Experimental And Clinical Study On ～(18)F-FLT PET In Solitary Pulmonary Nodules

Objective: 1.To investigate the biodistribution and positron emission tomography(PET)of 3'-deoxy-3' -¹⁸F-fluorothymidine((l8)^F-FLT) in murine model of lung carcinoma.2.To study the biodistribution and PET imaging of ¹⁸F-FLT in Wistar rat model of inflammation.3.to evaluated the use of 18F-FLT for monitoring of the early effects of anticancer chemotherapy on tumour cell proliferation. 4.To evaluate the use of ¹⁸F-FLT for monitoring tumor response to radiotherapy.5.To investigate the utility of ¹⁸F-FLT PET in diagnosis lung cancer and assessing tumor proliferation.Methods: 1.20 T739 mice bearing the lung adenocarcinoma were randomly divided into five groups according to the different tracers and after-injection time(n=8/group).The bodistribution of mice for ¹⁸F-FLT was measured with well-gamma detector at 30min,60min,90min and 120min respectively after injection by tail veins. The PET imaging using ¹⁸F-FLT was performed at 60min.2. 8 Wistar rats model bearing abscess was induced by intramedullary injection of 106 colony-forming units of Staphylococcus aureus in the right tibia, and the model bearing granuloma was induced by injection of calcinum sulfate+gentamicin in the left tibia. One month later, Rabbits received an intravenous bolus (30 MBq) of 18F-FLT and PET imaging were performed. Rabbits were then euthanized, and the tibias were harvested. The bones were cultured, and bacterial counts of Staphylococcus aureus and histopatholigic examinationg were performed.3. Cells derived from human adenocarcinoma were grown for 2days and incubated with cisplatin (CDDP), methotrexate(MTX) 5-fluorouracil(5-FU), for 4 h. Cultures were incubated with drug doses(CDDP: 67 μM; 5-FU 1,540 μM;MTX: 440μM;) corresponding to approximately 10%-95% proliferationinhibition. Treatment was stopped and cells were allowed to recover for 4, 8, 24 or 72 h. ¹⁸F-FLT was added for 60min. Control cultures were incubated with ¹⁸F -FDG.Cell counts, viability estimated by MTT were used to evaluate the cytotoxic effects of chemotherapy. 4.24 T739 mice bearing lung cancer were divided into two groups,one groups were treated with X-ray irradiation of 20 Gy.All mice were injected with ¹⁸F-FLT or ¹⁸F-FDG by tail vein.At 60min after tracers injection ,biodistribution and PET imaging were performed,Tumor proliferation wasdetermined by PCNA. 5.55 patients with SPNs on CT were examated with¹⁸F-FLT and ¹⁸F-FDG PET.The results were based on after-operation pathology or 1 year CT follow-up. Proliferative activity was estimated by human nuclear antigen Ki-67 index.Results: 1. The biodistribution study shows considerable uptake of ¹⁸F-FLT was observed,The ratio of Tumor to blood,tumor to muscle, tumor to lung were all above 2. The tumor were clearly imaged with ¹⁸F-FLT PET.2.¹⁸F-FLT significantly accumulated in the abscess induced by Staphylococcus aureus,but little in granuloma induced by calcinum sulfate+gentamicin (SUVmax5.76±0.25 versus 1.15±0.32, P0.01) .3. Strikingly,FLT uptake per 105 viable cells was increased seventotenfold 24 h after treatment with 5-FU or MTX irrespectiveof dose. Thus, total FLT uptake per tissue culture exceeded that of controls despite a considerable decreasein overall cell counts due to cytostasis up to 72 h after treatment. GEM treatment resulted in a more moderate increase in total FLT accumulation, to a maximum of fivefold at the dose close to the IC50. In contrast, FLT accumulation was significantly reduced at cytostatic concentrations of CDDP .With 5-FU or CDDP,the uptake of FDG did not differ significantly from control values 24 h after treatment. 4.Tumor uptake of ¹⁸F-FLT rapidly decreased after radiotherapy (0.37±0.12%å’Œ1.25±0.19, p<0.01) ,The reduction in ¹⁸F-FLT uptake was significantly pronounced than that of ¹⁸F-FDG The decrease in tumor F-FLT uptake correlated well with PCNA labeling index(r=0.8805, p<0.01), .5.The maximum standardized uptake value for ¹⁸F-FDGwas higher than that of ¹⁸F-FLT (6.5±3.2 versus 3.2±1.4, p<0.05) . ¹⁸F-FLT was not a rumor-specific agent, could be uptaken by some active infectious disease. For¹⁸F-FLT, the sensitivity,specificity and accuracy were 71 %,79%å’Œ 76% respectively,andfor¹⁸F-FDG,theywere89%,67%å’Œ73% respectively. ¹⁸F-FLT SUVmax Correlated significantly with Ki-67 than ¹⁸F-FDG does (0.8558å’Œ0.5214, p<0.01) .Conclusions:Our experimental Studies shows that the uptake of ¹⁸F-FLT in pulmonary malignant tissues is higher than that in normal tissues, thus the pulmonary neoplasm can be identified accurately with PET imaging. Abscessinduced by Staphylococcus aureus also upkakes ¹⁸F-FLT, so that ¹⁸F-FLT is not a tumor- specific agent. The decrease in tumor ¹⁸F-FLT uptake after chemotherapy and radiotherapy was more pronounced than that of ¹⁸F-FDG Changes in ¹⁸F-FLTuptake were correlated with PCNA labeling index. Therefore, ¹⁸F-FLT is a promising PET tracer for monitoring response to therapy in oncology. In clinical Study, our finding indicate that ¹⁸F-FLT is not a tumor-specific agent , can be uptaken by some active infectious disease ,but it is more specific than ¹⁸F-FDG PET imaging with ¹⁸F-FLT represents a useful supplement to ¹⁸F-FDG in assessing the malignancy. ¹⁸F-FLT uptake correlates better with proliferation of lung tumors than does uptake of ^I8F-FDG and might be more useful as a selective biomarker for tumor proliferation.