PAI-1 levels predict response to fractionated irradiation in 10 human squamous cell carcinoma lines of the head and neck.
OBJECTIVE
To investigate the relationships between hypoxia, VEGF and components of the plasminogen activation system (PAS) and to determine their influence on local tumour control after fractionated radiotherapy.


METHODS
Ten cell lines derived from human squamous cell carcinomas of the head and neck (SCCHN) were investigated in vitro and used to generate xenograft tumours. The pimonidazole hypoxic fraction in the total tumour area (pHF(tot)) was used to measure hypoxia in pre-treatment tumours and the local tumour control (TCD(50)) was used as the functional endpoint in vivo. For in vitro experiments, cells were cultured for 24h under either normoxic or mild hypoxic ( approximately 0.66% O(2)) conditions. VEGF, PAI-1 and uPA antigen levels were determined by ELISA and uPA activity by an activity assay kit.


RESULTS
Of all the factors investigated, only PAI-1 expression correlated with TCD(50) (r=0.80, p=0.010) and was significantly higher (p=0.001) in more hypoxic than in less hypoxic tumours. Accordingly, PAI-1 secretion was significantly induced (2.4x) by in vitro hypoxia.


CONCLUSIONS
These results suggest that pre-treatment PAI-1 levels are higher in more hypoxic tumours and can predict the response to fractionated irradiation in SCCHN.
Bayer
Christine
C
Department of Radiation Oncology, Technical University of Munich, Munich, Germany. christine.bayer@lrz.tum.de
Schilling
Daniela
D
Hoetzel
Joerg
J
Egermann
Hannes Peter
HP
Zips
Daniel
D
Yaromina
Ala
A
Geurts-Moespot
Anneke
A
Sprague
Lisa Deborah
LD
Sweep
Fred
F
Baumann
Michael
M
Molls
Michael
M
Adam
Markus
M
D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D019583:Dose Fractionation, Radiation; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis*; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D042461:Vascular Endothelial Growth Factor A; D014568:Urokinase-Type Plasminogen Activator