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Maintaining metabolism and the production of energy are important processes for cancer cells to grow and divide. It was discovered early in the development of chemotherapeutic drugs that disrupting cell metabolism using aminopterin resulted in antitumor activity. An analog of this drug, methotrexate, was subsequently identified and continues to be widely used for cancer treatment, even after 60 years. Methotrexate is a mimic of folic acid and works by binding to an enzyme known as dihydrofolate reductase or DHFR. This enzyme plays a central role in folate metabolism, and without folates, cells are unable to synthesize some of the building blocks of nucleic acids (DNA) and protein.  In addition to methotrexate, there are a variety of other antimetabolites that are used clinically for the treatment of cancer (see below). These drugs differ primarily by their specific metabolic targets. For example, upon entering tumor cells, 5-fluorouracil is converted to 5-fluoro-2'deoxyuridine (FUdR). This compound is subsequently phosphorylated and interacts with 5,10-methylenetetrahydrofolate to inhibit thymidylate synthase acitivity. Capecitabine (Xeloda) is a 5-fluorouracil analog that may be administered orally. Gemcitabine, cytarabine and fludarabine are essentially nucleoside mimics. These drugs trick DNA synthesis enzymes into incorporating these analogues into newly synthesized DNA resulting in growth arrest and cell death. As is the case with most chemotherapeutic agents, however, tumor cells can develop resistant to these drugs which may limit their long term effectiveness. Methotrexate 5-Fluorouracil (Adrucil) Capecitabine (Xeloda) Cladribine (Leustatin) Gemcitabine (Gemzar) Cytarabine (DepoCyt) Fludarabine (Fludara) Mercaptopurine (Purinethol) Pentostatin (Nipent) |
