title: Specific inhibition of carbonic anhydrase IX activity enhances the in vivo therapeutic effect of tumor irradiation.
abstract: OBJECTIVE
  Carbonic anhydrase (CA) IX expression is increased upon hypoxia and has been proposed as a therapeutic target since it has been associated with poor prognosis, tumor progression and pH regulation. The aim of this study was to evaluate the antitumor activity of a high CAIX-affinity indanesulfonamide (11c) combined with irradiation, compared with the general CA inhibitor acetazolamide (AZA).
  
  
  METHODS
  HT-29 carcinoma cells with or without (genetic knockdown, KD) CAIX expression were incubated with 11c/AZA under different oxygen levels and proliferation, apoptosis and radiosensitivity were evaluated. 11c/AZA was administered intravenously (1×/day; 5 days) to tumor-bearing mice and tumor irradiation (10 Gy) was performed at day 3 of the injection period. Tumor growth and potential treatment toxicity were monitored (3×/week).
  
  
  RESULTS
  Treatment with 11c/AZA alone resulted in tumor regression, which was further increased in CAIX expressing cells by combining 11c with irradiation. AZA demonstrated also an additional effect in the KD tumors when combined with irradiation. CAIX inhibition in vitro significantly reduced proliferation and increased apoptosis upon hypoxia exposure without affecting intrinsic radiosensitivity.
  
  
  CONCLUSIONS
  Specific inhibition of CAIX activity enhanced the effect of tumor irradiation and might, therefore, be an attractive strategy to improve overall cancer treatment.
authors.affiliation: Dept. of Radiation Oncology (MAASTRO Lab), Grow-School for Oncology and Developmental Biology, Maastricht University Medical Centre, The Netherlands. ludwig.dubois@maastrichtuniversity.nl
authors.forename: Ludwig
authors.initials: L
authors.lastname: Dubois
authors.forename: Sarah
authors.initials: S
authors.lastname: Peeters
authors.forename: Natasja G
authors.initials: NG
authors.lastname: Lieuwes
authors.forename: Nele
authors.initials: N
authors.lastname: Geusens
authors.forename: Anne
authors.initials: A
authors.lastname: Thiry
authors.forename: Simon
authors.initials: S
authors.lastname: Wigfield
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Carta
authors.forename: Alan
authors.initials: A
authors.lastname: McIntyre
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Dogné
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.forename: Bernard
authors.initials: B
authors.lastname: Masereel
authors.forename: Philippe
authors.initials: P
authors.lastname: Lambin
mesh_terms: D000086:Acetazolamide / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D015687:Cell Hypoxia; D049109:Cell Proliferation; D005434:Flow Cytometry; D019073:HT29 Cells / Q000187:drug effects* / Q000528:radiation effects*; D006801:Humans; D015151:Immunoblotting; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D060888:Real-Time Polymerase Chain Reaction; D018709:Statistics, Nonparametric
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D019344:Lactic Acid; D000086:Acetazolamide