抗肿瘤药物临床价值的金标准。但在抗肿瘤新药的研发过程中, 对于预后较好的癌种, 如果进行药物临床试验时以总生存时间为主要终点, 随访时间太长, 药物上市时间也会相应延迟。此外, 总生存时间还常受到后续治疗等混杂因素的干扰。因此, 药品监管机构针对抗肿瘤新药审批上市建立了采用替代终点的加速审评模式, 但在抗肿瘤药物临床试验中运用替代终点还存在一些问题。文章从新药审评的角度, 深入阐述了在抗肿瘤药物临床试验中确证和合理运用替代终点的要点, 有助于提高抗肿瘤新药临床试验的水平, 加快抗肿瘤药物的研发。     

安罗替尼在晚期恶性肿瘤治疗中的研究进展

安罗替尼是我国自主研发的多靶点小分子酪氨酸激酶抑制剂,具有抗肿瘤血管生成和抑制肿瘤细胞生长的作用,因其具有不良反应小、靶点明确及安全性高等优点,目前已在多种恶性肿瘤中显示出了良好的临床疗效,本文就安罗替尼的抗肿瘤作用机制、其在多种类型肿瘤中的应用以及不良反应与管理等方面的最新研究进展进行综合阐述。     

DNA甲基化抑制剂在恶性淋巴瘤中的研究进展

DNA甲基化是生物基因表达调控的方式之一,其作为一种特殊的表观遗传事件在疾病的发生、发展中具有重要作用.近年来,随着基础医学研究的发展,研究人员在血液系统肿瘤尤其是恶性淋巴瘤中发现了基因的高甲基化,相关药物的研发及临床试验的开展也在不断推进.DNA甲基转移酶抑制剂(DNA methyltransferase inhib...     

Epigenetic therapy with decitabine for myelodysplasia and leukemia

New therapeutic approaches are being developed for the treatment of cancer patients. Increasingly, drugs are being produced based on new insight into the intracellular processes in the cancer cell. Recently the typical epigenetic changes in the tumor cell have been considered as a therapeutic target. Several drugs have shown potential epigenetic activity. Decitabine (5-aza-2 -deoxycytidine, Dacogen) is one of the drugs that is able to induce changes in the methylation status of DNA. In this article the authors present an overview of this drug with regard to the chemistry, pharmacokinetics and the data that support its role as the new therapeutic agent in leukemia and myelodysplastic syndrome.     

Cancer epigenetics in clinical practice

Cancer development is driven by the accumulation of alterations affecting the structure and function of the genome. Whereas genetic changes disrupt the DNA sequence, epigenetic alterations contribute to the acquisition of hallmark tumor capabilities by regulating gene expression programs that promote tumorigenesis. Shifts in DNA methylation and histone mark patterns, the two main epigenetic modifications, orchestrate tumor progression and metastasis. These cancer-specific events have been exploited as useful tools for diagnosis, monitoring, and treatment choice to aid clinical decision making. Moreover, the reversibility of epigenetic modifications, in contrast to the irreversibility of genetic changes, has made the epigenetic machinery an attractive target for drug development. This review summarizes the most advanced applications of epigenetic biomarkers and epigenetic drugs in the clinical setting, highlighting commercially available DNA methylation-based assays and epigenetic drugs already approved by the US Food and Drug Administration.     

DNA methyltransferase inhibitors and the development of epigenetic cancer therapies

Epimutations, such as the hypermethylation and epigenetic silencing of tumor suppressor genes, play a role in the etiology of human cancers. In contrast to DNA mutations, which are passively inherited through DNA replication, epimutations must be actively maintained because they are reversible. In fact, the reversibility of epimutations by small-molecule inhibitors provides the foundation for the use of such inhibitors in novel cancer therapy strategies. Among the compounds that inhibit epigenetic processes, the most extensively studied are DNA methyltransferase inhibitors. In this review, we examine the literature on DNA methyltransferase inhibitors and discuss the efficacy of such compounds as antitumor agents, as evaluated in phase I-III clinical trials. We also discuss future areas of research, including the development of nonnucleoside inhibitors, the application of novel bioanalytical tools for DNA methylation analysis (which will be important for the clinical application of these compounds by allowing rational approaches to trial design), the need to optimize treatment schedules for maximal biologic effectiveness, and the need to define molecular endpoints so that changes induced by demethylating drugs in patients can be monitored during treatment. Assays for genome-wide and tumor-specific DNA methylation also need to be further developed to establish the pharmacodynamic parameters of DNA methyltransferase inhibitors in patients and to provide rational approaches to maximizing the therapeutic efficacy of these compounds.     

The role of epigenetic therapies in colorectal cancer

Although developments in the diagnosis and therapy of colorectal cancer (CRC) have been made in the last decade, much work remains to be done as it remains the second leading cause of cancer death. It is now well established that epigenetic events, together with genetic alterations, are key events in initiation and progression of CRC. Epigenetics refers to heritable alterations in gene expression that do not involve changes in the DNA sequence. These alterations include DNA methylation, histone alterations, chromatin remodelers, and noncoding RNAs. In CRC, aberrations in epigenome may also involve in the development of drug resistance to conventional drugs such as 5-fluorouracil, oxaliplatin, and irinotecan. Thus, it has been suggested that combined therapies with epigenetic agents may reverse drug resistance. In this regard, DNA methyltransferase inhibitors and histone deacetylase inhibitors have been extensively investigated in CRC. The aim of this review is to provide a brief overview of the preclinical data that represent a proof of principle for the employment of epigenetic agents in CRC with a focus on the advantages of combinatorial therapy over single-drug treatment. We will also critically discuss the results and limitations of initial clinical experiences of epigenetic-based therapy in CRC and summarize ongoing clinical trials. Nevertheless, since recent translational research suggest that epigenetic modulators play a key role in augmenting immunogenicity of the tumor microenvironment and in restoring immune recognition, we will also highlight the recent developments of combinations strategies of immunotherapies and epigenetic therapies in CRC, summarizing preclinical, and clinical data to signify this evolving and promising field for CRC treatment.     

Molecular targeting therapy of cancer: drug resistance,apoptosis and survival signal

Recent progress in the development of molecular cancer therapeutics has revealed new types of antitumor drugs, such as Herceptin, Gleevec, and Iressa, as potent therapeutics for specific tumors. Our work has focused on molecular cancer therapeutics, mainly in the areas of drug resistance, apoptosis and apoptosis resistance, and survival-signaling, which is related to drug resistance. In this review, we describe our research on molecular cancer therapeutics, including molecular mechanisms and therapeutic approaches. Resistance to chemotherapeutic drugs is a principal problem in the treatment of cancer. P-Glycoprotein (P-gp), encoded by the MDR1 gene, is a multidrug transporter and has a major role in multidrug resistance (MDR). Targeting of P-gp by small-molecular compounds and/or antibodies is an effective strategy to overcome MDR in cancer, especially hematologic malignancies. Several P-gp inhibitors have been developed and are currently under clinical phased studies. In addition to the multidrug transporter proteins, cancer cells have several drug resistance mechanisms. Solid tumors are often placed under stress conditions, such as glucose starvation and hypoxia. These conditions result in topo II poison resistance that is due to proteasome-mediated degradation of DNA topoisomerases. Proteasome inhibitors effectively prevent this stress-induced drug resistance. Glyoxalase I, which is often elevated in drug- and apoptosis-resistant cancers, offers another possibility for overcoming drug resistance. It plays a role in detoxification of methylglioxal, a side product of glycolysis, which is highly reactive with DNA and proteins. Inhibitors of glyoxalase I selectively kill drug-resistant tumors that express glyoxalase I. Finally, the susceptibility of tumor cells to apoptosis induced by antitumor drugs appears to depend on the balance between pro-apoptotic and survival (anti-apoptotic) signals. PI3K-Akt is an important survival signal pathway, that has been shown to be the target of various antitumor drugs, including UCN-01 and geldanamycin, new anticancer drugs under clinical evaluation. Our present studies provide novel targets for future effective molecular cancer therapeutics.     

Metformin: A promising drug for human cancers

Small-molecule chemical drugs are of great significance for tumor-targeted and individualized therapies. However, the development of new small-molecule drugs, from basic experimental research and clinical trials to final application in clinical practice, is a long process that has a high cost. It takes at least 5 years for most drugs to be developed in the laboratory to prove their effectiveness and safety. Compared with the development of new drugs, repurposing traditional non-tumor drugs can be a shortcut. Metformin is a good model for a new use of an old drug. In recent years, the antitumor efficacy of metformin has attracted much attention. Epidemiological data and in vivo, and in vitro experiments have shown that metformin can reduce the incidence of cancer in patients with diabetes and has a strong antagonistic effect on metabolism-related tumors. Recent studies have shown that metformin can induce autophagy in esophageal cancer cells, mainly by inhibiting inflammatory signaling pathways. In recent years, studies have shown that the antitumor functions and mechanisms of metformin are multifaceted. The present study aims to review the application of metformin in tumor prevention and treatment.     

以DNA拓扑异构酶Ⅱ为靶点的一种抗癌药筛选的新方法

借鉴文献方法,我们以小鼠L_(1210)白血病细胞为村料,提取DNA拓扑异构酶Ⅱ,鉴别了其生物学特性,并观察了十多种已知及未知的抗癌药物对其活性的影响,初步建立了以DNA拓扑异构酶Ⅱ为靶点的新抗癌药筛选方法。实验表明DNA拓扑异构酶Ⅱ对DNA链切割反应是可逆的,并且高浓度的氯化钠对其活性有抑制作用。许多药物能促进拓扑酶Ⅱ引起的DNA链断裂如ADM、DNR、Vp16及ACM—B等,而另一些药物如萜类化合物BC_1、BC_4等则能抑制链断裂反应。     

Valproic acid as epigenetic cancer drug: preclinical, clinical and transcriptional effects on solid tumors

Among many anticancer drugs collectively named "targeted or molecular therapies" epigenetic drugs are clearly promising. Differently from other agents targeting a single gene product, epigenetic drugs have chromatin as their target through inhibition of histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) therefore, yet unspecific, they may act upon most or all tumor types, as deregulation of the methylation and deacetylation machinery are a common hallmark of neoplasia. In the last years, valproic acid (VPA) as emerged as a promising drug for cancer treatment. VPA has shown potent antitumor effects in a variety of in vitro and in vivo systems, and encouraging results in early clinical trials either alone or in combination with demethylating and/or cytotoxic agents. In addition, whole genome expression by microarray analysis from the primary tumors of patients treated with VPA show significant up-regulation of hundred of genes belonging to multiple pathways including ribosomal proteins, oxidative phosphorylation, MAPK signaling; focal adhesion, cell cycle, antigen processing and presentation, proteasome, apoptosis, PI3K, Wnt signaling, calcium signaling, TGF-beta signaling, and ubiquitin-mediated proteolysis among others. Despite in general, industry is not particularly interested in funding the clinical development of VPA, -at least in comparison to novel HDAC inhibitors-, existing preclinical and preliminary clinical data strongly suggest that VPA could be a drug that eventually will be used in combination therapies, either with classical cytotoxics, other molecular-targeted drugs or radiation in a number of solid tumors.