title: Effect of the hypoxic cell sensitizer isometronidazole on local control of two human squamous cell carcinomas after fractionated irradiation.
abstract: OBJECTIVE
  Hypoxia of clonogenic tumor cells is a major reason for radioresistance and hence local failure in radiotherapy. The objective of the present study was to test the efficacy of the hypoxic cell sensitizer isometronidazole (ISO) during fractionated irradiation in two different human squamous cell carcinomas.
  
  
  METHODS
  Local control was evaluated for FaDu (radiobiological hypoxic fraction [rHF] 7%) and GL tumors (rHF 0.1%) after single-dose (SD) irradiation under ambient conditions and after 30 fractions within 6 weeks (30 f/6 w). ISO was applied 60 min before SD irradiation at a concentration of 100 mg/kg body weight (b.w.) or 750 mg/kg b.w. in both tumors. During fractionated irradiation, ISO was applied daily 60 min before each fraction (100 mg/kg b.w., in FaDu also 750 mg/kg b.w.).
  
  
  RESULTS
  100 mg/kg b. w. ISO did not improve local control after SD irradiation or 30 f/6 w in both tumor models. Application of 750 mg/kg b. w. ISO significantly decreased the SD-TCD(50) in FaDu tumors (dose-modifying factor [DMF] = 1.2; p = 0.01) but not in the better oxygenated GL tumor. ISO at 750 mg/kg b.w. also significantly improved local control of FaDu tumors after 30 fractions in 6 weeks (DMF = 1.2; p = 0.01), indicating that hypoxic clonogenic cells in FaDu tumors are not only present before start of irradiation but also limit the efficacy of treatment during a fractionated course of radiotherapy.
  
  
  CONCLUSIONS
  ISO at a concentration of 750 mg/kg b.w. shows an efficacy as a hypoxic cell sensitizer in severely hypoxic FaDu tumors but not in less hypoxic GL tumors. This supports the principle of hypoxic cell sensitization and improvement of local control of hypoxic tumors by nitroimidazole derivatives. However, doses of 750 mg/kg b. w. before each fraction may be difficult to achieve in the clinical situation. This, in light of the fact that other well-tolerable hypoxic cell sensitizers such as nimorazole with clinically proven efficacy at daily oral doses of < 3 g are available, limits the potential usefulness of ISO for radiation oncology.
authors.affiliation: Department of Radiation Oncology, Medical Faculty Carl Gustav Carus, University of Technology, Dresden, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schreiber
authors.forename: Mechthild
authors.initials: M
authors.lastname: Krause
authors.forename: Daniel
authors.initials: D
authors.lastname: Zips
authors.forename: Annegret
authors.initials: A
authors.lastname: Dörfler
authors.forename: Klaus
authors.initials: K
authors.lastname: Richter
authors.forename: Sophie
authors.initials: S
authors.lastname: Vettermann
authors.forename: Cordula
authors.initials: C
authors.lastname: Petersen
authors.forename: Bettina
authors.initials: B
authors.lastname: Beuthien-Baumann
authors.forename: Daniela
authors.initials: D
authors.lastname: Thümmler
authors.forename: Michael
authors.initials: M
authors.lastname: Baumann
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000532:radiotherapy*; D019583:Dose Fractionation, Radiation; D005260:Female; D006801:Humans; D007012:Hypopharyngeal Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D008297:Male; D008795:Metronidazole / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
chemical_list: D011838:Radiation-Sensitizing Agents; D008795:Metronidazole; C031624:isometronidazole