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Evaluation of 3'-Deoxy-3'-¹⁸F-Fluorothymidine for Monitoring Tumor Response to Radiotherapy and Photodynamic Therapy in Mice

¹ Department of Radiology, Hamamatsu University School of Medicine, Hamamatsu, Japan
² Central Research Laboratory, Hamamatsu Photonics K.K., Hamakita, Japan
³ Photon Medical Research Center, Hamamatsu University School of Medicine, Hamamatsu, Japan

	ABSTRACT

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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. Methods: 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. Results: 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%; 24 h after radiotherapy, 36.8% ± 5.3%). ¹⁸F-FLT uptake in tumor expressed as the percentage of the injected dose per gram of tumor (%ID/g) decreased significantly at 6 h and remained low until 3 d after radiotherapy (control, 9.7 ± 1.2 %ID/g; 6 h, 5.9 ± 0.4 %ID/g; 24 h, 6.1 ± 1.3 %ID/g; 3 d after radiotherapy, 6.4 ± 1.1 %ID/g). ¹⁸F-FDG uptake tended to gradually decrease but a significant decrease was found only at 3 d (control, 12.1 ± 2.7 %ID/g; 6 h, 13.3 ± 2.3 %ID/g; 24 h, 8.6 ± 1.8 %ID/g; 3 d after radiotherapy, 6.9 ± 1.2 %ID/g). PDT resulted in a reduction of the PCNA labeling index (control, 82.0% ± 8.6%; 24 h after PDT, 13.5% ± 12.7%). Tumor uptake of ¹⁸F-FLT decreased (control, 11.1 ± 1.3 %ID/g; 24 h after PDT, 4.0 ± 2.2 %ID/g), whereas ¹⁸F-FDG uptake did not decrease significantly after PDT (control, 3.5 ± 0.6 %ID/g; 24 h after PDT, 2.3 ± 1.1 %ID/g). Changes in the uptake of ¹⁸F-FLT and ¹⁸F-FDG were similar to those of ³H-Thd and ¹⁴C-DG, respectively. Conclusion: In our model system, changes in ¹⁸F-FLT uptake after radiotherapy and PDT were correlated with those of ³H-Thd and the PCNA labeling index. The decrease in ¹⁸F-FLT uptake after treatments was more rapid or pronounced than that of ¹⁸F-FDG. Therefore, ¹⁸F-FLT may be a feasible PET tracer for monitoring response to therapy in oncology.

Key Words: 3'-deoxy-3'-¹⁸F-fluorothymidine • PET • radiotherapy • photodynamic therapy

	INTRODUCTION

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Deregulated proliferation is one of the key features of malignant tumors and imaging of tumor proliferation is expected to improve the management of patients with cancer. Morphologic imaging techniques, which have been the standard method to identify treatment efficacy, depict tumor response as changes in tumor size and composition. Changes in size, however, are often delayed and it is difficult to evaluate early response to treatment by morphologic imaging techniques.

PET can aid in this task, because metabolic and physiologic changes precede size change. The fluorine-labeled glucose analog ¹⁸F-FDG has been the most widely used agent in PET tumor imaging. However, increased glycolysis is not an essential property of proliferating cells and ¹⁸F-FDG is taken up by inflammatory cells such as macrophages (1). Therefore, considerable efforts have been invested in seeking more suitable PET tracers for imaging tumor proliferation (2). Recently, a fluorine-labeled thymidine analog, 3'-deoxy-3'-¹⁸F-fluorothymidine (¹⁸F-FLT), has been developed as a candidate for imaging cell proliferation. ¹⁸F-FLT is phosphorylated by thymidine kinase 1, the key enzyme of the pyrimidine salvage pathway of DNA synthesis, and metabolically trapped as a phosphorylated form (3).

¹⁸F-FLT was firstly applied for PET in 1998 (4) and, since then, ¹⁸F-FLT has been shown to accumulate in a variety of tumors and its uptake could reflect the tumor proliferation (4–9). However, there have been few reports on the use of ¹⁸F-FLT for monitoring tumor response to therapy.

The aim of this study was to investigate the use of ¹⁸F-FLT for monitoring response to anticancer treatments in mouse models. We clarified that the change of ¹⁸F-FLT uptake after radiotherapy or photodynamic therapy (PDT) correlated well with the proliferative activity of transplanted tumors.

	MATERIALS AND METHODS

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Radiopharmaceuticals
¹⁸F-FLT and ¹⁸F-FDG were produced by the Central Research Laboratory, Hamamatsu Photonics K.K. ¹⁸F-FLT was synthesized by nucleophilic substitution of nosylate precursor (precursor FLT [1-(2-deoxy-3-o-(4-nitrobenzenesulfonyl)-5-o-(4,4'-dimethoxytrityl)-D-threopentofuranosyl)-3-(2,4-dimethoxybenzyl)thymine]) according to the method developed by Grierson and Shields with minor modification (10). ¹⁸F-Fluoride was produced with the cyclotron, using the ¹⁸O (p, n)^18_F nuclear reaction by irradiation of a water target containing ¹⁸O-enriched water. ¹⁸F-FDG was synthesized with an automated FDG synthesis module. Methyl-³H-thymidine ([³H-Thd]; specific activity, 2.22–3.2 TBq/mmol) and 2-deoxy-D-1-¹⁴C-glucose ([¹⁴C-DG]; specific activity, 1.85–2.29 GBq/mmol) were purchased from Amersham Biosciences Corp.

Animals and Tumor Models
Five- to 7-wk-old female C₃H/He mice (Japan SLC, Inc.) and BALB/c nu/nu mice (CREA Japan, Inc.) were used. Subcutaneous tumors were established in the thigh of C₃H/He mice with SCCVII, a murine squamous cell carcinoma cell line, and in the thigh of BALB/c nu/nu mice with HeLa, a human uterine cervical adenocarcinoma cell line. When the size of tumor reached 6–10 mm in diameter at 10–14 d after the injection of 5 x 10⁶ cells, the mice were used for experiments. In all animal experiments, the mice were not anesthetized after tracer injection. The experimental protocol was fully accredited by the laboratory Animal Care Committee of the Hamamatsu University School of Medicine.

¹⁸F-FLT Uptake in Untreated Tumor and Normal Tissue
The biodistribution of ¹⁸F-FLT was assessed in untreated tumor-bearing mice. Twelve C₃H/He mice transplanted with SCCVII and 4 BALB/c nu/nu mice transplanted with HeLa were injected intravenously with 1.8–2.5 MBq ¹⁸F-FLT via lateral tail vein. SCCVII-bearing mice were sacrificed at 0.5, 1, and 2 h after radiotracer injection. HeLa-bearing mice were sacrificed at 1 h. Blood, normal tissue (heart, lung, kidney, spleen, muscle, femur, small intestine), and tumor samples were rapidly excised. All samples were weighed, and the radioactivity was measured in an auto-well -counter (Aloka ARC-2000), applying a decay correction. Accumulation of tracers in tumor or normal tissues was expressed as the percentage of the injected dose per gram of tumor per 20 g of mouse weight (%ID/g).

X-Ray Irradiation
C₃H/He mice transplanted with SCCVII were anesthetized with 1 mg sodium pentobarbital intraperitoneally and then fixed with adhesive tape to place the tumor-bearing thigh in the field of irradiation. The other parts of the body were left outside of the radiation field. Tumors were exposed to a single dose of 20 Gy at a dose rate of 2.25 Gy/min.

Changes in Tumor Volume After Radiotherapy
Eight C₃H/He mice transplanted with SCCVII were randomly assigned to 2 groups: 1 treatment group and 1 control group. Each group consisted of 4 mice. From the day of the irradiation, tumor size was determined with a caliper measuring the largest diameter (a) and the perpendicular diameter (b). Tumor volume was calculated according to the formula 0.5 x a x b², assuming an elliptic geometry. Growth curves were generated as a change of relative tumor volume based on the volume on the day of irradiation.

PDT
BALB/c nu/nu mice transplanted with HeLa were injected intravenously with 6 mg/kg of ATX-S10(Na) (13,17-bis[1-carboxypropionyl]carbamoylethyl-8-ethenyl-2-hydroxy-3-hydroxyiminoethylidene-2,7,12,18-tetramethylporphyrin sodium salt) via tail vein. ATX-S10(Na) is a second-generation photosensitizer, which was developed to reduce the hyperphotosensitivity of porfimer sodium (11). Three hours later, the mice were restrained for light exposure. A 10- to 14-mm-diameter area encompassing the tumor was irradiated with a semiconductor diode laser of 670-nm wavelength (LD670C; Hamamatsu Photonics K.K.) at a fluence of 100 J/cm². Tumors were inspected until 7 d after PDT in 5 mice.

Expression of Proliferating Cell Nuclear Antigen (PCNA)
Untreated SCCVII and HeLa tumors, SCCVII tumors at 6 and 24 h after radiotherapy, and HeLa tumors at 24 h after PDT were fixed in formalin, embedded in paraffin, and cut into 5.0-µm sections. Tumors were obtained from 4 mice in each group. One section per tumor was examined. Sections were incubated with biotinylated PCNA monoclonal antibody (Zymed Laboratory Inc.); streptoavidin peroxidase was used as a signal generator and diaminobenzidine tetrahydrochloride was used as a choromogen to stain PCNA-containing nuclei a dark brown. All sections were counterstained with hematoxylin for counting the total cell number. In each run, sections of small intestine were stained as positive controls and sections of brain were used as negative controls. First, the PCNA-stained section was scanned at low power to select areas exhibiting a high concentration of PCNA-positive cells and high cellular density. Then, the numbers of PCNA-positive and hematoxylin-positive cells were counted in 5 randomly selected fields of view per section using a BH2 microscope (Olympus Optical) at x400 magnification. At least 500 cells were counted in each field. The PCNA labeling index was established as the percentage of PCNA-positive cells.

Tumor Uptake of Radiopharmaceuticals After Radiotherapy
In SCCVII-bearing mice, tumor uptake of ¹⁸F-FLT or ¹⁸F-FDG was assessed at 6 h, 12 h, 24 h, 3 d, and 7 d after radiotherapy. Untreated mice served as controls. Twenty-seven mice were used for ¹⁸F-FLT (untreated control, n = 4; 6 h, n = 5; 12 h, n = 5; 24 h, n = 4; day 3, n = 5; day 7, n = 4). Twenty-nine mice were used for ¹⁸F-FDG (untreated control, n = 5; 6 h, n = 5; 12 h, n = 5; 24 h, n = 5; day 3, n = 5; day 7, n = 4). The mice received 1.8–2.5 MBq ¹⁸F-FLT or 1.8–2.5 MBq ¹⁸F-FDG.

The uptake of ³H-Thd and ¹⁴C-DG in x-ray–irradiated tumor was determined by the dual-tracer technique. A mixture of 0.0925 MBq ³H-Thd and 0.037 MBq ¹⁴C-DG was administered to untreated mice and to mice at 6 h, 12 h, 24 h, 3 d, and 7 d after radiotherapy. Thirty mice were used for this dual-tracer experiment (untreated control, n = 6; 6 h, n = 4; 12 h, n = 5; 24 h, n = 5; day 3, n = 5; day 7, n = 5).

The mice were killed at 1 h after radiotracer injection. Tumors were rapidly excised and weighed. Radioactivity was measured in an auto-well -counter for ¹⁸F and in a liquid scintillation counter using the double-window technique for ³H and ¹⁴C. Tumor uptake of radiotracers was calculated as in the biodistribution study.

Tumor Uptake of Radiopharmaceuticals After PDT
Tumor uptake of ¹⁸F-FLT, ¹⁸F-FDG, ³H-Thd, and ¹⁴C-DG was measured in HeLa-bearing BALB/c nu/nu mice at 24 h after PDT. Untreated mice served as controls. Eight mice were used for ¹⁸F-FLT (control, n = 4; PDT, n = 4). Eight mice were used for ¹⁸F-FDG (control, n = 4; PDT, n = 4). Twelve mice were used for the dual-tracer experiment of ³H-Thd and ¹⁴C-DG (control, n = 6; PDT, n = 6). The administered dose of radiopharmaceuticals and the methods for evaluating tumor uptake were the same as those in the experiments for radiotherapy.

Statistical Analysis
Statistical analysis was performed with SPSS for Windows software, version 11.0.1 (SPSS, Inc.). All data are expressed as mean ± SD. The differences between untreated controls and x-ray–irradiated groups with respect to radiotracer uptake and the PCNA labeling index were analyzed by the Kruscal–Wallis test with adjustment by the Bonferroni method for multiple comparisons. P < 0.05 was considered statistically significant.

Differences between untreated controls and PDT-treated groups with respect to radiotracer uptake and the PCNA labeling index were tested with the Mann–Whitney Wilcoxon test. P < 0.05 was considered statistically significant.

	RESULTS

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¹⁸F-FLT Uptake in Untreated Tumor and Normal Tissue
Because tumor uptake of ¹⁸F-FLT in SCCVII at 1 h after injection was not significantly different from that at 2 h (data not shown), we conducted the following experiments with ¹⁸F-FLT at the 1-h time point. Figure 1 shows the tissue distribution of ¹⁸F-FLT in SCCVII-bearing C₃H/He mice and in HeLa-bearing BALB/c nu/nu mice at 1 h after injection. High radioactivity was noted in the kidney and small intestine as well as the tumors. Splenic uptake was also high in C₃H/He mice.

View larger version (13K): [in this window] [in a new window]   FIGURE 1. Biodistribution of 18F-FLT in C3H/He mice transplanted with SCCVII and in BALB/c nu/nu mice transplanted with HeLa at 1 h after injection. Data are expressed as mean ± SD.

View larger version (13K): [in this window] [in a new window]   FIGURE 2. Changes in relative tumor volume in control mice and x-ray–irradiated mice. Mice bearing SCCVII received 20 Gy at day 0. Data are expressed as mean ± SD. Radiotherapy resulted in tumor shrinkage and no tumor regrowth was found until 14 d after radiation. Tumors grew again after 14 d.

View larger version (28K): [in this window] [in a new window]   FIGURE 3. Tumor uptake of 4 tracers after radiotherapy. Data are expressed as mean ± SD. Asterisks indicate statistically significant differences compared with untreated controls (P < 0.05). Tumor uptake of 18F-FLT decreased significantly at 6 h, 12 h, 24 h, and 3 d after radiotherapy compared with untreated controls. There was a significant decrease in 3H-Thd uptake at 6 h, 12 h, 24 h, 3 d, and 7 d compared with untreated controls. Tumor uptake of 18F-FDG and 14C-DG did not show a statistically significant decrease at 6, 12, and 24 h after radiotherapy.

View larger version (9K): [in this window] [in a new window]   FIGURE 4. Tumor uptake of 4 tracers at 24 h after PDT. Data are expressed as mean ± SD. Asterisks indicate statistically significant differences compared with untreated controls (P < 0.05). A significant decrease of tumor uptake of 18F-FLT and 3H-Thd was observed in PDT-treated tumors. There was no significant difference between untreated controls and PDT-treated tumors in the uptake of 18F-FDG and 14C-DG.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

¹⁸F-FLT uptake in tumor was also validated by comparison with the PCNA labeling index. PCNA is a 36-kDa nuclear polypeptide that is related to the cell proliferation (12). A previous study indicated that PCNA, synthesized during the late G₁-to-S phase, is an auxiliary for DNA polymerase (13). Correlation between ¹⁸F-FLT uptake and the PCNA labeling index after radiotherapy and PDT also suggests the usefulness of ¹⁸F-FLT for monitoring cell proliferation.

PDT is a new treatment modality for solid tumors. The procedure consists of the administration of a photosensitizer that accumulates preferentially in the tumor, followed by local illumination of neoplastic tissues with red light (14,15). PDT has been shown to induce tumor necrosis through initial vascular damage and to direct tumor cell killing induced by singlet oxygen (16). Because ¹⁸F-FLT is useful for monitoring the effect of PDT, which has a different antitumor mechanism from radiotherapy, ¹⁸F-FLT could be applicable to other types of anticancer therapy.

In C₃H/He mice, high uptake was found in the spleen and small intestine, which are organs with a high proliferative activity in mice. High uptake in the kidneys suggests a renal excretion of ¹⁸F-FLT. Uptake in the spleen was not high in BALB/c nu/nu mice in comparison with C₃H/He mice. Distribution of ¹⁸F-FLT in normal tissues may be different among strains of mice.

A decrease in tumor uptake of ¹⁸F-FDG was found only 3 d after radiotherapy, and ¹⁸F-FDG uptake did not decrease significantly after PDT. ¹⁴C-DG showed a change similar to that of ¹⁸F-FDG. These results may be attributable to a minimal change in glycolysis in tumor cells or an increase in glucose uptake by inflammatory tissues early after radiotherapy or PDT. Work with animal tumors and cultured cells has suggested that radiolabeled thymidine is a better indicator of cell proliferation than ¹⁸F-FDG (17,18). Furthermore, Barthel et al. showed an early decrease in ¹⁸F-FLT uptake by RIF-1 tumors after 5-fluorouracil treatment, which was more pronounced than that of ¹⁸F-FDG (19). Our results agree with the findings that the uptake of radiolabeled thymidine provided more accurate assessments of the early response to anticancer therapy than that of ¹⁸F-FDG.

	CONCLUSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 
We have shown that the decrease in ¹⁸F-FLT uptake after radiotherapy and PDT was more rapid or pronounced than that of ¹⁸F-FDG. ¹⁸F-FLT uptake correlated well with ³H-Thd uptake and the PCNA labeling index. The change in ¹⁸F-FLT uptake was supposed to reflect proliferative activity after anticancer treatment. Therefore, ¹⁸F-FLT is expected to be a feasible PET tracer for monitoring the response to therapy in oncology.

	ACKNOWLEDGMENTS

 
The authors are grateful to Yasuhiro Magata, PhD, and Mikako Ogawa, MS, of Photon Medical Research Center, Hamamatsu University School of Medicine, for their technical assistance. This study was supported in part by a Grant-in-Aid for Scientific Research (1240187) and Special Coordination Funds for the Promotion of Science and Technology (Research and Development of Technology for Measuring Vital Function Merged with Optical Technology) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

	FOOTNOTES

 
Received Feb. 19, 2004; revision accepted Apr. 29, 2004.

For correspondence or reprints contact: Masahiro Sugiyama, MD, Department of Radiology, Hamamatsu University School of Medicine, Handayama 1-20-1, Hamamatsu, Japan 431-3192.

E-mail: masahiro{at}akiha.hama-med.ac.jp

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