ISBN: 978-83-60043-10-3 - eurobic9

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Eurobic9, 2-6 September, 2008, Wrocław, Poland SL4. The Use of 64-Cu in Radio-diagnostics and Radionuclide Therapy - Required Properties of Chelators M. J. Bjerrum . a , J. R. Holm-Jørgensen b , K. Jensen , M. Jensen c a Department of Natural Sciences, University of Copenhagen, Thorvaldsensvej 40, DK-1871, Frederiksberg C, Denmark, b Department of Natural Sciences, University of Copenhagen and Risø DTU, Thorvaldsensvej 40, DK-1871, Frederiksberg C, Denmark c Risø National Laboratory for Sustainable Energy, Risø DTU, Technical University of Denmark, Frederiksborgvej 399, DK-4000, Roskilde, Denmark e-mail: mobj@life.ku.dk Radiodiagnostics and radionuclide therapy are heavily investigated topics. The use of the same compound for diagnostic and therapeutic purposes is highly desirable, and among the requirements are: tumor specificity, ease and speed of isotope uptake and high inertia with respect to isotope expulsion. Possible candidate isotopes are 64 Cu (PET imaging and therapy) and 67 Cu (therapy). With copper radioisotopes there is a need for developing novel chelators which forms kinetic and thermodynamic stable copper complexes. New candidates could be adamanzanes, a class of macrobicyclic tetraamine ligands with unique copper binding properties. [1] Cu(II) complexes are known for several of the adamanzane ligands. The uptake of Cu(II) is possible, choosing the right conditions, and expulsion has been shown to be extremely slow from the native adamanzanes. Furthermore, substituents on the non-bridged amine groups have been designed to function as linkers to a tumortargeting protein, and this has been performed in our group with cytochrome c as the model protein. It has been shown that it is possible to link the adamanzane ligand in a one-to-one ratio to one single protein site. It remains to be shown if the inherent Cu binding stability of the adamanzane complex is retained. Knowing the structures is essential to the interpretation of kinetic experiments necessary to prove the inertia with respect to Cu(II) expulsion or other unwanted interactions under biological conditions. References: [1] Springborg J. Adamanzanes - bi- and tricyclic tetraamines and their coordination compounds. Dalton Trans., 2003, 1653-1665. _____________________________________________________________________ 56
Eurobic9, 2-6 September, 2008, Wrocław, Poland SL5. Unique Properties of DNA Cross-links of Antitumor Oxaliplatin and the Effect of Chirality of the Carrier Ligand V. Brabec a , J. Malina a , J. Kasparkova b a Institute of Biophysics, v.v.i., Academy of Sciences of the Czech Republic, Kralovopolska 135, 61265, Brno, Czech Republic, b Laboratory of Biophysics, Department of Experiment, Palacky University, tr. Svobody 26, 77146, Olomouc, Czech Republic e-mail: brabec@ibp.cz Downstream processes that discriminate between DNA adducts of a third generation platinum antitumor drug oxaliplatin and conventional cisplatin are believed to be responsible for the differences in their biological effects. These different biological effects are explained by the ability of oxaliplatin to form DNA adducts more efficient as for their biological effects. We examined conformation, recognition by damaged-DNA binding-proteins, cellular processing and repair of the major 1, 2-GG intrastrand cross-link formed by oxaliplatin in three sequence contexts and of interstrand cross-link with the aid of biophysical and biochemical methods. We found that the properties of the cross-links of oxaliplatin and conventional cisplatin were notably different. In addition, the chirality at the carrier 1, 2-diaminocyclohexane ligand affected structural properties of cross-links of cisplatin analogs. We suggest that the unique properties of DNA cross-links of oxaliplatin are at least partly responsible for its unique antitumor effects [1, 2]. References: [1] Malina, J., Novakova, O., Vojtiskova, M., Natile, G. and Brabec, V. (2007) Conformation of DNA GG intrastrand cross-link of antitumor oxaliplatin and its enantiomeric analog. Biophys J, 93, 3950-3962. [2] Kasparkova, J., Vojtiskova, M., Natile, G. and Brabec, V. (2008) Unique properties of DNA interstrand cross-links of antitumor oxaliplatin and the effect of chirality of the carrier ligand. Chem Eur J, 14, 1330-1341. _____________________________________________________________________ 57
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ISBN: 978-83-60043-10-3 - eurobic9

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