title: A novel 125I-labeled daunorubicin derivative for radionuclide-based cancer therapy.
abstract: BACKGROUND
  Auger electron emitters, such as (125)I, are getting increasingly wider recognition as alternatives to current anticancer treatments. The effectiveness of Auger electrons is strongly dependent on their proximity to DNA and is therefore considered as harmless outside the nucleus.
  
  
  METHODS
  (125)I or (127)I was conjugated with Comp1, Comp2 or Comp3 - three derivatives of the chemotherapeutic drug daunorubicin. Their capacity factors, DNA-binding constants and exclusion parameters, and the degree of DNA fragmentation after incubating isolated DNA with our (127)I- or (125)I-conjugated daunorubicin derivatives were determined. Human breast adenocarcinoma (SK-BR-3) cells were incubated with the derivatives; fluorescent microscopy and autoradiography images were generated; and cell growth was monitored.
  
  
  CONCLUSIONS
  The capacity factor of (127)I-Comp1 was similar to those of daunorubicin and doxorubicin, whereas lower capacity factors of (127)I-Comp2 and (127)I-Comp3 suggested reduced interactions with lipid membranes. DNA exclusion parameters and binding constants of (127)I-Comp1 and (127)I-Comp2, but not of (127)I-Comp3, were similar to those of doxorubicin. Fluorescent microscopy and autoradiography images of SK-BR-3 cells revealed that (127)I-Comp1 and (125)I-Comp1 accumulated in tumor cell nuclei, whereas (127)I-Comp2 and (127)I-Comp3 were present predominantly in other cell compartments. The binding of (125)I-Comp1 to isolated chromosomal DNA led to major fragmentation. Incubation of SK-BR-3 cells with (125)I-Comp1 inhibited cell growth, whereas doxorubicin or (127)I-Comp1 administered at the same concentration had no effect on cell growth. Our results thus suggest that (125)I-Comp1 has the potential to become a new tool for anticancer therapy.
authors.affiliation: Department of Physical and Analytical Chemistry, Uppsala University, P.O. Box 579, 75121 Uppsala, Sweden.
authors.forename: Ludger M
authors.initials: LM
authors.lastname: Ickenstein
authors.forename: Katarina
authors.initials: K
authors.lastname: Edwards
authors.forename: Stefan
authors.initials: S
authors.lastname: Sjöberg
authors.forename: Jörgen
authors.initials: J
authors.lastname: Carlsson
authors.forename: Lars
authors.initials: L
authors.lastname: Gedda
mesh_terms: D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D053938:DNA Fragmentation; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D007457:Iodine Radioisotopes / Q000627:therapeutic use*; D009369:Neoplasms / Q000628:therapy*; D019275:Radiopharmaceuticals / Q000627:therapeutic use*; D014018:Tissue Distribution
chemical_list: D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D004247:DNA; D003630:Daunorubicin