Inhibition and Regression of Experimental Oral Cancer by Beta Carotene and Vitamin E: Emerging Concepts

Abstract

The hamster buccal pouch experimental model for oral cancer has proven to be a superior model for oral mucosal carcinogenesis and is now receiving wide attention as one of the better overall experimental models for carcinogenesis. The malignant tumors are epidermoid carcinomas that develop slowly, in response to polyaromatic hydrocarbon carcinogen application, and are preceded by a keratotic and dysplastic lesion comparable to human precancerous leukoplakia. The hamster lesions are indistinguishable histologically from human oral epidermoid carcinomas of the well-to-moderately differentiated variety, at both light microscopic and ultrastructural levels. Both animal and human lesions have similar metabolic markers, such asgamma glutamyl transpeptidase (GGT) and lactic dehydrogenase. The hamster carcinoma develops with the activation and expression of specific oncogenes, often similar to those expressed in human oral cancer. These include c-erbBl, H-ras, K-ras, and mutant p53. The hamster lesions are clearly visible at all times and can be counted and measured at different stages of development so that figures can be obtained for overall tumor burden. The hamster tumors are also closely related to immune control, as in humans. The hamster tumor development is enhanced by immunosuppressive drugs such as cortisone and methotrexate, and retarded by immunoenhancing agents such as levamisole or BCG.

In the quest for chemopreventative agents, it was foundthat hamster oral carcinogenesis could be retarded by retinoids such as 13-cis-retinoic acid. However, retinoids were found to be toxic and to have a co-carcinogenic potential. Beta carotene and vitamin E were found to be nontoxic and inhibited oral carcinogenesis when applied topically, injected in the tumor area, or administered systemically by mouth. Regression of established carcinomas was also possible when beta carotene or vitamin E was injected into the tumor site. Mixtures of beta carotene and vitamin E were found more effective antitumor agents than the individual substances, indicating a synergism. Mixtures of various antioxidants have been studied and found to be highly effective. Current research is aimed at an understanding of mechanism. These studies use both hamster tumors and cell lines in culture from both hamster carcinomas and human oral carcinomas. A concept has been established of a common pathway for the destruction of cancer cells. Beta carotene, vitamin E, and other antioxidants act as immunostimulators in one branch of the pathway. They stimulate the migration to tumor site and the antitumor activity of cytotoxic macrophages, bearing TNF-alpha, and cytotoxic T lymphocytes, bearing TNF-beta. In the other branch of the common pathway, the antioxidant nutrients stimulate enhanced expression of a variety of proteins, including 70 and 90 kD stress proteins. There is also a dramatic reduction in mutant p53 and an increased expression of the wild type (antioncogene) p53 protein product. The antioxidant nutrients appear to enhance the tumor suppressor p53 gene and to dysregulate or inactivate the mutant p53 oncogene. The cancer cells are selectively destroyed in a process described as apoptosis. The antioxidants also inhibit angiogenesis, which would also contribute to the death of cancer cells. Many clinical applications can be suggested, based on this animal research.