Evaluation of ~(18)F-FLT and ~(18)F-FDG for Monitoring Lung Adenocarcinoma and Lung Large Cell Carcinoma Response to Radiotherapy in Cytological and Animal Experiment
Background:Lung cancer is one of the most familiar malignant tumors in the world.The incidence rate and death rate increased significantly recent years, Radiotherapy plays a very important role in the treatment of lung cancer.Positron emission tomography(PET) is a rapidly developing new imaging technique in the diagnosis and staging of lung cancer,especially in the evaluation for monitoring lung cancer response to radiotherapy.There are two parts in this study.In PartⅠ, systematic review the biodistribution of ~(18)F-FLT and ~(18)F-FDG in the human lung adenocarcinoma cells line(AS49) and lung large cell carcinoma cells line(95-D) after the irradiation.In Part 2,the ~(18)F-FLT and ~(18)F-FDG biodistribution and PET imaging of lung adenocarcinoma,lung large cell carcinoma in murine model were investigated.Objective:1.The biodistribution of 3\'-deoxy-3\'-~(18)F-fluorothy- midine(~(18)F-FLT) and 2-deoxy-2-~(18)F-fluoro-D-glucose(~(18)F-FDG) in the human lung adenocarcinoma cells line(AS49) and lung large cell carcinoma cells line(95-D) after irradiation are investigated.2.The biodistribution and positron emission tomography(PET) imaging of ~(18)F-FLT and ~(18)F-FDG in routine model of lung adenocarcinoma and lung large cell carcinoma are investigated.3.The use of ~(18)F-FLT and ~(18)F-FDG for monitoring lung adenocarcinoma and lung large cell carcinoma response to radiotherapy are evaluate.4.The biodistribution and positron emission tomography imaging difference between lung adenocarcinoma and lung large cell carcinoma are evaluated.Methods:Cytological Experiment:1.Lung adenocarcinoma cells line(A549) were treated with 6Mv X-ray irradiation of 500cGy,1000cGy and 2000cGy one fraction.6,12,24 and 72 hours later,the cell concentration were regulated to 5× 10~4/ml,50kBq ~(18)F-FLT or ~(18)F-FDG added.The bodistribution was measured with well-gamma detector.2.Lung large cell carcinoma cells line(95-D) were treated with 6My X-ray irradiation of 500cGy,1000cGy and 2000cGy one fraction.6,12, 24 and 72 hours later,50kBq ~(18)F-FLT or ~(18)F-FDG added.The bodistribution was measured with well-gamma detector.Animal Experiment:1.6 mice bearing the lung adenocarcinoma were randomly divided into two groups according to the different tracers(~(18)F-FLT and ~(18)F-FDG), The bodistribution of mice was measured with well-gamma detector at 60min, after injection by tail veins.The MicroPET imaging was performed at 60min.2.6 mice bearing the lung large cell carcinoma were randomly divided into two groups according to the different tracers(~(18)F-FLT and ~(18)F-FDG),The bodistribution of mice was measured with well-gamma detector at 60min,after injection by tail veins.The MicroPET imaging was performed at 60min.3.18 mice bearing the lung adenocarcinoma were randomly divided into two groups according to the different tracers(~(18)F-FLT and ~(18)F-FDG),every group was divided into three parts,the first and second groups were treated with 6Mv X-ray irradiation of 2000cGy one fraction in the first and second day before the experiment,the third was control group.All mice were injected with ~(18)F-FLT or ~(18)F-FDG by tail vein.At 30min after tracers injection,bodistribution and PET imaging were performed.4.18 mice bearing the lung large cell carcinoma were randomly divided into two groups according to the different tracers(~(18)F-FLT and ~(18)F-FDG),every group was divided into three parts,the first and second groups were treated with 6Mv X-ray irradiation of 2000cGy one fraction in the first and second day before the experiment,the third was control group.All mice were injected with ~(18)F-FLT or ~(18)F-FDG by tail vein.At 30min after tracers injection, bodistribution and PET imaging were performed.Results:Cytological Experiment:1.~(18)F-FLT uptake of lung adenocarcinoma cell line(AS49) after irradia- tion decreased at 6,12 hour of 1000cGy group and 6, 12,24,72 hour of 2000cGy group.There are significant differences between 500cGy and 1000cGy group,500cGy and 2000cGy group.2.~(18)F-FLT uptake of lung large cell carcinoma cell line(95-D) after irradiation increased at 24,72 hour of 500cGy group and decreased at 6,12,24,72 hour of 1000cGy and 2000cGy group.There are signifi- cant differences between 500cGy and 1000cGy group, 500cGy and 2000cGy group.3.~(18)F-FLT uptake of lung large cell carcinoma 95-D cell line was signifi- cantly higher than that of lung adenocarcinoma A549 cell line(111±6%,141±5%,p＜0.05;107±8%,138±7%,p＜0.05).Animal Experiment:1.The biodistribution study in murine model of lung adenocarcinoma shows considerable uptake of ~(18)F-FLT and ~(18)F-FDG in tumor was observed,the ratio of tumor to muscle,tumor to lung were all above 2.The tumor were clearly imaged with ~(18)F-FLT and ~(18)F-FDG MicroPET.2.The biodistribution study in murine model of lung adenocarcinoma shows considerable uptake of ~(18)F-FLT and ~(18)F-FDG in tumor was observed,the ratio of tumor to muscle,tumor to lung were all above 2.The tumor were clearly imaged with ~(18)F-FLT and ~(18)F-FDG MicroPET.3.There was statistically difference between the two tumors at the tumor/muscle and tumor/lung value in ~(18)F-FLT and tumor/lung value in ~(18)F-FDG, but no statistically difference at the tumor/muscle value in ~(18)F-FDG.4.~(18)F-FLT uptake in murine model of lung adenocarcinoma after irradiation was significantly lower than that of control group(0.71±0.08%和0.33±0.07%,p＜0.05).~(18)F-FLT PET imaging T/NT value was significantly lower than that of control group.But there was no statistically significant in ~(18)F-FDG group.5.~(18)F-FLT uptake in murine model of lung large cell carcinoma after irradiation was significantly lower than that of control group(1.33±0.27%和0.58±0.08%,p＜0.05~(18)F-FDG uptake after irradiation 48h was significantly lower than that of control group. PET imaging after radiotherapy,the T/NT value of FLT group was significantly lower than the control group after 24h,48h(P＜0.05).FLT group was significantly lower than the control group after 48h(P＜0.05).6.~(18)F-FLT uptake in murine model of lung large cell carcinoma after irridiation was significantly higher than that of lung adenocarcinoma;and there was statistically difference in 24h after irridiation of ~(18)F-FDG uptake between the two tumors.MicroPET imaging showed that there was no statistically significant between the two tumors. Conclusions:Our experimental Studies shows that the uptake of ~(18)F-FLT in pulmonary malignant tissues is higher than that in normal tissues,thus the pulmonary neoplasm can be identified accurately with PET imaging.The decrease in tumor ~(18)F-FLT uptake after radiotherapy was more pronounced than that of ~(18)F-FDG.Therefore,~(18)F-FLT is a promising PET tracer for monitoring response to therapy in oncology.At the same time,~(18)F-FLT uptake studies about lung adenocarcinoma and lung large cell carcinoma have shown that uptake of large cell carcinoma was significantly higher than that of lung adenocarcinoma,there is still such a trend after radiotherapy.So ~(18)F-FLT is expected to be helpful to the differential diagnosis of lung adenocarcinoma and lung large cell carcinoma and efficacy evaluation after radiotherapy.PET imaging with ~(18)F-FLT represents a useful supplement to ~(18)F-FDG in assessing the malignancy.~(18)F-FLT uptake correlates better with proliferation of lung tumors than does uptake of ~(18)F-FDG and might be more useful as a selective biomarker for tumor proliferation.