Your browser doesn't support javascript.
loading
18F-FAZA PET imaging response tracks the reoxygenation of tumors in mice upon treatment with the mitochondrial complex I inhibitor BAY 87-2243.
Chang, Edwin; Liu, Hongguang; Unterschemmann, Kerstin; Ellinghaus, Peter; Liu, Shuanglong; Gekeler, Volker; Cheng, Zhen; Berndorff, Dietmar; Gambhir, Sanjiv S.
Afiliação
  • Chang E; Department of Radiology, Molecular Imaging Program at Stanford, Canary Center for Early Cancer Detection, Stanford University, Palo Alto, California.
  • Liu H; Department of Radiology, Molecular Imaging Program at Stanford, Canary Center for Early Cancer Detection, Stanford University, Palo Alto, California.
  • Unterschemmann K; Bayer Pharma AG, Global Drug Discovery, Wuppertal, Germany.
  • Ellinghaus P; Bayer Pharma AG, Global Drug Discovery, Wuppertal, Germany.
  • Liu S; Department of Radiology, Molecular Imaging Program at Stanford, Canary Center for Early Cancer Detection, Stanford University, Palo Alto, California.
  • Gekeler V; Bayer Pharma AG, Global Drug Discovery, Berlin, Germany.
  • Cheng Z; Department of Radiology, Molecular Imaging Program at Stanford, Canary Center for Early Cancer Detection, Stanford University, Palo Alto, California.
  • Berndorff D; Bayer Pharma AG, Global Drug Discovery, Berlin, Germany.
  • Gambhir SS; Department of Radiology, Molecular Imaging Program at Stanford, Canary Center for Early Cancer Detection, Stanford University, Palo Alto, California. sgambhir@stanford.edu.
Clin Cancer Res ; 21(2): 335-46, 2015 Jan 15.
Article em En | MEDLINE | ID: mdl-25381339
PURPOSE: We describe a noninvasive PET imaging method that monitors early therapeutic efficacy of BAY 87-2243, a novel small-molecule inhibitor of mitochondrial complex I as a function of hypoxia-inducible factor-1α (HIF1α) activity. EXPERIMENTAL DESIGN: Four PET tracers [(18)F-FDG, (18)F-Fpp(RGD)2, (18)F-FLT, and (18)F-FAZA] were assessed for uptake into tumor xenografts of drug-responsive (H460, PC3) or drug-resistant (786-0) carcinoma cells. Mice were treated with BAY 87-2243 or vehicle. At each point, RNA from treated and vehicle H460 tumor xenografts (n = 3 each) was isolated and analyzed for target genes. RESULTS: Significant changes in uptake of (18)F-FAZA, (18)F-FLT, and (18)F-Fpp(RGD)2 (P < 0.01) occurred with BAY 87-2243 treatment with (18)F-FAZA being the most prominent. (18)F-FDG uptake was unaffected. (18)F-FAZA tumor uptake declined by 55% to 70% (1.21% ± 0.10%ID/g to 0.35 ± 0.1%ID/g; n = 6, vehicle vs. treatment) in both H460 (P < 0.001) and PC3 (P < 0.05) xenografts 1 to 3 days after drug administration. (18)F-FAZA uptake in 786-0 xenografts was unaffected. Decline occurred before significant differences in tumor volume, thus suggesting (18)F-FAZA decrease reflected early changes in tumor metabolism. BAY 87-2243 reduced expression of hypoxia-regulated genes CA IX, ANGPTL4, and EGLN-3 by 99%, 93%, and 83%, respectively (P < 0.001 for all), which corresponds with reduced (18)F-FAZA uptake upon drug treatment. Heterogeneous expression of genes associated with glucose metabolism, vessel density, and proliferation was observed. CONCLUSIONS: Our studies suggest suitability of (18)F-FAZA-PET as an early pharmacodynamic monitor on the efficacy of anticancer agents that target the mitochondrial complex I and intratumor oxygen levels (e.g., BAY 87-2243).
Assuntos

Texto completo: 1 Base de dados: MEDLINE Métodos Terapêuticos e Terapias MTCI: Terapias_biologicas / Aromoterapia Assunto principal: Oxidiazóis / Pirazóis / Compostos Radiofarmacêuticos / Antineoplásicos / Nitroimidazóis Tipo de estudo: Prognostic_studies Idioma: En Revista: Clin Cancer Res Ano de publicação: 2015 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Métodos Terapêuticos e Terapias MTCI: Terapias_biologicas / Aromoterapia Assunto principal: Oxidiazóis / Pirazóis / Compostos Radiofarmacêuticos / Antineoplásicos / Nitroimidazóis Tipo de estudo: Prognostic_studies Idioma: En Revista: Clin Cancer Res Ano de publicação: 2015 Tipo de documento: Article