| Abstract: |
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 call 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, intrapentoneally), 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 × kg [(%ID/g) × kg]; mean ± SD) in tumor increased significantly (0.062 ± 0.012 (%ID/g) × kg in the gemcitabine-treated group and 0.050 ± 0.012(%ID/g) × kg in the cyclophosphamide group vs. 0.031 ± 0.005 (%ID/g) × kg in the control group; P < 0.01). In contrast, the 18F-FDG in tumor decreased significantly (0.483 ± 0.118(%ID/g) × kg in the gemcitabine group and 0.583 ± 0.142 (%ID/g) × kg in the cyclophosphamide group) compared with that in the control group (0.743 ± 0.084 (%ID/g) × 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 alter 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. |
