Early Detection of Response to Experimental Chemotherapeutic Top216 with [18F]FLT and [18F]FDG PET in Human Ovary Cancer Xenografts in Mice

Background: 3'-deoxy-3'-[F-18]fluorothymidine (F-18-FLT) is a tracer used to assess cell proliferation in vivo. The aim of the study was to use F-18-FLT positron emission tomography (PET) to study treatment responses to a new anti-cancer compound. To do so, we studied early anti-proliferative effects of the experimental chemotherapy Top216 non-invasively by PET. Methodology/Principal Findings: In vivo uptake of F-18-FLT in human ovary cancer xenografts in mice (A2780) was studied at various time points after Top216 treatment (50 mg/kg i.v. at 0 and 48 hours) was initiated. Baseline F-18-FLT scans were made before either Top216 (n = 7-10) or vehicle (n = 5-7) was injected and repeated after 2 and 6 hours and 1 and 5 days of treatment. A parallel study was made with 2'-deoxy-2'-[F-18] fluoro-D-glucose (F-18-FDG) (n = 8). Tracer uptake was quantified using small animal PET/CT. Imaging results were validated by tumor volume changes and gene-expression of Ki67 and TK1. Top216 (50 mg/kg 0 and 48 hours) inhibited the growth of the A2780 tumor compared to the control group (P<0.001). F-18-FLT uptake decreased significantly at 2 hours (-52%; P<0.001), 6 hours (-49%; P = 0.002) and Day 1 (-47%; P<0.001) after Top216 treatment. At Day 5 F-18-FLT uptake was comparable to uptake in the control group. Uptake of F-18-FLT was unchanged in the control group during the experiment. In the treatment group, uptake of F-18-FDG was significantly decreased at 6 hours (-21%; P = 0.003), Day 1 (-29%; P<0.001) and Day 5 (-19%; P = 0.05) compared to baseline. Conclusions/Significance: One injection with Top216 initiated a fast and significant decrease in cell-proliferation assessable by F-18-FLT after 2 hours. The early reductions in tumor cell proliferation preceded changes in tumor size. Our data indicate that F-18-FLT PET is promising for the early non-invasive assessment of chemotherapy effects in both drug development and for tailoring therapy in patients.