title: Evaluation of new iodinated acridine derivatives for targeted radionuclide therapy of melanoma using 125I, an Auger electron emitter.
abstract: The increasing incidence of melanoma and the lack of effective therapy on the disseminated form have led to an urgent need for new specific therapies. Several iodobenzamides or analogs are known to possess specific affinity for melanoma tissue. New heteroaromatic derivatives have been designed with a cytotoxic moiety and termed DNA intercalating agents. These compounds could be applied in targeted radionuclide therapy using (125)I, which emits Auger electrons and gives high-energy, localized irradiation. Two iodinated acridine derivatives have been reported to present an in vivo kinetic profile conducive to application in targeted radionuclide therapy. The aim of the present study was to perform a preclinical evaluation of these compounds. The DNA intercalating property was confirmed for both compounds. After radiolabeling with (125)I, the two compounds induced in vitro a significant radiotoxicity to B16F0 melanoma cells. Nevertheless, the acridine compound appeared more radiotoxic than the acridone compound. While cellular uptake was similar for both compounds, SIMS analysis and in vitro protocol showed a stronger affinity for melanin with acridone derivative, which was able to induce a predominant scavenging process in the melanosome and restrict access to the nucleus. In conclusion, the acridine derivative with a higher nuclear localization appeared a better candidate for application in targeted radionuclide therapy using (125)I.
authors.affiliation: Inserm UMR 990, BP 184, Clermont-Ferrand, cedex 63005, France.
authors.forename: Maryline
authors.initials: M
authors.lastname: Gardette
authors.forename: Janine
authors.initials: J
authors.lastname: Papon
authors.forename: Mathilde
authors.initials: M
authors.lastname: Bonnet
authors.forename: Nicolas
authors.initials: N
authors.lastname: Desbois
authors.forename: Pierre
authors.initials: P
authors.lastname: Labarre
authors.forename: Ting-Dee
authors.initials: TD
authors.lastname: Wu
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Miot-Noirault
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Madelmont
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Guerquin-Kern
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Chezal
authors.forename: Nicole
authors.initials: N
authors.lastname: Moins
mesh_terms: D000166:Acridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D004583:Electrons; D007364:Intercalating Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D007457:Iodine Radioisotopes / Q000008:administration & dosage*; D008543:Melanins / Q000378:metabolism; D008546:Melanoma, Experimental / Q000532:radiotherapy*; D020460:Melanosomes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D000166:Acridines; D007364:Intercalating Agents; D007457:Iodine Radioisotopes; D008543:Melanins