Induction of DNA-double-strand breaks by auger electrons from 99mTc complexes with DNA-binding ligands.
The potential of certain Auger electron emitting nuclides for systemic radiotherapeutic applications has recently gained much attention. In particular, the ability of several nuclides, including 111In, 125I, and 123I, to induce DNA double-strand breaks (dsb), a good indicator of cytotoxicity, has been extensively studied. However, this ability has never previously been shown experimentally for 99mTc, which, besides the well-known gamma radiation that is used for diagnostic applications, also emits an average of 1.1 conversion electrons and 4 Auger or Coster-Kronig electrons per decay. Owing to the short range of Auger electrons, the radionuclide needs to be located very close to the DNA for dsb to occur. We synthesized two cationic 99mTcI-tricarbonyl complexes with pendant DNA binders, pyrene and anthraquinone. The X-ray crystal structures of the two complexes could be elucidated. Linear dichroism and UV/Vis spectroscopy revealed that the complex with pyrene intercalates DNA with a stability constant, K, of 1.1 x 10(6) M(-1), while the analogous complex with anthraquinone interacts with DNA in a groove-binding mode and has an affinity value of K=8.9 x 10(4) M(-1). We showed with phiX174 double-stranded DNA that the corresponding 99mTc complexes induce a significant amount of dsb, whereas non-DNA-binding [TcO4]- and nonradioactive Re compounds did not. These results indicate that the Auger electron emitter 99mTc can induce dsb in DNA when decaying in its direct vicinity and this implies potential for systemic radiotherapy with 99mTc complexes.
Häfliger
Pascal
P
Institute of Inorganic Chemistry, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
Agorastos
Nikos
N
Spingler
Bernhard
B
Georgiev
Oleg
O
Viola
Giampietro
G
Alberto
Roger
R
D004247:DNA / Q000737:chemistry* / Q000378:metabolism / Q000528:radiation effects*; D004249:DNA Damage; D004583:Electrons; D005720:Gamma Rays; D008024:Ligands; D015394:Molecular Structure; D015609:Organotechnetium Compounds / Q000737:chemistry*; D013667:Technetium / Q000737:chemistry*
D008024:Ligands; D015609:Organotechnetium Compounds; D013667:Technetium; D004247:DNA