title: Combining radioimmunotherapy with antihypoxia therapy 2-deoxy-D-glucose results in reduction of therapeutic efficacy.
abstract: OBJECTIVE
  The efficacy of solid tumor radioimmunotherapy is reduced by heterogeneous tumor distribution of the radionuclide, with dose mainly deposited in the normoxic region and by the relative radioresistance of hypoxic tumor cells. In an attempt to overcome these challenges, radioimmunotherapy was combined with 2-deoxy-d-glucose (2DG), a hypoxia-selective cytotoxic inhibitor of glucose metabolism.
  
  
  METHODS
  In vitro toxicity of 2DG in LS174T cultures was tested using a colony-forming assay. The effect of combining 2DG with radioimmunotherapy in vivo was tested by administering radiolabeled anti-carcinoembryonic antigen antibody ([(131)I]A5B7 IgG1 whole monoclonal) to nude mice bearing s.c. LS174T tumors, followed by 10 daily injections of 2DG (2.0 g/kg). Tumors were measured to assess therapeutic efficacy.
  
  
  RESULTS
  Data from in vitro studies confirmed 2DG cytotoxicity in this cell line. Greater toxicity was observed under standard laboratory conditions and in hypoxic cultures than at intermediate, physiologically relevant levels of glucose and oxygen. Alone, 2DG had no effect on in vivo tumor growth (P = 0.377 compared with saline-treated controls). Combination of radioimmunotherapy with 2DG reduced the therapeutic effect of radioimmunotherapy (e.g., 150 microCi (131)I alone mean survival time, 48.33 +/- 16.83 days; combined with 2DG, 30.67 +/- 5.62 days, P = 0.038).
  
  
  CONCLUSIONS
  The combination investigated had a detrimental effect on survival. It is suggested that a cellular metabolic response to more aggressive therapy, previously reported in vitro, caused this. The results of this study have implications for the clinical application of combined cancer therapies with an antimetabolic modality component.
authors.affiliation: Cancer Research UK Targeting and Imaging Group, Department of Oncology, Royal Free and University College Medical School, University College London, London, UK. j.dearling@hotmail.com
authors.forename: Jason L J
authors.initials: JL
authors.lastname: Dearling
authors.forename: Uzma
authors.initials: U
authors.lastname: Qureshi
authors.forename: Richard H J
authors.initials: RH
authors.lastname: Begent
authors.forename: R Barbara
authors.initials: RB
authors.lastname: Pedley
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D015687:Cell Hypoxia; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D003131:Combined Modality Therapy / Q000009:adverse effects; D003847:Deoxyglucose / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016499:Radioimmunotherapy / Q000009:adverse effects / Q000379:methods*; D016019:Survival Analysis; D047368:Tumor Burden / Q000187:drug effects / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D003847:Deoxyglucose