Development of DNA-based radiopharmaceuticals carrying Auger-electron emitters for anti-gene radiotherapy

Q J Nucl Med. 2000 Sep;44(3):256-67.


Targeting of radiation damage to specific DNA sequences is the essence of antigene radiotherapy. This technique also provides a tool to study molecular mechanisms of DNA repair on a defined, single radiodamaged site. We achieved such sequence-specific radiodamage by combining the highly localized DNA damage produced by the decay of Auger-electron-emitters such as 125I with the sequence-specific action of triplex-forming oligonucleotides (TFO). TFO complementary to polypurine-polypyrimidine regions of human genes were synthesized and labeled with 125I-dCTP by the primer extension method. 125I-TFO were delivered into cells with several delivery systems. In addition, human enzymes capable of supporting DNA single-strand-break repair were isolated and assessed for their role in the repair of this lesion. Also, the mutagenicity and repairability of 125I-TFO-induced double strand breaks (DSB) were assessed by repair of a plasmid possessing a site-specific DSB lesion. Using plasmids containing target polypurine-polypyrimidine tracts, we obtained the fine structure of sequence-specific DNA breaks produced by decay of 125I with single-nucleotide resolution. We showed that the designed 125I-TFO in nanomolar concentrations could bind to and introduce double-strand breaks into the target sequences in situ, i.e., within isolated nuclei and intact digitonin-permeabilized cells. We also showed 125I-TFO-induced DSB to be highly mutagenic lesions resulting in a mutation frequency of nearly 80%, with deletions comprising the majority of mutations. The results obtained demonstrate the ability of 125I-TFO to target specific sequences in their natural environment--within eucaryotic nucleus. Repair of 125I-TFO-induced DNA damage should typically result in mutagenic gene inactivation.

MeSH terms

  • Animals
  • DNA / radiation effects*
  • DNA Damage / radiation effects
  • DNA Repair
  • Humans
  • Iodine Radioisotopes / pharmacology
  • Iodine Radioisotopes / therapeutic use
  • Neoplasms / diagnostic imaging
  • Neoplasms / genetics
  • Neoplasms / radiotherapy
  • Nucleic Acid Conformation
  • Oligonucleotides / pharmacology*
  • Oligonucleotides / therapeutic use
  • Radionuclide Imaging
  • Radiopharmaceuticals / pharmacology*
  • Radiopharmaceuticals / therapeutic use


  • Iodine Radioisotopes
  • Oligonucleotides
  • Radiopharmaceuticals
  • DNA