p53基因Msp I位点多态性与NSCLC易感性及辐射敏感性关系的研究

目的 研究中国北方人对非小细胞肺癌（NSCLC）的易感性及放疗敏感性与p53基因Msp Ⅰ单核苷酸多态性（SNP）的关系。方法 采用病例对照方法，通过合成序列特异性引物（PCR-RFLP）方法 检测50例NSCLC患者及56例健康对照者的p53基因Msp Ⅰ单核苷酸多态性位点的基因型。同时，观察不同基因型患者的放射治疗疗效，检测与辐射敏感性相关的基因型。结果NSCLC组的A1／A2杂和基因型频率明显高于对照组（72=4．38，P〈0．05）。A1／A2杂合子患非小细胞肺癌的风险相对风险度为2．51（1．06〈0R〈5．96）。未观察到p53基因Msp Ⅰ单核苷酸多态性与非小细胞肺癌病人的辐射敏感性有密切的相关关系。结论 p53基因MspⅠ单核苷酸多态性位点的A1／A2杂和基因型为非小细胞肺癌的易感基因，但尚未发现该基因型与NSCLC的辐射敏感性相关。     

肺癌中FHIT基因缺失和p53蛋白表达的研究

目的：探讨肺癌组织中FHIT（fragile histidine triadgene）基因缺失和p53蛋白表达及其与临床病理因素的关系。方法：采用逆转录-巢式聚合酶链反应方法及免疫组织化学ABC法分别检测42例肺癌组织中FHIT基因缺失和p53蛋白表达。结果；肺癌组织中FHIT基因缺失和p53蛋白表达阳性率分别为66．7％（28／42）和76．2％（32／42）．FHIT基因缺失肺癌的p53蛋白阳性率明显高于FHIT基因正常表达的肺癌（P〈0．01）。FHIT基因缺失与肺癌的淋巴结转移有关，p53蛋白表达与临床分期、淋巴结转移密切相关。结论：FHIT基因缺失和p53蛋白异常表达与肺癌发生、发展密切相关，二者相互促进．呈明显正相关。     

p53基因改变与淋巴瘤

淋巴瘤是一种淋巴细胞和(或)组织细胞恶性增殖性疾病.p53基因突变、缺失、单核苷酸多态性(SNP)以及上游不同阅读框架(ARF)、鼠双微体2(MDM-2)的异常等均可造成p53功能的失活,而p53功能失活与淋巴瘤发病机制、组织学类型、疾病进展、预后、治疗选择及化疗耐药等密切相关.下面我们就p53基因改变与各种淋巴瘤的关系综述如下.     

p53基因改变与淋巴瘤

淋巴瘤是一种淋巴细胞和(或)组织细胞恶性增殖性疾病.p53基因突变、缺失、单核苷酸多态性(SNP)以及上游不同阅读框架(ARF)、鼠双微体2(MDM-2)的异常等均可造成p53功能的失活,而p53功能失活与淋巴瘤发病机制、组织学类型、疾病进展、预后、治疗选择及化疗耐药等密切相关.下面我们就p53基因改变与各种淋巴瘤的关系综述如下.     

周围型肺癌CT征象与p53基因及生存率的关系

【目的】研究周围型肺癌CT表现与p53基因及生存率的关系。【方法】应用链菌素亲生物素一过氧化酶连接法的快速免疫组化和薄层CT扫描技术．探讨67例周围型肺癌CT征象与p53基因表达异常和术后生存率的关系。【结果】肺癌瘤体≥3cm．深分叶、有棘状突起、伪足征、淋巴结转移者与p53基因异常表达相关。肺癌瘤体≥3cm、深分叶、伪足征、有淋巴转移者与术后生存率低有关。【结论】薄层CT扫描征象和周围型肺癌p53基因的异常表达与生存率密切相关。     

Dual-FISH技术检测原发性肺癌p53基因缺失及其临床意义

目的 探讨原发性肺癌p53基因缺失情况及其临床意义.方法 应用Dual-FISH技术检测我院2005-2008年收治的41例原发性肺癌组织间期核中p53缺失情况.结果 p53基因缺失与肿瘤分化程度、发病年龄有相关性(OR 值为18.775,95%CI为2.437～144.636;OR值为0.077,95%CI为0.007～0.874;P均<0.05),即肿瘤分化程度是危险因子,分化程度越低,发生p53基因缺失的危险性越高.而发病年龄是保护性因子,即年龄越大,发生p53基因缺失的危险性越低.p53基因缺失率为34.2%(14/41),分化程度好的缺失率17.4%(4/23)低于分化程度差的71.4%(10/14)(P<0.05),而与性别、组织类型、肿瘤转移之间无相关性(P均>O.05).结论 p53基因缺失与肺癌分化程度、发病年龄密切相关,检测该基因在肺癌中的缺失情况可作为判断肺癌预后的重要生物学指标.     

血管内皮生长因子、p53蛋白与微血管密度在非小细胞肺癌中的表达及其相关性

目的:研究血管内皮生长因子(VEGF)、p53蛋白、微血管密度(MVD)在非小细胞肺癌中的表达及其相关性,探讨其在非小细胞肺癌发生、发展中的作用.方法:采用免疫组织化学S-P法检测80例非小细胞肺癌组织、20例肺良性病变组织中VEGF、p53蛋白的表达,并对肺癌组织中CD34单抗标记的血管计数MVD.结果:肺癌组织VEGF、p53蛋白阳性表达率明显高于肺良性病变组织(P＜0.05).VEGF、p53蛋白表达与肺癌患者的年龄、性别、组织学类型均无关(P＞0.05),与肺癌组织的分化程度、TNM分期及淋巴结转移均有关(P＜0.05).VEGF与p53蛋白表达呈正相关(P＜0.05).在肺癌组织中,VEGF、p53蛋白表达阳性组MVD分别明显高于VEGF、p53蛋白表达阴性组(P＜0.05);p53蛋白与VEGF表达均阳性组MVD明显高于p53蛋白与VEGF表达均阴性组(P＜0.05).结论:VEGF、p53可能与肺癌的发生、发展有关.VEGF与p53蛋白在肺癌组织中的表达呈正相关,提示突变型p53基因可能上调VEGF的表达.肺癌组织中MVD与VEGF、p53蛋白表达密切相关,突变型p53基因和VEGF在肺癌血管形成中具有协同作用.     

硫氧还蛋白基因TXN单核苷酸多态性与中国汉族人群肺癌易感性研究

目的 探讨硫氧还蛋白基因TXN的单核苷酸多态性与肺癌易感性间的关系.方法 采集经病理组织学确诊的肺癌患者292例,相同地区、性别、年龄频数匹配的体检健康对照307例,针对筛选出的TXN基因9个单核苷酸多态性(SNP)位点进行基因型检测,通过统计分析研究基因频率与肺癌风险的关系,并探讨吸烟在其中的影响.结果 3个TXN基...     

p73基因多态性与肿瘤相关性研究

目的 p73基因与p53基因具有同源性,p73基因与p53基因所编码的蛋白质结构与功能上差异不大,都具有激活靶基因,抑制细胞生长,促进肿瘤细胞凋亡等功能。随着p73基因研究的深入,p73基因多态性与肿瘤相关性的研究得到了飞速的发展。本文就p73基因多态性与肿瘤相关性研究进行综述。     

p53基因突变与肺癌放射治疗敏感性的研究进展

p53基因突变是肺癌中最常见的遗传改变。与肺癌发生、发展关系密切。现就抑癌基因p53与肺癌的预后、淋巴结转移、放疗敏感性及肺癌的基因治疗研究进展作一综述。     

重组人p53腺病毒基因药物抑制喉癌细胞生长的实验研究

目的:探讨p53基因治疗喉癌的可行性.方法:以人喉癌细胞系Hep-2为实验对象,将重组人p53腺病毒药物(1010rAd/p53)感染Hep-2细胞,用免疫组化方法观察Hep-2细胞体外生长情况.结果:1010rAd/p53对Hep-2生长有明显抑制.结论:重组人p53腺病毒药物对Hep-2细胞生长能有效抑制,为喉癌的基因治疗提供了实验依据.     

Histone deacetylase inhibitor FK228 enhances adenovirus-mediated p53 family gene therapy in cancer models

Therapeutic replacement of the wild-type p53 gene has been pursued as a potential gene therapy strategy in a variety of cancer types; however, some cancer models are resistant to p53 in vivo and in vitro. Therefore, to improve p53 gene therapy, it is important to overcome the resistance to p53-mediated apoptosis. Histone deacetylase inhibitors are a novel class of chemotherapeutic agents that are able to reverse the malignant phenotype of transformed cells. A natural histone deacetylase inhibitor, FK228, is reported to enhance adenovirus infection due in part to the up-regulation of coxsackievirus adenovirus receptor expression. In this study, preclinical experiments were done to establish a mechanistic rationale for the combination of adenovirus-mediated p53 family gene transfer and FK228 pretreatment in future clinical trials. Pretreatment with FK228 enhanced apoptosis in human cancer cells through enhanced transduction of Ad-p53. FK228 also induced hyperacetylation of the p53 protein and specifically enhanced p53-mediated Noxa expression. Additionally, the combination of FK228 and Ad-p53 induced Bax translocation to the mitochondria. The double knockdown of Bax and Noxa expression by small interfering RNA antagonized the synergistic effect of Ad-p53 and FK228 on apoptosis induction. In human cancer xenograft models, FK228 significantly increased the therapeutic effectiveness of p53 as well as p63 gene therapy. These results provide a strong rationale for combining p53 gene therapy and FK228 pretreatment in cancer therapy.     

EFFECTS OF p53 GENE THERAPY COMBINED WITH CYCLOOXYGENASE-2 INHIBITOR ON CYCLOOXYGENASE-2 GENE EXPRESSION AND GROWTH INHIBITION OF HUMAN LUNG CANCER CELLS

1 INTRODUCTIONCOXis the key enzyme involved in the synthesis of prostanoids,a collective termfor the PGs andthromboxanes.Of the two major isoforms of the COXenzyme,COX-1 is ubiquitous and constitutively ex-pressedin virtually all normal tissues.In contras…     

Correction of a genetic defect in multipotent germline stem cells using a human artificial chromosome

Human artificial chromosomes (HACs) have several advantages as gene therapy vectors, including stable episomal maintenance that avoids insertional mutations and the ability to carry large gene inserts including regulatory elements. Multipotent germline stem (mGS) cells have a great potential for gene therapy because they can be generated from an individual's testes, and when reintroduced can contribute to the specialized function of any tissue. As a proof of concept, we herein report the functional restoration of a genetic deficiency in mouse p53-/- mGS cells, using a HAC with a genomic human p53 gene introduced via microcell-mediated chromosome transfer. The p53 phenotypes of gene regulation and radiation sensitivity were complemented by introducing the p53-HAC and the cells differentiated into several different tissue types in vivo and in vitro. Therefore, the combination of using mGS cells with HACs provides a new tool for gene and cell therapies. The next step is to demonstrate functional restoration using animal models for future gene therapy.     

Advances in adenovirus-mediated p53 cancer gene therapy

Introduction: The tumor suppressor p53 gene regulates diverse cellular processes, such as cell-cycle arrest, senescence, apoptosis and autophagy, and it is frequently inactivated by genetic alterations in ～ 50% of all types of human cancers. To restore wild-type p53 function in p53-inactivated tumors, adenovirus-mediated p53 gene therapy has been developed as a promising antitumor strategy in preclinical experiments and clinical studies.

Areas covered: This review focuses on the clinical relevance of replication-deficient adenovirus vectors that carry the wild-type p53 gene (Ad-p53; Advexin, Gendicine and SCH-58500) in clinical studies of patients with various cancers and the future perspectives regarding conditionally replicating adenovirus vectors expressing the wild-type p53 gene (CRAd-p53; AdDelta24-p53, SG600-p53, OBP-702) in preclinical experiments. Moreover, the recent advances in our understanding of the molecular basis for the p53-mediated tumor suppression network induced by Ad-p53 and CRAd-p53 vectors and the combination therapies for promoting the therapeutic potential of adenovirus-mediated p53 gene therapy are discussed.

Expert opinion: Exploration of the molecular mechanism underlying the p53-mediated tumor suppression network and the effective strategy for enhancing the p53-mediated cell death signaling pathway would provide novel insights into the improvement of clinical outcome in p53-based cancer gene therapy.     

Tumor-targeted p53-gene therapy enhances the efficacy of conventional chemo/radiotherapy.

A long-standing goal in gene therapy for cancer is a stable, low toxic, systemic gene delivery system that selectively targets tumor cells, including metastatic disease. Progress has been made toward developing non-viral, pharmaceutical formulations of genes for in vivo human therapy, particularly cationic liposome-mediated gene transfer systems. Ligand-directed tumor targeting of cationic liposome-DNA complexes (lipoplexes) is showing promise for targeted gene delivery and systemic gene therapy. Lipoplexes directed by ligands such as folate, transferrin or anti-transferrin receptor scFv, showed tumor-targeted gene delivery and expression in human breast, prostate, head and neck cancers. The two elements, ligand/receptor and liposome composition, work together to realize the goal of functional tumor targeting of gene therapeutics. The tumor suppressor gene, p53, has been shown to be involved in the control of DNA damage-induced apoptosis. Loss or malfunction of this p53-mediated apoptotic pathway has been proposed as one mechanism by which tumors become resistant to chemotherapy or radiation. The systemically delivered ligand-liposome-p53 gene therapeutics resulted in efficient expression of functional wild-type p53, sensitizing the tumors to chemotherapy and radiotherapy. This is a novel strategy combining current molecular medicine with conventional chemotherapy and radiotherapy for the treatment of cancer. The systemic delivery of normal tumor suppressor gene p53 by a non-viral, tumor-targeted delivery system as a new therapeutic intervention has the potential to critically impact the clinical management of cancer.     

肿瘤抑制基因p53的研究进展

肿瘤抑制基因p53是目前研究最为广泛和系统的抑癌基因之一。野生型p53参与了DNA损伤修复、细胞周期调控、细胞凋亡及抑制血管生成等过程。p53基因的突变使上述功能丧失,从而导致肿瘤的形成。约50%的人类肿瘤中可发现p53基因的突变,且几乎可见于各种类型的肿瘤细胞中。现综述目前p53研究及相关基因治疗的进展。     

Adenovirus-mediated transfer of the p53 family genes, p73 and p51/p63 induces cell cycle arrest and apoptosis in colorectal cancer cell lines: potential application to gene therapy of colorectal cancer

p53 gene therapy is being tested clinically for the treatment of human cancer, however, some cancer models (in vivo and in vitro) are resistant to p53. To explore the potential use of two p53 homologues, p73 and p51/p63, in cancer gene therapy, we introduced p53, p73 and p51/p63 into colorectal cancer cell lines via adenoviral vectors, and compared their effects on cell growth. Among 10 cell lines tested, six cell lines displayed a similar response following transduction of p53, p73beta or p51A/p63gamma; two lines underwent cell-cycle arrest, three lines exhibited apoptosis and one line showed no-effect following transduction. The effect on cell-cycle progression was variable in the other four cell lines. Interestingly, three cell lines were resistant to p53-mediated apoptosis, including two lines having endogenous wild-type p53 alleles, but underwent apoptosis after transduction of p73beta or p51A/p63gamma. Similar to p53, transduction of p51A/p63gamma induced extensive apoptosis when combined with adriamycin or X-radiation in SW480 cells, which are normally resistant to apoptosis. Transduction of p73beta and p51A/p63gamma also reduced the tumorigenicity of two colorectal cancer cells in vivo. These results suggest that adenovirus-mediated p73beta and p51A/p63gamma transfer are potential novel approaches for the treatment of human cancers, particularly for tumors that are resistant to p53 gene therapy.     

p53基因与骨肉瘤治疗及其预后的相关性

骨肉瘤的发生是多基因、多步骤、多阶段、多重损伤并存的过程,众多情况下认为是由于细胞核 DNA分子受破坏,细胞不能修复受损的 DNA分子,其继续存在并复制可激活癌基因和(或)抑癌基因异常,发展成为骨肉瘤.在细胞抑癌基因中 p53基因研究最广泛, 50%人类肿瘤与 p53基因突变有关.动物试验证实存在 p53基因突变的转基因鼠中除了淋巴瘤和肺腺癌外,骨肉瘤的发生率最高.p53基因的突变和失活影响着骨肉瘤的发生、发展、预后.随着少数 p53基因治疗进入临床实验阶段,目前 p53的基因治疗研究也出现了一些新的策略.随着分子生物学手段的不断发展和完善,基因治疗的安全性和有效性的提高, p53基因治疗将在骨肉瘤的治疗中体现出不可估量的作用.