Monitoring antiproliferative responses to kinase inhibitor therapy in mice with 3'-deoxy-3'-18F-fluorothymidine PET.

Abstract

UNLABELLED:

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.

CONCLUSION:

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.

• Authors: Christian Waldherr, Ingo K Mellinghoff, Chris Tran, Benjamin S Halpern, Nora Rozengurt, Arash Safaei, Wolfgang A Weber, David Stout, Nagichettiar Satyamurthy, Jorge Barrio, Michael E Phelps, Daniel H Silverman, Charles L Sawyers, Johannes Czernin
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 46 Issue 1 Pg. 114-20 (Jan 2005) ISSN: 0161-5505 [Print] United States
• PMID: 15632041 (Publication Type: Comparative Study, Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• Dideoxynucleosides
• Protein Kinase Inhibitors
• Pyrimidines
• Pyrroles
• Radiopharmaceuticals
• Fluorodeoxyglucose F18
• PKI 166
• alovudine

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Carcinoma, Squamous Cell (diagnostic imaging, drug therapy, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dideoxynucleosides (pharmacokinetics)
• Disease Models, Animal
• Fluorodeoxyglucose F18 (pharmacokinetics)
• Humans
• Mice
• Mice, SCID
• Neoplasm Invasiveness (diagnostic imaging, prevention & control)
• Positron-Emission Tomography (methods)
• Protein Kinase Inhibitors (therapeutic use)
• Pyrimidines (therapeutic use)
• Pyrroles (therapeutic use)
• Radiopharmaceuticals (pharmacokinetics)
• Treatment Outcome