Monitoring antiproliferative responses to kinase inhibitor therapy in mice with 3'-deoxy-3'-18F-fluorothymidine PET.
The aim of this study was to evaluate, whether PET with (18)F-FDG and 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) may be used to monitor noninvasively the antiproliferative effects of tyrosine kinase inhibitors.


METHODS
Using a high-resolution small animal scanner, we measured the effect of the ErbB-selective kinase inhibitor PKI-166 on the (18)F-FDG and (18)F-FLT uptake of ErbB1-overexpressing A431 xenograft tumors.


RESULTS
Treatment with PKI-166 markedly lowered tumor (18)F-FLT uptake within 48 h of drug exposure; within 1 wk (18)F-FLT uptake decreased by 79%. (18)F-FLT uptake by the xenografts significantly correlated with the tumor proliferation index as determined by proliferating cell nuclear antigen staining (r = 0.71). Changes in (18)F-FLT uptake did not reflect inhibition of ErbB kinase activity itself but, rather, the effects of kinase inhibition on tumor cell proliferation. Tumor (18)F-FDG uptake generally paralleled the changes seen for (18)F-FLT. However, the baseline signal was significantly lower than that for (18)F-FLT.


CONCLUSIONS
These results indicate that (18)F-FLT PET provides noninvasive, quantitative, and repeatable measurements of tumor cell proliferation during treatment with ErbB kinase inhibitors and provide a rationale for the use this technology in clinical trials of kinase inhibitors.
Waldherr
Christian
C
Department of Molecular and Medical Pharmacology, Ahmanson Biological Imaging Center, David Geffen School of Medicine, University of California at Los Angeles, 10833 Le Conte Ave., Los Angeles, CA 90095, USA.
Mellinghoff
Ingo K
IK
Tran
Chris
C
Halpern
Benjamin S
BS
Rozengurt
Nora
N
Safaei
Arash
A
Weber
Wolfgang A
WA
Stout
David
D
Satyamurthy
Nagichettiar
N
Barrio
Jorge
J
Phelps
Michael E
ME
Silverman
Daniel H
DH
Sawyers
Charles L
CL
Czernin
Johannes
J
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015224:Dideoxynucleosides / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000000981:diagnostic imaging* / Q000517:prevention & control*; D049268:Positron-Emission Tomography / Q000379:methods; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D015224:Dideoxynucleosides; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; C410026:PKI 166; C002854:alovudine