• 【衍生自生物活性核苷的5 '-磷酸盐和环状3',5 '-磷酸盐的合成和抗肿瘤活性。】 复制标题 收藏 收藏
    DOI:10.1021/jm00239a005 复制DOI
    作者列表:Hong CI,Tritsch GL,Mittelman A,Hebborn P,Chheda GB
    BACKGROUND & AIMS: :Syntheses and biological activities of 12 N6-substituted adenosine 5'-phosphates and 15 cyclic 3',5'-phosphates are described. Included among these are the cyclic phosphates of the naturally occurring anticodon adjacent modified nucleosides, N6-(delta2-isopentenyl)adenosine and N-(purin-6-ylcarbamoyl)-L-threonine ribonucleoside. Also reported in this paper are the 5'-phosphates and cyclic phosphates of the cytokinins, N6-benzyladenosine, kinetin ribonucleoside, 3-(chloro-trans-2-buten-2-yl)adenosine,6-o-chlorophenylureidopurine ribonucleoside, and 6-allylureidopurine ribonucleoside. The 5'-nucleotides were prepared by direct phosphorylation of the corresponding ribonucleosides with POCl3 and triethyl phosphate. These compounds were converted to the cyclic 3',5'-phosphates by cyclization of the corresponding 5'-nucleotides with dicyclohexylcarbodiimide. Comparison of the cytotoxicity of the ribonucleosides with their 5'-nucleotides and cyclic 3',5'-nucleotides showed that some of the 5'-phosphates and cyclic phosphates were almost as active as the parent nucleosides. The 5'-nucleotides and the cyclic phosphates were more soluble than the parent nucleosides. The cyclic 3',5'-nucleotides were examined as alternate activators of cAMP-dependent protein kinase from beef heart. While all of the analogs studied showed some activity toward this enzyme, several compounds were more effective than cAMP itself. The analogs were also tested as substrates for cyclic 3',5'-nucleotide phosphodiesterase from beef heart. The N6-alkyl-cAMP analogs were poor substrates for the enzyme, while N6-carbamoyl-cAMP derivatives were inert toward this enzyme. These compounds did not inhibit the phosphodiesterase. Some of the cyclic phosphates exhibited marginal effect in the inhibition of glycogen synthesis in skin slices.
    背景与目标: 描述了12种N6-substituted腺苷5 '-磷酸盐和15种环状3',5 '-磷酸盐的合成和生物活性。其中包括天然存在的反密码子邻近修饰核苷的环状磷酸盐,N6-(delta2-isopentenyl) 腺苷和N-(purin-6-ylcarbamoyl)-L-苏氨酸核糖核苷。本文还报道了细胞分裂素的5 '-磷酸盐和环状磷酸盐,N6-benzyladenosine激动素核糖核苷,3-(chloro-trans-2-buten-2-yl) 腺苷,6-o-氯苯基脲基嘌呤核糖核苷,和6-烯丙基脲基嘌呤核糖核苷。通过用POCl3和磷酸三乙酯直接磷酸化相应的核糖核苷制备5'-核苷酸。这些化合物被转化为环状3 ',5'-磷酸通过相应的5 '-核苷酸与二环己基碳二亚胺的环化反应。核糖核苷与其5'-核苷酸和环状3 '的细胞毒性比较,5'-核苷酸显示,一些5 '-磷酸盐和环状磷酸盐几乎和亲本核苷一样活跃。5'-核苷酸和环状磷酸盐比亲本核苷更易溶解。环状3 ',5'-核苷酸被检测为牛肉心脏cAMP依赖性蛋白激酶的替代激活剂。虽然所有研究的类似物都显示出对这种酶的一些活性,但几种化合物比cAMP本身更有效。类似物也被测试为环状3 '的底物,来自牛肉心脏的5'-核苷酸磷酸二酯酶。N6-alkyl-cAMP类似物是该酶的不良底物,而N6-carbamoyl-cAMP衍生物对该酶是惰性的。这些化合物不抑制磷酸二酯酶。一些环状磷酸盐在抑制皮肤切片中糖原合成方面表现出边际效应。
  • 【靶向CCR6的肿瘤相关胚胎抗原表达疫苗引发有效的CD8 + T细胞介导的保护性和治疗性抗肿瘤免疫。】 复制标题 收藏 收藏
    DOI:10.4049/jimmunol.179.2.1381 复制DOI
    作者列表:Biragyn A,Schiavo R,Olkhanud P,Sumitomo K,King A,McCain M,Indig FE,Almanzar G,Baatar D
    BACKGROUND & AIMS: :Despite its potency, the wider use of immunotherapy for B cell malignancies is hampered by the lack of well-defined tumor-specific Ags. In this study, we demonstrate that an evolutionarily conserved 37-kDa immature laminin receptor protein (OFA-iLRP), a nonimmunogenic embryonic Ag expressed by a variety of tumors, is rendered immunogenic if targeted to the APCs using the CCR6 ligands MIP3alpha/CCL20 and mDF2beta. The CCR6 targeting facilitated efficient Ag cross-presentation and induction of tumor-neutralizing CTLs. Although the Ag targeting alone, without activation of dendritic cells (DCs), is proposed to induce tolerance, and MIP3alpha does not directly activate DCs, the MIP3alpha-based vaccine efficiently induced protective and therapeutic antitumor responses. The responses were as strong as those elicited by the OFA-iLRP fusions with moieties that activated DCs and Th1-type cytokine responses, mDF2beta, or mycobacterial Hsp70 Ag. Although the same cDNA encodes the dimerized high-affinity mature 67-kDa mLRP that is expressed in normal tissues to stabilize the binding of laminin to cell surface integrins, the vaccines expressing OFA-iLRP elicited long-term protective CD8(+) T cell-mediated memory responses against syngeneic B cell lymphoma, indicating the potential application of these simple vaccines as preventive and therapeutic formulations for human use.
    背景与目标: : 尽管具有效力,但由于缺乏明确的肿瘤特异性Ags,阻碍了免疫疗法对b细胞恶性肿瘤的广泛使用。在这项研究中,我们证明了进化上保守的37 kDa未成熟层粘连蛋白受体蛋白 (OFA-iLRP),一种由多种肿瘤表达的非免疫原性胚胎Ag,如果使用CCR6配体MIP3alpha靶向apc,则具有免疫原性/CCL20和mDF2beta。CCR6靶向促进了有效的Ag交叉呈递和诱导肿瘤中和ctl。尽管提出了单独的Ag靶向而不激活树突状细胞 (dc) 来诱导耐受性,并且mip3α 不直接激活dc,但MIP3alpha-based疫苗有效地诱导了保护性和治疗性抗肿瘤反应。反应与OFA-iLRP融合所引起的反应一样强,其中包含激活dc并Th1-type细胞因子反应的部分,mDF2beta或分枝杆菌Hsp70 Ag。尽管相同的cDNA编码在正常组织中表达的二聚化的高亲和力成熟67-kda mLRP,以稳定层粘连蛋白与细胞表面整合素的结合,但表达a-iLRP的疫苗引起了长期保护性CD8 () T细胞介导的针对同基因b细胞淋巴瘤的记忆反应,表明这些简单疫苗作为人类使用的预防和治疗制剂的潜在应用。
  • 【合成的CD4 + T细胞靶向抗原呈递细胞引发保护性抗肿瘤反应。】 复制标题 收藏 收藏
    DOI:10.1158/0008-5472.CAN-07-5796 复制DOI
    作者列表:Caserta S,Alessi P,Guarnerio J,Basso V,Mondino A
    BACKGROUND & AIMS: :CD4(+) helper T cells are critical for protective immune responses and yet suboptimally primed in response to tumors. Cell-based vaccination strategies are under evaluation in clinical trials but limited by the need to derive antigen-presenting cells (APC) from patients or compatible healthy donors. To overcome these limitations, we developed CD4(+) T cell-targeted synthetic microbead-based artificial APC (aAPC) and used them to activate CD4(+) T lymphocytes specific for a tumor-associated model antigen (Ag) directly from the naive repertoire. In vitro, aAPC specifically primed Ag-specific CD4(+) T cells that were activated to express high levels of CD44, produced mainly interleukin 2, and could differentiate into Th1-like or Th2-like cells in combination with polarizing cytokines. I.v. administration of aAPC led to Ag-specific CD4(+) T-cell activation and proliferation in secondary lymphoid organs, conferred partial protection against subcutaneous tumors, and prevented the establishment of lung metastasis. Taken together, our data support the use of cell-free, synthetic aAPC as a specific and versatile alternative to expand peptide-specific CD4(+) T cells in adoptive and active immunotherapy.
    背景与目标: : CD4(+) 辅助性T细胞对保护性免疫反应至关重要,但对肿瘤的反应却不是最佳的。基于细胞的疫苗接种策略正在临床试验中进行评估,但由于需要从患者或相容的健康供体获得抗原呈递细胞 (APC) 的限制。为了克服这些局限性,我们开发了基于CD4 () T细胞靶向的基于合成微珠的人工APC (aAPC),并使用它们直接从原始库中激活针对肿瘤相关模型抗原 (Ag) 的CD4 () T淋巴细胞。在体外,aAPC特异性引发Ag特异性CD4(+) T细胞,其被激活以表达高水平的CD44,主要产生白介素2,并且可以与极化细胞因子结合分化为Th1-like或Th2-like细胞。I.静脉给药aAPC导致Ag特异性CD4 () T细胞在次级淋巴器官中活化和增殖,对皮下肿瘤提供了部分保护,并阻止了肺转移的建立。综上所述,我们的数据支持使用无细胞,合成的aAPC作为一种特异性和多功能的替代品,以在过继和主动免疫疗法中扩展肽特异性CD4 () T细胞。
  • 【口服活性磺酰胺抗肿瘤剂E7010的作用机理: 通过与微管蛋白的秋水仙碱位点结合来抑制有丝分裂。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Yoshimatsu K,Yamaguchi A,Yoshino H,Koyanagi N,Kitoh K
    BACKGROUND & AIMS: E7010 (N-[2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4-methoxybenzenesulfonami de), an orally active sulfonamide antitumor agent that is currently in a Phase I clinical trial, showed rather consistent growth-inhibitory activities against a panel of 26 human tumor cell lines (IC50 = 0.06-0.8 microg/ml), in contrast to vincristine (VCR; IC50 = 0.0002-0.04 microg/ml), 5-fluorouracil (IC50 = 0.2-30 microg/ml), Adriamycin (IC50 = 0.002-0.7 microg/ml), mitomycin C (IC50 = 0.007-3 microg/ml), 1-beta-D-arabinofuranoxylcytosine (IC50 = 0.005 to >30 microg/ml), camptothecin (IC50 = 0.002-0.4 microg/ml), and cisplatin (IC50 = 0.5-20 microg/ml). It caused a dose-dependent increase in the percentage of mitotic cells in parallel with a decrease in cell proliferation, like VCR. It also showed a dose-dependent inhibition of tubulin polymerization, which correlated well with the cell growth-inhibitory activity. 14C-labeled E7010 bound to purified tubulin, and this binding was inhibited by colchicine but not by VCR. However, its binding properties were different from those of colchicine, as well as those of VCR. E7010 was active against two kinds of VCR-resistant P388 cell lines, one of which showed multidrug resistance due to the overexpression of P-glycoprotein (resistant to Taxol), and the other did not show multidrug resistance (sensitive to Taxol). Furthermore, four E7010-resistant P388 cell lines showed no cross-resistance to VCR, a different pattern of resistance to podophyllotoxin, and collateral sensitivity to Taxol. Therefore, E7010 is a novel tubulin-binding agent that has a wider antitumor spectrum than VCR and has different properties from those of VCR or Taxol.

    背景与目标: E7010 (N-[2-[(4-羟基苯基) 氨基]-3-吡啶基]-4-甲氧基苯磺酰胺),一种口服活性磺酰胺抗肿瘤剂,目前处于I期临床试验中,与长春新碱 (VCR; IC50 = 0.0002-0.04微克/毫升),5-氟尿嘧啶 (IC50 = 0.2-30微克/毫升) 相比,对一组26种人类肿瘤细胞系 (IC50 = 0.06-0.8微克/毫升) 表现出相当一致的生长抑制活性,阿霉素 (IC50 = 0.002-0.7微克/毫升),丝裂霉素c (IC50 = 0.007-3微克/毫升),1-β-d-阿拉伯呋喃氧基胞嘧啶 (IC50 = 0.005至> 30微克/毫升),喜树碱 (IC50 = 0.002-0.4微克/毫升),和顺铂 (IC50 = 0.5-20微克/毫升)。它引起有丝分裂细胞百分比的剂量依赖性增加,同时细胞增殖下降,如VCR。它还显示了微管蛋白聚合的剂量依赖性抑制,它与细胞生长抑制活性密切相关。14c标记的E7010与纯化的微管蛋白结合,这种结合被秋水仙碱抑制,而不受VCR抑制。然而,它的结合特性不同于秋水仙碱。与VCR一样。E7010对两种抗VCR的P388细胞系具有活性,其中一种由于P-糖蛋白的过表达而表现出多药耐药性 (对紫杉醇耐药),而另一种则没有表现出多药耐药性 (对紫杉醇敏感)。此外,四种E7010-resistant的P388细胞系对VCR没有交叉抗性,对鬼臼毒素的抗性不同模式以及对紫杉醇的附带敏感性。因此,e7010是一种新型的微管蛋白结合剂,具有比VCR更宽的抗肿瘤谱,并且具有与VCR或紫杉醇不同的特性。
  • 【白藜芦醇诱导sirtuin-1信号传导诱导人软骨肉瘤细胞凋亡并表现出抗肿瘤活性。】 复制标题 收藏 收藏
    DOI:10.1038/s41598-017-03635-7 复制DOI
    作者列表:Chao SC,Chen YJ,Huang KH,Kuo KL,Yang TH,Huang KY,Wang CC,Tang CH,Yang RS,Liu SH
    BACKGROUND & AIMS: :Chondrosarcoma is a malignant primary bone tumor. Sirtuin-1 (SIRT1), which is a member of sirtuin family, plays a dual role either in cancer promotion or suppression. There is no report about the role of SIRT1 in the human chondrosarcoma cells. Resveratrol is a potent activator of SIRT1. However, its effects on chondrosarcoma have not been extensively studied. Here, we investigated the role of SIRT1 induction by resveratrol in human chondrosarcoma cell growth and tumor progression. Resveratrol significantly decreased cell viability and induced cell apoptosis in human chondrosarcoma cells in a dose-dependent manner. The protein expression and activity of SIRT1 were activated after treatment with resveratrol. Resveratrol significantly inhibited NF-κB signaling by deacetylating the p65 subunit of NF-κB complex, which could be reversed by siRNA-SIRT1 transfection or deacetylation inhibitor MS-275. Resveratrol induced-apoptosis involved a caspase-3-mediated mechanism. Both siRNA-SIRT1 transfection and MS-275 significantly inhibited the resveratrol-induced caspase-3 cleavage and activity in human chondrosarcoma cells. Moreover, in vivo chondrosarcoma xenograft study revealed a dramatic reduction in tumor volume and the increased SIRT1 and cleaved caspase-3 expressions in tumors by resveratrol treatment. These results suggest that resveratrol induces chondrosarcoma cell apoptosis via a SIRT1-activated NF-κB deacetylation and exhibits anti-chondrosarcoma activity in vivo.
    背景与目标: : 软骨肉瘤是一种恶性的原发性骨肿瘤。Sirtuin-1 (SIRT1) 是sirtuin家族的成员,在癌症促进或抑制中起双重作用。没有关于SIRT1在人类软骨肉瘤细胞中的作用的报道。白藜芦醇是sirt1的有效激活剂。然而,其对软骨肉瘤的影响尚未得到广泛研究。在这里,我们研究了白藜芦醇诱导SIRT1在人软骨肉瘤细胞生长和肿瘤进展中的作用。白藜芦醇以剂量依赖性方式显着降低人软骨肉瘤细胞的细胞活力并诱导细胞凋亡。用白藜芦醇处理后激活SIRT1的蛋白表达和活性。白藜芦醇通过使NF-κ b复合物的p65亚基脱乙酰而显着抑制NF-κ b信号传导,这可以通过siRNA-SIRT1转染或脱乙酰抑制剂MS-275来逆转。白藜芦醇诱导的凋亡涉及caspase-3-mediated机制。siRNA-SIRT1转染和MS-275均显着抑制白藜芦醇诱导的人软骨肉瘤细胞的caspase-3裂解和活性。此外,体内软骨肉瘤异种移植研究显示,通过白藜芦醇治疗,肿瘤体积急剧减少,SIRT1增加,caspase-3表达减少。这些结果表明,白藜芦醇通过SIRT1-activated的NF-κ b脱乙酰作用诱导软骨肉瘤细胞凋亡,并在体内表现出抗软骨肉瘤活性。
  • 【Bcl-2/Bcl-xL抑制剂navitoclax通过抑制Bcl-xL诱导胰腺癌细胞凋亡而增加Chk1抑制剂prexasertib的抗肿瘤作用,但不Bcl-2。】 复制标题 收藏 收藏
    DOI:10.1007/s11010-020-03796-6 复制DOI
    作者列表:Morimoto Y,Takada K,Takeuchi O,Watanabe K,Hirohara M,Hamamoto T,Masuda Y
    BACKGROUND & AIMS: :In our previous study, we showed that prexasertib, a checkpoint kinase 1 (Chk1) inhibitor, enhances the effects of standard drugs for pancreatic cancer, including gemcitabine (GEM), S-1, and the combination of GEM and S-1 (GS). The combination of prexasertib and GS has a strong antitumor effect and induces apoptosis in pancreatic cancer cells by downregulating anti-apoptotic protein Bcl-2. In the present study, we investigated the combined effect of GEM, S-1, and prexasertib with a selective Bcl-2 inhibitor (venetoclax) and a non-selective Bcl-2 inhibitor (navitoclax) in SUIT-2 pancreatic cancer cells. An MTT assay revealed that the combination of prexasertib with navitoclax showed a synergistic effect but the combination with venetoclax did not. Investigation of the pancreatic cancer cell lines SUIT-2, MIA PaCa-2, and BxPC-3 revealed that BxPC-3 also showed a high synergistic effect when combined with prexasertib and navitoclax but not venetoclax. Mechanistic analysis of the combined effect showed that apoptosis was induced. Bcl-2 knockdown with siRNA and prexasertib treatment did not induce apoptosis, whereas Bcl-xL knockdown with siRNA and prexasertib treatment resulted in strong induction of apoptosis. In addition, among the three cell lines, the combined effect of prexasertib and navitoclax resulted in increased apoptotic cell death because the protein expression levels of Bcl-xL and Chk1 were higher. Our results demonstrate that the combination of prexasertib and navitoclax has a strong antitumor effect and induces apoptosis in pancreatic cancer cells by downregulating Bcl-xL. Simultaneous inhibition of Chk1 and Bcl-xL could be a new strategy for treating pancreatic cancer.
    背景与目标: : 在我们先前的研究中,我们表明,检查点激酶1 (Chk1) 抑制剂prexasertib增强了胰腺癌标准药物的作用,包括吉西他滨 (GEM),S-1以及GEM和S-1 (GS) 的组合。Prexertib和GS的组合具有很强的抗肿瘤作用,并通过下调抗凋亡蛋白Bcl-2来诱导胰腺癌细胞的凋亡。在本研究中,我们研究了GEM,S-1和prexasertib与选择性Bcl-2抑制剂 (venetoclax) 和非选择性Bcl-2抑制剂 (navitoclax) 在SUIT-2胰腺癌细胞中的联合作用。MTT分析显示,prexasertib与navitoclax的组合显示出协同作用,但与venetoclax的组合却没有。对胰腺癌细胞系SUIT-2,MIA PaCa-2和BxPC-3的研究表明,BxPC-3与prexasertib和navitoclax联合使用时也显示出很高的协同作用,而非venetoclax。综合效应的机理分析表明,诱导了细胞凋亡。siRNA和prexasertib处理的Bcl-2敲除不会诱导细胞凋亡,而siRNA和prexasertib处理的Bcl-xL敲除会导致细胞凋亡的强烈诱导。此外,在这三种细胞系中,prexasertib和navitoclax的联合作用导致凋亡细胞死亡增加,因为Bcl-xL和Chk1的蛋白表达水平较高。我们的结果表明,prexasertib和navitoclax的组合具有很强的抗肿瘤作用,并通过下调Bcl-xL诱导胰腺癌细胞凋亡。同时抑制Chk1和Bcl-xL可能是治疗胰腺癌的新策略。
  • 【在表达EGFR的肿瘤模型中,通过偶联抗EGFR固定体来提高阿霉素脂质体的抗肿瘤功效。】 复制标题 收藏 收藏
    DOI:10.1016/j.ijpharm.2020.119541 复制DOI
    作者列表:Jia D,Yang Y,Yuan F,Fan Q,Wang F,Huang Y,Song H,Hu P,Wang R,Li G,Liu R,Li J
    BACKGROUND & AIMS: :Epidermal growth factor receptor (EGFR) is overexpressed in a wide range of solid tumors. In this study, we exploited a high-affinity EGFR-antagonistic affibody (ZEGFR) coupled to a doxorubicin loaded pegylated liposome (LS-Dox) for concurrent passive and active targeting of EGFR+ A431 tumor cells in vitro and in vivo. The in vitro studies revealed that the Dox liposomes coupled with ZEGFR (AS-Dox) showed a higher Dox uptake than LS-Dox in EGFR+ A431 cells but not in EGFR- B16F10 cells, resulting in a selectively enhanced cytotoxicity. In vivo, AS-Dox confirmed its long circulation time and efficient accumulation in tumors. This targeted chemotherapy achieved greater tumor suppression. Further, this low-dose but effective targeted treatment reduced systemic toxicity such as body weight loss and organ injury demonstrated by H&E staining. Thus, selective targeting of LS-Dox coupled with ZEGFR enhanced antitumor effects and improved systemic safety. These results demonstrated that LS-Dox coupled with ZEGFR might be developed as a potential tool for therapy of EGFR+ tumors.
    背景与目标: : 表皮生长因子受体 (EGFR) 在多种实体瘤中过度表达。在这项研究中,我们开发了与阿霉素负载的聚乙二醇化脂质体 (ls-dox) 偶联的高亲和力EGFR拮抗性固定体 (ZEGFR),用于在体外和体内同时被动和主动靶向EGFR A431肿瘤细胞。体外研究表明,与ZEGFR (AS-Dox) 偶联的Dox脂质体在EGFR A431细胞中显示出比ls-dox更高的Dox摄取,而在egfr-b16f10细胞中则没有,从而选择性地增强了细胞毒性。在体内,AS-Dox证实了其循环时间长,在肿瘤中有效积累。这种靶向化疗实现了更大的肿瘤抑制。此外,这种低剂量但有效的靶向治疗降低了全身毒性,例如体重下降和H & E染色显示的器官损伤。因此,选择性靶向ls-dox与ZEGFR结合可增强抗肿瘤作用并提高全身安全性。这些结果表明,ls-dox与ZEGFR偶联可能被开发为治疗EGFR + 肿瘤的潜在工具。
  • 【喹唑啉酮衍生物作为EGFR抑制剂用于抗肿瘤治疗的设计,合成和体外生物学评价。】 复制标题 收藏 收藏
    DOI:10.1080/14756366.2020.1715389 复制DOI
    作者列表:Le Y,Gan Y,Fu Y,Liu J,Li W,Zou X,Zhou Z,Wang Z,Ouyang G,Yan L
    BACKGROUND & AIMS: :In this paper, a series of novel 3-methyl-quinazolinone derivatives was designed, synthesised and evaluated for antitumor activity in vitro on wild type epidermal growth factor receptor tyrosine kinase (EGFRwt-TK) and three human cancer cell lines including A549, PC-3, and SMMC-7721. The results displayed that some of the compounds had good activities, especially 2-{4-[(3-Fluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (5 g), 2-{4-[(3,4-Difluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (5k) and 2-{4-[(3,5-Difluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (5 l) showed high antitumor activities against three cancer cell lines. Moreover, compound 5k could induce late apoptosis of A549 cells at high concentrations and arrest cell cycle of A549 cells in the G2/M phase at tested concentrations. Also, compound 5k could inhibit the EGFRwt-TK with IC50 value of 10 nM. Molecular docking data indicates that the compound 5k may exert inhibitory activity by forming stable hydrogen bonds with the R817, T830 amino acid residues and cation-Π interaction with the K72 residue of EGFRwt-TK.
    背景与目标: : 本文设计,合成了一系列新型的3-甲基-喹唑啉酮衍生物,并评估了其对野生型表皮生长因子受体酪氨酸激酶 (EGFRwt-TK) 和三种人类癌细胞系 (包括A549) 的体外抗肿瘤活性,PC-3和SMMC-7721。结果表明,某些化合物具有良好的活性,尤其是2-{4-[(3-氟-苯基亚氨基)-甲基]-苯氧基甲基}-3-甲基-3h-喹唑啉-4-酮 (5  g),2-{4-[(3,4-二氟-苯基亚氨基)-甲基]-苯氧基甲基}-3-甲基-3h-喹唑啉-4-酮 (5k) 和2-{4-[(3,5-二氟-苯基亚氨基)-甲基]-苯氧基甲基}-3-甲基-3h-喹唑啉-4-酮 (5  l) 对三种癌细胞系显示出很高的抗肿瘤活性。此外,化合物5k可以在高浓度下诱导A549细胞晚期凋亡,并在测试浓度下将A549细胞的细胞周期阻滞在G2/M期。此外,化合物5k可以抑制EGFRwt-TK,IC50值为10  nM。分子对接数据表明,化合物5k可能通过与R817,T830氨基酸残基形成稳定的氢键以及与EGFRwt-TK的K72残基的阳离子-Π 相互作用而发挥抑制活性。
  • 【与蛋白酶体抑制剂在抗肿瘤治疗中的药物组合。】 复制标题 收藏 收藏
    DOI:10.2174/1381612811319220015 复制DOI
    作者列表:Gatti L,Zuco V,Zaffaroni N,Perego P
    BACKGROUND & AIMS: :The proteasome has been regarded as a major target for antitumor therapy in selected tumor types (i.e., multiple myeloma). Available evidence suggests that targeting the proteasome with selective compounds can represent an excellent approach for modulating the response to antitumor agents including both conventional cytotoxic agents and target-specific agents. In fact, promising drug interaction data showing synergistic effects have been reported in cellular studies, both in multiple myeloma and in solid tumors. The mechanistic bases of improved efficacy of drug combinations including bortezomib or other proteasome inhibitors and conventional cytotoxic agents have been in part unravelled and involve the capability of proteasome inhibitors to interfere with the stability of the targets of cytotoxic agents (e.g., topoisomerase inhibitors) as well as with cellular protective pathways (e.g., DNA repair and NF-kB-regulated gene expression). Moreover, the synergistic interaction of proteasome inhibitors and target-specific agents implicates a variety of mechanisms linked to the specific target (e.g., histone deacetylase) modulated by the tailored drug used in combination with the proteasome inhibitor. Several clinical studies are ongoing in an attempt to define drug combination approaches that enhance the efficacy of antitumor treatments. Considering the fast moving field of preclinical research regarding proteasome inhibition, a major contribution to the understanding of the bases of tumor response to treatment with proteasome inhibitors is expected.
    背景与目标: : 蛋白酶体被认为是某些肿瘤类型 (即多发性骨髓瘤) 抗肿瘤治疗的主要靶标。现有证据表明,用选择性化合物靶向蛋白酶体可以代表调节对抗肿瘤剂 (包括常规细胞毒性剂和靶标特异性剂) 的反应的极好方法。实际上,在多发性骨髓瘤和实体瘤的细胞研究中已经报道了显示协同作用的有希望的药物相互作用数据。改善药物组合 (包括硼替佐米或其他蛋白酶体抑制剂和常规细胞毒性剂) 功效的机理基础已部分阐明,并涉及蛋白酶体抑制剂干扰细胞毒性剂靶标稳定性的能力 (例如,拓扑异构酶抑制剂) 以及细胞保护途径 (例如,DNA修复和NF-kB调节的基因表达)。此外,蛋白酶体抑制剂和靶标特异性试剂的协同相互作用涉及多种机制,这些机制与由与蛋白酶体抑制剂组合使用的定制药物调节的特定靶标 (例如组蛋白脱乙酰基酶) 有关。正在进行一些临床研究,以尝试定义可增强抗肿瘤治疗功效的药物组合方法。考虑到有关蛋白酶体抑制的临床前研究的快速发展领域,有望对理解蛋白酶体抑制剂治疗的肿瘤反应基础做出重大贡献。
  • 【anti-CD26单克隆抗体1F7对人CD30 + 间变性大细胞T细胞淋巴瘤Karpas 299的体外和体内抗肿瘤作用。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Ho L,Aytac U,Stephens LC,Ohnuma K,Mills GB,McKee KS,Neumann C,LaPushin R,Cabanillas F,Abbruzzese JL,Morimoto C,Dang NH
    BACKGROUND & AIMS: :CD26 is a M(r) 110,000 surface glycoprotein with diverse functional properties, including having a potentially significant role in tumor development, and antibodies to CD26 mediate pleomorphic cellular functions. In this report, we show that binding of soluble anti-CD26 monoclonal Ab 1F7 inhibits the growth of the human CD30+ anaplastic large cell T-cell lymphoma cell line Karpas 299 in both in vitro and in vivo experiments. In vitro experiments show that 1F7 induces cell cycle arrest at the G1-S checkpoint, associated with enhanced p21 expression that is dependent on de novo protein synthesis. Furthermore, experiments with a severe combined immunodeficient mouse tumor model demonstrate that 1F7 treatment significantly enhances survival of tumor-bearing mice by inhibiting tumor formation. Our data therefore suggest that anti-CD26 treatment may have potential clinical use for CD26+ hematological malignancies.
    背景与目标: : CD26是具有多种功能特性的M(r) 110,000表面糖蛋白,包括在肿瘤发展中具有潜在的重要作用,以及CD26介导多形细胞功能的抗体。在本报告中,我们显示在体外和体内实验中,可溶性anti-CD26单克隆Ab 1F7的结合抑制人CD30变性大细胞T细胞淋巴瘤细胞系Karpas 299的生长。体外实验表明,1F7在G1-S检查点诱导细胞周期停滞,与依赖于从头蛋白质合成的p21表达增强相关。此外,使用严重的联合免疫缺陷小鼠肿瘤模型进行的实验表明,1F7治疗通过抑制肿瘤形成显着提高了荷瘤小鼠的存活率。因此,我们的数据表明,anti-CD26治疗可能对CD26血液系统恶性肿瘤具有潜在的临床用途。
  • 【阻断凋亡抑制剂 (IAPs) 与肿瘤靶向递送肿瘤坏死因子-α 导致协同抗肿瘤活性。】 复制标题 收藏 收藏
    DOI:10.1038/cgt.2012.83 复制DOI
    作者列表:Yuan Z,Syrkin G,Adem A,Geha R,Pastoriza J,Vrikshajanani C,Smith T,Quinn TJ,Alemu G,Cho H,Barrett CJ,Arap W,Pasqualini R,Libutti SK
    BACKGROUND & AIMS: :In the current study, we examined whether the combination of tumor vasculature-targeted gene therapy with adeno-associated virus bacteriophage-tumor necrosis factor-α (AAVP-TNF-α) and/or the orally administered LCL161, an antagonist of inhibitors of apoptosis proteins (IAPs), enhanced antitumor efficacy without systemic toxicity. M21 human melanoma xenografts were grown subcutaneously in nude mice. Mice were treated according to one of four treatment regimens: AAVP-TNF-α alone (AAVP-TNF-α plus sodium acetate-acetic acid (NaAc) buffer) via tail vein injection; LCL161 alone (phosphate-buffered saline (PBS) plus LCL161) via oral gavage; AAVP-TNF-α plus LCL161; and PBS plus NaAc Buffer as a control group. Tumor volume, survival and toxicity were analyzed. AAVP trafficking and TNF-α production in vivo were detected on days 7 and 21 by real-time PCR, enzyme-linked immunosorbent assay and immunofluorescence. The levels of apoptosis and activation of caspases were assessed on days 7 and 21 by TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling) and immunofluorescence assays. Our results showed that the combination of AAVP-TNF-α and LCL161 significantly inhibited tumor growth and prolonged survival in mice with melanoma xenografts. The combination of AAVP-TNF-α and LCL161 was also significantly more effective than either agent alone, showing a synergistic effect without systemic toxicity.
    背景与目标: : 在本研究中,我们检查了肿瘤脉管系统靶向基因治疗与腺相关病毒噬菌体肿瘤坏死因子-α (AAVP-TNF-α) 和/或口服LCL161 (凋亡蛋白抑制剂的拮抗剂) 的组合,增强抗肿瘤疗效,无全身毒性。M21人黑素瘤异种移植物在裸鼠皮下生长。根据四种治疗方案之一对小鼠进行治疗: 尾静脉注射单独使用AAVP-TNF-α (AAVP-TNF-α 加乙酸钠-乙酸 (NaAc) 缓冲液); 单独使用LCL161 (磷酸盐缓冲盐水 (PBS) 加LCL161) 通过口服灌胃; AAVP-TNF-α 加LCL161; PBS加NaAc缓冲液作为对照组。分析肿瘤体积、存活率和毒性。通过实时PCR,酶联免疫吸附测定和免疫荧光在第7天和第21天检测了体内AAVP的运输和TNF-α 的产生。通过TUNEL (末端脱氧核苷酸转移酶介导的dUTP缺口末端标记) 和免疫荧光测定,在第7天和第21天评估了胱天蛋白酶的凋亡和活化水平。我们的结果表明,AAVP-TNF-α 和LCL161的组合显着抑制了黑色素瘤异种移植物小鼠的肿瘤生长并延长了生存期。AAVP-TNF-α 和LCL161的组合也比单独使用任何一种药物有效,显示出协同作用而没有全身毒性。
  • 【6/8/11-氨基/氯氧代异aporphine和第10族金属配合物的制备及其体外和体内抗肿瘤活性的评价。】 复制标题 收藏 收藏
    DOI:10.1038/srep37644 复制DOI
    作者列表:Qin QP,Qin JL,Meng T,Yang GA,Wei ZZ,Liu YC,Liang H,Chen ZF
    BACKGROUND & AIMS: :A series of group-10 metal complexes 1-14 of oxoisoaporphine derivatives were designed and synthesized. 1-14 were more selectively cytotoxic to Hep-G2 cells comparing with normal liver cells. In vitro cytotoxicity results showed that complexes 1-6, 7, 8, 10 and 11, especially 3, were telomerase inhibitors targeting c-myc, telomeric, and bcl-2 G4s and triggered cell senescence and apoptosis; they also caused telomere/DNA damage and S phase arrest. In addition, 1-6 also caused mitochondrial dysfunction. Notably, 3 with 6-amino substituted ligand La exhibited less side effects than 6 with 8-amino substituted ligand Lb and cisplatin, but similar tumor growth inhibition efficacy in BEL-7402 xenograft model. Complex 3 has the potential to be developed as an effective anticancer agent.
    背景与目标: : 设计并合成了一系列氧代异aporphine衍生物的10族金属配合物1-14。与正常肝细胞相比,1-14对Hep-G2细胞更具选择性的细胞毒性。体外细胞毒性结果表明,复合物1-6、7、8、10和11,尤其是3,是靶向c-myc,端粒和bcl-2 G4s的端粒酶抑制剂,并触发细胞衰老和凋亡; 它们还引起端粒/DNA损伤和S期阻滞。此外,1-6还导致线粒体功能障碍。值得注意的是,具有6-氨基取代的配体La的3比具有8-氨基取代的配体Lb和顺铂的6表现出更少的副作用,但在BEL-7402异种移植模型中具有相似的肿瘤生长抑制功效。复合物3有可能被开发为一种有效的抗癌剂。
  • 【选择性BCL-XL PROTAC降解剂可实现安全有效的抗肿瘤活性。】 复制标题 收藏 收藏
    DOI:10.1038/s41591-019-0668-z 复制DOI
    作者列表:
    BACKGROUND & AIMS: :B-cell lymphoma extra large (BCL-XL) is a well-validated cancer target. However, the on-target and dose-limiting thrombocytopenia limits the use of BCL-XL inhibitors, such as ABT263, as safe and effective anticancer agents. To reduce the toxicity of ABT263, we converted it into DT2216, a BCL-XL proteolysis-targeting chimera (PROTAC), that targets BCL-XL to the Von Hippel-Lindau (VHL) E3 ligase for degradation. We found that DT2216 was more potent against various BCL-XL-dependent leukemia and cancer cells but considerably less toxic to platelets than ABT263 in vitro because VHL is poorly expressed in platelets. In vivo, DT2216 effectively inhibits the growth of several xenograft tumors as a single agent or in combination with other chemotherapeutic agents, without causing appreciable thrombocytopenia. These findings demonstrate the potential to use PROTAC technology to reduce on-target drug toxicities and rescue the therapeutic potential of previously undruggable targets. Furthermore, DT2216 may be developed as a safe first-in-class anticancer agent targeting BCL-XL.
    背景与目标: : b细胞淋巴瘤特大 (BCL-XL) 是一个经过充分验证的癌症靶标。然而,目标和剂量限制性血小板减少症限制了BCL-XL抑制剂 (如ABT263) 作为安全有效的抗癌药物的使用。为了降低ABT263的毒性,我们将其转化为DT2216,一种BCL-XL蛋白水解靶向嵌合体 (PROTAC),该嵌合体将BCL-XL靶向Von Hippel-Lindau (VHL) E3连接酶降解。我们发现DT2216在体外对各种BCL-XL依赖性白血病和癌细胞更有效,但对血小板的毒性比ABT263小得多,因为VHL在血小板中表达不佳。在体内,DT2216作为单一药物或与其他化学治疗剂组合有效抑制几种异种移植瘤的生长,而不会引起明显的血小板减少症。这些发现证明了使用PROTAC技术降低靶向药物毒性和挽救先前无法治疗的靶标的治疗潜力的潜力。此外,DT2216可以被开发为靶向BCL-XL的安全的一流抗癌剂。
  • 【一种线粒体靶向青蒿素衍生物,抗肿瘤作用急剧增加,但抗酵母和抗疟疾活性下降。】 复制标题 收藏 收藏
    DOI:10.1038/srep45665 复制DOI
    作者列表:Sun C,Cao Y,Zhu P,Zhou B
    BACKGROUND & AIMS: :The potent anti-malarial drug artemisinins are additionally anti-tumorigenic and inhibitory to yeast growth. The action mechanism of artemisinins, however, is not well understood. Heme and mitochondrial membrane are both suggested to be involved in the action of artemisinins. Because heme is also synthesized in the mitochondrion, mitochondria appear to be a critical organelle for artemisinins' activities. In this study, we synthesized a mitochondria-targeting artemisinin derivative by conjugating triphenylphosphonium (TPP) to artelinic acid (ARTa). ARTa-TPP displays far more potent anti-tumorigenic activity than its parent compound. In contrast, ARTa-TPP is much less active against yeast respiration growth and malarial parasites. Notably, ARTa-TPP is also associated with increased toxicity to other kinds of control mammalian cells. These results suggest divergent action modes for artemisinins against cancer cells and malaria or yeast cells. We conclude that mitochondrial targeting could substantially elevate the anticancer potency of artemisinins, but the accompanied increased toxicity to normal cells raises an alert. The mechanism regarding the opposing effects of TPP conjugation to ARTa on its anticancer and anti-malarial/anti-yeast potencies is discussed based on our current understandings of artemisinins' action.
    背景与目标: : 有效的抗疟疾药物青蒿素还具有抗肿瘤和抑制酵母生长的作用。然而,青蒿素的作用机理尚不清楚。血红素和线粒体膜均被认为与青蒿素的作用有关。由于血红素也在线粒体中合成,因此线粒体似乎是青蒿素活动的关键细胞器。在这项研究中,我们通过将三苯基膦 (TPP) 与artelinic acid (ARTa) 结合来合成靶向线粒体的青蒿素衍生物。ARTa-TPP显示出比其母体化合物更有效的抗肿瘤活性。相比之下,ARTa-TPP对酵母呼吸生长和疟疾寄生虫的活性要低得多。值得注意的是,ARTa-TPP还与对其他种类的对照哺乳动物细胞的毒性增加有关。这些结果表明,青蒿素对癌细胞和疟疾或酵母细胞的作用模式存在差异。我们得出的结论是,线粒体靶向可以显着提高青蒿素的抗癌能力,但伴随而来的对正常细胞的毒性增加引起了警觉。根据我们目前对青蒿素作用的理解,讨论了TPP与ARTa结合对其抗癌和抗疟疾/抗酵母效力的相反作用的机制。
  • 【合成疫苗纳米颗粒靶向淋巴结触发增强的先天和适应性抗肿瘤免疫。】 复制标题 收藏 收藏
    DOI:10.1016/j.biomaterials.2017.03.034 复制DOI
    作者列表:Kim SY,Noh YW,Kang TH,Kim JE,Kim S,Um SH,Oh DB,Park YM,Lim YT
    BACKGROUND & AIMS: :In this study, synthetic vaccine nanoparticles (SVNPs) that efficiently targeted lymph nodes, where immune responses against foreign antigens are primed, were developed to enhance antitumor immunity. The size (20-70 nm) and surface character (amination) of poly(γ-glutamic acid)-based SVNPs were selected for effective loading and delivery (i.e., migration and retention) of model tumor antigen (OVA) and toll-like receptor 3 agonist (poly (I:C)) to immune cells in lymph nodes. Antigen-presenting cells treated with SVNP-OVA and SVNP-IC showed higher uptake of OVA and poly (I:C) and higher secretion of inflammatory cytokines (TNF-α, IL-6) and type I interferon (IFN-α, IFN-β) than those treated with OVA and poly (I:C) alone. In vivo analysis revealed higher levels of activation markers, inflammatory cytokines, and type I IFNs in the lymph nodes of mice immunized with SVNP-IC compared to those of mice in other groups. SVNP-IC-treated mice showed significantly greater in vivo natural killer cell expansion/activation (NK1.1+ cells) and CD8+ T cell response (CD8+ INF-γ+ cells) in innate and adaptive immunity, respectively. Both preventive and therapeutic vaccination of EG7-OVA tumor-bearing mice using the simultaneous injection of both SVNP-OVA and SVNP-IC induced higher antitumor immunity and inhibited tumor growth.
    背景与目标: : 在这项研究中,开发了有效靶向淋巴结的合成疫苗纳米颗粒 (svnp),以增强抗肿瘤免疫力,在淋巴结中引发针对外来抗原的免疫反应。选择基于聚 (γ-谷氨酸) 的svnp的尺寸 (20-70 nm) 和表面特性 (胺化),以有效加载和递送 (即,模型肿瘤抗原 (OVA) 和toll样受体3激动剂 (poly (I:C)) 向淋巴结免疫细胞的迁移和保留。用SVNP-OVA和SVNP-IC处理的抗原呈递细胞显示出更高的OVA和poly (I:C) 摄取和更高的炎性细胞因子 (TNF-α,IL-6) 和I型干扰素 (IFN-α,IFN-β) 比单独用OVA和poly (I:C) 处理的那些。体内分析显示,与其他组的小鼠相比,用svnp-ic免疫的小鼠淋巴结中的活化标志物,炎性细胞因子和I型ifn水平更高。SVNP-IC处理的小鼠在固有免疫和适应性免疫中分别显示出明显更大的体内自然杀伤细胞扩增/活化 (NK1.1细胞) 和CD8 T细胞反应 (CD8 INF-γ 细胞)。同时注射svnp-ova和svnp-ic对EG7-OVA荷瘤小鼠进行预防和治疗性疫苗接种均诱导更高的抗肿瘤免疫并抑制肿瘤生长。

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