title: Strand breakage by decay of DNA-bound124I provides a basis for combined PET imaging and Auger endoradiotherapy.
abstract: Purpose DNA ligands labelled with125I induce cytotoxic DNA double-strand breaks (DSB), suggesting a potential for Auger endoradiotherapy. Since the 60-day half-life of125I is suboptimal for therapy, we have investigated another Auger-emitter124I, with shorter half-life (4.18 days), and the additional feature of positron-emission, enabling positron emission tomography (PET) imaging. The purpose of this study was to compare the two radionuclides on the basis of DNA DSB per decay. Materials and methods Using a124I- (or125I)-labelled minor groove binding DNA ligand, we investigated DNA breakage using the plasmid DNA assay. Biodistribution of the conjugate of the labelled ligand with transferrin was investigated in nude mice bearing a K562 human lymphoma xenograft. Results The probability of DSB per decay was 0.58 and 0.85 for124I and125I, respectively, confirming the therapeutic potential of the former. The crystal structure of the ligand DNA complex shows the iodine atom deep within the minor groove, consistent with the high efficiency of induced damage. Biodistribution studies, including PET imaging, showed distinctive results for the conjugate, compared to the free ligand and transferrin, consistent with receptor-mediated delivery of the ligand. Conclusions Conjugation of124I-labelled DNA ligands to tumor targeting peptides provides a feasible strategy for Auger endoradiotherapy, with the advantage of monitoring tumor targeting by PET imaging.
authors.affiliation: a Molecular Radiation Biology Laboratory , Peter MacCallum Cancer Centre , Melbourne.|b The Sir Peter MacCallum Department of Oncology , The University of Melbourne , Melbourne , Australia.
authors.forename: Pavel
authors.initials: P
authors.lastname: Lobachevsky
authors.affiliation: c School of Chemical Sciences , The University of Auckland , New Zealand.
authors.forename: George R
authors.initials: GR
authors.lastname: Clark
authors.affiliation: c School of Chemical Sciences , The University of Auckland , New Zealand.
authors.forename: Patrycja D
authors.initials: PD
authors.lastname: Pytel
authors.affiliation: d School of Chemistry and Bio-21 Molecular Science and Biotechnology Institute , University of Melbourne , Australia.
authors.forename: Brenda
authors.initials: B
authors.lastname: Leung
authors.affiliation: d School of Chemistry and Bio-21 Molecular Science and Biotechnology Institute , University of Melbourne , Australia.
authors.forename: Colin
authors.initials: C
authors.lastname: Skene
authors.affiliation: d School of Chemistry and Bio-21 Molecular Science and Biotechnology Institute , University of Melbourne , Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: Andrau
authors.affiliation: d School of Chemistry and Bio-21 Molecular Science and Biotechnology Institute , University of Melbourne , Australia.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: White
authors.affiliation: a Molecular Radiation Biology Laboratory , Peter MacCallum Cancer Centre , Melbourne.
authors.forename: Tom
authors.initials: T
authors.lastname: Karagiannis
authors.affiliation: b The Sir Peter MacCallum Department of Oncology , The University of Melbourne , Melbourne , Australia.|e Cancer Research Division , Peter MacCallum Cancer Centre , Melbourne.
authors.forename: Carleen
authors.initials: C
authors.lastname: Cullinane
authors.affiliation: f Department of Nuclear Physics, Research School of Physics and Engineering , Australian National University , Canberra.
authors.forename: Boon Q
authors.initials: BQ
authors.lastname: Lee
authors.affiliation: f Department of Nuclear Physics, Research School of Physics and Engineering , Australian National University , Canberra.
authors.forename: Andrew
authors.initials: A
authors.lastname: Stuchbery
authors.affiliation: f Department of Nuclear Physics, Research School of Physics and Engineering , Australian National University , Canberra.
authors.forename: Tibor
authors.initials: T
authors.lastname: Kibedi
authors.affiliation: b The Sir Peter MacCallum Department of Oncology , The University of Melbourne , Melbourne , Australia.|g Centre for Molecular Imaging, Peter MacCallum Cancer Centre , Melbourne , VIC , Australia.
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Hicks
authors.affiliation: a Molecular Radiation Biology Laboratory , Peter MacCallum Cancer Centre , Melbourne.|b The Sir Peter MacCallum Department of Oncology , The University of Melbourne , Melbourne , Australia.|d School of Chemistry and Bio-21 Molecular Science and Biotechnology Institute , University of Melbourne , Australia.
authors.forename: Roger F
authors.initials: RF
authors.lastname: Martin
mesh_terms: D000818:Animals; D004247:DNA / Q000737:chemistry / Q000493:pharmacokinetics*; D004583:Electrons / Q000627:therapeutic use*; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007553:Isotope Labeling; D020014:K562 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000532:radiotherapy*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics / Q000627:therapeutic use; D011878:Radiotherapy / Q000379:methods; D011879:Radiotherapy Dosage; D061089:Radiotherapy, Image-Guided / Q000379:methods*; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D004247:DNA
keywords: Auger electrons; Auger emitters; Auger endoradiotherapy; DNA double-strand breaks; Monte Carlo simulation; iodine-124