[18F]FLT PET for Non-Invasive Assessment of Tumor Sensitivity to Chemotherapy: Studies with Experimental Chemotherapy TP202377 in Human Cancer Xenografts in Mice |
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| Authors: | Mette Munk Jensen Kamille Dumong Erichsen Fredrik Bj?rkling Jacob Madsen Peter Buhl Jensen Maxwell Sehested Liselotte H?jgaard Andreas Kj?r |
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| Institution: | 1. Cluster for Molecular Imaging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; 2. Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, Denmark.; 3. TopoTarget A/S, Symbion Science Park, Copenhagen, Denmark.; Cincinnati Children’s Hospital Medical Center, United States of America, |
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| Abstract: | Aim3′-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.MethodsXenografts 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.ResultsTP202377 (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.ConclusionTreatment 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. |
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