Receptor-specific targeting with complementary peptide nucleic acids conjugated to peptide analogs and radionuclides |
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Authors: | Eric Wickstrom Mathew L. Thakur Edward R. Sauter |
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Affiliation: | (1) Department of Biochemistry and Molecular Pharmacology, Thomas Jefferson University, Philadelphia, PA, 19107, U.S.A.;(2) Department of Radiology, Kimmel Cancer Center, Philadelphia, PA, 19107, U.S.A. and;(3) Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, PA, 19107, U.S.A.;;(4) Department of Radiology, Thomas Jefferson University, Philadelphia, PA, 19107, U.S.A.;(5) Department of Radiology, Thomas Jefferson University, Philadelphia, PA, 19107, U.S.A. and;(6) Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, 19107, U.S.A;(7) Department of Surgery, University of Missouri, Columbia, MO, 65212, U.S.A |
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Abstract: | Genomic sequencing makes it possible to identify all the genes of an organism, now including Homo sapiens. Yet measurement of the expression of each gene of interest still presents a dauntingprospect. Northern blots, RNase protection assays, as well as microarrays and related technologies permit measurement of gene expression in total RNA extracted from cultured cells or tissue samples. It would be most valuable, however, to quantitate gene expression noninvasively in living cells and tissues. Unfortunately,no reliable method has been available to measure levels of specificmRNAs in vivo. Peptide nucleic acids (PNAs) display superior ruggedness and hybridization properties as a diagnostic tool for gene expression, and could be used for this purpose. On the down side, they are negligibly internalized by normal or malignant cells in the absence of conjugated ligands. Nevertheless,we have observed that Tc-99m-peptides can delineate tumors, and PNA-peptides designed to bind to IGF-1 receptors on malignant cellsare taken up specifically and concentrated in nuclei. We have postulated that antisense Tc-99m-PNA-peptides will be taken up by human cancer cells, will hybridize to complementary mRNA targets, and will permit scintigraphic imaging of oncogene mRNAsin human cancer xenografts in a mouse model. The oncogenes cyclinD1, ERBB2, c-MYC, K-RAS, and tumor suppressor p53 are being probed initially. These experimentsprovide a proof-of-principle for noninvasive detection of oncogeneexpression in living cells and tissues. This scintigraphic imaging technique should be applicable to any particular gene of interest in a cell or tissue type with characteristic receptors. |
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Keywords: | antisense breast cancer chelators conjugates gene expression hybridization imaging non-invasive oligonucleotides oncogenes peptides radionuclides scintigraphy tumors |
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