大肠癌的药物治疗

大肠癌作为消化道常见的恶性肿瘤,严重威胁着人类的健康。随着医学的不断进步,目前针对大肠癌治疗也逐渐向多元化发展。除手术治疗外的多种药物治疗在大肠癌的治疗中发挥重要的作用。本文将对大肠癌的化疗、免疫治疗、生物治疗、基因治疗、靶向治疗、中医中药治疗及对症支持治疗的研究逐一论述。     

胰腺癌基因治疗的研究现状

胰腺癌的基因治疗作为一种新的治疗手段,近年来备受关注,其很多研究已进入临床阶段.胰腺癌基因治疗的研究主要包括:反义基因治疗、自杀基因治疗、免疫基因治疗及肿瘤裂解病毒基因治疗等.本文就近期胰腺癌的基因治疗研究成果与存在的问题作一综述.     

抗肿瘤血管生成基因治疗大肠癌的研究进展

抗肿瘤血管生成的治疗已逐渐转入基因水平。本文对与肿瘤血管生成密切相关的细胞因子、基因治疗基本方法及其在大肠癌的治疗应用作一介绍。     

抗肿瘤血管生成基因治疗大肠癌的研究进展

抗肿瘤血管生成的治疗已逐渐转入基因水平。本对与肿瘤血管生成密切相关的细胞因子、基因治疗基本方法及其在大肠癌的治疗应用作一介绍。     

原发性肝癌的体内基因治疗研究与进展

原发性肝癌恶性程度高,预后差,治疗效果不理想.肝癌的基因治疗是针对基因表达异常的病因治疗,因而有望成为一种理想的治疗方法,或成为肝癌综合治疗中一个重要的方面.原发性肝癌的体外基因治疗已有大量研究报道,近年来肝癌的体内基因治疗研究也取得一些进展,为肝癌的基因治疗过渡到临床应用提供了更直接的依据,综述近年来这方面的研究与进展.     

减毒沙门氏菌在消化系肿瘤中的研究进展

消化系肿瘤在我国是最常见的恶性肿瘤,随着现代生活节奏的加快,消化系肿瘤的发病率有增高趋势,年轻化的趋势也愈加明显.减毒沙门氏菌作为一个胞内寄生菌,本省具有抗肿瘤特性,同时可以作为肿瘤基因治疗的载体进行抗肿瘤治疗.本文就减毒沙门氏菌及作为治疗载体在肝癌、胃癌、大肠癌的体内外应用进展进行综述.     

大肠癌中医证治临床研究进展

大肠癌是常见的恶性肿瘤,目前公认的治疗方法是以手术治疗为主的综合疗法,中医药治法是其重要的组成部分.近年来针对大肠癌中医诊疗方法的研究日益深入,总结目前大肠癌中医证治的研无主要包括大肠癌证候研究、大肠癌中医治疗两个方面,并取得了一定的成绩.但也应该看到.目前的研究工作仍存在不少问题,如重复性的疗效观察较多,临床观察与机制探讨相结合的研究较少,且没有统一的证治规律等.综合分析当前研究成果和趋势,笔者认为大肠癌中医证候分布及动态变化规律的研究是目前大肠癌中医临床研究者必须首先解决的重要问题.     

蛋白质组学在大肠癌研究中的应用

大肠癌是我国常见恶性肿瘤之一, 且发病率和死亡率呈逐年上升趋势. 蛋白质组学的出现,使大肠癌的研究有了进一步的发展. 本文就国内外蛋白质组学在大肠癌诊断、发病机制、治疗等方面的研究进行综述.     

慢病毒载体及其在基因治疗中的研究进展

基因治疗作为一种相对理想、高效、特异的治疗手段,已成为目前生命科学领域最重要的研究之一.如何选择一个合适的基因转移载体,是基因治疗的一个重要方面.目前,病毒载体的应用非常广泛.包括反转录病毒载体、腺病毒载体、腺相关病毒载体等.本文拟就慢病毒载体系统及其在基因治疗中的应用和研究进展作一综述.     

microRNA与结直肠癌关系的研究进展

结直肠癌的发病是一个多因素、多步骤的演进过程,基因表达异常在其中起重要作用.近年研究发现多种microRNA（miRNA）在结直肠癌中表达异常,可能参与了肿瘤的发生、发展过程,有望成为结直肠癌早期诊断、临床分期、个体化治疗、靶向治疗和预后评估的分子标记物.本文就近年来有关miRNA与结直肠癌天系的研究进展作一综述.     

Gamma-secretase inhibitor, a potential target therapy for MUC2-positive colorectal carcinoma

Notch signaling may be mechanistically involved the colorectal carcinogenesis. Blocking of Notch signaling by gamma-secretase inhibitor may constitute a novel molecular therapy for cancer. In the present study, we blocked the Notch signaling by DAPT (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, a gamma-secretase inhibitor) and investigated the effects on the proliferative and invasive potential of human colorectal cancer LS174T cells, a goblet cell-like colorectal cancer cell line which produces high-levels of MUC2 continuously. DAPT inhibited the proliferation and invasion of LS174T cells. Blocking of Notch signaling by DAPT could down-regulate its downstream target gene Hes1, while enhancing the expression of Math1 and MUC2 in LS174T cells. In conclusion, we demonstrated that blocking of Notch signaling by DAPT could inhibit the proliferation and invasion of human colorectal cancer LS174T cells and suggested that gamma-secretase inhibitors may provide a targeted therapy for MUC2-positive colorectal tumors.     

基于COSMIC数据库的结直肠转移性癌的体细胞突变基因变化的研究

目的利用癌症体细胞突变目录（COSMIC）数据库,筛选结直肠原发性癌和结直肠转移性癌两类癌组织之间的具有显著差异的体细胞基因突变,并分析其可能的功能及通路。 方法从COSMIC数据库下载结直肠癌全外显子测序数据,在R 3.5.0环境下,利用卡方检验或Fisher确切概率法对结直肠原发性癌和结直肠转移性癌两类癌组织之间的差异体细胞突变基因进行挖掘,记录具有显著差异的体细胞突变基因并进行功能及通路富集分析,探索其可能生物学功能及通路。 结果共发现120个具有显著差异的体细胞突变基因,包括RHEB、RP11-368J21.2、AGAP10等,对其进行GO和KEGG富集分析显示,这些显著性差异体细胞突变基因可能与如脱氢酶活性、还原酶活性、细胞周期停滞、代谢途径、PI3K-Akt信号通路、细胞周期、细胞粘附分子、癌症中的转录失调、铂类耐药性等功能及通路相关。 结论挖掘结直肠原发性癌和结直肠转移性癌之间的显著差异体细胞突变基因可为研究结直肠癌的转移调控机制提供借鉴,显著差异体细胞突变基因可能作为结直肠癌转移诊断标志物或转移治疗靶点应用于临床。     

Ornithine decarboxylase gene is overexpressed in colorectal carcinoma

AIM: To investigate the ornithine decarboxylase (ODC) gene expression in colorectal carcinoma, ODC mRNA was assayed by RT-PCR and ODC protein was detected by a monoclonal antibody against fusion of human colon ODC prepared by hybridoma technology. METHODS: Total RNA was extracted from human colorectal cancer tissues and their normal counterpart tissues. ODC mRNA levels were examined by RT-PCR. ODC genes amplified from RT-PCR were cloned into a prokaryotic vector pQE-30. The expressed proteins were purified by chromatography. Anti-ODC mAb was prepared with classical hybridoma techniques and used to determine the ODC expression in colon cancer tissues by immunohistochemical and Western blotting assay. RESULTS: A cell line, which could steadily secrete anti-ODC mAb, was selected through subcloning four times. Western blotting reconfirmed the mAb and ELISA showed that its subtype was IgG2a. RT-PCR showed that the ODC mRNA level increased greatly in colon cancer tissues (P<0.01). Immunohistochemical staining showed that colorectal carcinoma cells expressed a significantly higher level of ODC than normal colorectal mucosa (98.6±1.03% vs5.26±5%,P<0.01). CONCLUSION: ODC gene overexpression is significantly related to human colorectal carcinoma. ODC gene expression may be a marker for the gene diagnosis and therapy of colorectal carcinoma.     

Intratumoral functional heterogeneity and chemotherapy

Intratumoral heterogeneity including genetic and nongenetic mechanisms refers to biological differences amongst malignant cells originated within the same tumor.Both,cell differentiation hierarchy and stochasticity in gene expression and signaling pathways may result in phenotypic differences of cancer cells.Since a tumor consists of cancer cell clones that display distinct behaviours,changes in clonal proliferative behavior may also contribute to the phenotypic variability of tumor cells.There is a need to reveal molecular actions driving chemotherapeutic resistance in colon cancer cells.In general,it is widely hypothesized that therapeutic resistance in colorectal cancer is a consequence of the preferential survival of cancer stem cells.However,recent data regarding colorectal cancer suggest that resistance to anticancer therapy and post-therapeutic tumor reappearence could be related to variations of clonal dynamics.Understanding the interaction of genetic and nongenetic determinants influencing the functional diversity and therapy response of tumors should be a future direction for cancer research.     

Synergetic effects of retrovirus IFN-alpha gene transfer and 5-FU on apoptosis of colon cancer cells

Gene transfer has advantages in the treatment of a variety of disorders due to its selective expression within specific mammalian cells including the most primitive stem cells and cancer cells. Several investigators have reported on the clinical effects of interferon-alpha (IFN-alpha) or the combination of 5-FU plus IFN-alpha on patients with advanced colorectal carcinoma. Therefore, we examined the ability of a retrovirus-mediated IFN-alpha gene transfer to infect colon cancer cells COLO 201 and the effect of IFN-alpha gene expression alone or in combination with other chemotherapeutic drugs as 5-FU. IFN-alpha showed positive antitumor activity against COLO 201 cells, whereas 5-FU showed time- and concentration-dependent antitumor activity against COLO 201 cells. Furthermore, we demonstrated that combination therapy of IFN-alpha gene transfer and 5-FU resulted in enhancement of cancer cell lethality. The potentiation increased with higher concentrations of 5-FU by 1.5- to 2.1-fold. Our results suggest that retrovirus-mediated IFN-alpha gene transfer in COLO 201 cells resulted in functional gene expression as assessed by the levels of IFN-alpha mRNA and protein; furthermore, the combination of IFN-alpha gene transfer and 5-FU have additional effects on the induction of apoptosis. This finding provides an experimental basis for possible clinical therapy using retrovirus-mediated IFN-alpha gene transfer alone or in combination with other chemotherapeutic drugs for treatment of colorectal cancer.     

Comparative analysis of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase expression in colorectal cancer and surrounding normal tissue

Thymidylate synthase [TS], thymidine phosphorylase [TP] and dihydropyrimidine dehydrogenase [DPD] play the essential role in the activation and catabolism of the fluoropyrimidines used in cancer therapy. Its expression may influence the antitumor activity or toxicity of these drugs. We studied the expression levels of selected enzymes in colorectal tumors and adjacent normal mucosa. The analysis of TS, TP and DPD gene expression was performed using quantitative Real time PCR technique (Roche) in 15 (TS), 64 (TP) and 12 (DPD) of 64 colorectal cancer patients. The mean gene expression of TS, TP and DPD was found to be 3.29; 3.79 and 8.24 in tumors and 1.88; 3.80 and 19.69 in normal mucosa. The corresponding median gene expression was 1.87; 2.32 and 4.50 for tumors and 2.14; 2.63 and 11.64 for normal tissue. We did not find any significant differences in TS, TP and DPD gene expression between colorectal tumor and surrounding mucosa.     

人粪便中波形蛋白基因甲基化在结直肠癌早期诊断中的意义

目的 分析结直肠癌患者粪便中波形蛋白基因甲基化状态,探讨其作为结直肠癌早期诊断分子标志物的可行性和临床意义.方法 从郑州大学第一附属医院收治的60例结直肠癌患者、门诊行结肠镜检查的17例结直肠腺瘤患者及30名正常对照者的粪便中分别提取DNA,采用甲基化特异性PCR(MSP)方法分析其波形蛋白基因甲基化状态.结果 60例结直肠癌患者粪便中波形蛋白基因甲基化阳性率为51.67％(31/60),17例结直肠腺瘤患者粪便中波形蛋白基因甲基化阳性率为4/17,30名正常对照中无一例检测到波形蛋白基因甲基化.结论 粪便中波形蛋白基因甲基化是结直肠癌进展过程中的早期事件,粪便中波形蛋白基因甲基化分析有望成为结直肠癌早期诊断的标志物之一.     

Adenovirus-mediated prodrug-enzyme therapy for CEA-producing colorectal cancer cells

PURPOSE: Carcinoembryonic antigen expression is increased in more than 80% of patients with colorectal cancer. Values are especially higher in patients with advanced stage disease. Virus directed prodrug/enzyme therapy (VDEPT) using genetically engineered viral vectors has been considered as one of the more notable cancer gene therapies for the transduction of various enzymes into cancer cells. We made adenovirus vectors under the control of a CEA promoter that included the HSV-tk gene and investigated its usefulness to specifically target human CEA-producing colorectal cancer cells. METHODS: An adenovirus vector with the lacZ or HSV-tk gene under the control of a CAG or CEA promoter was designed for the VDEPT experiment. Human colorectal cancer cell lines were used for in vitro experiments to assure the transduction efficacy of the inserted genes by these vectors. To conduct the in vivo experiment, liver metastases of the cell line were created in CB17 SCID mouse. We then performed intrasplenic injections of adenovirus vectors and intraperitoneal injections of the prodrug, ganciclovir. RESULTS: RCM-1, the CEA-producing human rectal cancer cell line, was more strongly stained by X-gal staining. Furthermore, COLO320 was faintly stained secondary to a shortage of CEA production. The in vivo VDEPT experiment with RCM-1 and the adenovirus vector driven by the CEA promoter revealed attenuation of liver metastases in the treatment group. CONCLUSIONS: Adenovirus vectors under the control of the CEA promoter can transduce inserted genes effectively into targeted human colorectal cancer cells according to the amount of expressed CEA protein. We anticipate the future use of VDEPT of the HSV-tk/GCV system using this vector in the treatment of advanced colorectal cancers.