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

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.

Cell-Proliferation Imaging for Monitoring Response to CDK4/6 Inhibition Combined with Endocrine-Therapy in Breast Cancer: Comparison of [18F]FLT and [18F]ISO-1 PET/CT

“…Histologic assessments of proliferation markers validated the strong correlation between [ 18 F]FLT uptake and Ki-67 expression after 14 days of treatment, in line with previous reports (47). Expression of TMEM97 also paralleled the uptake of [ 18 F]ISO-1, which confirmed the PET results by indicating that the decrease in tracer uptake was due to a real change in expression of proliferation marker, s 2 -receptor, and not a consequence of decreased delivery of radiotracer.…”

Preclinical Applications of 3'-Deoxy-3'-[18F] Fluoro-thymidine in Oncology - A Systematic Review

“…n = 14 of the 122 reports with reduced [ 18 F]FLT accumulation after therapy, demonstrate that at the end of a treatment cycle, [ 18 F]FLT levels might not be distinguishable from baseline, reflecting recovery of tumor proliferation as shown by respective immunohistochemistry 9,15,26-37. Hence, for successful treatment monitoring, the imaging time point is of crucial importance.…”

18F-FDG and 18F-FLT-PET Imaging for Monitoring Everolimus Effect on Tumor-Growth in Neuroendocrine Tumors: Studies in Human Tumor Xenografts in Mice

“…Uptake of FLT is assumed to reflect the amount of proliferating cells since TK1 is mainly expressed during the S-phase of the cell cycle [20], [21]. Several studies have found a correlation between uptake of FLT and tumor cell proliferation measured by Ki67 [22]. In a meta analysis of 27 studies, the FLT/Ki67 correlation was found to be strong and independent of cancer-type [23].…”