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Journal of Urology
Pinthus, J.H., Department of Urology, Chaim Sheba Medical Center, Tel Hashomer, Israel
Sheffer, Y., Institute of Animal Science, Agricultural Research Organization, Volcani Center, Bet Dagan, Israel
Nagler, A., Department of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Hashomer, Israel
Fridman, E., Department of Pathology, Chaim Sheba Medical Center, Tel Hashomer, Israel
Mor, Y., Department of Urology, Chaim Sheba Medical Center, Tel Hashomer, Israel
Genina, O., Institute of Animal Science, Agricultural Research Organization, Volcani Center, Bet Dagan, Israel
Pines, M., Institute of Animal Science, Agricultural Research Organization, Volcani Center, Bet Dagan, Israel, Institute of Animal Science, ARO, Volcani Center, P.O. Box 6, Bet Dagan 50250, Israel
Purpose: Wilms tumor (WT) is the most common malignant neoplasm of the urinary tract in children. Although it is curable with long-term survival, the combination of surgery, chemotherapy and often radiotherapy in some cases results in severe complications in adulthood. Therefore, novel therapeutic strategies that would decrease treatment burden and improve outcome for high risk patients are required. We evaluated the efficacy of halofuginone, an inhibitor of collagen type I synthesis and angiogenesis, to inhibit WT development in xenografts models. Materials and Methods: WTs derived from 2 patients with favorable histology at different disease stages were implanted subcutaneously or orthotopically in the kidneys of nude mice. Halofuginone was administered intraperitoneally (2 μg per mouse every other day) or given in the diet (1 part per million). Results: Independent of disease stage, tumor location or administration route, halofuginone caused a decrease in angiogenesis that resulted in marked inhibition of tumor development. This result was accompanied by a reduction in collagen synthesis, reduced levels of hepatocyte growth factor receptor MET and increased levels of the tumor suppressor protein WT1. In culture halofuginone increased the synthesis of WT1 in the human WT cell-line SK-NEP-1 and in other cancer cell lines such as hepatocellular carcinoma and prostate cancer. In SK-NEP-1 halofuginone also lowered erb B2 levels and reduced cell proliferation. Conclusions: These results suggest that halofuginone is a potent inhibitor of WT progression. Because of its unique mode of action, halofuginone may decrease the treatment burden when combined with chemotherapy. Copyright © 2005 by American Urological Association.
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Inhibition of Wilms tumor xenograft progression by halofuginone is accompanied by activation of WT-1 gene expression
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Pinthus, J.H., Department of Urology, Chaim Sheba Medical Center, Tel Hashomer, Israel
Sheffer, Y., Institute of Animal Science, Agricultural Research Organization, Volcani Center, Bet Dagan, Israel
Nagler, A., Department of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Hashomer, Israel
Fridman, E., Department of Pathology, Chaim Sheba Medical Center, Tel Hashomer, Israel
Mor, Y., Department of Urology, Chaim Sheba Medical Center, Tel Hashomer, Israel
Genina, O., Institute of Animal Science, Agricultural Research Organization, Volcani Center, Bet Dagan, Israel
Pines, M., Institute of Animal Science, Agricultural Research Organization, Volcani Center, Bet Dagan, Israel, Institute of Animal Science, ARO, Volcani Center, P.O. Box 6, Bet Dagan 50250, Israel
Inhibition of Wilms tumor xenograft progression by halofuginone is accompanied by activation of WT-1 gene expression
Purpose: Wilms tumor (WT) is the most common malignant neoplasm of the urinary tract in children. Although it is curable with long-term survival, the combination of surgery, chemotherapy and often radiotherapy in some cases results in severe complications in adulthood. Therefore, novel therapeutic strategies that would decrease treatment burden and improve outcome for high risk patients are required. We evaluated the efficacy of halofuginone, an inhibitor of collagen type I synthesis and angiogenesis, to inhibit WT development in xenografts models. Materials and Methods: WTs derived from 2 patients with favorable histology at different disease stages were implanted subcutaneously or orthotopically in the kidneys of nude mice. Halofuginone was administered intraperitoneally (2 μg per mouse every other day) or given in the diet (1 part per million). Results: Independent of disease stage, tumor location or administration route, halofuginone caused a decrease in angiogenesis that resulted in marked inhibition of tumor development. This result was accompanied by a reduction in collagen synthesis, reduced levels of hepatocyte growth factor receptor MET and increased levels of the tumor suppressor protein WT1. In culture halofuginone increased the synthesis of WT1 in the human WT cell-line SK-NEP-1 and in other cancer cell lines such as hepatocellular carcinoma and prostate cancer. In SK-NEP-1 halofuginone also lowered erb B2 levels and reduced cell proliferation. Conclusions: These results suggest that halofuginone is a potent inhibitor of WT progression. Because of its unique mode of action, halofuginone may decrease the treatment burden when combined with chemotherapy. Copyright © 2005 by American Urological Association.
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