Gemcitabine Mechanism of Action Confounds Early Assessment of Treatment Response by 3′-Deoxy-3′-[18F]Fluorothymidine in Preclinical Models of Lung Cancer

Abstract

3′-Deoxy-3′-[18F]fluorothymidine positron emission tomography ([18F]FLT-PET) and diffusion-weighted MRI (DW-MRI) are promising approaches to monitor tumor therapy response. Here, we employed these two imaging modalities to evaluate the response of lung carcinoma xenografts in mice after gemcitabine therapy. Caliper measurements revealed that H1975 xenografts responded to gemcitabine treatment, whereas A549 growth was not affected. In both tumor models, uptake of [18F]FLT was significantly reduced 6 hours after drug administration. On the basis of the gemcitabine concentration and [18F]FLT excretion measured, this was presumably related to a direct competition of gemcitabine with the radiotracer for cellular uptake. On day 1 after therapy, [18F]FLT uptake was increased in both models, which was correlated with thymidine kinase 1 (TK1) expression. Two and 3 days after drug administration, [18F]FLT uptake as well as TK1 and Ki67 expression were unchanged. A reduction in [18F]FLT in the responsive H1975 xenografts could only be noted on day 5 of therapy. Changes in ADCmean in A549 xenografts 1 or 2 days after gemcitabine did not seem to be of therapy-related biological relevance as they were not related to cell death (assessed by caspase-3 IHC and cellular density) or tumor therapy response. Taken together, in these models, early changes of [18F]FLT uptake in tumors reflected mechanisms, such as competing gemcitabine uptake or gemcitabine-induced thymidylate synthase inhibition, and only reflected growth-inhibitory effects at a later time point. Hence, the time point for [18F]FLT-PET imaging of tumor response to gemcitabine is of crucial importance. Cancer Res; 76(24); 7096–105. ©2016 AACR.

Defining Clinical Response Criteria and Early Response Criteria for Precision Oncology: Current State-of-the-Art and Future Perspectives

“…Early changes of [ 18 F] FLT uptake in tumors reflected mechanisms such as competing gemcitabine uptake or gemcitabine-induced thymidylate synthase inhibition and only reflected growth inhibitory effects at a later time point [36]. Another study reported early response evaluation using NaF PET in osteosarcoma [37].…”

Fluorothymidine Positron Emission Tomography (FLT-PET) Repeatability and Response Evaluation in Advanced Pancreatic Cancer Patients Treated with Gemcitabine-Based Chemotherapy

“…Preclinical models have explored changes on FLT uptake following gemcitabine administration and confirmed direct competition of gemcitabine with the radiotracer for cellular uptake; correlation with TK1 expression has also been confirmed [23]. In this study, the aim was to assess the feasibility of imaging proliferation using FLT-PET in patients with advanced PDAC.…”

“…However, the absence of tumoural FLT flare with gemcitabine unlike fluoropyrimdines, in preclinical models has been attributed to the competition in tumoural uptake between FLT and gemcitabine, both of which use the same nucleoside transporter, hENT1. It is difficult to delineate if the decreased uptake in tumour and normal tissues in this subject is a true representation of decreased proliferative activity, or as a result of competition between gemcitabine and FLT for transport in to tissue [23,37]. No relationship between the imaging and pathologic parameters were identified.…”

Preclinical Evidence That 3′-Deoxy-3′-[18F]Fluorothymidine PET Can Visualize Recovery of Hematopoiesis after Gemcitabine Chemotherapy

“…8-to 12-week-old female NMRI nude mice (Janvier Labs) were used for the experiments. A total of 47 mice were employed in this study, which were initially used to monitor the response of subcutaneous lung cancer xenografts to chemotherapy (10). Mice were treated with intraperitoneal injections of 100 mg/kg gemcitabine in 100 mL 0.9% NaCl or 0.9% NaCl vehicle control on days 0 and 3.…”