Changes in [18F]Fluorothymidine Pharmacokinetics Following Capecitabine Treatment in Human Breast Cancer Detected by Positron Emission Tomography.

Abstract

Abstract Background: Pre-clinical models used by our group have demonstrated that thymidylate synthase (TS) inhibition leads to redistribution of the nucleoside transporter, ENT1, to the cell membrane and hence increases the tissue uptake of [18F]fluorothymidine (FLT).Methods: In this study we assessed, for the first time, the altered pharmacokinetics of FLT in patients following TS inhibition. We analyzed 10 lesions from 6 breast cancer patients by positron emission tomography (PET) before and after treatment with capecitabine.Results: Whereas drug treatment did not alter tumor delivery pharmacokinetic variables or blood flow, tumor FLT retention variables increased with drug treatment in all but one patient. The baseline average standardized uptake value (SUV) at 60 min, rate constant for the net irreversible transfer of radiotracer from plasma to tumor (Ki) and unit impulse response function (IRF) at 60 min were 11.11 x 10-5 m2/ml, 4.38 x 10-2 ml plasma/min/ml tissue and 4.93 x 10-2 /min, respectively. At 1 h after capecitabine, the SUV was 13.55 x 10-5 m2/ml (p=0.004), Ki 7.40 x 10-2 ml plasma/min/ml tissue (p=0.004) and IRF 7.40 x 10-2 /min (p= 0.002).Conclusion: FLT pharmacokinetics did not change in normal tissues suggesting that the effect was largely restricted to tumor (p=0.55). In summary, we have identified FLT-PET retention parameters that could be used in future early clinical studies to measure the pharmacodynamics of TS inhibitors, as well as for identifying patients who are unlikely to benefit from TS inhibition. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5003.