EGFR blockade with ZD1839 ("Iressa") potentiates the antitumor effects of single and multiple fractions of ionizing radiation in human A431 squamous cell carcinoma. Epidermal growth factor receptor.
OBJECTIVE
Signaling pathways initiated by the epidermal growth factor receptor (EGFR) play important roles in the response to ionizing radiation. In this study the consequences of inhibiting the EGFR on the response of A431 cells (human vulvar squamous cell carcinoma cells that overexpress EGFR) to radiation, were investigated in vitro and in vivo, using the selective EGFR-tyrosine kinase inhibitor, ZD1839 ("Iressa").


METHODS
The effect of ZD1839 on proliferation, apoptosis, and clonogenic survival after radiation was determined in vitro. For in vivo studies, athymic nude mice with established subcutaneous A431 xenografts (approximately 100 mm(3)) were treated with either a single 10 Gy fraction or 4 daily 2.5 Gy fractions of radiation with or without ZD1839 (75 mg/kg/day intraperitoneally for 10 days) to determine effects on tumor growth delay.


RESULTS
Treatment of A431 cells with ZD1839 in vitro reduced proliferation, increased apoptosis, and reduced clonogenic survival after radiation. Strikingly greater than additive effects of ZD1839 in combination with radiation on tumor growth delay were observed in vivo after either a single 10 Gy fraction (enhancement ratio: 1.5) or multiple 4 x 2.5 Gy fractions (enhancement ratio: 4). ZD1839 reduced tumor vascularity, as well as levels of vascular endothelial growth factor (VEGF) protein and mRNA induced by stimulation with epidermal growth factor (EGF), suggesting a possible role of inhibition of angiogenesis in the effect.


CONCLUSIONS
Inhibiting EGFR-mediated signal transduction cascades with ZD1839 potentiates the antitumor effect of single and multiple fractions of radiation. These data provide preclinical rationale for clinical trials of EGFR inhibitors including ZD1839 in combination with radiation.
Solomon
Benjamin
B
Research Division, Department of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia. b.solomon@pmci.unimelb.edu.au
Hagekyriakou
Jim
J
Trivett
Melanie K
MK
Stacker
Steven A
SA
McArthur
Grant A
GA
Cullinane
Carleen
C
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000528:radiation effects*; D002294:Carcinoma, Squamous Cell / Q000532:radiotherapy*; D002455:Cell Division / Q000528:radiation effects; D004354:Drug Screening Assays, Antitumor; D016228:Endothelial Growth Factors / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000528:radiation effects; D011799:Quinazolines / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D011879:Radiotherapy Dosage; D014407:Tumor Cells, Cultured / Q000528:radiation effects; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000970:Antineoplastic Agents; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D000077156:Gefitinib