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Rein D.T.,University of Dusseldorf Medical Center | Schmidt T.,University of Cologne | Bauerschmitz G.,University of Dusseldorf Medical Center | Hampl M.,University of Dusseldorf Medical Center | And 4 more authors.
Fertility and Sterility | Year: 2010

Objective: To evaluate a vascular endothelial growth factor (VEGF)-targeted gene therapy for the treatment of endometriosis. Design: Analysis of the VEGF gene expression and promoter activity in ectopic and eutopic endometrium. Evaluation of the specific replication and cell-killing effect of a VEGF-targeted adenovirus (Ad5VEGFE1) in endometriotic cells. Patient(s): Four patients who underwent hysterectomy for benign disease, 30 women with moderate superficial, and 30 women with deep infiltrating endometriosis. Intervention(s): Immunostaining and gene expression of VEGF was examined in eutopic endometrium, endometriotic lesions, and normal peritoneum. The VEGF promoter activity was evaluated in eutopic endometrium and endometriotic lesions. A VEGF-targeted conditionally replicative adenovirus (Ad5VEGFE1) was evaluated regarding specific viral replication in endometriosis cells and induction of apoptosis. The biodistribution of the VEGF-targeted conditionally replicative adenovirus was examined in a mouse model. Result(s): The VEGF gene was highly expressed in ectopic endometrium compared with eutopic endometrium and normal peritoneum. The VEGF promoter was active in endometriotic cells. Ad5VEGFE1 showed efficient viral replication and induction of apoptosis in purified primary endometriotic cells and demonstrated a similar lower targeting to the liver and the uterus in a mouse model. Conclusion(s): Ad5VEGFE1 is a promising candidate for treating endometriosis and holds potential for clinical testing. © 2010 American Society for Reproductive Medicine.


Rein D.T.,University of Dusseldorf Medical Center | Volkmer A.,University of Dusseldorf Medical Center | Beyer I.M.,University of Dusseldorf Medical Center | Beyer I.M.,University of Washington | And 8 more authors.
Gynecologic Oncology | Year: 2011

Objective: Multidrug resistance gene 1 (MDR1) mediated resistance to chemotherapeutic agents is a major obstacle for the therapy of various cancer types. The use of conditionally replicating adenoviruses (CRAds) is dependent on molecular differences between tumor cells and non tumor cells. Transcriptional targeting of CRAd replication is an effective way to control replication regulation. The aim of this study was to evaluate the effect of a MDR1 targeted fiber-modified CRAd against chemotherapy resistant ovarian cancer. Methods: MDR1 expression was evaluated in chemotherapy naïve and pretreated ovarian cancer cells and various control cells. We constructed 2 variants of a fiber-modified CRAd, Ad5/3MDR1E1 and Ad5/3MDR1E1Δ24 containing the MDR1 promoter to control viral replication via the E1A gene. The MDR promoter activity and cell killing efficacy were evaluated in vitro. Orthotopic murine models of peritoneally disseminated ovarian cancer were utilized to evaluate the preclinical efficacy of MDR targeted CRAds in vivo. To evaluate the liver toxicity of MDR1 targeted CRAds, we compared Ad5/3MDR1E1 with Ad5/3Δ24, a CRAd that replicates in cancer cells inactive in the Rb/p16 pathway by use of an in vivo hepatotoxicity model. Results: We demonstrate efficient oncolysis of Ad5/3MDR1E1 in both chemotherapy resistant ovarian cancer cell lines and in primary tumor cells from pretreated patients as well as therapeutic efficacy in an orthotopic mouse model. Ad5/3MDR1E1 demonstrated significantly decreased liver toxicity compared to other 5/3-fiber modified control vectors examined. Conclusions: In summary, Ad5/3MDR1E1 is an efficient and safe gene therapy approach for specific targeting of chemotherapy resistant cancer cells. © 2011 Elsevier Inc. All rights reserved.


Rein D.T.,University of Dusseldorf Medical Center | Volkmer A.,University of Dusseldorf Medical Center | Bauerschmitz G.,University of Dusseldorf Medical Center | Beyer I.M.,University of Dusseldorf Medical Center | And 7 more authors.
Journal of Cancer Research and Clinical Oncology | Year: 2012

Purpose: Targeted oncolytic adenoviruses capable of replication selectively in cancer cells are an appealing approach for the treatment of various cancer types refractory to conventional therapies. The aim of this study was to evaluate the effect of Ad5/3MDR1E1, a multidrug resistance gene 1 (MDR1)-targeted fiber-modified replication-competent adenovirus for the therapy of platinum-pretreated ovarian cancer in combination with cytostatic agents. Methods: MDR1-specific tumor cell killing of Ad5/ 3MDR1E1 was systematically evaluated in chemotherapy naïve and pretreated ovarian cancer cells in vitro. Combinations of Ad5/3MDR1E1 and cytostatic agents were studied in vivo and in vitro. An in vivo hepatotoxicity model was used to evaluate liver toxicity. Results: We demonstrate efficient oncolysis of Ad5/ 3MDR1E1 in chemotherapy-resistant ovarian cancer cells as well as therapeutic efficacy in an orthotopic mouse model. Further, combining Ad5/3MDR1E1 with paclitaxel resulted in greater therapeutic benefit than either agent alone. Conclusion: These preclinical data suggest that a fibermodified adenovirus vector under the control of the MDR1 promoter represents a promising treatment strategy for platinum-pretreated ovarian cancer as a single agent or in combination with conventional anticancer drugs. © Springer-Verlag 2011.


Rein D.T.,University of Dusseldorf Medical Center | Volkmer A.K.,University of Dusseldorf Medical Center | Jens V.,University of Dusseldorf Medical Center | Beyer I.M.,University of Dusseldorf Medical Center | And 7 more authors.
Oncology Letters | Year: 2012

Ovarian cancer patients often suffer from malignant ascites and pleural effusion. Apart from worsening the outcome, this condition frequently impairs the quality of life in patients who are already distressed by ovarian cancer. This study investigated whether single intraperitoneal administration of the anti-VEGF antibody bevacizumab is capable of reducing the ascites-related body surface and prolonging survival. The study was performed in an orthotopic murine model of peritoneal disseminated platin-resistant ovarian cancer. Mice were treated with bevacizumab and/or paclitaxel or buffer (control). Reduction of body surface and increased survival rates were assessed as therapeutic success. Survival of mice in all treatment groups was significantly enhanced when compared to the non-treatment control group. The combination of paclitaxel plus bevacizumab significantly improved body surface as well as overall survival in comparison to a treatment with only one of the drugs. Treatment of malignant effusion with a single dose of bevacizumab as an intraperitoneal application, with or without cytostatic co-medication, may be a powerful alternative to systemic treatment.


Bakirov A.V.,RAS Institute of Chemistry | Yakunin A.N.,RAS Enikolopov Institute of Synthetic Polymer Materials | Shcherbina M.A.,RAS Institute of Chemistry | Chvalun S.N.,RAS Institute of Chemistry | And 3 more authors.
Nanotechnologies in Russia | Year: 2010

The structure and phase behavior of amphiphilic compound sodium 2,3,4-tri(dodecyl)benzenesulfonate, which is capable of self-assembling and contains methacryloyl groups in aliphatic ends, were studied by X-ray diffraction and differential scanning calorimetry. The initial samples are characterized by an ordered columnar φoh phase, which, during a rise in temperature to 53°C (at the expense of mobility, an increase in mesogenic groups, and a loss of order in their mutual arrangement), transforms into a disordered columnar φh phase. Under the action of irradiation, the cross-linking of benzenesulfonate molecules by methacryloyl groups and the formation of a continuous polymer matrix occur, which leads to a consistency of the column diameter at high temperatures. Cross linking proceeds much more intensively in the area where the disordered columnar phase exists. To analyze the structure of the columnar phase, we used an established technique: the reconstruction of electron density distribution maps in cylindrically symmetric systems from the relation of the intensities of small-angle X-ray reflections. Mutual ordering of benzenesulfonic groups in the area where the φoh phase exists leads to the formation of ordered ion channels; this opens up possibilities to use this material to make ion-selective membranes with controlled conductivity. © 2010 Pleiades Publishing, Ltd.

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