Development of cell cycle active drugs for the treatment of gastrointestinal cancers: a new approach to cancer therapy.

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.