title: Enhancing the effect of radionuclide tumor targeting, using lysosomotropic weak bases.
abstract: OBJECTIVE
  The aim of the present study was to investigate if treatment with lysosomotropic weak bases could increase the intracellular retention of radiohalogens and thereby increase the therapeutic effect of radionuclide tumor targeting.
  
  
  METHODS
  Four different lysosomotropic bases, chloroquine, ammonium chloride, amantadine, and thioridazine, were investigated for their ability to increase radiohalogen retention in vitro. The two most promising substances, chloroquine and ammonium chloride, were studied in several cell lines (A431, U343MGaCl2:6, SKOV-3, and SKBR-3) in combination with radiolabeled epidermal growth factor (EGF) or the HER2 binding affibody (Z(HER2:4))(2).
  
  
  RESULTS
  The uptake and retention of radionuclides was found to be substantially increased by simultaneous treatment with the lysosomotropic bases. The effect was, however, more pronounced in the epidermal growth factor:epidermal growth factor receptor (EGF:EGFR) system than in the (Z(HER2:4))(2):HER2 system. The therapeutic effect of ammonium chloride treatment combined with (211)At-EGF was also studied. The effect obtained after combined treatment was found to be much better than after (211)At-EGF treatment alone.
  
  
  CONCLUSIONS
  The encouraging results from the present study indicate that the use of lysosomotropic weak bases is a promising approach for increasing the therapeutic effect of radionuclide targeting with radiohalogens.
authors.affiliation: Department of Oncology, Radiology and Clinical Immunology, Division of Biomedical Radiation Sciences, Uppsala University, Uppsala, Sweden. Asa.Liljegren@bms.uu.se
authors.forename: Asa Liljegren
authors.initials: AL
authors.lastname: Sundberg
authors.forename: Ann-Charlott
authors.initials: AC
authors.lastname: Steffen
mesh_terms: D000547:Amantadine / Q000627:therapeutic use; D000643:Ammonium Chloride / Q000627:therapeutic use*; D000962:Antimalarials / Q000627:therapeutic use; D014150:Antipsychotic Agents / Q000627:therapeutic use; D000998:Antiviral Agents / Q000627:therapeutic use; D001246:Astatine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D045744:Cell Line, Tumor / Q000378:metabolism; D002738:Chloroquine / Q000627:therapeutic use*; D004815:Epidermal Growth Factor / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005910:Glioma / Q000378:metabolism; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016499:Radioimmunotherapy / Q000379:methods*; D011868:Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013881:Thioridazine / Q000627:therapeutic use
chemical_list: D000962:Antimalarials; D014150:Antipsychotic Agents; D000998:Antiviral Agents; D007457:Iodine Radioisotopes; D011868:Radioisotopes; D011993:Recombinant Fusion Proteins; C515865:Z(HER2.4)2 affibody; D000643:Ammonium Chloride; D004815:Epidermal Growth Factor; D002738:Chloroquine; D000547:Amantadine; D013881:Thioridazine; D001246:Astatine