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.
Highlights
A challenge during development of new anti-cancer drugs is to discriminate between responders and non-responders early in the course of treatment
During pre-clinical development of anticancer agents testing of in-vivo effect of new drug-candidates with imaging biomarkers can help in guidance of which drug candidates to further develop, improve knowledge of drug candidates and help in selecting which predictive biomarkers could be included in future clinical studies
The use of the non-invasive positron emission tomography (PET) imaging technique to image cell-proliferation with the tracer 39-deoxy-39-[18F]fluorothymidine ([18F]FLT) has been tested in different pre-clinical settings [1,2,3,4,5,6,7,8,9,10]. [18F]FLT is used to assess cell proliferation in vivo by PET, by measuring the activity of thymidine kinase 1 (TK1) which is upregulated in the S-phase of cell cycle [11,12,13,14,15,16]
Summary
A challenge during development of new anti-cancer drugs is to discriminate between responders and non-responders early in the course of treatment. Many new and already approved chemotherapeutics do only have anti-tumor effect in a subgroup of patients. Identification of these patients early following treatment start could result in a shift toward other treatments in the non-responding patients and reduce unnecessary treatments. [18F]FLT is used to assess cell proliferation in vivo by PET, by measuring the activity of thymidine kinase 1 (TK1) which is upregulated in the S-phase of cell cycle [11,12,13,14,15,16]. Cell proliferation is often either the primary or secondary target of many anti-cancer drugs, and investigation of changes in cell proliferation by use of [18F]FLT PET can be used following treatment with various anti-cancer drugs. [18F]FLT changes following treatment are very variable and dependent on the tumors and treatments [19]
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