Global ETD Search

121	The microtubule depolymerizing agent CYT997 causes extensive ablation of tumor vasculature in vivo Burns, C.J., Fantino, E., Powell, A.K., Shnyder, Steven, Cooper, Patricia A., Nelson, S., Christophi, C., Malcontenti-Wilson, C., Dubljevic, V., Harte, M.F., Joffe, M., Phillips, I.D., Segal, D., Wilks, A.F., Smith, G.D. January 2011 (has links) No / The orally active microtubule-disrupting agent (S)-1-ethyl-3-(2-methoxy-4-(5-methyl-4-((1-(pyridin-3-yl)butyl)amino)pyrimidin-2- yl)phenyl)urea (CYT997), reported previously by us (Bioorg Med Chem Lett 19:4639-4642, 2009; Mol Cancer Ther 8:3036-3045, 2009), is potently cytotoxic to a variety of cancer cell lines in vitro and shows antitumor activity in vivo. In addition to its cytotoxic activity, CYT997 possesses antivascular effects on tumor vasculature. To further characterize the vascular disrupting activity of CYT997 in terms of dose and temporal effects, we studied the activity of the compound on endothelial cells in vitro and on tumor blood flow in vivo by using a variety of techniques. In vitro, CYT997 is shown to potently inhibit the proliferation of vascular endothelial growth factor-stimulated human umbilical vein endothelial cells (IC(50) 3.7 +/- 1.8 nM) and cause significant morphological changes at 100 nM, including membrane blebbing. Using the method of corrosion casting visualized with scanning electron microscopy, a single dose of CYT997 (7.5 mg/kg i.p.) in a metastatic cancer model was shown to cause destruction of tumor microvasculature in metastatic lesions. Furthermore, repeat dosing of CYT997 at 10 mg/kg and above (intraperitoneally, b.i.d.) was shown to effectively inhibit development of liver metastases. The time and dose dependence of the antivascular effects were studied in a DLD-1 colon adenocarcinoma xenograft model using the fluorescent dye Hoechst 33342. CYT997 demonstrated rapid and dose-dependent vascular shutdown, which persists for more than 24 h after a single oral dose. Together, the data demonstrate that CYT997 possesses potent antivascular activity and support continuing development of this promising compound. Angiogenesis inhibitors Animals Antineoplastic agents Cell line Cell proliferation Colonic neoplasms Dose-response relationship Drug screening assays Human umbilical vein endothelial cells Humans Liver neoplasms Male Mice Nude Neovascularization Pyridines Pyrimidines Time factors Tubulin modulators Xenograft model antitumor assays REF 2014
122	Antitumor activity of a duocarmycin analogue rationalized to be metabolically activated by cytochrome P450 1A1 in human transitional cell carcinoma of the bladder Sutherland, Mark, Gill, Jason H., Loadman, Paul, Laye, Jonathan P., Sheldrake, Helen M., Illingworth, Nicola A., Alandas, Mohammed N., Cooper, Patricia A., Searcey, M., Pors, Klaus, Shnyder, Steven, Patterson, Laurence H. 01 October 2012 (has links) No / We identify cytochrome P450 1A1 (CYP1A1) as a target for tumor-selective drug development in bladder cancer and describe the characterization of ICT2700, designed to be metabolized from a prodrug to a potent cytotoxin selectively by CYP1A1. Elevated CYP1A1 expression was shown in human bladder cancer relative to normal human tissues. RT112 bladder cancer cells, endogenously expressing CYP1A1, were selectively chemosensitive to ICT2700, whereas EJ138 bladder cells that do not express CYP1A1 were significantly less responsive. Introduction of CYP1A1 into EJ138 cells resulted in 75-fold increased chemosensitivity to ICT2700 relative to wild-type EJ138. Negligible chemosensitivity was observed in ICT2700 in EJ138 cells expressing CYP1A2 or with exposure of EJ138 cells to CYP1B1- or CYP3A4-generated metabolites of ICT2700. Chemosensitivity to ICT2700 was also negated in EJ138-CYP1A1 cells by the CYP1 inhibitor alpha-naphthoflavone. Furthermore, ICT2700 did not induce expression of the AhR-regulated CYP1 family, indicating that constitutive CYP1A1 expression is sufficient for activation of ICT2700. Consistent with the selective activity by CYP1A1 was a time and concentration-dependent increase in gamma-H2AX protein expression, indicative of DNA damage, associated with the activation of ICT2700 in RT112 but not EJ138 cells. In mice-bearing CYP1A1-positive and negative isogenic tumors, ICT2700 administration resulted in an antitumor response only in the CYP1A1-expressing tumor model. This antitumor response was associated with detection of the CYP1A1-activated metabolite in tumors but not in the liver. Our findings support the further development of ICT2700 as a tumor-selective treatment for human bladder cancers. Animals Antineoplastic agents Biotransformation CHO cells Carcinoma Cell line Tumor Cell survival Cricetinae Cytochrome P-450 CYP1A1 Female Gene expression Humans Indoles Liver Maximum tolerated dose Mice Inbred BALB C Microsomes Pyrroles Tumor burden Urinary bladder neoplasms Xenograft model antitumor assays REF 2014 Metabolism Pharmacokinetics Pharmacology Transitional cell Drug therapy Enzymology Pathology Genetics
123	Colon cancer-specific cytochrome P450 2W1 converts duocarmycin analogues into potent tumor cytotoxins Travica, S., Pors, Klaus, Loadman, Paul, Shnyder, Steven, Johansson, I., Alandas, Mohammed N., Sheldrake, Helen M., Mkrtchian, S., Patterson, Laurence H., Ingelman-Sundberg, M. January 2013 (has links) No / PURPOSE: Cytochrome P450 2W1 (CYP2W1) is a monooxygenase detected in 30% of colon cancers, whereas its expression in nontransformed adult tissues is absent, rendering it a tumor-specific drug target for development of novel colon cancer chemotherapy. Previously, we have identified duocarmycin synthetic derivatives as CYP2W1 substrates. In this study, we investigated whether two of these compounds, ICT2705 and ICT2706, could be activated by CYP2W1 into potent antitumor agents. EXPERIMENTAL DESIGN: The cytotoxic activity of ICT2705 and ICT2706 in vitro was tested in colon cancer cell lines expressing CYP2W1, and in vivo studies with ICT2706 were conducted on severe combined immunodeficient mice bearing CYP2W1-positive colon cancer xenografts. RESULTS: Cells expressing CYP2W1 suffer rapid loss of viability following treatment with ICT2705 and ICT2706, whereas the CYP2W1-positive human colon cancer xenografts display arrested growth in the mice treated with ICT2706. The specific cytotoxic metabolite generated by CYP2W1 metabolism of ICT2706 was identified in vitro. The cytotoxic events were accompanied by an accumulation of phosphorylated H2A.X histone, indicating DNA damage as a mechanism for cancer cell toxicity. This cytotoxic effect is most likely propagated by a bystander killing mechanism shown in colon cancer cells. Pharmacokinetic analysis of ICT2706 in mice identified higher concentration of the compound in tumor than in plasma, indicating preferential accumulation of drug in the target tissue. CONCLUSION: Our findings suggest a novel approach for treatment of colon cancer that uses a locoregional activation of systemically inactive prodrug by the tumor-specific activator enzyme CYP2W1. Animals Bystander effect Cell line Colonic neoplasms Cytochrome P-450 enzyme system Cytotoxins DNA damage Drug resistance Female Gene expression Heterocyclic compounds Humans Indoles Mice Tissue distribution Tumor burden Xenograft model antitumor assays REF 2014 Tumor 3-Ring Neoplasm Drug effects Pharmacokinetics Toxicity Metabolism Enzymology Genetics Pathology
124	The dual-acting chemotherapeutic agent Alchemix induces cell death independently of ATM and p53 Thomas, A., Perry, T., Berhane, S., Oldreive, C., Zlatanou, A., Williams, L.R., Weston, V.J., Stankovic, T., Kearns, P., Pors, Klaus, Grand, R.J., Stewart, G.S. 06 January 2015 (has links) Yes / Topoisomerase inhibitors are in common use as chemotherapeutic agents although they can display reduced efficacy in chemotherapy-resistant tumours, which have inactivated DNA damage response (DDR) genes, such as ATM and TP53. Here, we characterise the cellular response to the dual-acting agent, Alchemix (ALX), which is a modified anthraquinone that functions as a topoisomerase inhibitor as well as an alkylating agent. We show that ALX induces a robust DDR at nano-molar concentrations and this is mediated primarily through ATR- and DNA-PK- but not ATM-dependent pathways, despite DNA double strand breaks being generated after prolonged exposure to the drug. Interestingly, exposure of epithelial tumour cell lines to ALX in vitro resulted in potent activation of the G2/M checkpoint, which after a prolonged arrest, was bypassed allowing cells to progress into mitosis where they ultimately died by mitotic catastrophe. We also observed effective killing of lymphoid tumour cell lines in vitro following exposure to ALX, although, in contrast, this tended to occur via activation of a p53-independent apoptotic pathway. Lastly, we validate the effectiveness of ALX as a chemotherapeutic agent in vivo by demonstrating its ability to cause a significant reduction in tumour cell growth, irrespective of TP53 status, using a mouse leukaemia xenograft model. Taken together, these data demonstrate that ALX, through its dual action as an alkylating agent and topoisomerase inhibitor, represents a novel anti-cancer agent that could be potentially used clinically to treat refractory or relapsed tumours, particularly those harbouring mutations in DDR genes. Animals Anthraquinones Antigens Antineoplastic agents Ataxia telangiectasia mutated proteins Cell death Cell line DNA damage DNA repair DNA replication DNA topoisomerases DNA-Binding proteins Dose-response relationship G2 phase cell cycle checkpoints Humans Leukemia M phase cell cycle checkpoints Mice Topoisomerase inhibitors Tumor suppressor protein p53 Xenograft model antitumor assays
125	Analysis of global gene expression profiles and invasion related genes of colorectal liver metastasis Bandapalli, Obul Reddy 19 December 2007 (has links) Die Leber ist das am häufigsten von Metastasen betroffene Organ und kann daher als Modellorgan für metastatische Invasion dienen. Aus diesem Grund war es das Ziel dieser Dissertation Genexpressionsprofile zu verstehen und metastasierungs- sowie invasionsassoziierte Gene zu identifizieren. Differentielle Genexpression wurde in drei Systemen überprüft: Einem syngenen Mausmodell, einem Xenograftmodell sowie in fünf Gewebeproben von Patienten. Genexpressionprofile des syngenen Mausmodells und der Patientenproben zeigten, dass man die Invasionsfront als Ganzes betrachten, um möglichst viele über-lappende Gene zu finden. Globale Genexpressionstudien, die auf den Wirtsteil der Invasionsfront zeigten bemerkenswerte Überrepräsentation z. B. der „GO-terms“ „extrazelluläre Matrix“, Zellkommunikation“, „Antwort auf biotischen Stimulus“, Strukturmolekülaktivität“ und „Zellwachstum“. Marker der Aktivierung hepatischer Sternzellen überrepräsentiert in der invasionsfront, was die Durchführbarkeit einer Analyse differentieller Genexpression im genomweiten Rahmen anzeigt. Globale Genexpressionsstudien, auf den Tumorzellen in der in vitro Situation, in vivo und in der Invasionsfront zeigten insgesamt einen Anstieg zellulärer Spezialisierung von der in vitro zur Invasionsfront. Sezernierte proangiogenetische Chemokine zeigten eine Hochregulation in der Invasionsfront. Das beta catenin Gen war in der Invasionsfront 9.6 fach erhöht im Vergleich zur in vitro Situation. Die Überprüfung der transkriptionellen Aktivierung von beta catenin über die Prüfung der Promotoraktivität zeigte einen 18.4 fachen Anstieg in den Tumorzellen der Invasionsfront. Weiterhin war die Promotoraktivität (an Hand der Aktivität der mRNA des Alkalischen Phosphatase Reportergens) im Tumorinneren 3.5 fach höher als in der Zellkultur, was für einen transkriptionellen Mechanismus der beta catenin Regulation zusätzlich zu den posttranslationalen Mechanismen spricht. / Liver is most frequently populated by metastases and may therefore serve as a model organ for metastatic invasion. So the aim of this thesis is to understand the gene expression profiles and identify metastasis and invasion related genes. Differential gene expression was examined in three systems: A syngeneic mouse model, a xenograft model and five clinical specimens. Gene expression profiles of a syngenic mouse model and human clinical specimen revealed that the invasion front should be considered as a whole to find more overlapping potential target genes. Global gene expression studies on the host part of the invasion front, revealed a pronounced overrepresentation of GO-terms (e.g. “extracellular matrix”, “cell communication”, “response to biotic stimulus”, “structural molecule activity” and “cell growth”). Hepatic stellate cell activation markers were over-represented in the invasion front demonstrating the feasibility of a differential gene expression approach on a genome wide scale. Global gene expression studies of the tumor cells in vitro, in vivo and tumor part of the invasion front revealed an overall increase of cellular specialization from in vitro to the invasion front. Secreted angiogenic cytokines were found to be up regulated in the invasion front. Beta catenin gene of “cell adhesion” GO term was elevated 9.6 fold in invasion front compared to in vitro. Evaluation of transcriptional up-regulation of beta catenin by promoter activity showed an 18.4 fold increase in the tumor cells of the invasion front as compared to those from the faraway tumor. Promoter activity assessed by soluble human placental alkaline phosphatase reporter gene mRNA was 3.5 fold higher in the inner parts of the tumor than in vitro cells indicating a transcriptional mechanism of beta catenin regulation in addition to the posttranslational regulatory mechanisms. Tumor-stroma Zelle interaktionen Invasion und Metastasierung Gene Expression Profiling genograft modelle leber Beta catenin Inter-spezies Tumor-stromal cell interactions invasion and metastasis gene expression profiling xenograft models liver beta catenin cross-species 570 Biologie 32 Biologie WG 1940 XH 7400 ddc:570
126	Role of Ring1B in ephitelial to mesenchimal transition, invasion and migration of mammary epithelial cells Bosch Gutiérrez, Almudena 21 December 2009 (has links) The Polycomb group (PcG) family of proteins form chromatin-modifying complexes essential for embryonic development, and stem cell renewal and are commonly deregulated in cancer. There are several reports that address the possible implication of PcG proteins in tumor progression and metastasis, but very little is known about the specific role of these proteins in tumor progression and invasion. On the other hand, the molecular processes of the worst cancer prognosis, metastasis, which leads to an incurable disease, are yet incompletely elucidated. Here we show a role for Ring1B, a PcG protein, in three processes related to metastasis: in the Epithelial-mesenchymal transition (EMT), a critical morphogenic event that occurs during embryonic development and during the progression of various epithelial tumors, an in the migration and the invasion of mammary epithelial cells. / Las proteínas del grupo Polycomb (PcG) forman complejos modificadores de la cromatina esenciales en el desarrollo embrionario y en la renovación de las células madre, y su desregulación ha sido asociada al cáncer. Varios estudios muestran la posible implicación de las proteínas de PcG en la progresión tumoral y en la metástasis, pero a pesar de ello se sabe muy poco de los procesos moleculares en los que estas proteínas están participando. Por otro lado, los procesos moleculares responsables del peor pronóstico en cáncer, la metástasis, que continua siendo una enfermedad incurable, siguen sin estar completamente elucidados. En esta disertación mostramos el papel de Ring1B, una proteína del PcG, en tres procesos implicados en la metástasis: en la transición epitelio-mesénquima (EMT), un proceso morfogénico crítico en el desarrollo embrionario y durante la progresión de varios cánceres epiteliales, y en la migración y la invasión de las células epiteliales mamarias. Tgf- SIS3 (inhibidor específico de Smad3) Egf Hgf Tgf-β citoquina xenografo Kaplan-meier cáncer de mama humano inmunocitofluorescencia inmunohistoquímica ChIP (immunoprecipitación de cromatina) western blot ADN proteína ARN DCIS (carcinoma ductal in situ) IDC (carcinoma ductal infiltrante) E-caderina célula epitelial glándula mamaria invasión migración metástasis transición epitelio mesénquima cancer mama familia p53 Fak epigenética p63 Ring1b Polycomb SIS3 (specific inhibitor of smad3) Egf Tgf- Hgf Tgf-β cytokine xenograft Kaplanmeier human breast cancer immunocytofluorescence immunohistochemistry ChIP (chromatin immunoprecipitation) DNA protein western blot RNA IDC (infiltrating ductal carcinoma) DCIS (ductal carcinoma in situ) E-cadherin epithelial cell mammary gland invasion migration metastasis epithelial to mesenchymal transition cancer breast p53 family Fak p63 Ring1B epigenetic Polycomb 57 61

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