TY - JOUR T1 - Abrogation of gemcitabine (GEM) induced [18F]FLT flare response in tumor cells by checkpoint inhibitors (CPIs) as a potential pharmacodynamic biomarker JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 634 LP - 634 VL - 50 IS - supplement 2 AU - Elaine Jagoda AU - Tsing-bau Chen AU - Shailendra Patel AU - Paula Ehrlich AU - Raymond Gibson Y1 - 2009/05/01 UR - http://jnm.snmjournals.org/content/50/supplement_2/634.abstract N2 - 634 Objectives CPIs, have been shown to potentiate antitumor effects of chemotherapy. A GEM induced [18F]FLT(3'-deoxy-3'[18F]fluorothymidine) flare response in PC-3 mouse xenografts has been shown to be abrogated by CHK1. Using this abrogation of flare response paradigm, the potential of [18F]FLT as a pharmacodynamic biomarker for CPIs (CPI1 or CPI2) was examined by evaluating human prostate (PC-3), lung (A549) and colon (WiDr) tumor cells and xenografts. Methods [18F]FLT uptake was determined in cell lines at 24 and 48 hours post-GEM exposure in control and CPI-treated samples. CPIs were added after 17h of GEM exposure. Xenograft mice were imaged with [18F]FLT at 24 and 48h after GEM. Results GEM induced a bell shaped concentration dependent [18F]FLT flare response (FR) (6-fold increase) at 24h in PC-3 treated cells vs controls, while at 48h the FR decreased (< 2-fold). In WiDr, the maximal [18F]FLT FR (4 to 6-fold) occurred at 48h. In A549, maximal [18F]FLT FRs were achieved at 24h (7.5 nM GEM) and 48h (20nM and 40 nM GEM). A concentration dependent abrogation was observed with CPI1 and CPI2 in all the cell lines with A549 the most sensitive to CPI2 and PC3 the least sensitive. GEM dose dependent [18F]FLT FRs were also observed in xenografts at 24 and 48h. Conclusions The GEM [18F]FLT flare response and its abrogation by CPI1 or CPI2 was dose, time, and cell line dependent. These results support the hypothesis that the [18F]FLT flare response and its abrogation should be clinically applicable as a pharmacodynamic biomarker of CPIs actions. ER -