Other New Tracers

Continuous progress made in the field of molecular biology has led to the development of new radiopharmaceuticals for imaging. One aim is to image gene expression non-invasively using radiotracers. This may be achieved by the use of antisense imaging. Antisense imaging methods are being investigated to modulate the gene expression. Base pairing of messenger RNA with oligonucleotide ultimately results in a down-regulation of specific genes. This technique, based on suppression of DNA transcription or RNA translation, can be used for therapeutic and diagnostic purposes. Due to the unique selectivity, oligonucleotides are promising tools for the development of new radiotracers for molecular imaging. Automated synthesis procedures have been developed, which are a pre-requisite for the application of these new radiopharmaceuticals (50).

One currently investigated application of molecular biological techniques is the use of gene therapeutic approaches, e.g., the modification of iodine uptake in malignant tumors to provide a possibility for radioisotope treatment. The therapeutic outcome of differentiated thyroid cancer is dependent on the ability to accumulate iodine for radioisotope therapy. The transport of iodine is mediated by the sodium/iodide transporter (NIS). NIS is regulated by TSH, but also by several other factors. It has been reported that thyroid cancers may show a down-regulation of the NIS, which limits radioisotope therapy. Besides thyroid tissue, NIS expression was found in several other tissues, including pancreas, breast tissue, prostate gland, ovary, and lung (51). Dohan et al. (52) report about an expression rate of 80% in breast cancer samples. The upregulation of NIS in these structures can be used to target radioiodine therapy in thyroid carcinoma as well as in other tumors (Fig. 13). Chung

Figure 13 Modification of NIS expression in a prostate carcinoma (Dunning R3327). Significant increase of the iodine uptake in the genetically modified tumor (yellow circle) as compared to the wild type (green circle). (See color insert.)

reviewed the role of the sodium iodide transporter in nuclear medicine and emphasized the role of NIS as an alternative imaging reporter gene (53). However, one major problem for the clinical application is the efflux of iodine out of tumor cells following upregulation of NIS (54). Haberkorn et al. used a Dunning prostate adenocarcinoma model and reported an initially 200-fold enhanced tracer uptake in the genetically modified tumor. However, up to 81% of the radioactivity was released within 20 minutes. Dosimetry calculations revealed that an injected activity resulting in a dose of 1200 MBq/m2 resulted in 3 ± 0.5 Gy dose in the tumor, which is by far too low for any therapeutic effect (54). To extend the retention time for iodine, different modifications were proposed, including the simultaneous transfer of the thyroperoxidase gene, use of lithium, and the application of other more effective radioisotopes such as Re-188. These problems need to be solved prior to the application of the method in patients; however, this approach represents a new and promising procedure to treat malignant tumors.

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