FLT-PET imaging of radiation responses in murine tumors

3'-[F-18]fluoro-3'-deoxythymidine (FLT) traces thymidine phosphorylation catalyzed by thymidine kinase during cell proliferation. Knowing the rate of cell proliferation during cancer treatment, such as radiation therapy, would be valuable in assessing whether tumor recurrence is likely and might indicate the need for additional treatments. However, the relationship between FLT kinetics and the effects of radiation is not well-understood. Nor has the method for optimal quantification of FLT uptake within the irradiated tumor microenvironment been extensively examined.

We performed dynamic FLT-positron emission tomography (PET) studies (60 min) on 22 mice implanted subcutaneously with syngeneic mammary MCaK tumors bilaterally in the shoulder area. A day before the FLT-PET imaging, the tumor on the right side was irradiated with a single dose (0, 2.5, 5, 10, or 20 Gy) or with fractionated exposures (4x2.5 Gy given in 12 h intervals). Standardized uptake value (SUVs) of FLT on tumors at 10 and 60 min post injection were calculated; model fitting was used to estimate the kinetic parameters. Significant radiation-induced changes were shown by comparing the irradiated tumor with the control tumor in the same animal and by comparing it to nonirradiated mice. The effect of radiation on MCaK cell cycle parameters and FLT uptake was also examined in vitro.

In vivo FLT kinetics were sensitive to radiation doses of 5 Gy and higher (administered 1 day earlier), as judged by SUV semiquantitative measures and by modeling. Single irradiation with 10 Gy had greater impact on SUVs and kinetic parameters than fractionated exposures. Overall, the uptake constant Ki appeared to be the best marker for these radiation effects. FLT uptake by irradiated cells in vitro at various doses gave similar findings, and the in vitro FLT uptake correlated well with Ki. Radiation-induced G2/M arrest appeared to influence FLT uptake, and this was more pronounced after single than fractionated doses.

The kinetics of FLT uptake into murine mammary tumors was altered 1 day after radiation treatment. The dose-dependent response correlated well with in vitro FLT cellular uptake. Parameters (e.g., Ki) derived from FLT kinetics are expected to be useful for assessing the efficacy of irradiation treatment of tumors.