No supra-additive effects of goserelin and radiotherapy on clonogenic survival of prostate carcinoma cells in vitro

<p>Abstract</p> <p>Background</p> <p>Oncological results of radiotherapy for locally advanced prostate cancer (PC) are significantly improved by simultaneous application of LHRH analoga (e.g. goserelin). As 85% of PC express LHRH receptors, we investigated the interaction of goserelin incubation with radiotherapy under androgen-deprived conditions in vitro.</p> <p>Methods</p> <p>LNCaP and PC-3 cells were stained for LHRH receptors. Downstream the LHRH receptor, changes in protein expression of c-fos, phosphorylated p38 and phosphorylated ERK1/2 were analyzed by means of Western blotting after incubation with goserelin and irradiation with 4 Gy. Both cell lines were incubated with different concentrations of goserelin in hormone-free medium. 12 h later cells were irradiated (0 – 4 Gy) and after 12 h goserelin was withdrawn. Endpoints were clonogenic survival and cell viability (12 h, 36 h and 60 h after irradiation).</p> <p>Results</p> <p>Both tested cell lines expressed LHRH-receptors. Changes in protein expression demonstrated the functional activity of goserelin in the tested cell lines. Neither in LNCaP nor in PC-3 any significant effects of additional goserelin incubation on clonogenic survival or cell viability for all tested concentrations in comparison to radiation alone were seen.</p> <p>Conclusion</p> <p>The clinically observed increase in tumor control after combination of goserelin with radiotherapy in PC cannot be attributed to an increase in radiosensitivity of PC cells by goserelin in vitro.</p

Induction of apoptosis in gynecological cancers and breast cancer in vitro and in vivo by antagonistic analogues of gonadotropin-releasing hormone type II

In humanen Endometrium-, Ovarial- und Mammakarzinomen werden GnRH-I und GnRH-II und ihre Rezeptoren als Teil eines negativen, autokrinen Regulationssystems der Zellproliferation exprimiert. Basierend auf einer Tumorzell-spezifischen Signaltransduktion inhibieren GnRH-I und GnRH-II Agonisten die mitogene Signaltransduktion der Wachstumsfaktor-Rezeptoren. Dies resultiert in einer Inhibition der Proliferation von gynäkologischen Karzinomzellen. Die Induktion von Apoptose ist hier nicht beteiligt. Das Ziel der vorliegenden Arbeit war, die Effekte von GnRH-II Antagonisten auf gynäkologische Karzinomzelllinien in vitro und in vivo zu untersuchen. Es konnte erstmals gezeigt werden, dass GnRH-II Antagonisten bereits in nanomolaren Konzentrationen Apoptose dosisabhängig induzieren und somit zu einer Reduktion der Zellzahl in gynäkologischen Karzinomzelllinien führen. Die apoptotischen Effekte sind über den mitochondrialen Signalweg vermittelt, resultieren in einer Aktivierung der Effektor-Caspase-3 und in der Degradation der DNA im Nukleus. Diese Effekte konnten auf verschiedene in vivo Tumormodelle übertragen werden. Dabei war das Wachstum gynäkologischer Karzinome xenotransplantierter Nacktmäuse signifikant gehemmt und führte sogar zum Wachstumsstillstand der Tumoren. Auch hier waren die Effekte Apoptose-vermittelt. In vitro konnte nachgewiesen werden, dass GnRH-II Antagonisten sowohl an den GnRH-I Rezeptor als auch an den putativen GnRH-II Rezeptor binden und die Aktivierung der Stress-aktivierten MAPKs p38/SAPK2 und JNK/SAPK1 induzieren. Zusammengenommen konnte in dieser Arbeit der Vorteil von GnRH-II Antagonisten in einer nebenwirkungsarmen Antitumor-Therapie dargestellt werden. Sie wirken nicht wie andere GnRH Analoga nur über die Rezeptoren der Hypophyse durch eine Blockade der Steroidhormonsynthese, sondern induzieren direkt in den Tumorzellen Rezeptor-vermittelt Apoptose. Die grundlegenden Mechanismen zur Signaltransduktion, die der Induktion von Apoptose zugrunde liegen, konnten außerdem aufgeklärt werden

Gonadotropin-releasing hormone type II antagonist induces apoptosis in MCF-7 and triple-negative MDA-MB-231 human breast cancer cells in vitro and in vivo

Triple-negative breast cancer does not express estrogen and progesterone receptors, and no overexpression/amplification of the HER2-neu gene occurs. Therefore, this subtype of breast cancer lacks the benefits of specific therapies that target these receptors. Today chemotherapy is the only systematic therapy for patients with triple-negative breast cancer. About 50% to 64% of human breast cancers express receptors for gonadotropin-releasing hormone (GnRH), which might be used as a target. New targeted therapies are warranted. Recently, we showed that antagonists of gonadotropin-releasing hormone type II (GnRH-II) induce apoptosis in human endometrial and ovarian cancer cells in vitro and in vivo. This was mediated through activation of stress-induced mitogen-activated protein kinases (MAPKs) p38 and c-Jun N-terminal kinase (JNK), followed by activation of proapoptotic protein Bax, loss of mitochondrial membrane potential, and activation of caspase-3. In the present study, we analyzed whether GnRH-II antagonists induce apoptosis in MCF-7 and triple-negative MDA-MB-231 human breast cancer cells that express GnRH receptors. In addition, we ascertained whether knockdown of GnRH-I receptor expression affects GnRH-II antagonist-induced apoptosis and apoptotic signaling

Calibration of simulated rainfall characteristics for the study of soil erosion on agricultural land

Rainfall simulation is a widely used method for soil erosion studies on agricultural land. Major problem of this experimental research method is the comparability between different simulators due to differences in simulated rainfall. Therefore the purpose of this study is to characterize the rainfall produced by a rainfall simulator which was widely used during the last decades. Four different calibration methods were used to assess the drop size distribution: 1) Indication Paper, 2) Plaster Micro Plot, 3) Joss-Waldvogel Disdrometer and 4) Laser Distrometer (Thies). Additionally, the latter one was used to measure drop fall velocity in combination with drop diameter. The spatial drop distribution pattern on the plot was measured with 100 rainfallgauges. The spatial rainfall distribution pattern clearly shows a heterogeneity, which is caused by the used nozzle configuration. Considerable differences in drop-size distribution can be observed depending on the used measurement technique. Laser Disdrometer and Plaster Micro Plot cover the whole produced drop size spectrum ranging from &lt; 0.5 mm to &gt; 3.0 mm, whereas Indication Paper as well as the Joss-Waldvogel Disdrometer primarily show drops smaller than 2.0 mm. Characterisation of rainfall is therefore strongly dependent on the used method and if different methods are used, may lead to contradictory results. The volume drop size distribution reflected by the Laser Distrometer is very similar to that one produced by rain with an intensity of 40 mm h -1 . Nevertheless, with maximum velocities above 10 m s -1 small drops are by far too fast and large drops with velocities dominantly below 5 m s -1 are too slow compared to natural rainfall. As an overall result, the simulator can be characterised as suitable for runoff and infiltration measurements, but with constraints due to the low reproducibility of the spatial rain distribution. As a consequence of the produced drop spectrum and fall velocity the erosion quantities may be underestimated systematically. For this, methodological development has to be focussed on homogeneous spatial rainfall distributions and on increasing the amount of large drops with higher fall velocities

Antiproliferative effects of antiestrogens and inhibitors of growth factor receptor signaling on endometrial cancer cells

In patients with advanced estrogen-dependent type I endometrial cancer (EC), pharmacological treatment with progestins or antiestrogens is recommended, but primary and secondary resistance are common. The aim of our study was to investigate single-agent and dual-agent therapeutic strategies in estrogen receptor-positive human EC cells

No supra-additive effects of goserelin and radiotherapy on clonogenic survival of prostate carcinoma cells -0

<p><b>Copyright information:</b></p><p>Taken from "No supra-additive effects of goserelin and radiotherapy on clonogenic survival of prostate carcinoma cells "</p><p>http://www.ro-journal.com/content/2/1/31</p><p>Radiation Oncology (London, England) 2007;2():31-31.</p><p>Published online 26 Aug 2007</p><p>PMCID:PMC2034383.</p><p></p>ession of LHRH-receptors