Altered tissue 3'-deoxy-3'-[18F]fluorothymidine pharmacokinetics in human breast cancer following capecitabine treatment detected by positron emission tomography.
OBJECTIVE
We showed in preclinical models that thymidylate synthase (TS) inhibition leads to redistribution of the nucleoside transporter, ENT1, to the cell membrane and hence increases tissue uptake of [(18)F]fluorothymidine (FLT). In this study, we assessed for the first time the altered pharmacokinetics of FLT in patients following administration of capecitabine, a drug whose mode of action has been reported to include TS inhibition.


METHODS
We analyzed 10 lesions from six patients with breast cancer by positron emission tomography before and after treatment with capecitabine. Although drug treatment did not alter tumor delivery pharmacokinetic variables (K1 and permeability product surface area) or blood flow, tumor FLT retention variables increased with drug treatment in all but one patient.


RESULTS
The baseline average standardized uptake value at 60 minutes, rate constant for the net irreversible transfer of radiotracer from plasma to tumor (Ki), and unit impulse response function at 60 minutes were 11.11 x 10(-5) m(2)/mL, 4.38 x 10(-2) mL plasma/min/mL tissue, and 4.93 x 10(-2)/min, respectively. One hour after capecitabine administration, the standardized uptake value was 13.55 x 10(-5) m(2)/mL (P = 0.004), Ki 7.40 x 10(-2) mL plasma/min/mL tissue (P = 0.004), and impulse response function was 7.40 x 10(-2)/min (P = 0.002). FLT pharmacokinetics did not change in normal tissues, suggesting that the effect was largely restricted to tumors (P = 0.55).


CONCLUSIONS
We have identified FLT positron emission tomography 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.
Department of Oncology, Imperial College London, London, United Kingdom.
Laura M
LM
Kenny
Kaiyumars B
KB
Contractor
Justin
J
Stebbing
Adil
A
Al-Nahhas
Carlo
C
Palmieri
Sami
S
Shousha
R Charles
RC
Coombes
Eric O
EO
Aboagye
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging / Q000378:metabolism*; D000069287:Capecitabine; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015224:Dideoxynucleosides / Q000493:pharmacokinetics*; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D049268:Positron-Emission Tomography; D012039:Regional Blood Flow; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors
D000964:Antimetabolites, Antineoplastic; D015224:Dideoxynucleosides; D003841:Deoxycytidine; D000069287:Capecitabine; D013940:Thymidylate Synthase; D005472:Fluorouracil