Intermediate cancer biomarkers and their use in beta-carotene studies in humans

The most effective means of avoiding the development of squamous cell carcinomas is the elimination of risk factors such as tobacco smoke and alcohol and of exposure to occupational and dietary carcinogens. In addition, chemoprevention by micronutrients such as beta-carotene may be promising. However, studies verifying such effects using cancer incidence or mortality as study endpoint are extremely costly of financial and manpower resources. Therefore, premalignant intermediate biomarkers such as histological lesions (dysplasias/leukoplakias/ polyps), genetic changes (DNA damage, mutations) or enzymatic changes (protein kinase C or ornithine decarboxylase activation) are increasingly being used as surrogate endpoints. Even though most preneoplastic biomarkers still need to be verified and shown to be linked to malignancy, their use in clusters may enhance their predictability. In human trials beta-carotene has reversed some lesions such as micronuclei, leukoplakias and dysplasias in the oral cavity, whereas other lesions, e.g. colorectal polyps (i.e. their recurrence after resection) have not been found to respond. But proliferation markers in the colon mucosa have been modified by beta-carotene. Preliminary findings are also available of a potential reduction of esophageal dysplasias in a high-risk Chinese population and of cervical dysplasias in a group of American women. The available beta-carotene data are sufficiently encouraging to justify continuation of trials using intermediate cancer markers.