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Orthmann A.,Max Delbruck Center for Molecular Medicine | Zeisig R.,Experimental Pharmacology and Oncology Berlin Buch GmbH | Suss R.,Albert Ludwigs University of Freiburg | Lorenz D.,Leibniz Institute for Molecular Pharmacology | And 2 more authors.
Pharmaceutical Research | Year: 2012

Purpose: To test targeted liposomes in an effort to improve drug transport across cellular barriers into the brain. Methods: Therefore we prepared Mitoxantrone (MTO) entrapping, rigid and fluid liposomes, equipped with a 19-mer angiopeptide as ligand for LDL lipoprotein receptor related protein (LRP) targeting. Results: Fluid, ligand bearing liposomes showed in vitro the highest cellular uptake and transcytosis and were significantly better than the corresponding ligand-free liposomes and rigid, ligand-bearing vesicles. Treatment of mice, transplanted with human breast cancer cells subcutaneously and into the brain, with fluid membrane liposomes resulted in a significant reduction in the tumor volume by more than 80% and in a clear reduction in drug toxicity. The improvement was mainly depended on liposome fluidity while the targeting contributed only to a minor degree. Pharmacokinetic parameters were also improved for liposomal MTO formulations in comparison to the free drug. So the area under the curve was increased and t 1/2 was extended for liposomes. Conclusion: Our data show that it is possible to significantly improve the therapy of brain metastases if MTO-encapsulating, fluid membrane liposomes are used instead of free MTO. This effect could be further enhanced by fluid, ligand bearing liposomes. © 2012 Springer Science+Business Media, LLC.

Spilka R.,Laboratory Of Pathology Dr Obrist And Dr Brunhuber Og | Ernst C.,Medical University of Graz | Bergler H.,University of Graz | Rainer J.,Innsbruck Medical University | And 11 more authors.
Cellular Oncology | Year: 2014

Purpose: The eukaryotic translation initiation factor (eIF) 3a, the largest subunit of the eIF3 complex, is a key functional entity in ribosome establishment and translation initiation. In the past, aberrant eIF3a expression has been linked to the pathology of various cancer types but, so far, its expression has not been investigated in transitional cell carcinomas. Here, we investigated the impact of eIF3 expression on urinary bladder cancer (UBC) cell characteristics and UBC patient survival. Methods and results: eIF3a expression was reduced through inducible knockdown in the UBC-derived cell lines RT112, T24, 5637 and HT1197. As a consequence of eIF3a down-regulation, UBC cell proliferation, clonogenic potential and motility were found to be decreased and, concordantly, UBC tumour cell growth rates were found to be impaired in xenotransplanted mice. Polysomal profiling revealed that reduced eIF3a levels increased the abundance of 80S ribosomes, rather than impairing translation initiation. Microarray-based gene expression and ontology analyses revealed broad effects of eIF3a knockdown on the transcriptome. Analysis of eIF3a expression in primary formalin-fixed paraffin embedded UBC samples of 198 patients revealed that eIF3a up-regulation corresponds to tumour grade and that high eIF3a expression corresponds to longer overall survival rates of patients with low grade tumours. Conclusions: From our results we conclude that eIF3a expression may have a profound effect on the UBC phenotype and, in addition, may serve as a prognostic marker for low grade UBCs. © 2014 International Society for Cellular Oncology.

Karlsson J.O.G.,Linkoping University | Karlsson J.O.G.,PledPharma AB | Kurz T.,Linkoping University | Flechsig S.,Experimental Pharmacology and Oncology Berlin Buch GmbH | And 2 more authors.
Translational Oncology | Year: 2012

Mangafodipir is a magnetic resonance imaging contrast agent with manganese superoxide dismutase (MnSOD) mimetic activity. The MnSOD mimetic activity protects healthy cells against oxidative stress-induced detrimental effects, e.g., myelosuppressive effects of chemotherapy drugs. The contrast property depends on in vivo dissociation of Mn2+ from mangafodipir-about 80% dissociates after injection. The SOD mimetic activity, however, depends on the intact Mn complex. Complexed Mn2+ is readily excreted in the urine, whereas dissociated Mn2+ is excreted slowly via the biliary route. Mn is an essential but also a potentially neurotoxic metal. For more frequent therapeutic use, neurotoxicity due to Mn accumulation in the brain may represent a serious problem. Replacement of 4/5 of Mn2+ in mangafodipir with Ca2+ (resulting in calmangafodipir) stabilizes it from releasing Mn2+ after administration, which roughly doubles renal excretion of Mn. A considerable part of Mn2+ release from mangafodipir is governed by the presence of a limited amount of plasma zinc (Zn2+). Zn2+ has roughly 103 and 109 times higher affinity than Mn2+ and Ca2+, respectively, for fodipir. Replacement of 80%of Mn2+ with Ca2+ is enough for binding a considerable amount of the readily available plasma Zn2+, resulting in considerably less Mn2+ release and retention in the brain and other organs. At equivalent Mn2+ doses, calmangafodipir was significantly more efficacious than mangafodipir to protect BALB/c mice against myelosuppressive effects of the chemotherapy drug oxaliplatin. Calmangafodipir did not interfere negatively with the antitumor activity of oxaliplatin in CT26 tumor-bearing syngenic BALB/c mice, contrary calmangafodipir increased the antitumor activity. © 2012 Neoplasia Press, Inc. All rights reserved.

Sheean M.E.,Max Delbruck Center for Molecular Medicine | McShane E.,Max Delbruck Center for Molecular Medicine | Cheret C.,Max Delbruck Center for Molecular Medicine | Walcher J.,Max Delbruck Center for Molecular Medicine | And 12 more authors.
Genes and Development | Year: 2014

Myelination depends on the synthesis of large amounts of myelin transcripts and proteins and is controlled by Nrg1/ErbB/Shp2 signaling. We developed a novel pulse labeling strategy based on stable isotope labeling with amino acids in cell culture (SILAC) to measure the dynamics of myelin protein production in mice. We found that protein synthesis is dampened in the maturing postnatal peripheral nervous system, and myelination then slows down. Remarkably, sustained activation of MAPK signaling by expression of the Mek1DD allele in mice overcomes the signals that end myelination, resulting in continuous myelin growth. MAPK activation leads to minor changes in transcript levels but massively up-regulates protein production. Pharmacological interference in vivo demonstrates that the effects of activated MAPK signaling on translation are mediated by mTORindependent mechanisms but in part also by mTOR-dependent mechanisms. Previous work demonstrated that loss of ErbB3/Shp2 signaling impairs Schwann cell development and disrupts the myelination program. We found that activated MAPK signaling strikingly compensates for the absence of ErbB3 or Shp2 during Schwann cell development and myelination. © 2014 Sheean et al.; Published by Cold Spring Harbor Laboratory Press.

Schallschmidt K.,BAM Federal Institute of Materials Research and Testing | Becker R.,BAM Federal Institute of Materials Research and Testing | Zwaka H.,Free University of Berlin | Menzel R.,Free University of Berlin | And 4 more authors.
Journal of Breath Research | Year: 2015

In vitro cultured lung cancer cell lines were investigated regarding the possible identification of volatile organic compounds as potential biomarkers. Gas samples from the headspace of pure culture medium and from the cultures of human lung adenocarcinoma cell lines A549 and Lu7466 were exposed to polypropylene fleece in order to absorb odour components. Sniffer dogs were trained with loaded fleeces of both cell lines, and honey bees were trained with fleeces exposed to A549. Afterwards, their ability to distinguish between cell-free culture medium odour and lung cancer cell odour was tested. Neither bees nor dogs were able to discriminate between odours from the cancer cell cultures and the pure culture medium. Solid phase micro extraction followed by gas chromatography with mass selective detection produced profiles of volatiles from the headspace offered to the animals. The profiles from the cell lines were largely similar; distinct differences were based on the decrease of volatile culture medium components due to the cells' metabolic activity. In summary, cultured lung cancer cell lines do not produce any biomarkers recognizable by animals or gas chromatographic analysis. © 2015 IOP Publishing Ltd.

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