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Monitoring Antiproliferative Responses to Kinase Inhibitor Therapy in Mice with 3'-Deoxy-3'-¹⁸F-Fluorothymidine PET

¹ Department of Molecular and Medical Pharmacology, Ahmanson Biological Imaging Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
² Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
³ Howard Hughes Medical Institute, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
⁴ Department of Pathology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
⁵ Department of Urology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
⁶ Molecular Biology Institute, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California

The aim of this study was to evaluate, whether PET with ¹⁸F-FDG and 3'-deoxy-3'-¹⁸F-fluorothymidine (¹⁸F-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 ¹⁸F-FDG and ¹⁸F-FLT uptake of ErbB1-overexpressing A431 xenograft tumors. Results: Treatment with PKI-166 markedly lowered tumor ¹⁸F-FLT uptake within 48 h of drug exposure; within 1 wk ¹⁸F-FLT uptake decreased by 79%. ¹⁸F-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 ¹⁸F-FLT uptake did not reflect inhibition of ErbB kinase activity itself but, rathe, the effects of kinase inhibition on tumor cell proliferation. Tumor ¹⁸F-FDG uptake generally paralleled the changes seen for ¹⁸F-FLT. However, the baseline signal was significantly lower than that for ¹⁸F-FLT. Conclusion: These results indicate that ¹⁸F-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.

Key Words: thymidine kinase • ErbB • small molecule kinase inhibitor • ¹⁸F-FDG PET • ¹⁸F-FLT PET

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