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Detection and Quantification of the Evolution Dynamics of Apoptosis Using the PET Voltage Sensor ¹⁸F-Fluorobenzyl Triphenyl Phosphonium

¹ Division of Nuclear Medicine, Russell H. Morgan Department of Radiology, Johns Hopkins Medical Institutions, Baltimore, Maryland; and ² Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland

Correspondence: For correspondence or reprints contact: Igal Madar, Johns Hopkins Medical Institutions, 601 N. Caroline St., Baltimore, MD 21287. E-mail: imadar{at}jhmi.edu

Apoptosis is a key mechanism in numerous pathologies. However, there are no effective noninvasive means available for an early detection and quantitative assessment of evolution dynamics of the apoptotic process. Here, we have characterized the ability of the novel PET voltage sensor ¹⁸F-fluorobenzyl triphenyl phosphonium (¹⁸F-FBnTP) to quantify the time-dependent apoptotic action of the taxanes paclitaxel and docetaxel in vitro and in vivo. Methods: The duration-dependent treatment effect of paclitaxel on ¹⁸F-FBnTP uptake was assayed in human MDA-MB-231 breast carcinoma cells. The expression of the proapoptotic Bax and antiapoptotic Bcl-2 mitochondrial proteins, release of the apoptogen cytochrome c, and activation of executioner caspase-3 were determined by Western blotting. The fraction of viable cells was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. The effect of docetaxel on ¹⁸F-FBnTP and ¹⁸F-FDG uptake in orthotopic prostate tumors in mice was compared. Results: ¹⁸F-FBnTP cellular uptake in viable cells declined linearly with the increasing duration of paclitaxel treatment, from 3 to 24 h, and plateaued at 48 h. The extent of decrease of ¹⁸F-FBnTP correlated strongly with the Bax-to-Bcl-2 ratio (R² = 0.83) and release of cytochrome c (R² = 0.92), but preceded in time the caspase-3 cleavage. The P-glycoprotein blocker verapamil did not interfere with ¹⁸F-FBnTP cellular uptake. ¹⁸F-FBnTP prostate tumor contrast was greater than ¹⁸F-FDG prostate tumor contrast. Docetaxel caused a marked decrease (52.4%) of ¹⁸F-FBnTP tumor uptake, within 48 h, whereas ¹⁸F-FDG was much less affected (12%). Conclusion: The voltage sensor ¹⁸F-FBnTP is a viable means for quantification of paclitaxel pharmacodynamics. ¹⁸F-FBnTP permits the detection of paclitaxel apoptotic action in vivo earlier than does ¹⁸F-FDG. ¹⁸F-FBnTP may afford a novel approach for early detection and quantitative assessment of the cumulative-effect kinetics of proapoptotic drugs and conditions using PET.

Key Words: molecular biology • molecular imaging • PET • ¹⁸F-fluorobenzyl triphenyl phosphonium • apoptosis • breast carcinoma cell line • taxanes

COPYRIGHT © 2009 by the Society of Nuclear Medicine, Inc.

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JNM 2009 50: 11A-12A. [Full Text]