Different classes of EGFR inhibitors may have different potential to improve local tumour control after fractionated irradiation: a study on C225 in FaDu hSCC.
OBJECTIVE
Previous experiments reported from this laboratory have shown that simultaneous application of the selective epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitor BIBX1382BS during fractionated irradiation significantly prolonged growth delay of FaDu human squamous cell carcinoma but did not improve local tumour control. The present study investigates the effect of the EGFR monoclonal antibody (mAb) C225 on local tumour control of FaDu tumours after combined treatment with single dose and fractionated irradiation to address whether different classes of EGFR inhibitors have different potential to improve the outcome of radiotherapy in the same tumour model.


METHODS
In unirradiated tumours, C225 was given either once or 4 times i.p. to the nude mice. Irradiation experiments were performed with graded single doses under clamp hypoxic conditions or with 30 fractions in 6 weeks with graded total doses under ambient blood flow. C225 was given 6h before or 6 h before and 2, 5 and 7 days after single dose irradiation. During fractionated irradiation C225 was given once per week. Experimental endpoints were tumour growth delay and local tumour control 120 after end of irradiation.


RESULTS
C225 treatment resulted in prolongation of tumour growth delay after drug treatment alone as well as after single dose and fractionated irradiation. TCD50 values were reduced from 56.3 Gy [95% CI 50; 62 Gy] after single dose irradiation alone to 46.0 Gy [41;51] (enhancement ratio [ER]=1.22, P<0.01) after 1 C225 injection and 47.7 Gy [44; 51] after 4 injections of the drug (ER=1.18, P=0.06). After fractionated irradiation, tumour control dose 50% (TCD50) was 73.0 Gy [64; 82] in control tumours and 63.1 Gy [57; 69] after simultaneous C225 treatment, corresponding to an ER of 1.2 (P=0.01).


CONCLUSIONS
Treatment of FaDu hSCC with the anti-EGFR mAb C225 resulted in a significant prolongation of tumour growth delay after single dose and fractionated irradiation. In contrast to previous results on the EGFR-TK inhibitor BIBX1382BS, this prolongation of growth delay translated into a slight but significant improvement of local tumour control. The data indicate that different classes of EGFR inhibitors may have different potential to improve the outcome of radiotherapy in the same tumour model.
Krause
M
M
Department of Radiation Oncology, Medical Faculty Carl Gustav Carus, University of Technology Dresden, Fetscherstr. 74, 01307 Dresden, Germany.
Schütze
C
C
Petersen
C
C
Pimentel
N
N
Hessel
F
F
Harstrick
A
A
Baumann
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000473:pathology / Q000532:radiotherapy*; D015687:Cell Hypoxia; D049109:Cell Proliferation; D000068818:Cetuximab; D004195:Disease Models, Animal; D019583:Dose Fractionation, Radiation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000502:physiology; D005260:Female; D007012:Hypopharyngeal Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009930:Organic Chemicals / Q000494:pharmacology; D014183:Transplantation, Heterologous; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C423062:BIBX 1382BS; D009930:Organic Chemicals; D066246:ErbB Receptors; D000068818:Cetuximab