Experimental study on different combination schedules of VEGF-receptor inhibitor PTK787/ZK222584 and fractionated irradiation.
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.
Zips
Daniel
D
Department of Radiation Oncology, Medical Faculty C. G. Carus, University of Technology, Dresden, Germany.
Krause
Mechthild
M
Hessel
Franziska
F
Westphal
Jana
J
Brüchner
Kerstin
K
Eicheler
Wolfgang
W
Dörfler
Annegret
A
Grenman
Reidar
R
Petersen
Cordula
C
Haberey
Martin
M
Baumann
Michael
M
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
D020533:Angiogenesis Inhibitors; D010793:Phthalazines; D011725:Pyridines; C404768:vatalanib