A simplified analysis of [18F]3′-deoxy-3′-fluorothymidine metabolism and retention

Shields, Anthony F.; Briston, David; Chandupatla, Samatha; Douglas, Kirk; Lawhorn-Crews, Jawana M.; Collins, Jerry M.; Mangner, Thomas J.; Heilbrun, Lance K.; Muzik, Otto

doi:10.1007/s00259-005-1813-0

Cited by 57 publications

(56 citation statements)

References 15 publications

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“…Furthermore, the mechanism of increased FMAU retention in tumors with little retention in proliferating bone marrow was not known. As shown in the present and previous studies, uptake of FLT in the fast proliferating cells in culture is much higher than FMAU [7,29]. One potential reason for higher FLT uptake could be the higher transmembrane transport of FLT compared to FMAU.…”

Section: Discussionmentioning

confidence: 49%

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Tracking cellular stress with labeled FMAU reflects changes in mitochondrial TK2

Tehrani

Douglas

Lawhorn-Crews

et al. 2008

Eur J Nucl Med Mol Imaging

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Purpose-Fluoropyrimidines like 1-(2 -deoxy-2 -fluoro--D-arabinofuranosyl)-thymine (FMAU) and 3 -deoxy-3 -fluorothymidine (FLT) accumulate in tumors and are being used as positron emission tomography tumor-imaging tracers. Proliferating tissues with high thymidine kinase 1 (TK1) activity retain FLT; however, the mechanism of selective accumulation of FMAU in tumors and certain other tissues requires further study.Methods-Retention of [ 3 H]FLT and [ 3 H]FMAU was measured in prostate cancer cell lines PC3, LNCaP, DU145, and the breast cancer cell line MD-MBA-231, and the tracer metabolites were analyzed by high-performance liquid chromatography (HPLC). FMAU retention, thymidine kinase 2 (TK2) activity, and mitochondrial mass were determined in cells stressed by depleted cell culture medium or by treating with oxidative, reductive, and energy stress, or specific adenosine monophosphate-activated protein kinase activator, or eIF2 inhibitor. TK1 and TK2 activities and mitochondrial mass were determined by FLT phosphorylation, 1--D-arabinofuranosylthymine (Ara-T) phosphorylation, and flow cytometry, respectively.Results-FMAU retention in rapidly proliferating cancer cell lines was five to ten times lower than FLT after 10 min incubation. HPLC analysis of the cellular extracts showed that phosphorylated tracers are the main retained metabolites. Nutritional stress decreased TK1 activity and FLT retention but increased retained FMAU. TK2 inhibition decreased FMAU retention and phosphorylation with negligible effects on FLT. Oxidative, reductive, or energy stress increased FMAU retention and correlated with mitochondrial mass (r 2 = 0.88, p=0.006). FMAU phosphorylation correlated with increased TK2 activity (r 2 =0.87, p=0.0002).Conclusion-FMAU is preferably phosphorylated by TK2 and can track TK2 activity and mitochondrial mass in cellular stress. FMAU may provide an early marker of treatment effects.

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Section: Discussionmentioning

confidence: 49%

“…Pilot clinical studies show that tumor uptake of FMAU and FLT are similar [7,29]. AMPK activation and eIF2 inhibition have been shown in tumors [37,49,50].…”

Section: Discussionmentioning

confidence: 99%

Tracking cellular stress with labeled FMAU reflects changes in mitochondrial TK2

Tehrani

Douglas

Lawhorn-Crews

et al. 2008

Eur J Nucl Med Mol Imaging

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“…Occasional outliers should nevertheless be expected when using an average metabolite correction and its applicability in research protocols must be carefully evaluated. For [ 18 F]-FLT, the difference in parent concentration between the population mean and the range values is often about 15% to 20% toward the end of the scan (Shields et al, 2005;Visvikis et al, 2004). Moreover, the average value obtained from a given population may not be transferable to a different population.…”

Section: The Issue Of Metabolite And/or Plasma Versus Whole-blood Cormentioning

confidence: 99%

Image-Derived Input Function for Brain PET Studies: Many Challenges and Few Opportunities

Zanotti‐Fregonara

Chen

Liow

et al. 2011

J Cereb Blood Flow Metab

198

217

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Quantitative positron emission tomography (PET) brain studies often require that the input function be measured, typically via arterial cannulation. Image-derived input function (IDIF) is an elegant and attractive noninvasive alternative to arterial sampling. However, IDIF is also a very challenging technique associated with several problems that must be overcome before it can be successfully implemented in clinical practice. As a result, IDIF is rarely used as a tool to reduce invasiveness in patients. The aim of the present review was to identify the methodological problems that hinder widespread use of IDIF in PET brain studies. We conclude that IDIF can be successfully implemented only with a minority of PET tracers. Even in those cases, it only rarely translates into a less-invasive procedure for the patient. Finally, we discuss some possible alternative methods for obtaining less-invasive input function.

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“…This model has already been used as a kinetic model for FDG and FLT (19)(20)(21)(22). FMAU flux rate was assessed using 60 min of kinetic data.…”

Section: Discussionmentioning

confidence: 99%

Tumor Imaging Using 1-(2'-deoxy-2'-18F- Fluoro- -D-Arabinofuranosyl)Thymine and PET

Tehrani¹,

Muzik²,

Heilbrun³

et al. 2007

Journal of Nuclear Medicine

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The kinetics of 1-(29-deoxy-29-fluoro-b-D-arabinofuranosyl)thymine (FMAU) were studied using PET to determine the most appropriate and simplest approach to image acquisition and analysis. The concept of tumor retention ratio (TRR) is introduced and validated. Methods: Ten patients with brain (n 5 4) or prostate (n 5 6) tumors were imaged using 18 F-FMAU PET (mean dose, 369 MBq). Sixty-minute dynamic images were obtained; this was followed by whole-body images. Mean and maximum standardized uptake values (SUVmean and SUVmax, respectively) of each tumor were determined as the mean over 3 planes of each time interval. For kinetic analyses, blood activity was measured in 18 samples over 60 min. Samples were analyzed by high-performance liquid chromatography at 3 selected times to determine tracer metabolites. FMAU kinetics were measured using a 3-compartment model yielding the flux (K1 · k3/(k2 1 k3)) (K1, k2, and k3 are rate constants) and compared with TRR measurements. TRR was calculated as the tumor 18 F-FMAU uptake area under the curve divided by the product of blood 18 F-FMAU AUC and time. A similar analysis was performed using muscle to estimate 18 F-FMAU delivery. Results: SUVmean measurements obtained from 5 to 11 min correlated with those obtained from 30 to 60 min (r 2 5 0.92, P , 0.0001) and 50 to 60 min (r 2 5 0.92, P , 0.0001) due to the rapid clearance of 18 F-FMAU. Similar results were obtained using SUVmax measurements (r 2 5 0.93, P , 0.0001; r 2 5 0.88, P , 0.0001, respectively). The measurement of TRR using either blood or muscle activity over 11 min provided results comparable to those of 60-min dynamic imaging and a 3-compartment model. This analysis required only 5 blood samples drawn at 1, 2, 3, 5, and 11 min without metabolite correction to produce comparable results. Conclusion: Tissue retention ratio measurements obtained over 11 min can replace flux measurements in 18 F-FMAU imaging. The SUVmean and the SUVmax in 5-11 min images correlated well with those of images obtained at 50-60 min. The quality of the images and tissue kinetics in 11 min of imaging makes it a desirable and shorter tumor imaging option.

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A simplified analysis of [18F]3′-deoxy-3′-fluorothymidine metabolism and retention

Abstract: Dynamic measurements of FLT retention can be used to calculate metabolic rates using a limited set of samples and correction for metabolites measured in a single sample obtained at 60 min.

Cited by 57 publications

References 15 publications

Tracking cellular stress with labeled FMAU reflects changes in mitochondrial TK2

Tracking cellular stress with labeled FMAU reflects changes in mitochondrial TK2

Image-Derived Input Function for Brain PET Studies: Many Challenges and Few Opportunities

Tumor Imaging Using 1-(2'-deoxy-2'-18F- Fluoro- -D-Arabinofuranosyl)Thymine and PET

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