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- W202519359 abstract "452 Objectives Optimal biological dosing of mammalian target of rapamycin (mTOR) inhibitors is challenging owing to a lack of standard pharmacokinetic/pharmacodynamic biomarkers that can be used in clinical practice. The aim of this study was to test whether FDG PET can be used to define the optimal biological dose (OBD) of the mTOR inhibitor everolimus in a tumor mouse model. Methods Gastric cancer xenografts were established in nude mice. Time- (day 1-8) and dose- (0.05-15 mg/kg/d) dependency of everolimus treatment on FDG uptake of tumors was measured using a small animal PET system. In parallel, tumor volume, phosphorylation status of S6 protein, Ki-67 staining and everolimus plasma levels were evaluated by caliper measurement, western blotting, immunohistochemistry and high performance liquid chromatography-mass spectrometry, respectively. Results Anti-tumor activity of everolimus reached a plateau at doses ≥ 5 mg/kg/d, which was defined as the OBD. Correspondingly, only doses ≥ 5 mg/kg/d everolimus displayed a significant decline in tumor FDG uptake beginning from 24 h after initiation of treatment. Dose escalation above 5 mg/kg/d did not decrease FDG uptake any further. Dose-dependent changes in tumor volume and FDG uptake were reflected by changes in S6 protein phosphorylation status and tumor cell proliferation. Conclusions Tumor FDG uptake as measured by PET is a biomarker for defining the OBD of everolimus in vivo, which shows great promise for translation from preclinical research into clinical practice." @default.
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- W202519359 date "2009-05-01" @default.
- W202519359 modified "2023-09-23" @default.
- W202519359 title "Tumor FDG uptake as biomarker for defining the optimal biological dose of the mTOR inhibitor everolimus" @default.
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