Pharmacokinetics of the thymidine analog 2′-fluoro-5-methyl-1-β-d-arabinofuranosyluracil (FMAU) in tumor-bearing rats

Bading, James R.; Shahinian, Antranik; Vail, Amy; Bathija, Pravin; Koszalka, George W.; Koda, Robert T.; Alauddin, Mian M.; Fissekis, John D.; Conti, Peter S.

doi:10.1016/j.nucmedbio.2004.01.001

Cited by 31 publications

(23 citation statements)

References 23 publications

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“…These also explain the low uptake in the human bone marrow in PET imaging studies [7] and weak correlation with tumor proliferation [28]. However, these data should be interpreted in the context of variations in pharmacokinetics and pharmacodynamics in different species.…”

Section: Discussionmentioning

confidence: 91%

“…Previous work has shown that FLT is phosphorylated specifically by TK1 [1,2,5], and its uptake in tumors correlate with TK1 activity and proliferation rate [27]. Unlike FLT, FMAU uptake did not correlate with tumor proliferation in animal studies [28]. Furthermore, the mechanism of increased FMAU retention in tumors with little retention in proliferating bone marrow was not known.…”

Section: Discussionmentioning

confidence: 95%

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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: 91%

Section: Discussionmentioning

confidence: 95%

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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Section: Methods For In Vivo Imaging Of Cell Proliferation Radiotracementioning

confidence: 99%

“…Preclinical studies have shown that FMAU retention in tumors and nontumor tissues with rapid cell turnover (e.g., marrow and small intestine), reflects incorporation into DNA (74)(75)(76)(77). FMAU is highly resistant to catabolism in both animals and humans, with the injected compound dominating time-activity curves in blood during the first hour after injection (75,76,78). Preliminary clinical studies have shown tumor uptake of 11 C-or 18 F-FMAU in a variety of cancers (78,79) comparable to that seen in human studies with 18 F-FLT (65,(80)(81)(82)(83).…”

Section: Methods For In Vivo Imaging Of Cell Proliferation Radiotracementioning

confidence: 99%

Imaging of Cell Proliferation: Status and Prospects

Bading¹,

Shields²

2008

J Nucl Med

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288

184

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Increased cellular proliferation is an integral part of the cancer phenotype. Several in vitro assays have been developed to measure the rate of tumor growth, but these require biopsies, which are particularly difficult to obtain over time and in different areas of the body in patients with multiple metastatic lesions. Most of the effort to develop imaging methods to noninvasively measure the rate of tumor cell proliferation has focused on the use of PET in conjunction with tracers for the thymidine salvage pathway of DNA synthesis, because thymidine contains the only pyrimidine or purine base that is unique to DNA. Imaging with 11 C-thymidine has been tested for detecting tumors and tracking their response to therapy in animals and patients. Its major limitations are the short half-life of 11 C and the rapid catabolism of thymidine after injection. These limitations led to the development of analogs that are resistant to degradation and can be labeled with radionuclides more conducive to routine clinical use, such as 18 F. At this point, the thymidine analogs that have been studied the most are 39-deoxy-39-fluorothymidine (FLT) and 1-(29-deoxy-29-fluoro-1-b-D-arabinofuranosyl)-thymine (FMAU). Both are resistant to degradation and track the DNA synthesis pathway. FLT is phosphorylated by thymidine kinase 1, thus being retained in proliferating cells. It is incorporated by the normal proliferating marrow and is glucuronidated in the liver. FMAU can be incorporated into DNA after phosphorylation but shows less marrow uptake. It shows high uptake in the normal heart, kidneys, and liver, in part because of the role of mitochondrial thymidine kinase 2. Early clinical data for 18 F-FLT demonstrated that its uptake correlates well with in vitro measures of proliferation. Although 18 F-FLT can be used to detect tumors, its tumor-to-normal tissue contrast is generally lower than that of 18 F-FDG in most cancers outside the brain. The most promising use for thymidine and its analogs is in monitoring tumor treatment response, as demonstrated in animal studies and pilot human trials. Further work is needed to determine the optimal tracer(s) and timing of imaging after treatment.

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“…A method for synthesis for 18 F-FMAU was developed (11)(12)(13), and this agent was studied in dogs, rats, and human subjects (14)(15)(16). Compared with dogs, mice, and rats, the tracer is cleared much more rapidly in humans because of uptake in the liver (10,(14)(15)(16).…”

mentioning

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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Pharmacokinetics of the thymidine analog 2′-fluoro-5-methyl-1-β-d-arabinofuranosyluracil (FMAU) in tumor-bearing rats

Cited by 31 publications

References 23 publications

Tracking cellular stress with labeled FMAU reflects changes in mitochondrial TK2

Tracking cellular stress with labeled FMAU reflects changes in mitochondrial TK2

Imaging of Cell Proliferation: Status and Prospects

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

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