617 DETECTING TUMOR HYPOXIA DURING SUNITINIB THERAPY IN A RENAL CELL CARCINOMA MOUSE MODEL USING POSITRON EMISSION TOMOGRAPHY

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research (IV)1 Apr 2013617 DETECTING TUMOR HYPOXIA DURING SUNITINIB THERAPY IN A RENAL CELL CARCINOMA MOUSE MODEL USING POSITRON EMISSION TOMOGRAPHY David Chapman, John Mercer, Leonard Wiebe, Melinda Wuest, and Ronald Moore David ChapmanDavid Chapman Edmonton, Canada More articles by this author , John MercerJohn Mercer Edmonton, Canada More articles by this author , Leonard WiebeLeonard Wiebe Edmonton, Canada More articles by this author , Melinda WuestMelinda Wuest Edmonton, Canada More articles by this author , and Ronald MooreRonald Moore Edmonton, Canada More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.168AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Sunitinib is currently the first line drug therapy for metastasizing renal cell carcinoma (RCC). It has been shown to have a profound effect on tumor angiogenesis leading to modifications of the tumor's microenvironment. Tumor hypoxia plays an important role in the metastatic potential of a solid tumor and its resistance to any chemotherapy. Therefore monitoring tumor hypoxia could potentially be used to detect and analyze therapeutic response. The present study utilized Positron-Emission Tomography (PET) to determine changes in tumor oxygenation during and following sunitinib therapy in a mouse RCC tumor model. METHODS Subcutaneous bilateral Caki-1 tumors were grown for 40 days in BALB/c nu/nu mice. Mice bearing tumors were sorted into 2 groups: a) receiving 40mg/kg/d sunitinib i.p. and b) vehicle control injections. PET imaging (3 h p.i.) utilizing the hypoxia radiotracer [18F]FAZA was performed after 4 days, 7 days, and 13 days of therapy, and again 12 days after 15 days of therapy. In vitro cell uptake experiments were conducted under hypoxic conditions to observe whether sunitinib would have a direct effect on uptake and intracellular trapping of [18F]FAZA. In addition, biodistribution of [18F]FAZA and immunohistochemical staining to detect pimonidazole adducts were determined. RESULTS PET experiments revealed a relatively low uptake level of [18F]FAZA into murine RCC tumors. After 7 days of sunitinib therapy (resulting in decreased tumor growth) the uptake (SUV) was significantly reduced: 0.24+/-0.02 in control versus 0.19+/-0.01 in sunitinib treated mice (n=8; p<0.05). Allowing a 12-day break following 15 days of sunitinib therapy resulted in an increased [18F]FAZA uptake into the treated mice: 0.18+/-0.01 (n=5, control) versus 0.23+/-0.01 (n=6; p<0.05, sunitinib). Biodistribution studies with [18F]FAZA and pimonidazole staining supported the reduced uptake during therapy and the increase again after the therapy was stopped. In vitro cell uptake experiments showed that the [18F]FAZA uptake of 0.25 ± 0.04 (normoxic) or of 2.46 ± 0.42 (hypoxic; n=9) into Caki-1 cells was not changed in the presence of 3 uM sunitinib indicating no direct sunitinib effect on the cellular uptake of the radiotracer. CONCLUSIONS Uptake of [18F]FAZA tended to decrease during therapy of sunitinib indicating a decrease in the tumor's hypoxia. However, when stopping drug therapy in tumor-bearing mice, this effect was reversed and tumor hypoxia was increased again. [18F]FAZA could potentially be used to monitor drug response to therapy with sunitinib in RCC. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e252 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information David Chapman Edmonton, Canada More articles by this author John Mercer Edmonton, Canada More articles by this author Leonard Wiebe Edmonton, Canada More articles by this author Melinda Wuest Edmonton, Canada More articles by this author Ronald Moore Edmonton, Canada More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...