Antimetabolites: Established cancer therapy

Cell death has been divided into two main types: programmed cell death, in which the cell plays an active role, and passive (necrotic) cell death. Senescence arrest, accelerated senescence and differentiation are also responses that can be induced in response to DNA-damaging agents. Apoptosis may occur as a primary event following chemotherapy, in which genes that regulate apoptosis will influence the outcome of therapy or, alternatively, as an event secondary to the induction of lethal damage that involves the subsequent processing of cellular damage. The particular type of response induced is highly dependent on the agent and dose employed, the type of DNA damage induced as well as the genetic and cellular phenotypes. It has been proposed that apoptosis may play a lesser role in tumor response to radiation in comparison with the induction of cell death through mitotic catastrophe or a senescence-like irreversible growth arrest. However, in comparison with the induction of apoptosis, there is a lack of as much definitive information on other cell death processes that occur in cancer cells in response to chemotherapeutic agents, including antimetabolites. This article reviews what is known about these processes at the present time in response to experimental or clinically used agents that are analogs of 5-fluorouracil, cytidine or purines, hydroxyurea, or that belong to the family of folate antagonists.