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Tracking cellular stress with labeled FMAU reflects changes in mitochondrial TK2.
Omid S Tehrani1, Kirk A Douglas, Jawana M Lawhorn-Crews
1Karmanos Cancer Institute, Wayne State University, 4100 John R, 4 HWCRC, Detroit, MI 48201-2013, USA.
European Journal of Nuclear Medicine and Molecular Imaging
|February 13, 2008
Summary
1-(2'-deoxy-2'-fluoro-beta-D: -arabinofuranosyl)-thymine (FMAU) tracks thymidine kinase 2 (TK2) activity and mitochondrial mass under cellular stress. This tracer may serve as an early indicator of treatment response in cancer imaging.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Fluoropyrimidines like 1-(2'-deoxy-2'-fluoro-beta-D: -arabinofuranosyl)-thymine (FMAU) and 3'-deoxy-3'-fluorothymidine (FLT) are utilized as positron emission tomography (PET) imaging tracers for tumors.
- While FLT retention is linked to thymidine kinase 1 (TK1) activity in proliferating tissues, the precise mechanism of FMAU's selective accumulation in tumors requires further investigation.
Purpose of the Study:
- To elucidate the mechanism of FMAU accumulation in tumors.
- To investigate the correlation between FMAU retention, thymidine kinase 2 (TK2) activity, and mitochondrial mass under various cellular stress conditions.
Main Methods:
- Assessed retention of [(3)H]FLT and [(3)H]FMAU in prostate and breast cancer cell lines.
- Analyzed tracer metabolites using high-performance liquid chromatography (HPLC).
- Determined TK1 and TK2 activities, and mitochondrial mass in cells subjected to nutritional, oxidative, reductive, or energy stress.
Main Results:
- FMAU retention was significantly lower than FLT in rapidly proliferating cancer cells.
- HPLC analysis confirmed phosphorylated tracers as the primary retained metabolites.
- Nutritional stress reduced TK1 activity and FLT retention but increased FMAU retention.
- FMAU retention and phosphorylation strongly correlated with TK2 activity and mitochondrial mass, particularly under oxidative, reductive, or energy stress.
Conclusions:
- FMAU is preferentially phosphorylated by TK2, indicating its potential as a tracer for TK2 activity.
- FMAU retention serves as a reliable indicator of mitochondrial mass under cellular stress.
- FMAU shows promise as an early biomarker for treatment effects in cancer therapy.
