title: Imaging pharmacodynamics of the alpha-folate receptor-targeted thymidylate synthase inhibitor BGC 945.
abstract: 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 alpha-folate receptor (FR). Here, we have evaluated the utility of [(18)F]fluorothymidine positron emission tomography ([(18)F]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 [(3)H]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 mug/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 [(18)F]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 [(18)F]FLT uptake in intestine, a proliferative and TS-responsive tissue. For both drugs, quantitative changes in tumor [(18)F]FLT uptake were associated with increased tumor dUrd levels. In conclusion, we have validated the utility of [(18)F]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.
authors.affiliation: Department of Molecular Therapy, Imperial College London, Faculty of Medicine, Hammersmith Hospital Campus, London, United Kingdom.
authors.forename: Radhakrishna G
authors.initials: RG
authors.lastname: Pillai
authors.forename: Martin
authors.initials: M
authors.lastname: Forster
authors.forename: Meg
authors.initials: M
authors.lastname: Perumal
authors.forename: Fraser
authors.initials: F
authors.lastname: Mitchell
authors.forename: Julius
authors.initials: J
authors.lastname: Leyton
authors.forename: Franklin I
authors.initials: FI
authors.lastname: Aibgirhio
authors.forename: Oksana
authors.initials: O
authors.lastname: Golovko
authors.forename: Ann L
authors.initials: AL
authors.lastname: Jackman
authors.forename: Eric O
authors.initials: EO
authors.lastname: Aboagye
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000494:pharmacology; D058975:Folate Receptor 1; D058973:Folate Receptors, GPI-Anchored; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D049268:Positron-Emission Tomography / Q000379:methods; D011799:Quinazolines / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D013997:Time Factors
chemical_list: C504662:BGC945; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D058975:Folate Receptor 1; D058973:Folate Receptors, GPI-Anchored; C520574:Folr1 protein, mouse; D011799:Quinazolines; D011956:Receptors, Cell Surface; D019788:Fluorodeoxyglucose F18; D013940:Thymidylate Synthase