title: Experimental study on different combination schedules of VEGF-receptor inhibitor PTK787/ZK222584 and fractionated irradiation.
abstract: BACKGROUND
  Inhibition of the vascular endothelial growth factor receptor (VEGFR) has been shown to improve the radiation response of several experimental tumors. The present experimental study compares the effect of neoadjuvant, concomitant and adjuvant treatment with PTK787/ZK222584, a specific inhibitor of the VEGFR, in combination with fractionated irradiation.
  
  
  METHODS
  Growth delay after daily oral application of 50 mg per kg bodyweight PTK787/ZK222584 or carrier was tested in five different human squamous cell carcinoma growing in nude mice. Two of these tumor models, a responder (UT-SCC-14) and a non-responder (FaDu), were selected for the irradiation experiments (15 fractions of 2 Gy within 15 days). PTK787/ZK222584 was applied daily for 4-18 days and stopped before start of irradiation (neoadjuvant), for 15 days during fractionated irradiation (concomitant) or for 45 days after the course of irradiation (adjuvant).
  
  
  RESULTS
  Adjuvant application of PTK787/ZK222584 after fractionated irradiation retarded regrowth of UT-SCC-14 tumors and, surprisingly, also of FaDu tumors which did not respond to the agent when given alone. No effects on radiation response were observed after short-term neoadjuvant or concomitant PTK787/ZK222584 application.
  
  
  CONCLUSIONS
  Combined with fractionated irradiation, only adjuvant application of PTK787/ZK222584 retarded regrowth of UT-SCC-14 and FaDu tumors. The data suggest that preirradiated vasculature might be more sensitive to VEGFR inhibition compared to unirradiated vasculature. Whether the effect of adjuvant VEGFR inhibition on growth delay translates into improved local tumor control after irradiation needs further investigation.
authors.affiliation: Department of Radiation Oncology, Medical Faculty C. G. Carus, University of Technology, Dresden, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Zips
authors.forename: Mechthild
authors.initials: M
authors.lastname: Krause
authors.forename: Franziska
authors.initials: F
authors.lastname: Hessel
authors.forename: Jana
authors.initials: J
authors.lastname: Westphal
authors.forename: Kerstin
authors.initials: K
authors.lastname: Brüchner
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Eicheler
authors.forename: Annegret
authors.initials: A
authors.lastname: Dörfler
authors.forename: Reidar
authors.initials: R
authors.lastname: Grenman
authors.forename: Cordula
authors.initials: C
authors.lastname: Petersen
authors.forename: Martin
authors.initials: M
authors.lastname: Haberey
authors.forename: Michael
authors.initials: M
authors.lastname: Baumann
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000188:drug therapy* / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D019583:Dose Fractionation, Radiation; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D020360:Neoadjuvant Therapy; D010793:Phthalazines / Q000008:administration & dosage*; D011725:Pyridines; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D010793:Phthalazines; D011725:Pyridines; C404768:vatalanib