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. 2012;7(11):e50618.
doi: 10.1371/journal.pone.0050618. Epub 2012 Nov 30.

[18F]FLT PET for non-invasive assessment of tumor sensitivity to chemotherapy: studies with experimental chemotherapy TP202377 in human cancer xenografts in mice

Mette Munk Jensen  1 , Kamille Dumong Erichsen, Fredrik Björkling, Jacob Madsen, Peter Buhl Jensen, Maxwell Sehested, Liselotte Højgaard, Andreas Kjær
Affiliations

[18F]FLT PET for non-invasive assessment of tumor sensitivity to chemotherapy: studies with experimental chemotherapy TP202377 in human cancer xenografts in mice

Mette Munk Jensen et al. PLoS One. 2012.

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.

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Conflict of interest statement

Competing Interests: Peter Buhl Jensen has ownership interests and employment in Topotarget A/S. Maxwell Sehested has ownership interests and employment in Topotarget A/S. Fredrik Björkling has employment in Topotarget A/S. Kamille Dumong Erichsen has employment in Topotarget A/S. All other authors have no conflict of interests. That some of the co-authors are employed by Topotarget A/S does not alter the authors’ adherence to the PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products to declare.

Figures

Figure 1
Figure 1. Chemical structure of TP202377.
Figure 2
Figure 2. Tumor volume.
Growth of tumors following TP202377-treatment of A2780 (top panel), A2780/Top216 (mid panel) and SW620 (lower panel). Tumor volume was determined by microCT. The mice were treated with TP202377 (40 mg/kg i.v) or vehicle at Day 0. N = 8–16 tumors/group. *) p<0.05, **) p<0.01, ***) p<0.001 treatment versus control group at same time point.
Figure 3
Figure 3. [18F]FLT uptake following treatment.
[18F]FLT uptake measured as SUVmean (left panels) and SUVmax (right panels) in A2780, A2780/Top216 and SW620 following treatment with TP202377 or vehicle. N = 8–16 tumors/group. *) p<0.05, **) p<0.01, ***) p<0.001 versus baseline in same treatment group. #) p<0.05, ##) p<0.01, ###) p<0.001 treatment versus control group at same time point.
Figure 4
Figure 4. PET/CT images.
Representative [18F]FLT PET/CT images of A2780 (upper panel), A2780/Top216 (mid panel) and SW620 (lower panel) xenografts (dotted circles). [18F]FLT uptake is measured in the same animals at baseline and 6 hours, Day 1 and Day 6 follow treatment initiation with TP202377.
Figure 5
Figure 5. Correlations between changes in [18F]FLT uptake and tumor growth.
Changes in tumor volume measured as ratio Day 6/baseline compared with uptake of [18F]FLT measured as ratio of 6 hours/baseline (right panel) and Day 1/baseline (left panel).
Figure 6
Figure 6. Ki67 and TK1 gene expression.
Expression of Ki67 and TK1 normalized to the geometric mean of three reference genes. Data are presented as fold changes following treatment relative to baseline levels. N = 6–8 tumors/group. *) p<0.05, **) p<0.01, ***) p<0.001 versus baseline in same treatment group. #) p<0.05, ##) p<0.01, ###) p<0.001 treatment versus control group at same time point.
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