Impact of adjuvant inhibition of vascular endothelial growth factor receptor tyrosine kinases on tumor growth delay and local tumor control after fractionated irradiation in human squamous cell carcinomas in nude mice.
OBJECTIVE
Previous experiments have shown that adjuvant inhibition of the vascular endothelial growth factor receptor after fractionated irradiation prolonged tumor growth delay and may also improve local tumor control. To test the latter hypothesis, local tumor control experiments were performed.


METHODS
Human FaDu and UT-SCC-14 squamous cell carcinomas were studied in nude mice. The vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584 (50 mg/kg body weight b.i.d.) was administered for 75 days after irradiation with 30 fractions within 6 weeks. Tumor growth time and tumor control dose 50% (TCD(50)) were determined and compared to controls (carrier without PTK787/ZK222584).


RESULTS
Adjuvant administration of PTK787/ZK222584 significantly prolonged tumor growth time to reach 5 times the volume at start of drug treatment by an average of 11 days (95% confidence interval 0.06;22) in FaDu tumors and 29 days (0.6;58) in UT-SCC-14 tumors. In both tumor models, TCD(50) values were not statistically significantly different between the groups treated with PTK787/ZK222584 compared to controls.


CONCLUSIONS
Long-term inhibition of angiogenesis after radiotherapy significantly reduced the growth rate of local recurrences but did not improve local tumor control. This indicates that recurrences after irradiation depend on vascular endothelial growth factor-driven angiogenesis, but surviving tumor cells retain their clonogenic potential during adjuvant antiangiogenic treatment with PTK787/ZK222584.
Zips
Daniel
D
Department of Radiation Oncology, Medical Faculty Carl Gustav Carus, University of Technology-Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
Hessel
Franziska
F
Krause
Mechthild
M
Schiefer
Yvonne
Y
Hoinkis
Cordelia
C
Thames
Howard D
HD
Haberey
Martin
M
Baumann
Michael
M
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D017024:Chemotherapy, Adjuvant; D019583:Dose Fractionation, Radiation; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D010793:Phthalazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*
D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C404768:vatalanib; D040262:Receptors, Vascular Endothelial Growth Factor