FLT-PET Imaging of Radiation Responses in Murine Tumors (original) (raw)
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Molecular Imaging and Biology, 2007
Objective: The uptake of 3 ¶-[ 18 F]fluoro-3 ¶-deoxythymidine (FLT), a proliferation marker, was measured before and during fractionated radiotherapy to evaluate the potential of FLT-positron emission tomography (PET) imaging as an indicator of tumor response compared to 2 ¶-deoxy-2 ¶-[ 18 F]fluoro-D-glucose (FDG). Materials and Methods: Nude mice bearing established human head and neck xenografts (HNX-OE; nu/nu mice) were locally irradiated (three fractions/week; 22 Gy) using a 150-kV p unit. Multiple FDG-and FLT-PET scans were acquired during treatment. Tumor volume was determined regularly, and tissue was analyzed for biomarkers involved in tracer uptake. Results: Both groups revealed a significant decline in tumor volume (PG0.01) compared to untreated tumors. For FDG as well as for FLT, a significant decline in retention was observed at day 4. For FLT, most significant decline in retention was observed at day 12; whereas, for FDG, this was already noted at day 4. Maximum decline in tumor-to-nontumor ratios (T/NT) for FDG and FLT was 42T18% and 49T16% (meanTSD), respectively. FLT uptake was higher then that of FDG. For FLT, statistical significant correlations were found for both tumor volume at baseline and at day 29 with T/NT and DT/NT. All tumors demonstrated expression of glucose transporter-1, thymidine kinase-1, and hexokinase II. No differences were found for amount of tumor cells and necrosis at the end of treatment. Conclusion: This new experimental in vivo model supports the promise of using FLT-PET, as with FDG-PET, to monitor response to external radiotherapy. This warrants further clinical studies to compare these two tracers especially in cancers treated with radiotherapy.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2004
3'-Deoxy-3'-18F-fluorothymidine (18F-FLT) has been suggested as a new PET tracer for imaging tumor proliferation. We investigated the use of 18F-FLT to monitor the response of tumors to radiotherapy and photodynamic therapy (PDT) in mice. C3H/He mice bearing an SCCVII tumor were treated with single-dose x-ray irradiation of 20 Gy. Tumor uptake was examined for 18F-FLT, 3H-thymidine (3H-Thd), 18F-FDG, and 14C-deoxyglucose (14C-DG) at 6 h, 12 h, 24 h, 3 d, and 7 d after radiotherapy. BALB/c nu/nu mice bearing a HeLa tumor were treated with PDT. Tumor uptake was examined for the 4 tracers at 24 h after PDT. Expression of proliferating cell nuclear antigen (PCNA) was determined in untreated and treated tumors. In the biodistribution study, considerable uptake of 18F-FLT was observed in both tumor types. Tumor volumes decreased to 39.3% +/- 22.4% at 7 d after radiotherapy. The PCNA labeling index was reduced in x-ray-irradiated tumors (control, 53.2% +/- 8.7%; 6 h, 38.5% +/- 5.3%...
Nuclear Medicine and Biology, 2009
Objectives: We assessed the reproducibility of the kinetic analysis of 3′-deoxy-3′-[ 18 F]fluorothymidine (FLT) positron emission tomography (PET) in A431 human epidermoid carcinoma and murine Lewis lung carcinoma (LLC) tumor models. Methods: We injected 7.4 MBq of FLT (n=10 for each group) and acquired 2-h dynamic PET images. A second scan was performed 1 day later. We calculated standardized uptake value (SUV), kinetic rate constants, volume of distribution of phosphorylated FLT (V dm), net influx constant (K FLT-CA) and influx constant by Patlak graphical analysis (K FLT-PA). The percent difference between measurements of a parameter was calculated to compare the reproducibilities of different parameters. Results: FLT phosphorylation was higher in mice with A431 tumors than in mice with LLC tumors (Pb.005). Differences in the standard deviations of the percent differences of parameters were statistically significant (Pb.001) in each model. In mice with A431 tumors, SUV, V dm , K FLT-CA and K FLT-PA had standard deviations of the percent difference of ≤20%. The most reproducible parameter was K FLT-PA , although the standard deviation (15.6%) was not statistically different from those of V dm (15.8%), K FLT-CA (17.5%) and SUV (18.9%). In mice with LLC tumors, K 1 , K 1 /k 2 and k 3 had standard deviations of the percent difference of ≤20%. No macroparameters reflecting a total FLT flux had standard deviations of ≤20%. Conclusion: Our results show the reproducibility of the kinetic macroparameters of FLT PET in mouse tumors with high FLT phosphorylation.
Molecular Imaging and Biology, 2011
Purpose: 3′-deoxy-3′-[ 18 F]fluorothymidine ([ 18 F]FLT), a cell proliferation positron emission tomography (PET) tracer, has been shown in numerous tumors to be more specific than 2deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) but less sensitive. We studied the capacity of a nontoxic concentration of 5-fluoro-2′-deoxyuridine (FdUrd), a thymidine synthesis inhibitor, to increase uptake of [ 18 F]FLT in tumor xenografts. Methods: The duration of the FdUrd effect in vivo on tumor cell cycling and thymidine analogue uptake was studied by varying FdUrd pretreatment timing and holding constant the timing of subsequent flow cytometry and 5-[ 125 I]iodo-2′-deoxyuridine biodistribution measurements. In [ 18 F]FLT studies, FdUrd pretreatment was generally performed 1 h before radiotracer injection.
Nuclear Medicine and Biology, 2002
The usefulness of radiolabeled 3Ј-fluoro-3Ј-deoxythymidine (FLT), a thymidine derivative with affinity to cytoplasmic thymidine kinase 1 (TK 1 ), as a tumor proliferation marker was evaluated using [ 3 H]FLT and 22 cultured tumor cell lines. Asynchronously growing tumor cells were used for studies to mimic in vivo status of tumors. FLT uptake in each cell line was compared with [ 3 H]thymidine ([ 3 H]Thd) uptake and %S-phase fraction, both known as acceptable markers of proliferation. Uptake of the mitochondrial TK 2 specific substrate [ 3 H]arabinothymidine ([ 3 H]AraT) was studied as a reference. Metabolic fate of FLT in tumor cells was also analyzed to elucidate the retention mechanism of FLT. [ 3 H]FLT uptake was mildly correlated with the %S-phase fraction (rϭ0.76, pϽ0.0001) and correlated better with [ 3 H]Thd uptake (rϭ0.88, pϽ0.0001). In contrast, the TK 2 specific substrate, [ 3 H]AraT, was not significantly correlated with the %S-phase fraction (rϭ0.19, pϭ0.39), although it showed some correlation with the [ 3 H]Thd uptake (rϭ0.47, pϽ0.05). Over 90% of radioactivity of [ 3 H]Thd was found in the DNA fraction after 60 minutes incubation. In contrast, most of the radioactivity of [ 3 H]FLT was found in the acid-soluble fraction (95%). [ 3 H]FLT incorporation into the DNA fraction was negligible (0.2%). The [ 3 H]AraT was mainly distributed in the acid-soluble fraction (70%) and the DNA fraction (20%). From our results, we concluded that FLT uptake in tumor cells reflects tumor cell proliferation. However, much more convincing validation is needed to clarify the difference between FLT and true substrates for DNA synthesis, like thymidine.
EJNMMI Research, 2016
Background: Recent studies have shown that 3′-deoxy-3′-[ 18 F] fluorothymidine ([ 18 F]FLT)) uptake depends on endogenous tumour thymidine concentration. The purpose of this study was to investigate tumour thymidine concentrations and whether they correlated with [ 18 F]FLT uptake across a broad spectrum of murine cancer models. A modified liquid chromatography-mass spectrometry (LC-MS/MS) method was used to determine endogenous thymidine concentrations in plasma and tissues of tumour-bearing and non-tumour bearing mice and rats. Thymidine concentrations were determined in 22 tumour models, including xenografts, syngeneic and spontaneous tumours, from six research centres, and a subset was compared for [ 18 F]FLT uptake, described by the maximum and mean tumour-to-liver uptake ratio (TTL) and SUV. Results: The LC-MS/MS method used to measure thymidine in plasma and tissue was modified to improve sensitivity and reproducibility. Thymidine concentrations determined in the plasma of 7 murine strains and one rat strain were between 0.61 ± 0.12 μM and 2.04 ± 0.64 μM, while the concentrations in 22 tumour models ranged from 0.54 ± 0.17 μM to 20.65 ± 3.65 μM. TTL at 60 min after [ 18 F]FLT injection, determined in 14 of the 22 tumour models, ranged from 1.07 ± 0.16 to 5.22 ± 0.83 for the maximum and 0.67 ± 0.17 to 2.10 ± 0.18 for the mean uptake. TTL did not correlate with tumour thymidine concentrations. Conclusions: Endogenous tumour thymidine concentrations alone are not predictive of [ 18 F]FLT uptake in murine cancer models.
2003
3 -Deoxy-3 -[F]fluorothymidine ([F]FLT) has been proposed as a new marker for imaging tumor proliferation by positron emission tomography (PET). The uptake of [F]FLT is regulated by cytosolic S-phasespecific thymidine kinase 1 (TK1). In this article, we have investigated the use of [F]FLT to monitor the response of tumors to antiproliferative treatment in vivo. C3H/Hej mice bearing the radiation-induced fibrosarcoma 1 tumor were treated with 5-fluorouracil (5-FU; 165 mg/kg i.p.). Changes in tumor volume and biodistribution of [F]FLT and 2-[F]fluoro-2-deoxy-D-glucose ([F]FDG) were measured in three groups of mice (n 8–12/group): (a) untreated controls; (b) 24 h after 5-FU; and (c) 48 h after 5-FU. In addition, dynamic [F]FLT-PET imaging was performed on a small animal scanner for 60 min. The metabolism of [F]FLT in tumor, plasma, liver, and urine was determined chromatographically. Proliferation was determined by staining histological sections for proliferating cell nuclear antigen (...
… cancer research: an …, 2002
Purpose: Tumor proliferation has prognostic value in resected early stage non-small cell lung cancer (NSCLC) and can, therefore, predict which NSCLCs are at high risk for recurrence after resection and would benefit from additional therapy. It may also predict which tumor will respond to cell cycle-targeted chemotherapy and help assess the tumor response, besides helping to differentiate benign from malignant lung lesions. We evaluated whether the uptake of the new positron emission tomography (PET) tracer 3deoxy-3-[ 18 F]fluorothymidine (FLT) in a series of suspected NSCLCs correlated with tumor proliferation assessed by Ki-67 immunohistochemistry and flow cytometry. Experimental Design: Ten patients with 11 biopsyproven or clinically suspected NSCLC underwent 2-h dynamic PET imaging after i.v. injection of 0.07 mCi/kg FLT. Tumor FLT uptake was quantitated with the maximum pixel standardized uptake value (maxSUV), the partial volume corrected maxSUV (PV-corr-maxSUV), the average SUV over a small region-of-interest (aveSUV) and with Patlak analysis of FLT flux (aveFLTflux). The lesion diameter from computed tomography was used to correct the maxSUV for PV effects using recovery coefficients determined for the General Electric Advance PET scanner. Two of the 11 lesions were benign inflammatory lesions and 9 were NSCLCs. Immunohistochemistry for Ki-67 (proliferation index marker) was performed on all 11 tissue specimens (10 resections, 1 NSCLC percutaneous biopsy), and the S-phase fraction (SPF) from flow cytometry could be determined for 10. The specimens were reviewed for histology and cellular differentiation (poor, moderate, well). Lesions ranged from 1.6 to 7.7 cm. Results: Excellent correlations were found between SUV measures of FLT uptake and Ki-67 scores [percentage of positive cells; maxSUV versus Ki-67: Rho ؍ 0.78, P ؍ 0.0043 (n ؍ 11); PV-corr-maxSUV versus Ki-67: Rho ؍ 0.83, P ؍ 0.0028 (n ؍ 10); aveSUV versus Ki-67: Rho ؍ 0.84, P ؍ 0.0011 (n ؍ 11)]. Correlation between Ki-67 proliferation scores and Patlak measures of FLT uptake were also strong: aveFLTflux versus Ki-67: Rho ؍ 0.94, P < 0.0001 (n ؍ 11). The correlation between the SPF and all indices of FLT uptake was weaker and reached statistical significance for only two uptake indices [maxSUV versus SPF: Rho ؍ 0.69, P ؍ 0.03 (n ؍ 10); PV-corr-maxSUV versus SPF: Rho ؍ 0.36, P ؍ 0.35 (n ؍ 9); aveSUV versus SPF: Rho ؍ 0.67, P ؍ 0.03 (n ؍ 10); aveFLTflux versus SPF: Rho ؍ 0.46, P ؍ 0.18 (n ؍ 10)]. Conclusion: FLT PET may be used to noninvasively assess proliferation rates of lung masses in vivo. Therefore, FLT PET may play a significant role in the evaluation of indeterminate pulmonary lesions, in the prognostic assessment of resectable NSCLC, and possibly in the evaluation of NSCLC response to chemotherapy.