Combined modality therapy of A431 human epidermoid cancer using anti-EGFr antibody C225 and radiation.
BACKGROUND
Monoclonal antibodies (mAb) to epidermal growth factor receptor (EGFr) inhibit tumor cell proliferation and enhance cytotoxicity of chemotherapeutic agents. The purpose of this study was to investigate the interaction of the anti-EGFr antibody C225 combined with radiotherapy (RT) on EGFr expressing A431 human epidermoid cancer cells.


METHODS
Cell proliferation, apoptosis, EGFr expression and phosphorylation, and clonogenic survival were assayed in vitro. A431 tumor growth inhibition and immunohistochemistry analysis of EGFr expression and apoptosis were assessed in vivo.


RESULTS
C225 plus RT produced greater inhibition of A431 cell proliferation than C225 or RT alone which was corroborated by enhanced apoptosis. Similar clonogenic survival occurred following the addition of C225 to RT, although colonies were smaller in the presence of C225. C225 produced inhibition of EGF-induced phosphorylation of EGFr without concurrent down-regulation of surface receptor, which was not altered by RT. Combined treatment of mice bearing tumors demonstrated enhancement of complete regressions, reduction in time to tumor size doubling, and prolongation of survival. Significant apoptosis occurred in xenograft tumors treated with C225 with or without RT.


CONCLUSIONS
These data demonstrate an interaction between C225 and RT. C225-mediated apoptosis and inhibition of EGFr phosphorylation may be critical in the interaction. Studies to define the precise influence of combined modality treatment on the EGFr signal transduction cascade need to be pursued. The combination of growth factor receptor antibodies and RT has potential application in clinical oncology.
Saleh
M N
MN
Department of Medicine, University of Alabama at Birmingham 35294, USA.
Raisch
K P
KP
Stackhouse
M A
MA
Grizzle
W E
WE
Bonner
J A
JA
Mayo
M S
MS
Kim
H G
HG
Meredith
R F
RF
Wheeler
R H
RH
Buchsbaum
D J
DJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use* / Q000633:toxicity; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D000068818:Cetuximab; D003131:Combined Modality Therapy; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000068818:Cetuximab