MP39-05 INHIBITION OF CARBONIC ANHYDRASE IX CONFERS RADIATION SENSITIVITY TO RENAL CELL CARCINOMA

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research I1 Apr 2015MP39-05 INHIBITION OF CARBONIC ANHYDRASE IX CONFERS RADIATION SENSITIVITY TO RENAL CELL CARCINOMA Jehonathan Pinthus, Sarah Hopmans, Daniel Gallino, Carrie Gerdes, Diana Glennie, and Thomas Farrell Jehonathan PinthusJehonathan Pinthus More articles by this author , Sarah HopmansSarah Hopmans More articles by this author , Daniel GallinoDaniel Gallino More articles by this author , Carrie GerdesCarrie Gerdes More articles by this author , Diana GlennieDiana Glennie More articles by this author , and Thomas FarrellThomas Farrell More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.755AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES While the normal kidney is relatively sensitive to radiation, renal cell carcinoma (RCC) is considered resistant to radiation. The expression of carbonic anhydrase 9 (CA9), an enzyme that maintains intracellular pH by carbon dioxide dissolution, is upregulated in the majority of RCC but not in normal kidney cells. Because regulation of intracellular pH enhances radiation effects, we hypothesize that inhibiting CA9 can radiosensitize RCC. METHODS Clonogenic survival assays in the presence of CA9 inhibitor (AEBS) or shRNA silencing of CA9 were used to investigate the in vitro response to radiation and extracellular pH changes of 786-O and RAG RCC cells. Nude mice bearing established subcutaneous 786-O xenografts receiving either AEBS (50-200 μg/mL in the drinking water) or controls (AEBS only, radiation only, vehicle only) were irradiated (6Gy). In a second set of experiments 786-O xenografts stably expressing CA9 shRNA or scrambled control shRNA were irradiated (6Gy). Tumor growth was longitudinally followed and tumor weights, vascularization, proliferation and CA9 expression were compared using CD31, ki67 staining and CA9 immune-blotting respectively. RESULTS In vitro inhibition of CA IX activity or expression significantly sensitized RCC cells to the effects of ionizing radiation (p<0.05). In vivo irradiated xenografts from RCC cells transfected with CA IX shRNA were significantly smaller compared to irradiated xenografts from scrambled shRNA controls (p<0.05). RCC xenografts from mice treated with AEBS in combination with irradiation grew significantly slower than all controls (p<0.05) and were less vascularized. CONCLUSIONS Inhibition of CA9 expression or activity results in radiation sensitization of RCC in pre-clinical models. Clinical trials are in plan © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e456 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jehonathan Pinthus More articles by this author Sarah Hopmans More articles by this author Daniel Gallino More articles by this author Carrie Gerdes More articles by this author Diana Glennie More articles by this author Thomas Farrell More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...