A COMMON PATHWAY FOR THE DESTRUCTION OF CANCER-CELLS - EXPERIMENTAL-EVIDENCE AND CLINICAL IMPLICATIONS

Chemopreventatives derived from different classes of chemical inhibit the growth of various cancers. This review concentrates on the chemopreventative activities of carotenoids, retinoids, and tocopherols. In this review we outline a common pathway for the antitumor action of chemopreventative agents. To establish this pathway we reviewed previous in vivo and in vitro studies indicating that the underlying modes of actions for chemopreventative activities were oxidative-reduction changes that developed in the tumor cell. Some of these changes were selective and did not appear in normal cells. The oxidative redox characteristics of the agents interacted with the oxidative redox systems of the tumor cell. Many chemopreventative agents are highly hydrophobic and interact with thiol peptides, and/or metalloproteins, such as glutathione reductase, superoxide dismutases, or flavoproteins. These could then become linked to prenylated membrane associated protein complexes or oxidized proteins. Interactions of the chemopreventative agents with these proteins can result in changes in expression of transcription factors nuclear binding proteins, such as, heat shock proteins (hsps) and p53. Dramatic reductions in mutant p53 and increased expression of wild type (antioncogene) p53 protein product has been associated with some chemopreventative agent inhibition of oral carcinogenesis. Enhanced hsp 70 and 90 expression has also been observed. These changes in protein expression occurred early during the process of oral carcinogenesis. The tumor cells accumulated in GO/G1 of the cell cycle and the induction of some apoptotic like changes (programmed cell death) were noted. Cell to cell communication and differentiation has also been increased with carotenoid, retinoid, and tocopherol treatment of transformed cells. Enhanced cytotoxic responses by macrophages and T lymphocytes at developing tumor sites were found to produce the oxygen reactive cytokine, tumor necrosis factor. The experimental evidence and hypothesized common pathway of antitumor action for chemoprevention may point to possible biomarkers that could be utilized in clinical intervention trials.