Posted by jayaram in Cancer is defined as the excessive division of cells. It is recognized pathologically by a higher fraction of cells actively in the cell cycle than is expected for the normal tissue from which it arose. This includes a higher fraction of cells in mitosis, recognizable by microscopy, and a higher fraction of cells in S-phase.
Most medicines used for cancer chemotherapy attack DNA replication or enzymes involved in the process. Cells that are actively dividing are more sensitive to these medicines than quiescent cells. In addition to cancer cells, the targets of therapy, there are rapidly dividing cells in the intestinal tract, bone marrow, and hair follicles. The sensitivity of these normal but rapidly dividing cells explains many of the limiting effects of chemotherapy.
Many kinds of medicines are used to disrupt replication. Anti-metabolites interfere with synthesis of precursors of 5’-dNTP. Methotrexate inhibits dihydrofolate reductase, needed to maintain reduced tetrahydrofolate required for nucleotide synthesis. 5-Fluorouracil inhibits thymidylate synthase; when metabolized into its triphosphate it can be incorporated into DNA and led to strand breaks. Vinca alkaloids inhibit microtubule assembly and thereby interfere with mitosis and chromosome segregation. Topoisomerase inhibitors slow or stop the process of replication by preventing untwisting of parental strands. Topoisomerase poisons inhibit resealing of the phosphodiester bond, leaving covalent protein- DNA junctions that are converted into strand breaks.
Many widely used chemotherapeutic medicines are alkylating agents, often ones that have two functional groups and thereby create both intrastrand and interstrand cross-links in dna. Cyclophosphamide, busulfan, and nitrosoureas are alkylating agents. Cisplatin, a key part of the combined chemotherapy for testicular cancer, cross-links DNA. Alkylating agents are not only cytotoxic but also mutagenic, some-times resulting in secondary cancers such as leukemias.