Positron-emission tomography of vector-mediated gene expression in gene therapy for gliomas

doi:10.1016/S0140-6736(01)05904-9

The Lancet

Volume 358, Issue 9283, 1 September 2001, Pages 727-729

https://doi.org/10.1016/S0140-6736(01)05904-9 Get rights and content

Summary

In clinical gene-therapy trials for recurrent glioblastomas, transduction of the herpes simplex virus type-1 thymidine kinase (HSV-1-tk) gene with subsequent prodrug activation by ganciclovir was found to be safe, but clinical response was poor. We used positron-emission tomography (PET) with I-124-labelled 2'-fluoro-2'-deoxy-1β-D-arabino-furanosyl-5-iodo-uracil([¹²⁴I]–FIAU)—a specific marker substrate for gene expression of HSV-1-tk—to identify the location, magnitude, and extent of vector-mediated HSV-1-tk gene expression in a phase I/II clinical trial of gene therapy for recurrent glioblastoma in five patients. The extent of HSV-1-tk gene expression seemed to predict the therapeutic response. The expression of an exogenous gene introduced by gene therapy into patients with gliomas can be monitored non-invasively by PET.

References (5)

SS Gambhir et al.
Imaging transgene expression with radionuclide technologies
Neoplasia
(2000)
JG Tjuvajev et al.
Imaging the expression of transfected genes in vivo
Cancer Res
(1995)

There are more references available in the full text version of this article.

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Citation Excerpt :
Since HSV1-tk was one of the first reporter genes investigated, it enjoys a wide breadth of PET and SPECT tracers, as well as mutant forms, such as HSV1-sr39tk, which has enhanced in vivo activity.27,29,81,82 Though HSV1-tk imaging is successful in most small animal models, the results in clinical trials have been mixed.29,83–86 Investigations into the use of HSV1-tk for human imaging are meager: out of the ten active or recruiting clinical trials currently registered with ClinicalTrials.gov using a virus expressing HSV1-tk, only one plans to perform HSV1-tk imaging (ClinicalTrials.gov: NCT04313868).
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Research LettersPositron-emission tomography of vector-mediated gene expression in gene therapy for gliomas

Summary

Neoplasia

Imaging the expression of transfected genes in vivo

Cancer Res

Research Letters
Positron-emission tomography of vector-mediated gene expression in gene therapy for gliomas