Imaging in vivo herpes simplex virus thymidine kinase gene transfer to tumour-bearing rodents using positron emission tomography and

Our plain-English summary of Imaging in vivo herpes simplex virus thymidine kinase gene transfer to tumour-bearing rodents using positron emission tomography and, by R. Hustinx, C.Y. Shiue, A. Alavi, et al (European Journal of Nuclear Medicine, 2001).

The study

• Authors: R. Hustinx, C.Y. Shiue, A. Alavi, D. McDonald, G.G. Shiue, H. Zhuang, M. Lanuti, E. Lambright, J.S. Karp, S.L. Eck
• Journal: European Journal of Nuclear Medicine
• Published: 2001;28(1):5-12
• Cited by: 40 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Radiolabelled ganciclovir analogues have shown promise as imaging agents to detect herpes simplex virus thymidine kinase (HSVtk) expression. This study evaluated the use of positron emission tomography (PET) imaging with 9-[(3-[18F]fluoro-1-hydroxy-2-propoxy)methyl]guanine ([18F]FHPG) to assess gene transfer into tumours. HSVtk-positive and HSVtk-negative cell lines were first treated in vitro with [18F]FHPG. To assess the efficacy of PET in detecting HSVtk expression following in vivo gene transfer, mice were injected intravenously with an adenovirus encoding HSVtk (Ad.HSVtk), a control vector (Ad.Bgl2) or saline. Subcutaneous human glioma xenografts were grown in mice and treated by direct injection of Ad.HSVtk or Ad.Bgl2. Imaging was performed 48 h after transduction. Similar experiments were performed using Fischer rats implanted with syngeneic tumours. The presence of the HSVtk protein was confirmed by immunohistochemistry. Biodistribution studies were also obtained in 14 naive mice. In vitro studies showed high and specific uptake of [18F]FHPG in HSVtk-positive cell lines, with an uptake ratio of up to 27:1. PET imaging and direct counting of major organs demonstrated HSVtk-specific tracer retention. In mice, HSVtk-positive tumours retained 3.4% dose/gram as compared to 0.6% for control tumours (P=0.03). They were clearly seen on the PET images as early as 100 min post injection. Similar results were obtained with syngeneic rat tumours. Biodistribution studies demonstrated the rapid distribution and clearance of the tracer in all major organs. Our results demonstrate that PET imaging of HSVtk gene transfer to tumours is feasible and is highly specific for HSVtk expression.

In plain English

This laboratory study tested whether a radioactive tracer called [18F]FHPG, combined with PET scanning, could show where a gene used in experimental cancer gene therapy had been delivered. The gene was herpes simplex virus thymidine kinase (HSVtk). The study did not examine asbestos exposure. A rat mesothelioma cell line (II-45) was used as one of the tumour models. In cell cultures, HSVtk-positive cells took up more tracer than control cells after 3 hours: 4.5 times more for the mesothelioma cells and 27 times more for 9L glioma cells. In mice with human glioma tumours injected with the gene-carrying virus, treated tumours retained 3.4% of the tracer dose per gram, compared with 0.6% for control tumours (P=0.03). In two rats with mesothelioma tumours, only the tumour given the higher virus dose showed on PET. The liver also took up tracer after the virus was given. The authors concluded that the method was feasible. They noted that small tumour size and PET resolution led to underestimated tracer levels, and that there appeared to be a detection threshold.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: in vitro cell culture experiments and animal experiments in mice and rats
• Who was studied: Two tumour cell lines (9L rat glioma and II-45 rat mesothelioma) in culture. Animals: 20 SCID mice with subcutaneous U87 human glioma tumours, 8 further SCID mice given the vector or saline intravenously, 14 untreated Balb/c mice for biodistribution, and 2 Fischer rats with II-45 mesothelioma tumours in both flanks.
• Exposure: No asbestos exposure was studied. The exposures were gene transfer with an adenovirus carrying HSVtk (Ad.HSVtk), compared with a control vector (Ad.Bgl2 or Ad.LacZ) or saline, followed by injection of the PET tracer [18F]FHPG.
• Main results:
  • In culture, the uptake ratio of HSVtk-positive to control II-45 mesothelioma cells was 2.1 after 1 h and 4.5 at 3 h.
  • In culture, the uptake ratio for 9L glioma cells stably producing HSVtk was 7 at 1 h and 27 at 3 h.
  • In mice given the vector intravenously, the liver was clearly seen on PET only in mice that received Ad.HSVtk. Liver uptake was 15.6±4.2% dose/g in Ad.HSVtk mice (n=4), compared with 0.076 for Ad.Bgl2 (n=2) and 0.045 for PBS (n=2); P=0.008 for each comparison.
  • In mice with glioma tumours injected with the vector, Ad.HSVtk tumours retained 3.4% dose/gram compared with 0.6% for control tumours (P=0.03). The tumour to muscle ratio was 5.5 compared with 0.8 (P=0.02).
  • In Ad.HSVtk-treated mice, the tumour to background ratio on PET rose from 1.0±0.1 on early images to 2.6±0.5 on delayed scans. In control animals it stayed at 1.1.
  • In the rats with II-45 mesothelioma tumours, only the tumour injected with 2×10^9 pfu of Ad.HSVtk showed on PET. The control sites and the tumour given 2×10^8 pfu did not.
  • In untreated Balb/c mice, no organ retained more than 0.6% of the injected dose per gram at 120 minutes.
• The authors' conclusion: The authors concluded that the results showed it is feasible to visualise HSVtk gene transfer to tumours and the liver with [18F]FHPG and PET, and that further studies are needed.
• Limitations the authors state:
  • Because the tumours were small and PET resolution is limited, the true tracer concentration was underestimated on the images.
  • The rat tumour given the lower vector dose was not seen, which suggests a threshold of gene expression below which PET may not detect a signal.
  • The authors stated that the relationship among tracer uptake, gene expression and clinical outcome still needs to be characterised and quantified.

Topics

Medical terms in this study, explained in our Lexicon: Immunohistochemistry.

Related studies

• Gene therapy using adenovirus carrying the herpes simplex-thymidine kinase gene to treat in vivo models of human malignant mesothelioma and lung cancer — H.C. Hwang, W.R. Smythe, et al. (1995)
• Efficacy of repeated adenoviral suicide gene therapy in a localized murine tumor model — E.S. Lambright, S.D. Force, et al. (2000)
• Use of protamine to augment adenovirus-mediated cancer gene therapy — M. Lanuti, C.E. Kouri, et al. (1999)
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