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Enhanced Apoptotic Reaction Correlates with Suppressed Tumor Glucose Utilization After Cytotoxic Chemotherapy: Use of ^99mTc-Annexin V, ¹⁸F-FDG, and Histologic Evaluation

¹ Department of Nuclear Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
² Department of Tracer Kinetics, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
³ Department of Radiopharmaceutical Chemistry, Health Sciences University of Hokkaido, Tobetsu, Japan
⁴ Department of Nuclear Medicine, Memorial Sloan–Kettering Cancer Center, New York, New York
⁵ Division of Nuclear Medicine, Department of Radiology, Stanford University School of Medicine, Stanford, California
⁶ Department of Laboratory Medicine, University of Washington, Seattle, Washington

Cancer chemotherapy enhances the apoptosis, whereas apoptosis is a suicidal mechanism requiring energy. We determined the relationship between apoptosis and glucose utilization during cancer chemotherapy using ^99mTc-annexin V (^99mTc-annexin A5) and ¹⁸F-FDG and compared their uptake with histologic findings in a rat tumor model. Methods: Allogenic hepatoma cells (KDH-8) were inoculated into the left calf muscle of male Wistar rats (WKA). Eleven days after the inoculation, the rats were randomly divided into 3 groups: The first group (n = 7) received a single dose of gemcitabine (90 mg/kg, intravenously), the second group (n = 8) received cyclophosphamide (150 mg/kg, intraperitoneally), and the third group (n = 7) was untreated and served as the control group. We injected ^99mTc-annexin V 48 h after the chemotherapy and then injected ¹⁸F-FDG to all rats 1 h before sacrifice. Six hours after ^99mTc-annexin V injection, the rats were sacrificed and the organs, including the tumor, were removed and radioactivity was counted. The radioactivities of ¹⁸F and ^99mTc in the organs were determined using normalization by tissue weight. Histologic evaluation by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) method and the immunostaining of glucose transporter-1 (GLUT-1) were also performed to obtain the indices of apoptosis and glucose utilization, respectively. The rate of positively stained cells was calculated and analyzed statistically. Results: After chemotherapy using gemcitabine and cyclophosphamide, the ^99mTc-annexin V uptake (percentage injected dose per gram x kg [(%ID/g) x kg]; mean ± SD) in tumor increased significantly (0.062 ± 0.012 (%ID/g) x kg in the gemcitabine-treated group and 0.050 ± 0.012 (%ID/g) x kg in the cyclophosphamide group vs. 0.031 ± 0.005 (%ID/g) x kg in the control group; P < 0.01). In contrast, the ¹⁸F-FDG in tumor decreased significantly (0.483 ± 0.118 (%ID/g) x kg in the gemcitabine group and 0.583 ± 0.142 (%ID/g) x kg in the cyclophosphamide group) compared with that in the control group (0.743 ± 0.084 (%ID/g) x kg; P < 0.01). In addition, ¹⁸F-FDG uptake in tumor negatively correlated with ^99mTc-annexin V uptake (r = –0.75; P < 0.01). In the gemcitabine and cyclophosphamide groups, the rate of TUNEL positively stained cells was significantly higher than that in the control group (10.2% ± 1.7% and 8.0% ± 1.5% vs. 5.2% ± 1.5%; P < 0.01), whereas the GLUT-1 expression level showed no definite changes in histologic analyses. Conclusion: These data indicate that an enhanced apoptotic reaction correlated with suppressed tumor glucose utilization after cytotoxic chemotherapy as determined using radiotracers and histologic evaluation. The increase in ^99mTc-annexin V and the decrease in ¹⁸F-FDG in tumor can be useful markers for predicting therapeutic outcomes and for prognosis at the early stage of chemotherapy.

Key Words: molecular imaging • ¹⁸F-FDG • ^99mTc-annexin V • apoptosis • cancer chemotherapy

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