Abstract
The gene for herpes simplex virus thymidine kinase (HSV-tk) is widely used as a suicide gene in experimental gene therapy of cancer. 9-(4-Fluoro-3-hydroxymethylbutyl)guanine (FHBG) is an antiviral nucleoside analog that is rapidly phosphorylated by viral thymidine kinase but is a poor substrate for mammalian thymidine kinase. Recently, FHBG labeled in the 4-fluoro position with 18F has shown promise relative to other similar compounds for imaging in vivo expression of HSV-tk using PET. In this study, we evaluated the uptake of [18F]FHBG in vitro and in vivo using transduced and wild-type human colon cancer cells (HT-29). We also imaged [18F]FHBG and measured the radioactivity concentrations of circulating [18F]FHBG and its metabolites in monkeys. Methods: Sterile, pyrogen-free [18F]FHBG was produced routinely in good yields. Cells were transduced transcluced with the retroviral vector G1Tk1SvNa containing HSV-tk gene. In vitro uptake studies were performed by incubating cells with [18F]FHBG at 37°C for 1 and 5 h. Biodistribution studies were performed at 2 and 5 h after injection in nude mice bearing tumors grown from wild-type or transduced cells. Sequential, wholebody PET scans of cynomolgus monkeys were obtained over a period of >2 h after intravenous injection of [18F]FHBG. Arterial plasma samples obtained from monkeys 15-120 min after intravenous injection were subjected to acid extraction, and the acid-soluble fractions were analyzed by high-performance liquid chromatography. Results: In vitro studies showed 31 and 71 (P < 0.001) times higher uptake of the probe at 1 and 5 h, respectively, in transduced cells compared with nontransduced cells. In vivo studies in mice showed that tumor uptake of the radiotracer was 4-fold (P < 0.05) and 13-fold (P < 0.001) higher at 2 and 5 h, respectively, in tumors grown from transduced cells compared with control cells. Transduced tumor-to-normal tissue ratios ranged from 2 to 25 at 2 h and from 2 to 22 at 5 h. Recirculating labeled metabolites had only a minor effect on the biodistribution of radiolabel from [18F]FHBG in monkeys. Conclusion: These results indicate that [18F]FHBG may yield high-contrast PET images of HSV-tk expression in tumors and, therefore, it is a very promising radiotracer for monitoring of gene therapy of cancer with PET.
Original language | English (US) |
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Pages (from-to) | 1682-1690 |
Number of pages | 9 |
Journal | Journal of Nuclear Medicine |
Volume | 42 |
Issue number | 11 |
State | Published - 2001 |
Keywords
- Colon cancer
- Gene therapy
- PET
- Virus
- [F]FHBG
ASJC Scopus subject areas
- Radiology Nuclear Medicine and imaging