Abstract
Purpose
Although gemcitabine is a mainstay of pancreatic cancer therapy, it is only moderately effective, and it would be desirable to measure drug uptake in patients. 1-(2′-deoxy-2′-fluoroarabinofuranosyl) cytosine (FAC), is an analog of gemcitabine, and when labeled with F-18, it may be a potential surrogate PET tracer for the drug.
Procedures
[18F]FAC was synthesized to a radiochemical purity of >96 %. The human tumor lines AsPC1, BxPC3, Capan-1, Panc1, and MiaPaca2 were grown orthotopically in nude mice. KPC mice that conditionally express oncogenic K-ras and p53 mutations in pancreatic tissue were also used. The intra-tumoral distributions of [14C]gemcitabine and [18F]FAC were mapped with autoradiography. The inter-tumor correlation between [14C]gemcitabine and [18F]FAC was established in the orthotopic tumors. Expression of the equilibrative and concentrative nucleoside transporters (ENT, CNT) in vitro was detected by western blotting. Drug uptake was characterized in vitro using [3H]gemcitabine and the effect of transporter inhibition on gemcitabine and FAC uptake was investigated. The relative affinity of cells for gemcitabine and FAC was tested in competition assays.
The cell lines differed in sensitivity to transport inhibitors and in competition studies. There was a good in vivo correlation between the total uptake of [18F]FAC and [14C]gemcitabine, measured across all orthotopic tumors. Using the KPC and BxPC3 models, we found that [14C]gemcitabine and [18F]FAC were largely co-localized.
Conclusions
In the lines examined here, [18F]FAC uptake correlates well with gemcitabine in vivo, supporting the notion that [18F]FAC can serve as a PET radiotracer surrogate to determine the uptake and distribution of gemcitabine within pancreatic tumors.
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This work was partially supported by an MSKCC Imaging and Radiation Sciences (IMRAS) seed grant. JR and JLH were supported by NIH grant 1 R01 CA194321-01A1; NP was supported by the Mr. William H. and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research and the Center for Experimental Therapeutics of Memorial Sloan Kettering Cancer Center. RMK was supported by Tri-Institutional Training Grant R25-OD010447-02. We thank the members of the Small Animal Imaging Core for their assistance. The SAICF is supported in part by US National Institutes of Health (NIH) P30 CA008748-48, S10 RR020892-01, S10 RR028889-01 and the Geoffrey Beene Cancer Research Center. P.B.R was supported in part by a K12 Paul Calebresi Career Development Award for Clinical Oncology (K12 CA187069).
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Russell, J., Pillarsetty, N., Kramer, R.M. et al. In Vitro and In Vivo Comparison of Gemcitabine and the Gemcitabine Analog 1-(2′-deoxy-2′-fluoroarabinofuranosyl) Cytosine (FAC) in Human Orthotopic and Genetically Modified Mouse Pancreatic Cancer Models. Mol Imaging Biol 19, 885–892 (2017). https://doi.org/10.1007/s11307-017-1078-6
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DOI: https://doi.org/10.1007/s11307-017-1078-6