INHIBITION OF TRANSFORMING-GROWTH-FACTOR-ALPHA STIMULATION OF HUMAN SQUAMOUS-CELL CARCINOMA OF THE HEAD AND NECK WITH ANTI-TGF-ALPHA ANTIBODIES AND TYRPHOSTIN

Background: Transforming growth factor alpha (TGF-alpha) and its recep tor (EGF-R) may regulate normal and malignant epithelial cell growth b y an autocrine mechanism. We investigated the role of TGF-alpha in reg ulating head and neck SCC tumor growth. Methods: TGF-alpha and EGF-R l evels were measured in 7 SCC cell lines and 14 SCC biopsies by RIA, Sc atchard, and Western analysis. TGF-alpha autocrine stimulation of DNA synthesis in SCC cell lines was assessed by incubation with TGF-alpha neutralizing antibodies and tyrphostin AG 1478, a selective and potent inhibitor of EGF-R kinase. Results: All SCC cell lines synthesized TG F-alpha and expressed elevated EGF-R levels compared to normal keratin ocytes. Twelve of the 14 SCC biopsies contained TGF-alpha protein and 8 had specific EGF-R. Exogenous TGF-alpha or EGF significantly increas ed DNA synthesis in 4 of 5 SCC cell lines. TGF-alpha neutralizing anti bodies or tyrphostin AG 1478 reduced DNA synthesis in the two SCC cell lines (FaDu and SCC9) tested. Conclusions: These results indicate tha t SCC cell lines and tumors usually synthesize TGF-alpha, have elevate d levels of EGF-R, and are mitogenically stimulated by a TGF-alpha aut ocrine system. Selective inhibition of the TGF-alpha system by EGF-R k inase inhibitors or TGF-alpha neutralizing anti-bodies may be useful s trategies for treating SCC that overexpress TGF-alpha and its receptor .