MP39-09 RAPAMYCIN INHIBITS FLCN-DEFICIENT RENAL TUMOR GROWTH IN MICE

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research I1 Apr 2015MP39-09 RAPAMYCIN INHIBITS FLCN-DEFICIENT RENAL TUMOR GROWTH IN MICE Jindong Chen, Shuhui Si, Xueying Li, Yan Li, Susan Schoen, Bin Tean Teh, and Guan Wu Jindong ChenJindong Chen More articles by this author , Shuhui SiShuhui Si More articles by this author , Xueying LiXueying Li More articles by this author , Yan LiYan Li More articles by this author , Susan SchoenSusan Schoen More articles by this author , Bin Tean TehBin Tean Teh More articles by this author , and Guan WuGuan Wu More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.759AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Mutations in the folliculin gene (FLCN) cause Birt-Hogg-Dubé (BHD) syndrome. Affected patients suffer from skin tumors, kidney neoplasms, lung cysts, and pneumothorax. We have previously created a kidney-specific FLCN knockout mouse model that develops benign kidney cysts and malignant kidney tumors. Previous studies have demonstrated that FLCN deficiency leads to the activation of the mTOR signaling pathway in both human BHD-associated renal carcinomas and mouse kidney-specific FLCN knockout-induced renal tumors. In this report, we test whether mTOR inhibitor rapamycin is effective in suppression of FLCN-deficient renal tumor growth in vivo with both allograft and xenograft mouse models. METHODS FLCN-deficient cystic/hyperplastic renal cells from kidney-specific FLCN knockout mice were harvested and cultured in vitro for 15-35 passages. The surviving cells were inoculated subcutaneously in the athymic nude mice for generating allograft tumors. Xenograft mice by subcutaneously injecting human FLCN-deficient renal tumor cells (UOK257) were also generated. Rapamycin treatment commenced when the allograft or xenograft tumors reached to the proper size. For each experiment, 30 allograft or xenograft athymic nude mice were equally randomized to treatment and control groups. The mice were treated with two different doses (7.5 mg/kg and 15 mg/kg) of rapamycin or vehicle solution (5% PEG-400, 4% ethanol, and 5% Tween-80). RESULTS FLCN-deficient cystic/hyperplastic renal cells from kidney-specific FLCN knockout mice evolved into malignant cells and grew into allograft tumors. Human FLCN-deficient UOK257 cells also developed into xenograft tumors. Both allograft and xenograft tumors exhibited the activation of the mTOR pathway. Rapamycin treatment led to tumor growth inhibition in both allograft and xenograft tumors. In addition, high concentration (15 mg/kg) of rapamycin and early treatment provided a more efficient suppressive effect on tumor growth. CONCLUSIONS The mTOR inhibitor rapamycin effectively inhibits FLCN-deficient renal tumor cell growth in both allograft and xenograft mouse models. The mTOR inhibitors might be potential drug candidates for FLCN-deficient kidney cancer treatment. Our allograft and xenograft models of FLCN-deficient renal tumors could also serve as preclinical drug testing models for drug development. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e457 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jindong Chen More articles by this author Shuhui Si More articles by this author Xueying Li More articles by this author Yan Li More articles by this author Susan Schoen More articles by this author Bin Tean Teh More articles by this author Guan Wu More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...