title: Targeting carbonic anhydrase IX by nitroimidazole based sulfamides enhances the therapeutic effect of tumor irradiation: a new concept of dual targeting drugs.
abstract: OBJECTIVE
  Carbonic anhydrase IX (CAIX) plays an important role in pH regulation processes critical for tumor cell growth and metastasis. We hypothesize that a dual targeting bioreductive nitroimidazole based anti-CAIX sulfamide drug (DH348) will reduce tumor growth and sensitize tumors to irradiation in a CAIX dependent manner.
  
  
  METHODS
  The effect of the dual targeting anti-CAIX (DH348) and its single targeting control drugs on extracellular acidification and radiosensitivity was examined in HT-29 colorectal carcinoma cells. Tumor growth and time to reach 4× start volume (T4×SV) was monitored for animals receiving DH348 (10 mg/kg) combined with tumor single dose irradiation (10 Gy).
  
  
  RESULTS
  In vitro, DH348 reduced hypoxia-induced extracellular acidosis, but did not change hypoxic radiosensitivity. In vivo, DH348 monotherapy decreased tumor growth rate and sensitized tumors to radiation (enhancement ratio 1.50) without systemic toxicity only for CAIX expressing tumors.
  
  
  CONCLUSIONS
  A newly designed nitroimidazole and sulfamide dual targeting drug reduces hypoxic extracellular acidification, slows down tumor growth at nontoxic doses and sensitizes tumors to irradiation all in a CAIX dependent manner, suggesting no "off-target" effects. Our data therefore indicate the potential utility of a dual drug approach as a new strategy for tumor-specific targeting.
authors.affiliation: Dept. of Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, The Netherlands. Electronic address: ludwig.dubois@maastrichtuniversity.nl.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Dubois
authors.forename: Sarah G J A
authors.initials: SG
authors.lastname: Peeters
authors.forename: Simon J A
authors.initials: SJ
authors.lastname: van Kuijk
authors.forename: Ala
authors.initials: A
authors.lastname: Yaromina
authors.forename: Natasja G
authors.initials: NG
authors.lastname: Lieuwes
authors.forename: Ruchi
authors.initials: R
authors.lastname: Saraya
authors.forename: Rianne
authors.initials: R
authors.lastname: Biemans
authors.forename: Marouan
authors.initials: M
authors.lastname: Rami
authors.forename: Nanda Kumar
authors.initials: NK
authors.lastname: Parvathaneni
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.forename: Marc
authors.initials: M
authors.lastname: Vooijs
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Winum
authors.forename: Philippe
authors.initials: P
authors.lastname: Lambin
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000502:physiology*; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000502:physiology*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000532:radiotherapy*; D006801:Humans; D051379:Mice; D009593:Nitroimidazoles / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
chemical_list: D000951:Antigens, Neoplasm; D002257:Carbonic Anhydrase Inhibitors; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases
keywords: 5-Nitroimidazole; Carbonic anhydrase IX (CAIX); Dual targeting; Radiotherapy; Sulfamide