RETINOID MODULATION OF BIOMARKERS IN ORAL LEUKOPLAKIA DYSPLASIA/

Among the tissue, cellular, and molecular changes which take place dur ing the development of squamous cell carcinoma (SCC) of the upper aero digestive tract, only a Limited number can be used as surrogate endpoi nt biomarkers (SEBs) in cancer chemoprevention trials. Molecular SEBs will be genes or gene products which can be measured accurately and re liably, are altered in intraepithelial neoplasia (dysplasia), correlat e strongly with the true outcome (invasive cancer), and are modulated by a chemoprevention agent(s). To identify and modulate molecular SEBs in intraepithelial neoplasia of the upper aerodigestive tract, we stu died expression of the epidermal growth factor receptor (EGFR), transf orming growth factor-alpha (TGF-alpha), and HER-2/neu genes in oral le ukoplakia before, during and after treatment with 13-cis-retinoic acid , a vitamin A derivative. pour of nine patients treated for 3 months w ith 1 mg/kg/day of 13-cis-retinoic acid had complete resolution of the ir leukoplakia. Biopsies were taken of leukoplakia and adjacent normal -appearing mucosa before, during and after treatment. Immunohistochemi stry was performed using the BioGenex Super Sensitive Biotin-Streptavi din horseradish peroxidase detection system. Pretreatment expression o f EGFR, TCF-alpha and HER-2/neu in leukoplakia was increased when comp ared to normal-appearing mucosa. TGF-alpha expression decreased during treatment in leukoplakia, but not in normal-appearing mucosa, suggest ing that TGF-alpha may serve as an intermediate endpoint in cancer che moprevention trials. (C) 1994 Wiley-Liss, Inc.