The Use of Longitudinal 18F-FET MicroPET Imaging to Evaluate Response to Irinotecan in Orthotopic Human Glioblastoma Multiforme Xenografts

Objectives: Brain tumor imaging is challenging. Although F-18-FET PET is widely used in the clinic, the value of 18F-FET MicroPET to evaluate brain tumors in xenograft has not been assessed to date. The aim of this study therefore was to evaluate the performance of in vivo F-18-FET MicroPET in detecting a treatment response in xenografts. In addition, the correlations between the F-18-FET tumor accumulation and the gene expression of Ki67 and the amino acid transporters LAT1 and LAT2 were investigated. Furthermore, Ki67, LAT1 and LAT2 gene expression in xenograft and archival patient tumors was compared. Methods: Human GBM cells were injected orthotopically in nude mice and F-18-FET uptake was followed by weekly MicroPET/CT. When tumor take was observed, mice were treated with CPT-11 or saline weekly. After two weeks of treatment the brain tumors were isolated and quantitative polymerase chain reaction were performed on the xenograft tumors and in parallel on archival patient tumor specimens. Results:The relative tumor-to-brain (T/B) ratio of SUV, was significantly lower after one week (123 +/- 6%, n = 7 vs. 147 +/- 6%, n = 7; p = 0.018) and after two weeks (142 +/- 8%, n = 5 vs. 204 +/- 27%, n = 4; p = 0.047) in the CPT-11 group compared with the control group. Strong negative correlations between SUVmax T/B ratio and LAT1 (r = 0.62, p = 0.04) and LAT2 (r = 0.67, p = 0.02) were observed. In addition, a strong positive correlation between LAT1 and Ki67 was detected in xenografts. Furthermore, a 1.6 fold higher expression of LAT1 and a 23 fold higher expression of LAT2 were observed in patient specimens compared to xenografts. Conclusions: F-18-FET MicroPET can be used to detect a treatment response to CPT-11 in GBM xenografts. The strong negative correlation between SUVmax T/B ratio and LAT1/LAT2 indicates an export transport function. We suggest that (FFET)-F-18 PET may be used for detection of early treatment response in patients.