Mechanisms of cell-cycle checkpoints: At the crossroads of carcinogenesis and drug discovery

Human tumors arise from multiple genetic changes that gradually transform g rowth-limited cells into highly invasive cells that are unresponsive to gro wth controls. The genetic evolution of normal cells into cancer cells is la rgely determined by the fidelity of DNA replication, repair, and division. Cell-cycle arrest in response to stress is integral to the maintenance of g enomic integrity. The control mechanisms that restrain cell-cycle transitio n or induce apoptotic signaling pathways after cell stress are known as cel l-cycle checkpoints. This review will focus on the mechanisms of cell-cycle checkpoint pathways and how different components of these pathways are fre quently altered in the genesis of human tumors. As our knowledge of cell-cy cle regulation and checkpoints increases, so will our understanding of how xenobiotic agents can affect these processes to either initiate or inhibit tumorigenesis.