INTRACELLULAR FREE CA2+ AND ANTICANCER DRUG ACTION

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A fundamental difference between normal cells and cancer cells is the expression of oncogenes in cancer cells and the independence of cancer cells from many growth factors for proliferation. Recent work suggests that the function of oncogenes is to code for components of intracellular signal transduction pathways for growth factors, thus, relieving the cancer cell of the normal requirements for growth factors. Eukaryotic cells maintain very low levels of intracellular free Ca2+ ([Ca2+]i) which are over 10,000-fold lower than extracellular Ca2+. The low levels and the exquisite control exerted by the cell over [Ca2+]i allow small changes in [Ca2+]i to be used as a highly responsive intracellular messenger for carrying signals from growth factors acting on receptors at the cell surface to the nucleus. The close relationship between growth factor and oncogene action indicates that changes in [Ca2+]i are also important in mediating the effects of oncogenes. The hypothesis upon which our studies are based is that by developing agents that effect the way [Ca2+]i and related second messengers mediate the effects of growth factors and oncogenes it should be possible to exploit basic biological differences between normal cells and cancer cells for the selective treatment of cancer. To do this effectively we need a better understanding of the role of [Ca2+]i and related second messengers in the control of normal and cancer cell growth factors and oncogenes. We also need to identify compounds that selectively block [Ca2+]i signalling pathways in tumor cells. Our studies are, therefore, focused on understanding the mechanisms of growth factor and oncogene and signal transduction involving [Ca2+]i and related second messengers, and the relationship to cell proliferation. We will employ a number of approaches for measuring [Ca2+]i, Ca2+ fluxes, as well as other intracellular second messengers in defined, growth factor- dependent cell systems. We have identified five novel classes of agents that block [Ca2+]i signalling that may be prototypes for new classes of cell growth inhibitors. The ultimate objective of our studies is to find new ways of treating cancer through target directed drug discovery.