[18F]FLT PET for Non-Invasive Assessment of Tumor Sensitivity to Chemotherapy: Studies with Experimental Chemotherapy TP202377 in Human Cancer Xenografts in Mice

Abstract

Aim: 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT) is a tracer used to assess cell proliferation in vivo. The aim of the study was to use [18F]FLT positron emission tomography (PET) to study non-invasively early anti-proliferative effects of the experimental chemotherapeutic agent TP202377 in both sensitive and resistant tumors. Methods: Xenografts in mice from 3 human cancer cell lines were used: the TP202377 sensitive A2780 ovary cancer cell line (n = 8-16 tumors/group), the induced resistant A2780/Top216 cell line (n = 8-12 tumors/group) and the natural resistant SW620 colon cancer cell line (n = 10 tumors/group). In vivo uptake of [18F]FLT was studied at baseline and repeated 6 hours, Day 1, and Day 6 after TP202377 treatment (40 mg/kg i.v.) was initiated. Tracer uptake was quantified using small animal PET/CT. Results: TP202377 (40 mg/kg at 0 hours) caused growth inhibition at Day 6 in the sensitive A2780 tumor model compared to the control group (P<0.001). In the A2780 tumor model TP202377 treatment caused significant decrease in uptake of [18F]FLT at 6 hours (-46%; P<0.001) and Day 1 (-44%; P<0.001) after treatment start compared to baseline uptake. At Day 6 uptake was comparable to baseline. Treatment with TP202377 did not influence tumor growth or [18F]FLT uptake in the resistant A2780/Top216 and SW620 tumor models. In all control groups uptake of [18F]FLT did not change. Ki67 gene expression paralleled [18F]FLT uptake. Conclusion: Treatment of A2780 xenografts in mice with TP202377 (single dose i.v.) caused a significant decrease in cell proliferation assessed by [18F]FLT PET after 6 hours. Inhibition persisted at Day 1; however, cell proliferation had returned to baseline at Day 6. In the resistant A2780/Top216 and SW620 tumor models uptake of [18F]FLT did not change after treatment. With [18F]FLT PET it was possible to distinguish non-invasively between sensitive and resistant tumors already 6 hours after treatment initiation. © 2012 Munk Jensen et al.