Control of cell proliferation

Much effort has gone into understanding the factors which regulate the growth of mammalian cells. Normal cells can exist in a proliferating state, or they can leave the cell division cycle and pass into a resting state, where they remain viable and functional for long periods. It is the switch between these alternative possibilities of cycling growth and quiescence that is of paramount importance in growth regulation. In the normal situation, there is a balance between cell proliferation and cell death. The movement of cells between the quiescent and growing state is under precise regulation in order to ensure the correct balance. In cancer this regulation is altered such that the rate of cell proliferation exceeds the rate of cell death. It is thus important to learn about the regulatory processes and how they are disrupted in the cancer cell. Evidence for alterations in these control events in tumor cells comes from in vitro experiments. Several culture conditions that are suboptimal for cell growth, as well as certain drugs, reversibly shift normal tissue culture cells into a quiescent state, whereas under the same culture conditions or in the presence of the same drugs certain transformed, tumor‐forming cells continue to traverse the cell cycle. This suggests a derangement of regulatory biochemical mechanisms. We are already in a position to take empirical advantage of these observations. In mice we are attempting to use “protective” drugs such as the ones which have been found to be effective in cell culture to shift reversibly and selectively the rapidly proliferating cells of the bone marrow, intestinal epithelium, and lymph nodes into a quiescent state. Such protective drugs would then protect these normal tissues, which are generally the most susceptible to the toxicity of anti‐cancer drugs, from the cytotoxicity of growth‐specific antineoplastic agents. The tumor cells, which would not be stopped by these protective drugs, would still be killed. This project is major, and full of uncertainties as to how all of the normal cells will respond and how each tumor type (which differs in its control characteristics, among other things) will respond. Studies of this sort should be applicable to the treatment of at least some tumors. As we apply these ideas, we will increasingly develop a stock of information on which to base further approaches to cancer chemotherapy.