P53: A Determinant of the Cell Cycle Response to DNA Damage

Abstract

Historically, most efficacious chemotherapuetic regimens have been developed empirically (i.e. by trial and error) rather than by a rational understanding of the differences between normal cells and tumor cells in the molecular and cellular responses to chemotherapeutic agents. Dosing and scheduling of agents optimally should be based on a detailed understanding of such differences between the responses of normal cells and tumor cells in order to maximize therapeutic index with antineoplastic agents. Molecular characterization of cell cycle checkpoints following DNA damage should provide insights into both: 1) mechanisms of cellular transformation, since these checkpoints appear to limit heritable genetic changes following DNA damage; and 2) mechanisms of tumor cell kill following chemotherapy, since these checkpoints appear to enhance cell survival following DNA damage (Hartwell and Weinert, 1989). Recent characterization in our laboratory of the p53 tumor suppressor gene as a determinant of the cell cycle response to certain types of DNA damage (Kastan et al, 1991; Kuerbitz et al, 1992) should have therapeutic implications, especially since p53 is the most commonly mutated gene in human cancers identified thus far (Vogelstein, 1990; Hollstein et al., 1991).