Zusammenfassung
Die Ergebnisse der Grundlagenforschung liefern Informationen über viele neue molekulare Strukturen, die als potenzielle neue diagnostische oder therapeutische Zielstrukturen dienen können. Die Selektion und Evaluation dieser Zielstrukturen wird Informationen über Physiologie, Biochemie und Pharmakologie benötigen. Diese Informationen können zum Teil durch nuklearmedizinische Methoden erhalten werden. So können nuklearmedizinische Verfahren zur Bestimmung der Funktion und Regulation von Genen eingesetzt werden. Dies kann mittels radioaktiv markierter Antisensemoleküle oder mit Hilfe von Reportergenen erfolgen. Neue Therapieansätze benötigen Bioverteilungsstudien in präklinischen Stadien und Verfahren zur Beurteilung ihrer Effizienz. Schließlich können biotechnologische Verfahren wie Phagen Display zur Entwicklung neuer Biomoleküle für die Isotopen-basierte Diagnostik und Therapie eingesetzt werden.
Abstract
The results obtained from basic science deliver more information about many new molecular structures, which may serve as potential new diagnostic or even therapeutic targets. The selection and evaluation of these targets needs information concerning physiology, biochemistry and pharmacology. These data can be obtained at least in part by nuclear medicine technology. Nuclear medicine procedures can be applied for the assessment of the function and regulation of genes. This can be achieved by use of radiolabeled antisense molecules or reporter gene technology. New therapeutic approaches necessitate biodistribution studies at preclinical stages and methods delivering data about their effectiveness. Finally, procedures from biotechnology such as phagen display may be used for the development of new biomolecules for the isotope-based diagnostics and treatment.
Schlüsselwörter
Functional genomics - Nuklearmedizin - Bildgebung - Radionuklide
Key words
functional genomics - nuclear medicine - imaging - radionuclides
Literatur
-
1
Haberkorn U, Altmann A, Eisenhut M.
Functional genomics and proteomics - the role of nuclear medicine.
Eur J Nuc Med.
2002;
29
115-132
-
2
Burley S K, Almo S C, Bonanno J B, Capel M, Chance M R, Gaasterland T, Lin D, Sali A, Studier F W, Swaminathan S.
Structural genomics: beyond the human genome project.
Nat Genet.
1999;
23
151-157
-
3
Schwikowski B, Uetz P, Fields S A.
Network of protein-protein interactions in yeast.
Nat Biotechnol.
2000;
18
1257-1261
-
4
Hunter T.
Signalling - 2000 and beyond.
Cell.
2000;
100
113-127
-
5
Fields S.
Proteomics in genomeland.
Science.
2001;
291
1221-1224
-
6
Zhu H, Klemic J F, Chang S, Bertone P, Casamajor A, Klemic K G, Smith D, Gerstein M, Reed M A, Snyder M.
Analysis of yeast protein kinases using protein chips.
Nat Genetics.
2000;
26
283-289
-
7
Wouters F S, Verveer P J, Bastiaens P IH.
Imaging biochemistry inside cells.
Trends Cell Biol.
2001;
11
203-211
-
8
Pellegrini M, Marcotte E M, Thompson M J, Eisenberg D, Yeates T O.
Assigning protein functions by comparative genome analysis: protein phylogenetic profiles.
Proc Natl Acad Sci USA.
1999;
96
4285-4288
-
9
Marcotte E M, Pellegrini M, Ng H L, Rice D W, Yeates T O, Eisenberg D.
Detecting protein function and protein-protein interactions from genome sequences.
Science.
1999;
285
751-753
-
10
Dandekar T, Snel B, Huynen M, Bork P.
Conservation of gene order: a fingerprint of proteins that physically interact.
Trend Biochem Sci.
1998;
23
324-328
-
11
Marcotte E M, Pellegrini M, Thompson M J, Yeates T O, Eisenberg D A.
A combined algorithm for genome-wide prediction of protein function.
Nature.
1999;
402
83-86
-
12
Kim S H.
Structural genomics of microbes: an objective.
Curr Opin Struct Biol.
2000;
10
380-383
-
13
Zamecnik P C, Stephenson M L.
Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide.
Proc Natl Acad Sci USA.
1978;
75
280-285
-
14
Mukhopadhyay T, Tainsky M, Cavender A C, Roth J A.
Specific inhibition of K-ras expression and tumorigenicity of lung cancer cells by antisense RNA.
Cancer Res.
1991;
51
1744-1748
-
15
Hannon G J.
RNA interference.
Nature.
2002;
418
244-251
-
16
Zeng Y. et al .
Both natural and designed micro RNAs can inhibit the expression of cognate mRNAs when expressed in human cells.
Mol Cell.
2002;
9
1327-1333
-
17
Sui G. et al .
A DNA vector-based RNAi technology to suppress gene expression in mammalian cells.
Proc Natl Acad Sci USA.
2002;
99
5515-5520
-
18
Moss E G.
Silencing unhealthy alleles naturally.
Trends Biotechnol.
2003;
21
185-187
-
19
Claverie J M.
What if there are only 30 000 human genes?.
Science.
2001;
291
1255-1257
-
20
Woolf T M, Melton D A, Jennings C GB.
Specificity of antisense oligonucleotides in vivo.
Proc Natl Acad Sci USA.
1992;
89
7305-7309
-
21
Iversen P L, Zhu S, Meyer A, Zon G.
Cellular uptake and subcellular distribution of phosphorothioate oligonucleotides into cultured cells.
Antisense Res Dev.
1992;
2
211-222
-
22
Loke S L, Stein C A, Zhang X H, Mori K, Nakanishi M, Subasinghe C, Cohen J S, Neckers L M.
Characterization of oligonucleotide transport into living cells.
Proc Natl Acad Sci USA.
1989;
86
3474-3478
-
23
Dewanjee M K, Ghafouripour A K, Kapadvanjwala M, Dewanjee S, Serafini A N, Lopez D M, Sfakianakis G N.
Noninvasive imaging of c-myc oncogene messenger RNA with indium-111-antisense probes in a mammary tumor-bearing mouse model.
J Nucl Med.
1994;
35
1054-1063
-
24
Cammilleri S, Sangrajrang S, Perdereau B, Brixy F, Calvo F, Bazin H, Magdelenat H.
Biodistribution of iodine-125 tyramine transforming growth factor ? antisense oligonucleotide in athymic mice with a human mammary tumor xenograft following intratumoral injection.
Eur J Nucl Med.
1996;
23
448-452
-
25
Kobori N, Imahori Y, Mineura K, Ueda S, Fujii R.
Visualization of mRNA expression in CNS using 11C-labeled phosphorothioate oligodeoxynucleotide.
Neuroreport.
1999;
10
2971-2974
-
26
Shi N, Boado R J, Pardridge W M.
Antisense imaging of gene expression in the brain in vivo.
Proc Natl Acad Sci USA.
2000;
97
14709-14714
-
27
Urbain J L, Shore S K, Vekemans M C, Cosenza S C, DeRiel K, Patel G V, Charkes N D, Malmud L S, Reddy E P.
Scintigraphic imaging of oncogenes with antisense probes: does it make sense.
Eur J Nucl Med.
1995;
22
499-504
-
28
Tavitian B, Terrazzino S, Kühnast B, Marzabal S, Stettler O, Dolle F, Deverre J R, Jobert A, Hinnen F, Bendriem B, Crouzel C, Di Giamberardino L.
In vivo imaging of oligonucleotides with positron emission tomography.
Nature Med.
1998;
4
467-471
-
29
Watanabe N, Sawai H, Endo K, Shinozuka K, Ozaki H, Tanada S, Murata H, Sasaki Y.
Labeling of phosphorothioate antisense oligonucleotides with yttrium-90.
Nucl Med Biol.
1999;
26
239-243
-
30
Anderson L, Seilhamer J.
A comparison of selected mRNA and protein abundances in human liver.
Electrophoresis.
1977;
18
533-537
-
31
Futcher B, Latter G I, Monardo P, McLaughlin C S, Garrels J I.
A sampling of the yeast proteome.
Mol Cell Biol.
1999;
19
7357-7368
-
32
Gygi S P, Rist B, Gerber S A, Turecek F, Gelb M H, Aebersold R.
Quantitative analysis of complex protein mixtures using isotope-coded affinity tags.
Nat Biotechnol.
1999;
17
994-999
-
33
Tjuvajev J G, Stockhammer G, Desai R. et al .
Imaging the expression of transfected genes in vivo.
Cancer Res.
1995;
55
6126-6132
-
34
Haberkorn U, Altmann A, Morr I. et al .
Gene therapy with Herpes Simplex Virus thymidine kinase in hepatoma cells: Uptake of specific substrates.
J Nucl Med.
1997;
38
287-294
-
35
Gambhir S S, Barrio J R, Phelps M E. et al .
Imaging adenoviral-directed reporter gene expression in living animals with positron emission tomography.
Proc Natl Acad Sci USA.
1999;
96
2333-2338
-
36
MacLaren D C, Gambhir S S, Satyamurthy N. et al .
Repetitive non-invasive imaging of the dopamine D2 receptor as a reporter gene in living animals.
Gene Ther.
1999;
6
785-791
-
37
Zinn K R, Buchsbaum D J, Chaudhuri T R. et al .
Noninvasive monitoring of gene transfer using a reporter receptor imaged with a high-affinity peptide radiolabeled with 99mTc or 188Re.
J Nucl Med.
2000;
41
887-895
-
38
Raben D, Buchsbaum D J, Khazaeli M B. et al .
Enhancement of radiolabeled antibody binding and tumor localization through adenoviral transduction of the human carcinoembryonic antigen gene.
Gene Ther.
1996;
3
567-580
-
39
Haberkorn U, Altmann A, Mier W, Eisenhut M.
Impact of functional genomics and proteomics on radionuclide imaging.
Sem Nucl Med.
2005;
34
4-22
-
40
Haberkorn U, Henze M, Altmann A. et al .
Transfer of the human sodium iodide symporter gene enhances iodide uptake in hepatoma cells.
J Nucl Med.
2001;
42
317-325
-
41
Smit J WA. et al .
Iodide kinetics and experimental 131I therapy in a xenotransplanted human sodium-iodide symporter-transfected human follicular thyroid carcinoma cell line.
J Clin Endocrinol Metab.
2002;
87
1247-1253
-
42
Spitzweg C. et al .
Treatment of prostate cancer by radioiodine therapy after tissue-specific expression of the sodium iodide symporter.
Cancer Res.
2000;
60
6526-6530
-
43
Oliver F J, Collins M KL, Lopez-Rivas A.
Overexpression of a heterologous thymidine kinase delays apoptosis induced by factor deprivation and inhibitors of deoxynucleotide metabolism.
J Biol Chem.
1997;
272
10624-10630
-
44
Liang Q, Satyamurthy N, Barrio J R. et al .
Noninvasive and Quantitative Imaging, in Living Animals, of a Mutant Dopamine D2 Receptor Reporter Gene in which Ligand Binding is Uncoupled from Signal Transduction.
Gene Ther.
2001;
19
1490-1498
-
45
Tucker C L, Gera J F, Uetz P.
Towards an understanding of complex protein networks.
Trends Cell Biol.
2001;
11
102-106
-
46
Marcotte E M, Pellegrini M, Ng H L. et al .
Detecting protein function and protein-protein interactions from genome sequences.
Science.
1999;
285
751-753
-
47
Wouters F S, Verveer P J, Bastiaens P IH.
Imaging biochemistry inside cells.
Trends Cell Biol.
2001;
11
203-211
-
48
Ray P, Pimenta H, Paulmurugan R. et al .
Noninvasive quantitative imaging of protein-protein interactions in living subjects.
Proc Natl Acad Sci USA.
2002;
99
3105-3110
-
49
Wu J C, Sundaresan G, Iyer M. et al .
Noninvasive optical imaging of firefly luciferase reporter gene expression in skeletal muscles of living mice.
Mol Ther.
2001;
4
297-306
-
50
Luker G D, Sharma V, Pica C M. et al .
Noninvasive imaging of protein-protein interactions in living animals.
Proc Natl Acad Sci USA.
2002;
99
6961-6966
-
51
Rossi F MV, Blakely B T, Blau H M.
Interaction blues: Protein interactions monitored in live mammalian cells by b-galactosidase complementation.
Trends Cell Biol.
2000;
10
119-122
-
52
Mills K V, Paulus H.
Reversible inhibition of protein splicing by zinc ion.
J Biol Chem.
2001;
276
10832-10838
-
53
Gimble F S.
Putting protein splicing to work.
Chem Biol.
1998;
5
R251-R256
-
54
Paulmurugan R, Umezawa Y, Gambhir S S.
Noninvasive imaging of protein-protein interactions in living subjects by using reporter protein complementation and reconstitution strategies.
Proc Natl Acad Sci USA.
2002;
99
15608-15613
-
55
Werner T.
Promoters can contribute to the elucidation of protein function.
Trends Biotechnol.
2003;
21
9-13
-
56
Haberkorn U, Altmann A.
Noninvasive imaging of protein-protein interaction in living organisms.
Trends Biotechnol.
2003;
21
241-243
-
57
Altmann A, Schulz R B, Glensch G, Eskerski H, Zitzmann S, Eisenhut M, Haberkorn U.
Effects of Pax8 and TTF-1 Thyroid Transcription Factor Gene Transfer in Hepatoma Cells: Imaging of Functional Protein-Protein Interaction and Iodide Uptake.
J Nucl Med.
2005;
46
831-839
-
58
Jiang S, Altmann A, Grimm D. et al .
Tissue-specific gene expression in medullary thyroid carcinoma cells employing calcitonin regulatory elements and AAV vectors.
Cancer Gene Ther.
2001;
8
469-472
-
59
Iyer M, Wu L, Carey M. et al .
Two-step transcriptional amplification as a method for imaging reporter gene expression using weak promoters.
Proc Natl Acad Sci U S A.
2001;
98
14595-14600
-
60
Haberkorn U, Eisenhut M.
Molecular imaging and therapy-a programme based on the development of new biomolecules.
Eur J Nucl Med Mol Imaging.
2005;
32
1354-1359
-
61
Zitzmann S, Mier W, Schad A, Kinscherf R, Askoxylakis V, Krämer S, Altmann A, Eisenhut M, Haberkorn U.
A new prostate carcinoma binding peptide (DUP-1) for tumor imaging and therapy.
Clin Cancer Res.
2005;
11
139-146
-
62
Zitzmann S, Krämer S, Mier W, Mahmut M, Fleig J, Altmann A, Eisenhut M, Haberkorn U.
Identification of a New Prostate-Specific Cyclic Peptide with the Bacterial FLiTRx System.
J Nucl Med.
2005;
46
782-785
-
63
Stemmer W PC.
Rapid evolution of protein in vitro by DNA shuffling.
Nature.
1994;
370
389-391
-
64
Kolkman J A, Stemmer W PC.
Directed evolution of proteins by exon shuffling.
Nature Biotechnol.
2001;
19
423-428
Prof. Dr. U. Haberkorn
Abt. Nuklearmedizin · Radiologische Universitätsklinik
Im Neuenheimer Feld 400
69120 Heidelberg
Phone: +49/62 21/56 77 31
Fax: +49/62 21/56 54 73
Email: Uwe_Haberkorn@med.uni-heidelberg.de
