Mechanism-Specific Pharmacodynamics of a Novel Complex-I Inhibitor Quantified by Imaging Reversal of Consumptive Hypoxia with [18F]FAZA PET In Vivo
Abstract
:1. Introduction
2. Materials and Methods
2.1. In Vitro Analysis of Oxygen Consumption Rate
2.2. [18F]FAZA Production and IACS-010759 Formulation
2.3. Animal Models
2.4. [18F]FAZA Imaging and Analysis
2.5. 2,4-Dinitrophenol and Pyruvate to Increase Oxygen Consumption Rate and Retention of [18F]FAZA
2.6. Pimonidazole Immunohistochemistry
2.7. Human PET/CT Scanning
2.8. Statistics
3. Results
3.1. Inhibition of Oxygen Consumption in Cellulo
3.2. [18F]FAZA Retention in Tumor-Bearing Mouse Models: Reproducibility and Optimizing Analysis
3.3. Reversal of [18F]FAZA Retention In Vivo Across Multiple and Diverse Tumor Models Treated with IACS-010759
3.4. Loss of [18F]FAZA Retention Post-Treatment with IACS-010759 Is Not Related to Changes in the Initial Uptake of [18F]FAZA
3.5. Increasing [18F]FAZA Retention with Biochemical Drivers of Oxygen Consumption Rate
3.6. Dose-Response of IACS-010759-Mediated Reversal of [18F]FAZA Retention in a BRAF Inhibitor-Resistant Melanoma Tumor Model In Vivo
3.7. Precision of [18F]FAZA PET/CT Test-Retest Method in a Patient with Glioblastoma
4. Discussion
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Data and materials availability: IACS-010759 and cell lines D423-Fluc and A375-R1 are available upon request with execution of an appropriate MTA. |
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Gammon, S.T.; Pisaneschi, F.; Bandi, M.L.; Smith, M.G.; Sun, Y.; Rao, Y.; Muller, F.; Wong, F.; De Groot, J.; Ackroyd, J.; et al. Mechanism-Specific Pharmacodynamics of a Novel Complex-I Inhibitor Quantified by Imaging Reversal of Consumptive Hypoxia with [18F]FAZA PET In Vivo. Cells 2019, 8, 1487. https://doi.org/10.3390/cells8121487
Gammon ST, Pisaneschi F, Bandi ML, Smith MG, Sun Y, Rao Y, Muller F, Wong F, De Groot J, Ackroyd J, et al. Mechanism-Specific Pharmacodynamics of a Novel Complex-I Inhibitor Quantified by Imaging Reversal of Consumptive Hypoxia with [18F]FAZA PET In Vivo. Cells. 2019; 8(12):1487. https://doi.org/10.3390/cells8121487
Chicago/Turabian StyleGammon, Seth T., Federica Pisaneschi, Madhavi L. Bandi, Melinda G. Smith, Yuting Sun, Yi Rao, Florian Muller, Franklin Wong, John De Groot, Jeffrey Ackroyd, and et al. 2019. "Mechanism-Specific Pharmacodynamics of a Novel Complex-I Inhibitor Quantified by Imaging Reversal of Consumptive Hypoxia with [18F]FAZA PET In Vivo" Cells 8, no. 12: 1487. https://doi.org/10.3390/cells8121487