Chemotherapy Primer: Antimetabolites
July 9, 2009 5:19 am Chemotherapy
In 1948, Dr. Sidney Farber showed that a folic acid analog could induce remission in childhood leukemia. Approximately 10 out of the 16 patients treated demonstrated evidence of hematologic improvement. This experience provided the foundation for scientists to synthesize a number of other agents that either target naturally occurring compounds or inhibit key enzymatic reactions in their biochemical pathways. In general, all antimetabolites interfere with normal metabolic pathways, including those necessary for making new DNA. The most widely used antifolate in cancer therapy, with activity against leukemia, lymphoma, breast cancer, head and neck cancer, sarcomas, colon cancer, bladder cancer and choriocarcinomas, is Methotraxate. Methotraxate inhibits a crucial enzyme required for DNA synthesis and therefore exerts its effect on the S phase of the cell cycle.
5-Fluorouracil (5-FU), another widely used antimetabolite, prevents DNA synthesis by interfering with the nucleotide ( DNA components) production. It, too, has a wide range of activity including colon cancer, breast cancer, head and neck cancer, pancreatic cancer, gastric cancer, anal cancer, esophageal cancer and hepatomas (primary liver tumor). A unique and interesting aspect of this drug is its toxicity profile. 5-Fluorouracil is metabolized by a naturally occurring enzyme in the body called dihydropyrimidine dehydrogenase, or DPD. There is a small population of people who are deficient of this particular enzyme. Lacking DPD does not interfere with normal body function and thus people are not aware that they are lacking it. However, when these patients are given this chemotherapy drug, they are unable to metabolize it and therefore get acute and severe toxicities (side effects). The most often seen toxicities include bone marrow suppression, severe GI toxicities, and neurotoxicities which may include seizures and even coma. It is important for the oncologist to recognize this early and give the patient Thymidine as an antidote. A drug called Capecitabine is an oral type of 5-Fluorouracil compound that has similar side effect potentials.