Format

Send to

Choose Destination
Br J Cancer. 2004 Dec 13;91(12):2079-85.

Monitoring HSVtk suicide gene therapy: the role of [(18)F]FHPG membrane transport.

Author information

1
PET Center, Groningen University Hospital, PO Box 30.001, Hanzeplein 1, 9700 RB Groningen, The Netherlands. a.r.buursma@pet.azg.nl

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.

PMID:
15599382
PMCID:
PMC2409793
DOI:
10.1038/sj.bjc.6602216
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center