This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pillai, R. G. Articles by Aboagye, E. O. Search for Related Content PubMed PubMed Citation Articles by Pillai, R. G. Articles by Aboagye, E. O.

Imaging Pharmacodynamics of the -Folate Receptor–Targeted Thymidylate Synthase Inhibitor BGC 945

¹ Department of Molecular Therapy, Imperial College London, Faculty of Medicine, Hammersmith Hospital Campus, London, United Kingdom; ² Section of Medicine, The Institute of Cancer Research, Sutton, Surrey, United Kingdom; and ³ Wolfson Brain Imaging Center, University of Cambridge, Addenbrookes Hospital, Cambridge, United Kingdom

Requests for reprints: Eric O. Aboagye, Molecular Therapy and PET Oncology Research Group, Imperial College London, Faculty of Medicine, Hammersmith Hospital, Room 240, MRC Cyclotron Building, Du Cane Road, London, W12 ONN, United Kingdom. Phone: 44208-383-3759; Fax: 44208-383-1783; E-mail: eric.aboagye{at}imperial.ac.uk.

Key Words: antifolate • thymidylate synthase • pharmacodynamics • positron emission tomography • [¹⁸F]fluorothymidine

The assessment of tissue-specific pharmacodynamics is desirable in the development of tumor-targeted therapies. Plasma deoxyuridine (dUrd) levels, a measure of systemic thymidylate synthase (TS) inhibition, has limited application for studying the pharmacodynamics of novel TS inhibitors targeted to the high affinity -folate receptor (FR). Here, we have evaluated the utility of [¹⁸F]fluorothymidine positron emission tomography ([¹⁸F]FLT-PET) for imaging the tissue pharmacodynamics of BGC 945, an FR-targeted antifolate TS inhibitor; the nontargeted antifolate BGC 9331 was used for comparison. TS inhibition by both drugs induced a concentration-dependent increase in [³H]thymidine uptake in FR-positive human epidermoid KB cells. Membrane-associated equilibrative nucleoside transporter type 1 levels increased from 55,720 ± 6,101 to 118,700 ± 5,193 and 130,800 ± 10,800 per cell at 100 µg/mL of BGC 9331 and BGC 945, respectively, suggesting this as a potential mechanism of increased nucleoside uptake. In keeping with these in vitro findings, tumor [¹⁸F]FLT accumulation in KB xenografts increased by 2-fold after drug treatment with maximal levels at 1 to 4 hours and 4 to 24 hours after BGC 9331 and BGC 945 treatment, respectively. Of interest to FR targeting, BGC 9331, but not BGC 945, induced accumulation of [¹⁸F]FLT uptake in intestine, a proliferative and TS-responsive tissue. For both drugs, quantitative changes in tumor [¹⁸F]FLT uptake were associated with increased tumor dUrd levels. In conclusion, we have validated the utility of [¹⁸F]FLT-PET to image TS inhibition induced by antifolates and shown the tumor-specific activity of BGC 945. This imaging biomarker readout will be useful in the early clinical development of BGC 945. [Cancer Res 2008;68(10):3827–34]

This article has been cited by other articles:

				L. M. Kenny, K. B. Contractor, J. Stebbing, A. Al-Nahhas, C. Palmieri, S. Shousha, R. C. Coombes, and E. O. Aboagye Altered Tissue 3'-Deoxy-3'-[18F]Fluorothymidine Pharmacokinetics in Human Breast Cancer following Capecitabine Treatment Detected by Positron Emission Tomography Clin. Cancer Res., November 1, 2009; 15(21): 6649 - 6657. [Abstract] [Full Text] [PDF]

				M. P.S. Dunphy and J. S. Lewis Radiopharmaceuticals in Preclinical and Clinical Development for Monitoring of Therapy with PET J. Nucl. Med., May 1, 2009; 50(Suppl_1): 106S - 121S. [Abstract] [Full Text] [PDF]