The Studies of Using [18F]FBAU for the Brain Tumor Imaging and Therapeutic Efficacy Evaluation of Curcumin Combined with Radiation in F98 Glioma-bearing Rat Model

• Main Authors: Yi-Chun Chien, 簡溢均
• Other Authors: Jeng-Jong Hwang
• Format: Others
• Language: en_US
• Published: 2014
• Online Access: http://ndltd.ncl.edu.tw/handle/11510258010545969257

博士 === 國立陽明大學 === 生物醫學影像暨放射科學系 === 102 === Abstract (part 1) 1-(2-deoxy-2-18F-fluoro-β-D-arabinofuranosyl)-5-bromouracil (18F-FBAU) has been reported to be an effective reporter gene probe for tracing the expression of herpes simplex virus type 1 thymidine kinase (HSV1-tk) with PET imaging. The selective uptake of 18F-FBAU combined with imaging modality in a rat model bearing glioma transfected with dual reporter genes, HSV1-tk and firefly luciferase, could be an attractive strategy for evaluating tumor progression. The purpose of this study was to explore the diagnostic efficacy of 18F-FBAU for brain tumor progression and its potential clinical application for the evaluation of tumor therapeutic efficacy. F98 glioma cells were transfected with pC1-CMV-tk-IRES-luc plasmid followed by evaluation the expressions of these two reporter genes with bioluminescent imaging (BLI) and the uptakes of both gancyclovir (GCV) and I-131 labeled 2’-fluoro-2’-deoxy-5-iodo-1-β-D-arabinofuranosyluracil (131I-FIAU). The stable clone was renamed as F98/tk-luc cell line. 12 to 14-week-old male Fischer 344 rats bearing orthotopic F98-tk/luc glioma in the left brain were used for investigation, including biodistribution of 18F-FBAU, ex vivo autoradiography and PET imaging. MR imaging (MRI) was also performed on the same cohort to verify the correlation among the tumor volume and different modalities of molecular imaging. The surviving fraction of the F98/tk-luc cells treated with 15 μM GCV was 15.9%. The uptake of 131I-FIAU in F98/tk-luc cells was increased with treatment time. The correlation coefficient of tumor volume in F98 tk-luc glioma-bearing rats obtained from MRI versus BLI was 0.90. The biodistribution demonstrated the accumulation ratios of 18F-FBAU for glioma-to-normal brain were 9.16, 14.24, 5.70 and 13.7 at 30, 60, 90 and 120 min post-injection, respectively. Similar finding was found in 18F-FBAU/PET images with the highest during 30-90 min post-injection. Ex vivo autoradiography also confirmed that significantly higher 18F-FBAU uptake in the glioma compared with that of normal brain counterpart.　In conclusion, 18F-FBAU combined with PET imaging in the F98/tk-luc glioma-bearing rat model was demonstrated with effective diagnosis for tumor progression, and may have potential as a radiophamaceutical for therapeutic evaluation. Abstract (part 2) Curcumin is a well-documented anti-oxidant with numerous pharmacological activities such as anti-inflammation and anti-carcinogenesis. Curcumin also has been shown to play an import role in neuronal protection. Gliomas are graded into four categories: grade I, II, III and IV which is also named as glioblastoma multiforme (GBM). GBM is associated with a median survival of less than 1 year. In our previous study, we used lentivirus vectors constructed with trifusion reporter genes (Fluc/gfp/tk) and transduced into rat F98 glioblastoma cells, and renamed as the F98/FGT glioblastoma cell line. An orthotopic F98/FGT glioblastoma-bearing rat model was estblished. The F98/FGT glioblastoma-bearing rats were randomly divided into four groups: control, curcumin alone (50 mg/kg/d intraperitoneal injection between day 4-19 post tumor cells inoculation), radiation alone (local irradiation with 4 Gy on day 7), and combination of curcumin and 4 Gy. The therapeutic efficacy was evaluated with noninvasive bioluminescent imaging and the overall survival rate. The results suggest that curcumin combined with radiotherapy is able to inhibit the brain tumor growth with the best overall survival as compared with those of the control and mono-therapeutic groups. These results suggest that curcumin may enhance the radiosensitivity of brain tumors to radiotherapy, and may have the potential to be applied for the combination treatment of glioblastoma in clinic. In addition, BLI could be a suitable imaging modality to evaluate the theranostic efficacy of new pharmaceuticals and treatment trials in F98/FGT glioblastoma-bearing rat model.