Enzyme-targeted, nucleoside-based radiopharmaceuticals for scintigraphic monitoring of gene transfer and expression.
Enzymes, the expression products of transferred or native genes, offer unique windows of opportunity for clinical diagnosis and therapy. Although some expression products can be monitored in plasma, nuclear medicine imaging (SPECT and PET) offers the unique ability to selectively measure the intensity and regional/spatial distribution of gene expression both in vivo, in situ. Importantly, the superior sensitivity and moderate spatial resolution of the nuclear techniques also enable in vivo kinetic characterization of enzyme-substrate interaction. Indeed, the non-invasive, whole-body assessment of gene expression can only be achieved through imaging techniques. Given today's technology, nuclear imaging techniques uniquely provide the necessary sensitivity required to evaluate the success of the gene delivery and expression (transcription and translation), and to detect unwanted expression by non-target tissues. Enzymes are a special class of proteinacious gene expression products that selectively bind specific substrates for the purpose of molecular biotransformation rather than for signal transduction. In general, enzymes have received much less attention for imaging than receptors and antibodies, despite the enzymes' high substrate specificity and the potential for kinetic evaluation. Enzymes are attractive targets for diagnostic imaging and radioisotope radiotherapy because they convert multiple molecular copies of the substrate (radiotracer) per molecule of enzyme, thereby greatly increasing the ultimate sensitivity relative to the sensitivity offered by receptors that bind with 1:1 stoichiometry. Not surprisingly, enzymes have been the preferred molecular targets to date for scintigraphic imaging of gene therapy. This overview describes opportunities and advances in the utilization of radiolabelled nucleosides and nucleoside bases for imaging in gene therapy, with emphasis on the exploitation of enzyme systems for scintigraphic imaging of gene expression in gene therapy of cancer. Herpes simplex virus type-1 thymidine kinase and bacterial/fungal cytosine deaminase are discussed within the context of gene therapy issues such as gene vectors for targeting and delivery, the bystander effect, and radionucleoside delivery. The utilization of nucleosides as markers of tissue proliferation is discussed with respect to selected enzyme targets.
Wiebe
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LI
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, T6G 2N8, Canada. leonard.wiebe@ualberta.ca
Knaus
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EE
D000818:Animals; D001419:Bacteria / Q000201:enzymology; D043525:Cytosine Deaminase; D004798:Enzymes / Q000187:drug effects* / Q000235:genetics; D015870:Gene Expression / Q000502:physiology*; D017930:Genes, Reporter; D015316:Genetic Therapy; D018259:Herpesvirus 1, Human / Q000201:enzymology / Q000235:genetics; D006801:Humans; D009700:Nucleoside Deaminases / Q000378:metabolism; D009705:Nucleosides; D019275:Radiopharmaceuticals; D013937:Thymidine Kinase / Q000235:genetics
D004798:Enzymes; D009705:Nucleosides; D019275:Radiopharmaceuticals; D013937:Thymidine Kinase; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase