The tumor promotion and carcinogenesis process in humans is a lengthy process that culminates in the aberrant proliferative behavior of cells which eventually leads to death. The time between molecular initiation of the disease and acquisition of the metastatic state is usually many years and can be several decades. This fact, that there is the long period of time between initiation and aberrant proliferative behavior that is life threatening, affords us the unique opportunity to interfere with the carcinogenesis and tumor promotion process. The obvious means to success in this endeavor is to discover the mechanism(s) of action of tumor promoting agents and how factors which are known to prevent carcinogenesis function. Retinoids is a collective term for a group of vitamin A derivatives known to have chemopreventive effects on carcinogenesis. Our goals in this project are to investigate the biochemical mechanisms by which these compounds prevent the carcinogenesis and tumor promotion process. We have found in preliminary results that retinyl acetate, a very effective inhibitor of carcinogenesis in vitro, blocks plasma membrane calcium channels and mitogen induced DNA synthesis. This investigation will focus on the effect of retinoids of various types on calcium homeostasis and signal transduction mechanisms regulating intracellular calcium levels and on what calcium is doing once its transient presence in cells is complete. The significance of calcium and the inhibition of its influx by retinoids in the carcinogenesis and tumor promotion process stems from the ability of neoplastic cells to proliferate in calcium-deficient medium while their non-neoplastic counterparts cannot. We believe that success in achieving our goals will enhance the ability to rationally design chemopreventive agents based upon biochemical mechanisms of action of tumor promoting agents.
