Labile cell

Abstract: The cell cycle represents a series of tightly integrated events that allow the cell to grow and proliferate. An essential part of the cell cycle machinery is the cyclin-dependent kinases (CDKs). When activated, the CDKs provide a means for the cell to move from one phase of the cell cycle to the next (G1 to S or G2 to M). The cell cycle serves to protect the cell from genotoxic stress. In the setting of DNA damage, the CDKs are inhibited and the cell undergoes cell-cycle arrest. This provides the cell the opportunity to repair its own damaged DNA before it resumes cell proliferation. If a cell continues to cycle with its damaged DNA intact, the apoptotic machinery is triggered and the cell will undergo apoptosis. In essence, cell cycle arrest at these critical checkpoints represents a survival mechanism, which provides the tumor cell the opportunity to escape the effects of lethal DNA damage induced by chemotherapy. Over the past several years, a series of new targeted agents has been developed that promote apoptosis of DNA damaged tumor cells either during cell cycle arrest or following premature cell cycle checkpoint exit, such that tumor cells re-enter the cell cycle before DNA repair is complete. An understanding of the cell cycle and its relationship to p53 are critical for the successful clinical development of these agents for the treatment of patients with gastrointestinal cancers.

Abstract: 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.