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Pracoviště: Department of Internal Medicine 3 Nephrology Rh...

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Inhibitory Effect of the Noncamptothecin Topoisomerase I Inhibitor LMP-400 on Female Mice Models and Human Pheochromocytoma Cells

Schovanek, Jan
Autor Schovanek, Jan Program in Reproductive and Adult Endocrinology (J.S., P.B., Y.T., A.G., N.L., S.N., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Warren G. Magnuson Clinical Center (R.W.), and National Cancer Institute (Y.P., S.K.), National Institutes of Health, Bethesda, Maryland 20892-1109 Department of Internal Medicine III-Nephrology, Rheumatology, and Endocrinology (J.S., Z.F.), Faculty of Medicine and Dentistry, Palacky University, 771 47 Olomouc, Czech Republic Department of Molecular Medicine (P.B., J.K.), Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic and Department of Internal Medicine II (S.N.), Campus Grosshadern, University-Hospital of the Ludwig-Maximilians-University of Munich, 80539 Munich, Germany
Bullova, Petra
Autor Bullova, Petra Program in Reproductive and Adult Endocrinology (J.S., P.B., Y.T., A.G., N.L., S.N., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Warren G. Magnuson Clinical Center (R.W.), and National Cancer Institute (Y.P., S.K.), National Institutes of Health, Bethesda, Maryland 20892-1109 Department of Internal Medicine III-Nephrology, Rheumatology, and Endocrinology (J.S., Z.F.), Faculty of Medicine and Dentistry, Palacky University, 771 47 Olomouc, Czech Republic Department of Molecular Medicine (P.B., J.K.), Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic and Department of Internal Medicine II (S.N.), Campus Grosshadern, University-Hospital of the Ludwig-Maximilians-University of Munich, 80539 Munich, Germany
Tayem, Yasin
Autor Tayem, Yasin Program in Reproductive and Adult Endocrinology (J.S., P.B., Y.T., A.G., N.L., S.N., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Warren G. Magnuson Clinical Center (R.W.), and National Cancer Institute (Y.P., S.K.), National Institutes of Health, Bethesda, Maryland 20892-1109 Department of Internal Medicine III-Nephrology, Rheumatology, and Endocrinology (J.S., Z.F.), Faculty of Medicine and Dentistry, Palacky University, 771 47 Olomouc, Czech Republic Department of Molecular Medicine (P.B., J.K.), Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic and Department of Internal Medicine II (S.N.), Campus Grosshadern, University-Hospital of the Ludwig-Maximilians-University of Munich, 80539 Munich, Germany
Giubellino, Alessio
Autor Giubellino, Alessio Program in Reproductive and Adult Endocrinology (J.S., P.B., Y.T., A.G., N.L., S.N., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Warren G. Magnuson Clinical Center (R.W.), and National Cancer Institute (Y.P., S.K.), National Institutes of Health, Bethesda, Maryland 20892-1109 Department of Internal Medicine III-Nephrology, Rheumatology, and Endocrinology (J.S., Z.F.), Faculty of Medicine and Dentistry, Palacky University, 771 47 Olomouc, Czech Republic Department of Molecular Medicine (P.B., J.K.), Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic and Department of Internal Medicine II (S.N.), Campus Grosshadern, University-Hospital of the Ludwig-Maximilians-University of Munich, 80539 Munich, Germany
Wesley, Robert
Autor Wesley, Robert Program in Reproductive and Adult Endocrinology (J.S., P.B., Y.T., A.G., N.L., S.N., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Warren G. Magnuson Clinical Center (R.W.), and National Cancer Institute (Y.P., S.K.), National Institutes of Health, Bethesda, Maryland 20892-1109 Department of Internal Medicine III-Nephrology, Rheumatology, and Endocrinology (J.S., Z.F.), Faculty of Medicine and Dentistry, Palacky University, 771 47 Olomouc, Czech Republic Department of Molecular Medicine (P.B., J.K.), Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic and Department of Internal Medicine II (S.N.), Campus Grosshadern, University-Hospital of the Ludwig-Maximilians-University of Munich, 80539 Munich, Germany
Lendvai, Nikoletta
Autor Lendvai, Nikoletta Program in Reproductive and Adult Endocrinology (J.S., P.B., Y.T., A.G., N.L., S.N., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Warren G. Magnuson Clinical Center (R.W.), and National Cancer Institute (Y.P., S.K.), National Institutes of Health, Bethesda, Maryland 20892-1109 Department of Internal Medicine III-Nephrology, Rheumatology, and Endocrinology (J.S., Z.F.), Faculty of Medicine and Dentistry, Palacky University, 771 47 Olomouc, Czech Republic Department of Molecular Medicine (P.B., J.K.), Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic and Department of Internal Medicine II (S.N.), Campus Grosshadern, University-Hospital of the Ludwig-Maximilians-University of Munich, 80539 Munich, Germany
Nölting, Svenja
Autor Nölting, Svenja Program in Reproductive and Adult Endocrinology (J.S., P.B., Y.T., A.G., N.L., S.N., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Warren G. Magnuson Clinical Center (R.W.), and National Cancer Institute (Y.P., S.K.), National Institutes of Health, Bethesda, Maryland 20892-1109 Department of Internal Medicine III-Nephrology, Rheumatology, and Endocrinology (J.S., Z.F.), Faculty of Medicine and Dentistry, Palacky University, 771 47 Olomouc, Czech Republic Department of Molecular Medicine (P.B., J.K.), Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic and Department of Internal Medicine II (S.N.), Campus Grosshadern, University-Hospital of the Ludwig-Maximilians-University of Munich, 80539 Munich, Germany
Kopacek, Juraj
Autor Kopacek, Juraj Program in Reproductive and Adult Endocrinology (J.S., P.B., Y.T., A.G., N.L., S.N., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Warren G. Magnuson Clinical Center (R.W.), and National Cancer Institute (Y.P., S.K.), National Institutes of Health, Bethesda, Maryland 20892-1109 Department of Internal Medicine III-Nephrology, Rheumatology, and Endocrinology (J.S., Z.F.), Faculty of Medicine and Dentistry, Palacky University, 771 47 Olomouc, Czech Republic Department of Molecular Medicine (P.B., J.K.), Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic and Department of Internal Medicine II (S.N.), Campus Grosshadern, University-Hospital of the Ludwig-Maximilians-University of Munich, 80539 Munich, Germany
Frysak, Zdenek
Autor Frysak, Zdenek Program in Reproductive and Adult Endocrinology (J.S., P.B., Y.T., A.G., N.L., S.N., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Warren G. Magnuson Clinical Center (R.W.), and National Cancer Institute (Y.P., S.K.), National Institutes of Health, Bethesda, Maryland 20892-1109 Department of Internal Medicine III-Nephrology, Rheumatology, and Endocrinology (J.S., Z.F.), Faculty of Medicine and Dentistry, Palacky University, 771 47 Olomouc, Czech Republic Department of Molecular Medicine (P.B., J.K.), Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic and Department of Internal Medicine II (S.N.), Campus Grosshadern, University-Hospital of the Ludwig-Maximilians-University of Munich, 80539 Munich, Germany
Pommier, Yves
Autor Pommier, Yves Program in Reproductive and Adult Endocrinology (J.S., P.B., Y.T., A.G., N.L., S.N., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Warren G. Magnuson Clinical Center (R.W.), and National Cancer Institute (Y.P., S.K.), National Institutes of Health, Bethesda, Maryland 20892-1109 Department of Internal Medicine III-Nephrology, Rheumatology, and Endocrinology (J.S., Z.F.), Faculty of Medicine and Dentistry, Palacky University, 771 47 Olomouc, Czech Republic Department of Molecular Medicine (P.B., J.K.), Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic and Department of Internal Medicine II (S.N.), Campus Grosshadern, University-Hospital of the Ludwig-Maximilians-University of Munich, 80539 Munich, Germany

Endocrinology. 2015 ; 156 (11) : 4094-104. [pub] 20150812

ISSN 1945-7170
Medvik
Zdroj

Metastatic pheochromocytoma continues to be an incurable disease, and treatment with conventional cytotoxic chemotherapy offers limited efficacy. In the present study, we evaluated a novel topoisomerase I inhibitor, LMP-400, as a potential treatment for this devastating disease. We found a high expression of topoisomerase I in human metastatic pheochromocytoma, providing a basis for the evaluation of a topoisomerase 1 inhibitor as a therapeutic strategy. LMP-400 inhibited the cell growth of established mouse pheochromocytoma cell lines and primary human tumor tissue cultures. In a study performed in athymic female mice, LMP-400 demonstrated a significant inhibitory effect on tumor growth with two drug administration regimens. Furthermore, low doses of LMP-400 decreased the protein levels of hypoxia-inducible factor 1 (HIF-1α), one of a family of factors studied as potential metastatic drivers in these tumors. The HIF-1α decrease resulted in changes in the mRNA levels of HIF-1 transcriptional targets. In vitro, LMP-400 showed an increase in the growth-inhibitory effects in combination with other chemotherapeutic drugs that are currently used for the treatment of pheochromocytoma. We conclude that LMP-400 has promising antitumor activity in preclinical models of metastatic pheochromocytoma and its use should be considered in future clinical trials.

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