Purpose: Positron emission tomography with the thymidine analogue 3'-deoxy-3'-[18F]fluorothymidine (FLT) has been reported to closely reflect lymphoma proliferation in vivo. In this preclinical study, we have investigated if FLT can also be utilized for imaging therapy-induced alterations of the nucleoside metabolism and if FLT is a surrogate marker for early response to cytotoxic treatment.
Materials and methods: Immunodeficient mice bearing high-grade lymphoma xenotransplants were treated with the cytotoxic agent doxorubicin (day 0). In the time course of day +1 to +9, antiproliferative effects were assessed non-invasively with FLT-PET and correlated to changes of the proliferation fraction and induction of apoptosis, as assessed by immunohistochemistry.
Results: Tumor growth in untreated animals was significantly higher than in treated animals. In FLT-PET scans, these observations correlated with a significant decrease of tumor-to-background ratio in the therapy group already at day 1. Likewise, median tumor-to-muscle ratio of FLT uptake already declined at day 1. The proliferation fraction assessed by Ki-67 immunohistochemistry decreased after chemotherapy, while activated caspase 3 increased, suggesting both cell cycle arrest and induction of apoptosis as underlying mechanisms of the observed PET-signal alterations.
Conclusion: In a lymphoma xenotransplant model, we show that positron emission tomography using the proliferation marker FLT is suitable to detect early response to cytotoxic treatment. A significant decrease of FLT uptake but not tumor growth was detectable already 24 h after therapy and correlated with reduced proliferation and induction of apoptosis. Thus, FLT-PET has a potential for imaging early response to treatment in malignant lymphoma.