title: Cell membrane is a more sensitive target than cytoplasm to dense ionization produced by auger electrons.
abstract: To improve radioimmunotherapy with Auger electron emitters, we assessed whether the biological efficiency of (125)I varied according to its localization. A-431 and SK-OV-3 carcinoma cells were incubated with increasing activities (0-4 MBq/ml) of (125)I-labeled vectors targeting the cell membrane, the cytoplasm or the nucleus. We then measured cell survival by clonogenic assay and the mean radiation dose to the nucleus by assessing the cellular medical internal radiation dose (MIRD). The relationship between survival and the radiation dose delivered was investigated with a linear mixed regression model. For each cell line, we obtained dose-response curves for the three targets and the reference values (i.e., the dose leading to 75, 50 or 37% survival). When cell survival was expressed as a function of the total cumulative decays, nuclear (125)I disintegrations were more harmful than disintegrations in the cytoplasm or at the cell membrane. However, when survival was expressed as a function of the mean radiation dose to the nucleus, toxicity was significantly higher when (125)I was targeted to the cell membrane than to the cytoplasm. These findings indicate that the membrane is a more sensitive target than the cytoplasm for the dense ionization produced by Auger electrons. Moreover, cell membrane targeting is as cytotoxic as nuclear targeting in SK-OV-3 cells. We suggest that targeting the membrane rather than the cytoplasm may contribute to the development of more efficient radioimmunotherapies based on Auger electron radiation, also because most of the available vectors are directed against cell surface antigens.
authors.affiliation: Direction de la Radioprotection de l'Homme, Institut de Radioprotection et de Sûreté Nucléaire, Fontenay-aux-Roses, France. jppouget@valdorel.fnclcc.fr
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Pouget
authors.forename: Lore
authors.initials: L
authors.lastname: Santoro
authors.forename: Laure
authors.initials: L
authors.lastname: Raymond
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chouin
authors.forename: Manuel
authors.initials: M
authors.lastname: Bardiès
authors.forename: Caroline
authors.initials: C
authors.lastname: Bascoul-Mollevi
authors.forename: Helena
authors.initials: H
authors.lastname: Huguet
authors.forename: David
authors.initials: D
authors.lastname: Azria
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Kotzki
authors.forename: Monique
authors.initials: M
authors.lastname: Pèlegrin
authors.forename: Eric
authors.initials: E
authors.lastname: Vivès
authors.forename: André
authors.initials: A
authors.lastname: Pèlegrin
mesh_terms: D002277:Carcinoma / Q000473:pathology / Q000503:physiopathology* / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000528:radiation effects*; D002470:Cell Survival / Q000528:radiation effects*; D003593:Cytoplasm / Q000528:radiation effects*; D004307:Dose-Response Relationship, Radiation; D016503:Drug Delivery Systems / Q000379:methods*; D004583:Electrons; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes / Q000008:administration & dosage*; D011829:Radiation Dosage
chemical_list: D007457:Iodine Radioisotopes