bcl-2基因对乳腺癌细胞多药耐药性的影响

乳腺癌细胞的多药耐药性是临床上常见的影响乳腺癌化疗效果的原因之一.近年来发现,抗凋亡基因bcl-2在乳腺癌细胞多药耐药性的产生过程中起到了重要的作用.bcl-2基因通过抑制乳腺癌细胞的凋亡、延长细胞生存时间等机制,诱导乳腺癌细胞对化疗药物产生耐药性.用反义寡核苷酸抑制 bcl-2的表达可以增加肿瘤细胞对化疗药物的敏感性.     

Bcl-2基因反义寡核苷酸对乳腺癌细胞株药物敏感性的影响

目的:探讨bcl-2基因反义寡核苷酸对人乳腺癌细胞株MCF-7的bcl-2蛋白的表达和药物敏感性的影响.方法:用人工合成bcl-2基因反义寡核苷酸预培养人乳腺癌细胞株MCF-7,以免疫组化法检测细胞bcl-2蛋白的表达水平;以MTT法检测bcl-2反义寡核苷酸、阿霉素单独及联合应用对MCF-7细胞生长的抑制情况,比较bcl-2蛋白表达与肿瘤细胞药物敏感性之间的相关性.结果:联合应用bcl-2反义寡核苷酸与阿霉素能够明显增加MCF-7细胞对阿霉素的敏感性,细胞存活率明显下降.免疫组化结果显示MCF-7细胞bcl-2表达水平与细胞药物敏感性有相关性.结论:bcl-2反义寡核苷酸能够抑制MCF-7乳腺癌细胞bcl-2基因的表达,提高MCF-7细胞对阿霉素的敏感性.     

赫赛汀靶向治疗HER-2过度表达乳腺癌的效果及护理

目的分析HER-2过度表达乳腺癌患者应用赫赛汀进行靶向治疗的临床效果及护理方法。方法将我院收治的54例HER-2过度表达乳腺癌患者随机分为两组,不使用赫赛汀,仅使用常规化疗药物的为对照组,联合应用包括赫赛汀在内的多种化疗药物,并给予针对性护理干预(包括正确配置赫赛汀、合理贮藏药品等)为观察组。统计两组患者的治疗效果,并进行对比。结果观察组患者的治疗缓解率(88.9%)明显高于对照组(48.1%),数据差异较大,P<0.05,有统计学意义。此外,观察组患者治疗均非常顺利,未有1例出现严重不良反应情况。结论通过对HER-2过度表达乳腺癌患者展开赫赛汀靶向治疗,并给予其针对性护理干预,可充分发挥出药物的作用,减少不良反应的发生,达到缓解病灶的目的。     

转移性乳腺癌治疗药 Trastuzumab

1商品名Hercetin2开发与上市厂商（美）Genentech公司研制并于1998年6月首次在美国上市。3药效分类免疫激动剂4药理本品是一种重组“人化”的单克隆抗体（rhuMAb），可与致癌基因HERZ编码的蛋白结合，本品可单独用于对化疗无效者或与紫杉醇合用作为转移性乳腺癌（MBC）的一线治疗药物，本品限用于HERZ蛋白过度表达的肿瘤病人。HERZ在25％-30％的MBC病人中过度表达，它是与表皮生长因子受体结构相似的一种跨膜受体蛋白，回顾性研究显示，HERZ过度表达可致肿瘤恶化且预后较差。而本品正是抑制了与HERZ过度表达有关的人肿瘤细胞的…     

乳腺癌分子靶向治疗的研究进展

乳腺癌分子靶向治疗是指针对乳腺癌发生、发展有关的癌基因及其相关表达产物进行治疗。分子靶向药物通过阻断肿瘤细胞或相关细胞的信号转导,来控制细胞基因表达的改变,而产生抑制或杀死肿瘤细胞。近年来,乳腺癌的分子靶向治疗取得了令人瞩目的进展。Lapatinib用于HER2过度表达的晚期乳腺癌的治疗对于过度表达人表皮生长因子受体2(HER2)的晚期转移性乳腺癌,标准治疗是采用含有曲妥珠单抗的方案。然而,上皮生长因子受体(EGFR)的过度表达也与患者的不良预后相关。在过度表达HER2的细胞,同时抑制EGFR和HER2,有相加作用。Lapatinib是一…     

血管内皮生长因子反义核酸提高前列腺癌PC3细胞对化疗药物敏感性的研究

目的探讨血管内皮生长因子(VEGF)反义核酸对前列腺癌细胞PC3对常用化疗药物作用的影响,联合反义核酸和紫杉醇治疗裸鼠移植肿瘤。方法采用新型脂质体Oligofectamine携带VEGF反义核酸转染前列腺癌细胞PC3。定量反转录-聚合酶链反应(RT-PCR)和Western杂交的方法检测细胞VEGFmRNA和蛋白的表达,四甲基偶氮唑蓝法(MTT)检测转染反义核酸的细胞对化疗药物的敏感性,联合反义核酸和紫杉醇对裸鼠移植肿瘤进行治疗,观察肿瘤抑制率,计算药物相互作用指数(CDI)。结果新型脂质体携带VEGF反义核酸转染前列腺癌细胞PC3,与对照组和正义组比较,反义组细胞VEGFmRNA和蛋白的表达明显下降,对2种前列腺癌常用化疗药物紫杉醇和米托蒽醌的敏感性明显增强(P<0.05)。治疗裸鼠移植肿瘤28d后肿瘤生长抑制率分别为反义组58.5%,紫杉醇组60.2%,联合组84.1%,CDI=0.97。结论 VEGF反义寡核苷酸抑制VEGF的表达,提高细胞对化疗药物的敏感性,联合反义核酸和紫杉醇可以更有效地抑制肿瘤生长,并且2种药物具有协同作用。     

生物制剂赫赛汀治疗HER-2过度表达转移性乳腺癌的观察和护理

赫塞汀是一种重组DNA衍生的人源化单克隆抗体,其活性成分为曲妥珠单抗,适用于治疗中高度表达HER-2的转移性乳腺癌,它与多西紫杉醇、阿霉素、环磷酰胺联合治疗过度表达HER-2的转移性乳腺癌能以HER-2受体为靶点进行靶向性治疗,给复发转移性乳腺癌患者的治疗带来新的希望.我院对HER-2过度表达的转移性乳腺癌6例患者进行联合化疗,取得满意效果.     

曲妥珠单抗(赫赛汀)最新临床研究进展

<正> 乳腺癌是女性最常见的恶性肿瘤之一。近年来随着分子生物学技术的进展,人们发现HER-2过度表达与乳腺癌的恶性程度和侵袭性有很大的相关性。约25％～30％的乳腺癌患者有HER-2基因的过度表达。由罗氏公司控股,Genetech公司开发的针对HER-2的抗体曲妥珠单抗(赫赛汀),给乳腺癌治疗带来了新的希望。曲妥珠单抗主要作用机制可能包括:①曲妥珠单抗与HER-2受体结合,抑制细胞生长信号传递通路;②加速HEH-2受体降解,使HER-2受体     

以bcl—2基因为靶标的反义治疗克服肿瘤化疗耐药

化疗耐药是肿瘤治疗中的难题,研究耐药机制和寻求克服途径成为当今肿瘤防治的重点。ｂｃｌ－２是一个重要的细胞凋亡抑制基因,在许多肿瘤上超量表达。临床和分子生物学证明,ｂｃｌ－２超量表达与化疗耐药有关。应用反度药物抑制ｂｃｌ－２基因表达,肿瘤细胞能恢复对化疗药物治疗的敏感性。ｂｃｌ－２反义药物与传统化疗药物协同使用有望成为解决肿瘤化疗耐药的新突破口。     

反义药物的开发与研究进展

反义药物是近20多年来发展起来的一种以反义核酸技术为基础开发的以治疗为目的安全有效的新型药物。反义药物(Antisense drugs)指的是反义脱氧寡核苷酸类药物,主要包括反义DNA(AS-ODN),反义RNA(AS-ON),多肽核酸(PNA),核酶(ribozymer)等。其主要是根据碱基互补配时原则和核酸杂交原理,利用人工合成、天然存在的互补寡核苷酸片段,以反向互补方式特异性地与目的基因(单链、双链)或信使核糖核酸(mRNA)的特定序列相结合,从基因复制、特录、剪接、转运翻译等水平上调节靶基因的表达,干托遗传信息从核酸向蛋白质的传递,从而达到抑制、封闭或破坏靶基因表达,达到治疗疾病的目的。因此,反义药物是对多种疾病都有潜在治疗价值的新型药物。自1978年Stephenson和Zamenick首次报道与病毒核酸序列互补的13met反义寡聚脱氧核苷酸能够抑制Rous病毒复制,提出了反义寡聚脱氧核糖核酸能够抑制特定基因表达的概念,并预测了在活疗病毒性疾病和癌症方面的前景。     

微小RNA在白血病中的作用及治疗策略

微小RNA（microRNA,miRNA）是一类由19～25个核苷酸组成的非编码蛋白质的单链小分子RNA,其在白血病中扮演着癌基因和抑癌基因的角色,针对miRNA在白血病中的不同作用,可采取相应的治疗策略。对于在白血病中高表达的具有癌基因功能的miRNA,可采用反义寡核苷酸等技术下调或抑制miRNA;而对于在白血病中显著低表达、发挥着抑癌基因作用的miRNA,可采用基因治疗的方法,导入相应的外源miRNA,使其正常表达。因此,miRNA对于白血病的基因治疗或作为白血病治疗的新靶标具有广阔的应用前景。     

Antisense strategies and non-viral gene therapy for cancer

Effective gene therapy for cancer remains an elusive goal, even after more than a decade of intensive research. There has been, however, tremendous progress in the development of increasingly sophisticated non-viral (or synthetic) delivery vectors for local and systemic administration of nucleic acids. Recent clinical data has also indicated the feasibility of using antisense oligonucleotides to inhibit inappropriately expressed or mutated genes in human cancers. The purpose of this review is to provide an update of the patent literature on the development of non-viral approaches for cancer gene therapy. In particular, patents on lipoplexes and polyplexes for delivery of therapeutic genes and antisense oligonucleotides are reviewed. The diverse range of antisense strategies being developed and recent clinical data are also highlighted.     

Overview: Oncologic,Endocrine & Metabolic Antisense oligonucleotides for the treatment of cancer

Conventional chemotherapeutic agents which either block enzymatic pathways or randomly interact with DNA irrespective of the cell phenotype, lack specificity for killing neoplastic cells. Growing evidence indicates that antisense oligodeoxynucleotides can be used to control cancer cell growth by specific targeting of cancer-specific genes. The mRNAs of several oncogenes, growth factors or cytokines have been chosen as targets for antisense oligodeoxynucleotides. Discrimination between the protooncogene and the oncogene can be achieved in the case of ras oncogene, of which activation occurs through point mutation in the coding sequence. Targeting at the mRNA of the RIα subunit of cAMP-dependent protein kinase, the positive intracellular regulator of cell growth, with an antisense oligodeoxynucleotide has also shown arrest of cancer cell growth. Synthetic oligonucleotides, thus, provide the potential biological tool for cancer chemotherapy.     

Genetics of breast cancer

Breast cancer has all the hallmarks of a multistep genetic disease. Somatic and germ-line mutations have been described in several tumor suppressor genes, and oncogenes are found to be amplified. Genes in the ATM-CHK2-TP53 cell-cycle checkpoint pathway are mutated in relation to breast cancer, particularly TP53 at the somatic level. Germ-line mutations in BRCA1 and BRCA2, in which DNA repair function is interrupted, account for the majority of familial breast cancers. The mechanism behind the frequent instability of the genomes of breast cancer cells has been poorly understood, but recent functional findings on oncogenes and tumor suppressor genes have provided substantial information on the matter. Some recent developments in drug therapy are based on molecular and genomic findings about breast cancer pathogenesis.     

RNA interference may be more potent than antisense RNA in human cancer cell lines

1. RNA interference (RNAi) is a newly discovered cellular pathway for the silencing of sequence-specific genes at the mRNA level by the introduction of the cognate double-stranded (ds) RNA. Because antisense (AS) mechanisms have similar effects, we compared these two effects in human cancer cell lines, considering a possible application of RNAi for cancer therapy. 2. We tested RNAi effects by transfecting human hepatoma and pancreatic cancer cell lines with AS and sense (S) RNA expression plasmids corresponding to the exogenous luciferase gene or the endogenous c-raf gene in the form of complexes with a cationic lipopolyamine or a tumour-targeting peptide vector we developed. In addition, we compared the effects of small interfering RNA and AS oligoDNA complexed with the peptide vector. 3. From the viewpoint of AS actions, the effect of the AS RNA may be cancelled by the S RNA, although, interestingly, we found that the combination of the AS and S RNA expression plasmids was more effective than the AS RNA expression plasmids alone in reducing target gene expression, whereas the S RNA expression plasmids had no effects. The combination of the luciferase AS and S RNA had no effects on the expression of either the beta-galactosidase gene or the c-raf gene. In the presence of 2-aminopurine (an inhibitor of dsRNA-activated protein kinase), the inhibitory effect of the combination of AS and S RNA on gene expression did not change in the case of the endogenous c-raf gene, but was reduced in the case of the exogenous luciferase gene. The effect of 22 nucleotide RNA duplexes corresponding to the luciferase gene was by one order stronger than that of the phosphorothioate AS DNA. 4. Thus, it is suggested that RNAi may be more potent than AS RNA in reducing target gene expression in human cancer cell lines, regardless of the length of dsRNA. With further studies on the RNAi phenomenon in cancer cells, RNAi could provide a novel approach for cancer gene therapy.