Direct DNA-Interactive Agents DNA replication occurs during the synthesis or S-phase of the cell cycle, with chromosome segregation of the replicated DNA occurring in the M, or mitosis, phase. The G1 and G2 "gap phases" precede S and M, respectively. Historically, chemotherapeutic agents have been divided into "phase-nonspecific" agents, which can act in any phase of the cell cycle, and "phase-specific" agents, which require the cell to be at a particular cell cycle phase to cause greatest effect. Once the agent has acted, cells may progress to "checkpoints" in the cell cycle where the drug-related damage may be assessed. | Chapter 081. Principles of Cancer Treatment Part 12 Direct DNA-Interactive Agents DNA replication occurs during the synthesis or S-phase of the cell cycle with chromosome segregation of the replicated DNA occurring in the M or mitosis phase. The G1 and G2 gap phases precede S and M respectively. Historically chemotherapeutic agents have been divided into phase-nonspecific agents which can act in any phase of the cell cycle and phase-specific agents which require the cell to be at a particular cell cycle phase to cause greatest effect. Once the agent has acted cells may progress to checkpoints in the cell cycle where the drug-related damage may be assessed and either repaired or allowed to initiate apoptosis. An important function of certain tumor-suppressor genes such as p53 may be to modulate checkpoint function. Formation of Covalent DNA Adducts Alkylating agents as a class are cell cycle phase-nonspecific agents. They break down either spontaneously or after normal organ or tumor cell metabolism to reactive intermediates that covalently modify bases in DNA. This leads to cross-linkage of DNA strands or the appearance of breaks in DNA as a result of repair efforts. Broken or cross-linked DNA is intrinsically unable to complete normal replication or cell division in addition it is a potent activator of cell cycle checkpoints and further activates cell-signaling pathways that can precipitate apoptosis. As a class alkylating agents share similar toxicities myelosuppression alopecia gonadal dysfunction mucositis and pulmonary fibrosis. They differ greatly in a spectrum of normal organ toxicities. As a class they share the capacity to cause second neoplasms particularly leukemia many years after use particularly when used in low doses for protracted periods. Cyclophosphamide is inactive unless metabolized by the liver to 4-hydroxy-cyclophosphamide which decomposes into an alkylating species as well as to chloroacetaldehyde and acrolein. The latter causes chemical .
