title: Monitoring HSVtk suicide gene therapy: the role of [(18)F]FHPG membrane transport.
abstract: Favourable pharmacokinetics of the prodrug are essential for successful HSVtk/ganciclovir (GCV) suicide gene therapy. [(18)F]FHPG PET might be a suitable technique to assess the pharmacokinetics of the prodrug GCV noninvasively, provided that [(18)F]FHPG mimics the behaviour of GCV. Since membrane transport is an important aspect of the pharmacokinetics of the prodrug, we investigated the cellular uptake mechanism of [(18)F]FHPG in an HSVtk expressing C6 rat glioma cell line and in tumour-bearing rats. The nucleoside transport inhibitors dipyridamol, NBMPR and 2-chloroadenosine did not significantly affect the [(18)F]FHPG uptake in vitro. Thymidine and uridine significantly decreased [(18)F]FHPG uptake by 84 and 58%, respectively, but an enzyme assay revealed that this decline was due to inhibition of the HSVtk enzyme rather than membrane transport. Nucleobase transport inhibitors, thymine and adenine, caused a 58 and 55% decline in tracer uptake, respectively. In vivo, the ratio of [(18)F]FHPG uptake in C6tk and C6 tumours decreased from 3.0+/-0.5 to 1.0+/-0.2 after infusion of adenine. Thus, in our tumour model, [(18)F]FHPG transport exclusively occurred via purine nucleobase transport. In this respect, FHPG does not resemble GCV, which is predominantly taken up via the nucleoside transporter, but rather acyclovir, which is also taken up via the purine nucleobase carrier.
authors.affiliation: PET Center, Groningen University Hospital, PO Box 30.001, Hanzeplein 1, 9700 RB Groningen, The Netherlands. a.r.buursma@pet.azg.nl
authors.forename: A R
authors.initials: AR
authors.lastname: Buursma
authors.forename: I J
authors.initials: IJ
authors.lastname: van Dillen
authors.forename: A
authors.initials: A
authors.lastname: van Waarde
authors.forename: W
authors.initials: W
authors.lastname: Vaalburg
authors.forename: G A P
authors.initials: GA
authors.lastname: Hospers
authors.forename: N H
authors.initials: NH
authors.lastname: Mulder
authors.forename: E F J
authors.initials: EF
authors.lastname: de Vries
mesh_terms: D000818:Animals; D000998:Antiviral Agents; D001692:Biological Transport / Q000502:physiology*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics*; D015774:Ganciclovir / Q000493:pharmacokinetics; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy; D005910:Glioma / Q000000981:diagnostic imaging; D018259:Herpesvirus 1, Human / Q000235:genetics; D049268:Positron-Emission Tomography; D011849:Radioactive Tracers; D051381:Rats; D013937:Thymidine Kinase / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D005462:Fluorine Radioisotopes; D011849:Radioactive Tracers; D013937:Thymidine Kinase; D015774:Ganciclovir