Biochemopreventive Therapy for Patients With Premalignant Lesions of the Head and Neck and p53 Gene Expression

Oral premalignant lesions are a useful model for developing chemoprevention trials involving lesions throughout the upper aerodigestive tract (1). These lesions most often develop in association with exposure to carcinogens, such as tobacco and alcohol, and frequently precede the development of invasive carcinoma (2,3). Although early oral premalignant lesions (hyperplasia and mild dysplasia) are particularly responsive to single-agent retinoid therapy (4-8), advanced oral premalignant lesions (i.e., moderate to severe dysplasia) are known to be resistant to single-agent retinoid therapy (9,10). Since the combination of retinoids and interferons (IFNs) has been shown to have an enhancing effect on the induction of cell differentiation and on the suppression of cell proliferation as seen in preclinical (10-14) and clinical (15-17) studies, we designed a biochemoprevention study for testing a combination of isotretinoin (13-cis-retinoic acid), IFN-α, and α-tocopherol for advanced premalignant lesions in the head and neck. The mutations in the p53 (also known as TP53) gene and alterations in the p53 protein resulting in its accumulation in cells may play a critical role in tumorigenesis (18-20), and both are common in human cancers, including premalignant lesions and cancers of the head and neck region (21-23). We conducted a prospective, nonrandomized phase II trial to assess the effect of biochemopreventive therapy on the responsiveness of lesions in the head and neck area, particularly consisting of mild to severe dysplasia in a laryngeal site or moderate to severe dysplasia in the oral cavity, and to compare laboratory findings involving p53 alterations.