小干扰RNA敲低Dicer对人脑胶质瘤细胞生物学特征的影响

目的 研究敲低Dicer酶的表达全面抑制徽小RNA(microRNA,miRNA)成熟对TJ905人脑胶质瘤细胞的生物学特征的影响.方法 采用RNA干扰(RNA interference,RNAi)技术敲低Dicer酶的表达,逆转录PCR、Western印迹及免疫荧光检测TJ905细胞转染小干扰RNA(small interferen,siRNA)后Dicer酶表达情况;应用流式细胞术检测、噻唑兰比色分析法试验及Tranwell试验评价细胞生长、增殖和侵袭等生物学特征变化.结果 转染siRNA靶向Dicer酶后,Dicer酶被敲低,S期细胞增多,细胞增殖加速,细胞侵袭生长能力增强.结论 敲低Dicer酶全面抑制miRNAs成熟后,肿瘤细胞表型具有更为恶性变的倾向,由此初步推测全面抑制细胞miRNAs表达有可能促进肿瘤生成.     

核糖核酸酶的抗肿瘤研究进展

核糖核酸酶〔ribonuclease ,RNase〕是一类能够特异性切割RNA的酶 ,既有催化活性 ,又有细胞毒性。它们的生物学活性由激动剂和抑制剂所控制。迄今为止 ,已分离纯化出多种不同种类的RNase ,并对其结构和功能进行了深入的研究。研究表明 ,其中BS RNase、Onconase和RC RNase等具有抗肿瘤作用 ,可作为细胞毒素进入肿瘤细胞 ,抑制肿瘤细胞的生长 ,因此RNase的研究为临床治疗肿瘤提供了新的前景 ,有望成为一类新型的抗肿瘤药物     

乙酰肝素酶与恶性黑素瘤的研究现状

恶性黑素瘤是一种以高侵袭高转移为显著特征的皮肤肿瘤,肿瘤细胞对细胞外基质和基底膜这一天然屏障的破坏导致恶性黑素瘤的侵袭和转移。乙酰肝素酶是一种糖苷内切酶,是参与细胞外基质及基底膜降解,协助癌细胞转移的关键酶。近年来的研究表明,乙酰肝素酶与恶性黑素瘤的侵袭转移密切相关。乙酰肝素酶抑制剂的研制可望为黑色素瘤的治疗开辟新的途径。     

多不饱和脂肪酸在乳腺癌中的作用

多不饱和脂肪酸(polyunsaturated fatty acids,PUFAs)是构成脂膜必不可少的成分,高剂量的PUFAs通过改变乳腺癌细胞的物理特性以及增加瘤细胞内的脂质过氧化反应而影响乳腺癌的发生、发展并增加某些抗癌药物对乳腺癌细胞的细胞毒性.此方面的研究尚处于实验阶段,如果PUFAs确能增加某些抗癌药物对乳腺癌的细胞毒性,可望导致抗癌治疗新战略的产生.     

间皮素与肿瘤靶向治疗

正间皮素(mesothelin,MSLN)是一种细胞表面糖蛋白,在正常组织中很少表达,但在卵巢癌、胰腺癌和恶性间皮瘤等肿瘤组织中高表达~([1]),因此间皮素有望成为癌症治疗的重要靶点。由于间皮素基因敲除小鼠未发现表型异常,所以间皮素的生物学功能目前仍不清楚,但有研究表明间皮素可能在肿瘤细胞增殖、黏附及耐药性方面起着重要作用。采用抗     

吡非尼酮抗肝纤维化机制

吡非尼酮是正在研发的新型广谱抗纤维化药物,目前抗肝纤维化治疗已进入Ⅱ期临床试验阶段,其作用机制与抑制脂质过氧化、减轻炎症反应、抑制肝星状细胞活化和增殖、调节细胞外基质的合成与降解有关.本文对吡非尼酮抗肝纤维化的研究现状及作用机制作一综述.     

穿孔素和颗粒酶-生物导弹的理想材料

穿孔素和颗粒酶是细胞毒性细胞两类重要的效应分子,能导致被病原体感染的细胞和肿瘤细胞发生凋亡。随着对疾病靶向性治疗研究的进展,生物导弹的研究也倍受瞩目。根据穿孔素和颗粒酶的生物学特点,有望在生物导弹的应用中占有一席之地,本文就这方面的问题作一综述。     

BRCA相关蛋白1在恶性间皮瘤中的表达缺失及其在鉴别诊断中的应用价值北大核心CSCD

目的探讨BRCA相关蛋白1（BRCA assoeiated protein1,BAP1）在恶性间皮瘤、肺腺癌、肺鳞癌和癌肉瘤中表达情况及其在鉴别诊断中的作用。方法选取恶性间皮瘤22例,其中上皮样型17例,肉瘤样型2例,双相型3例。另选取侵犯胸膜的非小细胞肺癌共80例（肺腺癌40例、肺鳞癌40例）和全身各部位癌肉瘤15例作为对照。应用免疫组织化学方法检测BAP1在各组病例的表达情况,并分析各组表达差异。同时所有病例均检测了常规用于间皮瘤鉴别诊断的抗体组合,包括calretinin、wTl、细胞角蛋白5／6、D2．40、CAM5．2、癌胚抗原、甲状腺转录因子1、Napsin A、p63和p40。结果所有80例非小细胞肺癌和15例癌肉瘤均BAP1核表达阳性,而64％（14／22）恶性间皮瘤出现BAP1表达缺失,两者差异有统计学意义（P〈0．01）。间皮瘤诊断标志物组合中,增加BAP1后,诊断恶性间皮瘤的诊断正确度达93％。BAP1灶性表达表明肿瘤细胞具有多克隆性。结论BAP1核表达缺失有助于鉴别恶性间皮瘤和非小细胞肺癌。因此推荐BAP1与其他间皮瘤抗体一起应用于恶性间皮瘤的诊断,提高恶性间皮瘤的诊断准确性。     

吲哚加双氧酶1抑制剂在恶性肿瘤治疗中的研究进展

近年来,免疫治疗已成为肿瘤治疗的新兴疗法,随着对肿瘤免疫微环境研究的不断深入,人们开始关注吲哚加双氧酶1(indoleamine 2,3-dioxygenase 1,IDO1)这样一个介导肿瘤免疫逃逸的代谢酶。针对IDO1的小分子抑制剂在Ⅰ/Ⅱ期临床试验中联合PD-1免疫检查点抑制剂显示可以明显改善患者的反应率,然而,备受关注的一项Ⅲ期临床试验ECHO-301,IDO1抑制剂Epacadostat与抗PD-1抗体Pembrolizumab联合治疗进展期黑色素瘤却由于未能达到预期疗效而提前终止。鉴于Ⅰ/Ⅱ期临床试验取得的成功,针对IDO1小分子抑制剂的大量临床试验仍在进行中。文章主要针对进入临床试验阶段的IDO1小分子抑制剂在恶性肿瘤治疗中的研究进展、ECHO-301项目Ⅲ期临床试验失败的可能原因以及IDO抑制剂的临床应用前景进行综述。     

临床护理路径在水化病人中的应用

顺铂(DDP)自应用临床以来,因其对多种恶性肿瘤有效[1],抗瘤谱广,成为当前最常用的抗癌药物之一.为提高DDP的抗癌效果, 临床用药中逐步增加了DDP的用量.在增加DDP用量的同时,也增大了它的毒性,尤其是肾毒性[2],它已成为提高DDP剂量的主要限制性毒性.目前采用的水化与利尿疗法是减轻肾毒性的较好方法.     

Interferon enhances the activity of the anticancer ribonuclease, onconase.

Interferons (IFN) are biologic agents involved in the antiviral response and the inhibition of tumor growth. Biochemical pathways of IFN action include the double-stranded RNA-activated oligoadenylate synthetase, RNase L, and double-stranded RNA-dependent protein kinase (PKR). Extracellular ribonucleases, especially onconase, also display antiviral and antitumor properties and involve degradation of RNA. We find that IFN increases the anticancer activity of onconase. These two agents work synergistically, and the effect is seen at the level of translation probably because of the degradation of tRNA.     

Novel phosphatidylinositol 3-kinase inhibitor NVP-BKM120 induces apoptosis in myeloma cells and shows synergistic anti-myeloma activity with dexamethasone

NVP-BKM120 is a novel phosphatidylinositol 3-kinase (PI3K) inhibitor and is currently being investigated in phase I clinical trials in solid tumors. This study aimed to evaluate the therapeutic efficacy of BKM120 in multiple myeloma (MM). BKM120 induces cell growth inhibition and apoptosis in both MM cell lines and freshly isolated primary MM cells. However, BKM120 only shows limited cytotoxicity toward normal lymphocytes. The presence of MM bone marrow stromal cells, insulin-like growth factor, or interleukin-6 does not affect BKM120-induced tumor cell apoptosis. More importantly, BKM120 treatment significantly inhibits tumor growth in vivo and prolongs the survival of myeloma-bearing mice. In addition, BKM120 shows synergistic cytotoxicity with dexamethasone in dexamethasone-sensitive MM cells. Low doses of BKM120 and dexamethasone, each of which alone has limited cytotoxicity, induce significant cell apoptosis in MM.1S and ARP-1. Mechanistic study shows that BKM120 exposure causes cell cycle arrest by upregulating p27 (Kip1) and downregulating cyclin D1 and induces caspase-dependent apoptosis by downregulating antiapoptotic XIAP and upregulating expression of cytotoxic small isoform of Bim, BimS. In summary, our findings demonstrate the in vitro and in vivo anti-MM activity of BKM120 and suggest that BKM120 alone or together with other MM chemotherapeutics, particularly dexamethasone, may be a promising treatment for MM.     

Drug resistance in multiple myeloma

Multidrug resistance (MDR) is a pleiotropic resistance against several unrelated drugs. It may be induced by prolonged exposure of cells to drugs such as doxorubicin, etoposide and vinca alkaloids. Once MDR develops in clinical tumors, it is a major obstacle for the improvement of treatment of multiple myeloma (MM). Several specific mechanisms have been identified in clinical refractory MM patients including typical MDR, which is associated with P-glycoprotein (Pgp) and Lung Resistance Protein (LRP). The expression of the proteins associated with these genes seems to depend on exposure to chemotherapeutic agents. Recently, reversal of MDR by non-cytotoxic agents such as verapamil, cyclosporin A and PSC 833 (Valdospar) was explored in acute leukemia and multiple myeloma. Preliminary results from clinical phase I/II trials indicate that reversal of MDR is possible and that it may lead to alterations of the plasma pharmacokinetics of the cytostatic agents, in addition to P-glycoprotein inhibition in tumor cells. The potential implications of P-glycoprotein reversal are discussed.     

Ribonucleases as Novel Chemotherapeutics

Ranpirnase, a cytotoxic ribonuclease from the frog Rana pipiens, is the archetype of a novel class of cancer chemotherapeutic agents based on homologs and variants of bovine pancreatic ribonuclease (RNase A). Ranpirnase in combination with doxorubicin is in clinical trials for the treatment of unresectable malignant mesothelioma and other cancers. The putative mechanism for ranpirnase-mediated cytotoxicity involves binding to anionic components of the extracellular membrane, cytosolic internalization, and degradation of transfer RNA leading to apoptosis. The maintenance of ribonucleolytic activity in the presence of the cytosolic ribonuclease inhibitor protein is a key aspect of the cytotoxic activity of ranpirnase. The basis for its specific toxicity for cancer cells is not known. This review describes the development of ranpirnase as a cancer chemotherapeutic agent.     

Hsp90 inhibitors as promising agents for radiotherapy

The 90-kD heat shock protein (Hsp90) is an abundant molecular chaperone catalyzing maturation and activation of client proteins. A number of the Hsp90 client proteins are components of cancer cell-associated signaling pathways that ensure unlimited growth of tumors and their resistance to chemotherapy and radiotherapy. Upon inhibition of the Hsp90 chaperone function, such client proteins are destabilized and degraded which disrupts multiple pathways essential for tumor cell survival; hence, pharmacological Hsp90 inhibitors could be applied in anticancer therapy. Several Hsp90-inhibiting compounds are currently tested in preclinical or phase I–III clinical trials as single anticancer agents or in combination with conventional drugs and radiation. The present review summarizes the data characterizing Hsp90 inhibitors as agents that sensitize human tumors to irradiation which may improve the outcome of radiotherapy. We also discuss molecular mechanisms of the Hsp90 inhibition-induced radiosensitization and its selectivity toward cancer cells.     

Wpływ cytotoksyczny R-amfinazy,endorybonukleazy o działaniu przeciwnowotworowym,na komórki chłoniaka rozlanego z dużych komórek B w warunkach in vitro

Onconase (ONC) and R-Amphinase (R-AM) are enzymes with anti-tumor activity, belonging to pancreatic ribonuclease A family, received from eggs collected from frog Rana pipiens. Both proteins can induce death of some types of neoplastic cells by inhibition of protein synthesis, cell growth and proliferation. The aim of this study was to assess the cytotoxicity of R-AM, used alone or in combination with one of the most active anti-leukemic drug, doxorubicin (DOX), on diffuse large B-cell lymphoma (DLBCL)-derived cell line, Toledo. We found high cytotoxic activity of R-AM against DLBCL cells as well as influence on expression of several apoptosis-regulating proteins. Moreover, we observed increase in proapoptotic activity after combination of R-AM and DOX, compared with both drugs used alone. These results may justify further studies on interactions of R-AM with other drugs active in DLBCL.     

Cancer immunotherapy with mRNA-transfected dendritic cells

Summary: Bone marrow‐derived dendritic cells (DCs) are the most potent antigen‐presenting cells capable of activating naïve T cells. Loading DCs ex vivo with tumor antigens can stimulate potent antitumor immunity in tumor‐bearing mice. This review describes the use of mRNA‐encoded tumor antigens as a form of antigen loaded onto DCs, including our early experience from clinical trials in urological cancers. Transfection of DCs with mRNA is simple and effective. Comparative studies suggest that mRNA transfection is superior to other antigen‐loading techniques in generating immunopotent DCs. The ability to amplify RNA from microscopic amounts of tumor tissue extends the use of DC vaccination to virtually every cancer patient. The striking observation from two phase I clinical trials, in patients with prostate cancer immunized with prostate‐specific antigen mRNA‐transfected DCs and patients with renal cancer immunized with autologous tumor RNA‐transfected DCs, was that the majority of patients exhibited a vaccine‐induced T‐cell response. Suggestive evidence of clinically related responses was seen in both the trials. Immunization with mRNA‐transfected DCs is a promising strategy to stimulate potent antitumor immunity and could serve as a foundation for developing effective treatments for cancer.     

Cytotoxicity of combinations of IFN-beta and chemotherapeutic drugs.

Interferon-beta (IFN-beta) induces various antiproliferative activities. In solid tumor cells, IFN-beta inhibits cell cycle progression, which mainly occurs as S phase accumulation. The IFN-beta-induced cell cycle effect has been implicated in the antitumor effect of combinations of IFN-beta and chemotherapeutic drugs. In this report, we characterized the viability of various human tumor cells in vitro after combination treatment with IFN-beta protein and the chemotherapeutic drugs, cis-platinum (II) diamine dichloride (cisplatin), 5-fluorouracil (5-FU), paclitaxel (Taxol) and gemcitabine. IFN-beta could significantly potentiate the cytotoxicity of these chemotherapeutic drugs. The potentiating effect was observed after pretreatment of tumor cells with IFN-beta but did not require the constant presence of IFN-beta. The potentiating effect correlated with the sensitivity of the tumor cells to the IFN-beta-induced cytotoxicity. Furthermore, chemotherapeutic drugs also potentiated the cytotoxicity of IFN-beta. We conclude that the cell cycle effect per se did not determine the ability of IFN-beta to potentiate the cytotoxicity of chemotherapeutic drugs. We suggest that the combination of local IFN-beta gene therapy with chemotherapy could be an effective cancer treatment.     

Anticancer drug sensitivity by human tumor clonogenic assay

The anticancer drug sensitivity of human cancers was tested by the human tumor clonogenic assay (HTCA). Of 152 human cancer specimens tested, 63 (41%) formed more than 30 tumor cell colonies in control plates and could be used to evaluate the drug sensitivity of tumor cells. In 42 (93%) of 45 clinical trials in 24 patients, a parallel correlation was observed between the in vitro anticancer drug sensitivity measured by the HTCA and the clinical response of tumors to anticancer drugs. These results suggest that the HTCA is a good technique for the in vitro test of the anticancer drug sensitivity of human cancers.     

Reducing cytotoxicity while improving anti-cancer drug loading capacity of polypropylenimine dendrimers by surface acetylation

Polypropylenimine (PPI) dendrimers have been widely used as effective delivery vehicles for drugs and nucleic acids during the past decade. However, biomedical applications of PPI dendrimers were limited because of their serious cytotoxicity and low drug loading capacity. In the present study, acetylated PPI dendrimers with different degrees of acetylation ranging from 14.2% to 94.3% were synthesized and used to encapsulate drugs, including methotrexate sodium, sodium deoxycholate and doxorubicin. Acetylated PPI dendrimers with a degree of acetylation >80% showed a significantly decreased cytotoxicity (>90% cell viability) on MCF-7 and A549 cells. The drug loading capacity of acetylated PPI dendrimers increased proportionally with the degree of acetylation on the dendrimer surface. In addition, 94.3% acetylated PPI dendrimers exhibited a pH-responsive release profile of anticancer drugs loaded within the nanoparticles. The cytotoxicities of methotrexate sodium and doxorubicin on MCF-7 and A549 cells were significantly reduced when they were complexed with acetylated PPI dendrimers with high degrees of acetylation (>80%), owing to sustained drug release from the dendrimers. The results suggest that surface acetylation can reduce the cytotoxicity and improve the anticancer drug loading capacity of cationic dendrimers, and that acetylated PPI dendrimers are promising vehicles for anticancer drugs in clinical trials.