title: Preferential tumor targeting and selective tumor cell cytotoxicity of 5-[131/125I]iodo-4'-thio-2'-deoxyuridine.
abstract: OBJECTIVE
  Auger electron emitting radiopharmaceuticals are attractive for targeted nanoirradiation therapy, provided that DNA of malignant cells is selectively addressed. Here, we examine 5-[123/125/131I]iodo-4'-thio-2'-deoxyuridine (ITdU) for targeting DNA in tumor cells in a HL60 xenograft severe combined immunodeficient mouse model.
  
  
  METHODS
  Thymidine kinase and phosphorylase assays were done to determine phosphorylation and glycosidic bond cleavage of ITdU, respectively. The biodistribution and DNA incorporation of ITdU were determined in severe combined immunodeficient mice bearing HL60 xenografts receiving pretreatment with 5-fluoro-2'-deoxyuridine (FdUrd). Organ tissues were dissected 0.5, 4, and 24 h after radioinjection and uptake of [131I]ITdU (%ID/g tissue) was determined. Cellular distribution of [125I]ITdU was imaged by microautoradiography. Apoptosis and expression of the proliferation marker Ki-67 were determined by immunohistologic staining using corresponding paraffin tissue sections.
  
  
  RESULTS
  ITdU is phosphorylated by thymidine kinase 1 and stable toward thymidylate phosphatase-mediated glycosidic bond cleavage. Thymidylate synthase-mediated deiodination of [123/125/131I]ITdU was inhibited with FdUrd. Pretreatment with FdUrd increased preferentially tumor uptake of ITdU resulting in favorable tumor-to-normal tissue ratios and tumor selectivity. ITdU was exclusively localized within the nucleus and incorporated into DNA. In FdUrd-pretreated animals, we found in more than 90% of tumor cells apoptosis induction 24 h postinjection of ITdU, indicating a highly radiotoxic effect in tumor cells but not in cells of major proliferating tissues.
  
  
  CONCLUSIONS
  ITdU preferentially targets DNA in proliferating tumor cells and leads to apoptosis provided that the thymidylate synthase is inhibited.
authors.affiliation: Nuclear Medicine Clinic, University Ulm, Ulm, Germany.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Morgenroth
authors.forename: Sandra
authors.initials: S
authors.lastname: Deisenhofer
authors.forename: Gerhard
authors.initials: G
authors.lastname: Glatting
authors.forename: Falk H-G
authors.initials: FH
authors.lastname: Kunkel
authors.forename: Cornelia
authors.initials: C
authors.lastname: Dinger
authors.forename: Boris
authors.initials: B
authors.lastname: Zlatopolskiy
authors.forename: Andreas T J
authors.initials: AT
authors.lastname: Vogg
authors.forename: Thomas
authors.initials: T
authors.lastname: Kull
authors.forename: Sven N
authors.initials: SN
authors.lastname: Reske
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001345:Autoradiography; D004247:DNA / Q000187:drug effects; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000187:drug effects; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: C465667:5-iodo-4'-thio-2'-deoxyuridine; D004791:Enzyme Inhibitors; D019275:Radiopharmaceuticals; D004247:DNA; D013940:Thymidylate Synthase; D003857:Deoxyuridine