Tumor microenvironment is an area, where the local immunosuppressive effects dominate and prevents the immune system to perform its physiological functions. The cells infiltrating the microenvironment have an important function among many cell types since they produce a large quantity of factors suppressing the immune response. In our work, we monitored the immune changes in the microenvironment during tumor growth and chemotherapy. For these purposes, we utilized the methods for analysis of the proportion and phenotype of the distinct populations of immunocytes and for analysis of the total level of expressions of selected genes associated with immunosuppression or with distinct populations of immunocytes. The aim of our work was to discover, using two types of mouse tumors (TRAMP-C2 and TC-1/A9), how 5-azacytidine (5AC), a cytostatic drug with epigenetic activity, affects the proportion of leukocytes infiltrating the tumor microenvironment and, further, whether these changes are accompanied by decreased expression of immunosuppressing genes. In addition, we have also focused on the changes of relative expression of genes encoding markers of lymphoid lines and, on other immunoregulating genes, encoding IL-6, IL-10, IL-12, IL-4 and IFNγ cytokines, in the microenvironment of these tumors....

No description available.

No / AQ4N (banoxantrone) is a prodrug that, under hypoxic conditions, is enzymatically converted to a cytotoxic DNA-binding agent, AQ4. Incorporation of AQ4N into conventional chemoradiation protocols therefore targets both oxygenated and hypoxic regions of tumors, and potentially will increase the effectiveness of therapy. This current pharmacodynamic and efficacy study was designed to quantify tumor exposure to AQ4 following treatment with AQ4N, and to relate exposure to outcome of treatment. A single dose of 60 mg/kg AQ4N enhanced the response of RT112 (bladder) and Calu-6 (lung) xenografts to treatment with cisplatin and radiation therapy. AQ4N was also given to separate cohorts of tumor-bearing mice 24 hours before tumor excision for subsequent analysis of metabolite levels. AQ4 was detected by high performance liquid chromatography/mass spectrometry in all treated samples of RT112 and Calu-6 tumors at mean concentrations of 0.23 and 1.07 microg/g, respectively. These concentrations are comparable with those shown to be cytotoxic in vitro. AQ4-related nuclear fluorescence was observed in all treated tumors by confocal microscopy, which correlated with the high performance liquid chromatography/mass spectrometry data. The presence of the hypoxic marker Glut-1 was shown by immunohistochemistry in both Calu-6 tumors and RT112 tumors, and colocalization of AQ4 fluorescence and Glut-1 staining strongly suggested that AQ4N was activated in these putatively hypoxic areas. This is the first demonstration that AQ4N will increase the efficacy of chemoradiotherapy in preclinical models; the intratumoral levels of AQ4 found in this study are comparable with tumor AQ4 levels found in a recent phase I clinical study, which suggests that these levels could be potentially therapeutic.

Polymer-based drug delivery systems represent one of the promising strategies for successful tumor treatment. Conjugation of a low-molecular-weight drug to a syn- thetic polymer carrier enables targeted drug delivery to tumor tissue/cells and limited systemic toxicity of the drug. The conjugates show extended circulation time, and preferentially accumulate in tumor tissue due to the Enhanced Permeability and Re- tention (EPR) effect. The EPR effect depends on a structural anomaly in tumor neovasculature, and vasodilators were shown to enhance the EPR effect via an in- crease of blood supply in the tumor. Polymer drug carriers based on water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) benefit from variable architecture, drug loading and controlled release. HPMA-based conjugates with cancerostatics have al- ready proved high anti-tumor activity, inducing complete tumor regression followed by resistance to a second tumor challenge in experimental murine models. Three HPMA-based conjugates with organic nitrates (labeled 1, 2, and 3) were pre- pared as polymer donors of nitric oxide (NO) with the aim to intensify the EPR effect, thereby enhancing accumulation of co-administered macromolecular cancerostatics in the tumor. In this study, the conjugates were non-toxic to cancer cells and did not potentiate...

Die Protonentherapie von Aderhautmelanomen wird vor allem für die Behandlung von Tumoren nahe kritischer Strukturen (Sehnerv) und bei großen Tumoren angewandt. Dabei ist die begrenzte Reichweite der Protonen vorteilhaft, die scharf begrenzte Dosisfelder im Auge ermöglicht, und das an den Tumor grenzende gesunde Gewebe bestmöglich schont. Daher erfolgt die Positionierung der Patienten und der Strahlenfelder in der Augentumortherapie, wie auch die regelmäßigen Konstanzprüfungen, mit einer Reichweitengenauigkeit in Wasser von 0,1 mm. Mit einem Multi-Leaf Faraday Cup (MLFC) kann die Reichweite der Protonen in kurzer Zeit sehr genau gemessen werden. Dabei misst der MLFC die differentielle Fluenz der Protonenstrahlen, also das Reichweitenprofil. Er besteht aus einem Stapel Folien, abwechselnd leitend und isolierend. Eindringende Protonen deponieren eine zusätzliche Ladung in der Folie in der sie stoppen. Durch eine gleichzeitige Strommessung an allen Folien misst der MLFC relativ schnell die Reichweite der Protonen. Aufgabe dieser Arbeit ist es, einen MLFC entsprechend den Anforderungen der Augentumortherapie zu entwickeln, aufzubauen und mögliche Anwendungspotentiale zu untersuchen. Dafür wurden Monte-Carlo-Rechnungen mit MCNPX 2.6 und SRIM durchgeführt, verschiedene Folienstapel an Luft und im Vakuum untersucht, verschiedene Messelektroniken zur gleichzeitigen Messung von Strömen im pA-Bereich in vielen Kanälen getestet, ein Absorbersystem für einen variablen Messbereich von 30 MeV bis 70 MeV aufgebaut und die entsprechende Mess- und Steuersoftware in LabVIEW 2011 entwickelt. Es wurde die Genauigkeit der Reichweitenmessungen untersucht und gezeigt, dass der MLFC durch seine Mobilität eine schnelle Energiebestimmung an unterschiedlichen Experimentierplätzen erlaubt. In der Therapie ist neben der einfachen Bestimmung der maximalen Reichweite der Protonen auch die regelmäßige Kontrolle der Modulation der ausgedehnten Bragg-Kurven möglich. / Proton therapy of uveal melanomas is primarily used for the treatment of tumors near critical structures (optic nerve) and in large tumors. The great advantage of protons is their sharply limited range in tissue, which leads to sharp defined dose fields in the eye and the dose absorbed by the healthy tissue around the tumor can be reduced. Therefore, the positioning of the patient and the radiation fields, as well as the regular control measurements in the eye tumor therapy requires an accuracy of 0.1 mm in water. A Multi-Leaf Faraday Cup (MLFC) gives the opportunity to measure the proton range relatively fast and accurate. The MLFC measures the differential fluence, which means the range profile of the proton beam. It consists of a stack of sheets, alternating conductive and insulating, and the penetrating protons bring their additional charge into the sheet in which they stop. By measuring the corresponding current in each conducting sheet at the same time, the MLFC can quickly measure the range of the protons. The task of this work is to develop a MLFC with respect to the requirements of the eye tumor therapy and to explore possible application potentials. Therefore, Monte Carlo calculations with MCNPX 2.6 and SRIM were conducted, various foil stacks were studied in air and in vacuum, different measurement electronics for measuring currents in the pA range in many channels simultaneously were tested, a system of degraders for a variable measuring range from 30 MeV to 70 MeV was developed and the corresponding measurement and control software was written in LabVIEW 2011. The accuracy of the range measurements was examined and it was shown that a quick energy measurement at different target stations can be made by the MLFC due to its mobility. In therapy, in addition to the determination of the maximum range of the proton beam, the regular monitoring of the modulation of the extended Bragg-curves is in principle possible.

No description available.

No description available.