Beenken S W, Huang P, Sellers M, Peters G, Listinsky C, Stockard C, Hubbard W, Wheeler R, Grizzle W
Department of Surgery, University of Alabama at Birmingham 35294.
J Cell Biochem Suppl. 1994;19:270-7.
Among the tissue, cellular, and molecular changes which take place during the development of squamous cell carcinoma (SCC) of the upper aerodigestive tract, only a limited number can be used as surrogate endpoint biomarkers (SEBs) in cancer chemoprevention trials. Molecular SEBs will be genes or gene products which can be measured accurately and reliably, are altered in intraepithelial neoplasia (dysplasia), correlate 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 studied expression of the epidermal growth factor receptor (EGFR), transforming growth factor-alpha (TGF-alpha), and HER-2/neu genes in oral leukoplakia before, during, and after treatment with 13-cis-retinoic acid, a vitamin A derivative. Four of nine patients treated for 3 months with 1 mg/kg/day of 13-cis-retinoic acid had complete resolution of their leukoplakia. Biopsies were taken of leukoplakia and adjacent normal-appearing mucosa before, during, and after treatment. Immunohistochemistry was performed using the BioGenex Super Sensitive Biotin-Streptavidin horseradish peroxidase detection system. Pretreatment expression of EGFR, TGF-alpha, and HER-2/neu in leukoplakia was increased when compared to normal-appearing mucosa. TGF-alpha expression decreased during treatment in leukoplakia, but not in normal-appearing mucosa, suggesting that TGF-alpha may serve as an intermediate endpoint in cancer chemoprevention trials.
在上消化道鳞状细胞癌（SCC）发生过程中出现的组织、细胞及分子变化中，仅有少数可在癌症化学预防试验中用作替代终点生物标志物（SEB）。分子SEB将是能够被准确可靠地检测的基因或基因产物，它们在上皮内瘤变（发育异常）中发生改变，与真实结局（浸润性癌）密切相关，并且可被化学预防剂调节。为了识别和调节上消化道上皮内瘤变中的分子SEB，我们研究了表皮生长因子受体（EGFR）、转化生长因子-α（TGF-α）及HER-2/neu基因在口服白斑患者接受维生素A衍生物13-顺式视黄酸治疗前、治疗期间及治疗后的表达情况。9名患者接受1mg/kg/天的13-顺式视黄酸治疗3个月，其中4名患者的白斑完全消退。在治疗前、治疗期间及治疗后，分别对白斑及相邻外观正常的黏膜进行活检。使用BioGenex超敏生物素-链霉亲和素辣根过氧化物酶检测系统进行免疫组织化学检测。与外观正常的黏膜相比，白斑中EGFR、TGF-α及HER-2/neu的预处理表达增加。白斑在治疗期间TGF-α表达下降，但外观正常的黏膜中未下降，这表明TGF-α可能在癌症化学预防试验中作为一个中间终点。
