Levels of human equilibrative nucleoside transporter-1 are higher in proliferating regions of A549 tumor cells grown as tumor xenografts in vivo

Plotnik, David A.; Asher, Camille; Chu, Stephanie K.; Miyaoka, Robert S.; Garwin, Gregory G.; Johnson, Brian W.; Li, Tiffany; Krohn, Kenneth A.; Schwartz, Jeffrey L.

doi:10.1016/j.nucmedbio.2012.07.007

Cited by 10 publications

(7 citation statements)

References 13 publications

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“…While TK1 is an absolute requirement for FLT radiotracer accumulation [ 6 , 10 ], variations in levels of the equilibrative nucleoside transporter-1 (ENT1) have been shown to modify intracellular peak levels of FLT [ 10 – 12 ]. We have reported that proliferating cells have higher levels of ENT1 than nonproliferating cells [ 10 , 12 ]. Dependence of a proliferation tracer on ENT1 improves the ability of these tracers to distinguish between proliferating and nonproliferating regions of a tumor.…”

Section: Introductionmentioning

confidence: 99%

In vitro analysis of transport and metabolism of 4′-thiothymidine in human tumor cells

Plotnik

Linn

et al. 2015

Nuclear Medicine and Biology

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Introduction The use of thymidine (TdR) and thymidine analogs such as 3′-fluoro-3′-deoxythymidine (FLT) as positron emission tomography (PET)-based proliferation markers can provide information on tumor response to treatment. Studies on another TdR analog, 4'-thiothymidine (4DST), suggest that it might be a better PET-based proliferation tracer than either TdR or FLT. 4DST is resistant to the catabolism that complicates analysis of TdR in PET studies, but unlike FLT, 4DST is incorporated into DNA. Methods To further evaluate 4DST, the kinetics of 4DST transport and metabolism were determined and compared to FLT and TdR. Transport and metabolism of FLT, TdR and 4DST were examined in the human adenocarcinoma cell line A549 under exponential-growth conditions. Single cell suspensions were incubated in buffer supplemented with radiolabeled tracer in the presence or absence of nitrobenzylmercaptopurine ribonucleoside (NBMPR), an inhibitor of equilibrative nucleoside transporters (ENT). Kinetics of tracer uptake was determined in whole cells and tracer metabolism measured by high performance liquid chromatography of cell lysates. Results TdR and 4DST were qualitatively similar in terms of ENT-dependent transport, shapes of uptake curves, and relative levels of DNA incorporation. FLT did not incorporate into DNA, showed a significant temperature effect for uptake, and its transport had a significant NBMPR-resistant component. Overall 4DST metabolism was significantly slower than either TdR or FLT. Conclusions 4DST provides a good alternative for TdR in PET and has advantages over FLT in proliferation measurement. However, slow 4DST metabolism and the short half-life of the 11C label might limit widespread use in PET.

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Section: Introductionmentioning

confidence: 99%

In vitro analysis of transport and metabolism of 4′-thiothymidine in human tumor cells

Plotnik

Linn

et al. 2015

Nuclear Medicine and Biology

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“…These findings are consistent with the evidence that thymidine kinase-1 (TK1) activity, an enzyme up-regulated during S-phase and decreased in cells that do not undergo division,(12) is needed for the accumulation of FLT. (26–28)…”

Section: Discussionmentioning

confidence: 99%

Pharmacoimaging of Blood-Brain Barrier Permeable (FDG) and Impermeable (FLT) Substrates After Intranasal (IN) Administration

Ponto

Walsh

Huang

et al. 2017

AAPS J

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Purpose To illustrate the use of imaging to quantify the transfer of materials from the nasal cavity to other anatomical compartments, specifically, transfer to the brain using the thymidine analogue, [18F]fluorothymidine (FLT), and the glucose analogue, [18F]fluorodeoxyglucose (FDG). Methods Anesthetized rats were administered FLT or FDG by intranasal instillation (IN) or tail-vein injection (IV). PET/CT imaging was performed for up to 60 minutes. Volumes-of-interest (VOIs) for the olfactory bulb (OB) and the remaining brain were created on the CT and transferred to the co-registered dynamic PET. Time-activity curves (TACs) were generated and compared. Results The disposition patterns were successfully visualized and quantified and differences in brain distribution patterns were observed. For FDG, the concentration was substantially higher in the OB than the brain only after IN administration. For FLT, the concentration was higher in the OB than the brain after both IN and IV and higher after IN than after IV administration at all times, whereas, the concentration in the brain was higher after IN than after IV administration at early times only. Approximately 50% and 9% of the IN FDG and FLT doses, respectively, remained in the nasal cavity at 20 minutes post-administration. The initial phase of clearance was similar for both agents (t1/2=2.53 and 3.36 minutes) but the slow clearance phase was more rapid for FLT than FDG (t1/2=32.1 and 85.2 minutes, respectively). Conclusion Pharmacoimaging techniques employing PET/CT can be successfully implemented to quantitatively investigate and compare the disposition of radiolabeled agents administered by a variety of routes.

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“…In a study examining the extent to which ENT1 levels vary in a proliferation-dependent manner in human A549 tumor cells grown as tumor xenografts in nude mice, [ 18 F]FLT uptake was measured in vivo using small animal PET and further examined ex vivo using autoradiography [87]. [87].…”

Section: F]flt Inside Cellsmentioning

confidence: 99%

Nucleoside transporters in PET imaging of proliferating cancer cells using 3ꞌ-deoxy-3ꞌ-[18F]fluoro-L-thymidine

Saidijam¹,

Afshar²,

Ahmad³

et al. 2018

J Diagn Imaging Ther

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The movement of physiologic nucleosides and nucleoside analogue drugs across biological membranes is mediated by nucleoside transport proteins. In cancer, nucleoside transporters have an important role in maintaining the hyperproliferative state of tumours and are important targets for diagnostic and therapeutic agents in the detection, treatment and monitoring of cancers. The nucleoside-based probe 3ꞌ-deoxy-3ꞌ-

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Levels of human equilibrative nucleoside transporter-1 are higher in proliferating regions of A549 tumor cells grown as tumor xenografts in vivo

Cited by 10 publications

References 13 publications

In vitro analysis of transport and metabolism of 4′-thiothymidine in human tumor cells

In vitro analysis of transport and metabolism of 4′-thiothymidine in human tumor cells

Pharmacoimaging of Blood-Brain Barrier Permeable (FDG) and Impermeable (FLT) Substrates After Intranasal (IN) Administration

Nucleoside transporters in PET imaging of proliferating cancer cells using 3ꞌ-deoxy-3ꞌ-[18F]fluoro-L-thymidine

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