Antimetabolites in chemotherapy
Antimetabolites are a class of chemotherapy drugs designed to disrupt the processes of DNA and RNA replication in rapidly dividing cells, such as cancer cells. These agents are chemically similar to the natural components used in nucleotide synthesis, tricking cells into utilizing them in place of actual nucleotides. This interference effectively inhibits the synthesis of nucleotides, which are crucial for DNA replication, leading to reduced cell division and promoting cell death.
Antimetabolites are commonly used to treat various cancers, including solid tumors like breast, colon, and lung cancers, as well as certain leukemias and lymphomas. The main subclasses of antimetabolites include folic acid antagonists, pyrimidine antagonists, and purine antagonists, each targeting specific enzymatic processes in nucleotide synthesis. Notable examples are methotrexate, which inhibits dihydrofolate reductase, and fluorouracil, which disrupts thymidine production.
While effective against cancer, antimetabolites can also harm healthy, rapidly dividing cells, leading to side effects such as bone marrow suppression, gastrointestinal distress, and general toxicity. Despite the challenges, ongoing research aims to enhance the targeting of these therapies to minimize their impact on normal tissues. Overall, antimetabolites play a vital role in cancer treatment, with a focus on improving efficacy and reducing adverse effects for patients.
On this Page
Antimetabolites in chemotherapy
ATC CODE: 101B
DEFINITION: Antimetabolites are drugs that interfere with deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) replication processes in cells. These agents are very similar to the components involved in synthesizing nucleotides, the structural units of DNA and RNA. This similarity causes the cell to mistake the antimetabolite for a natural component, allowing the drug to inhibit nucleotide synthesis effectively. Nucleotide synthesis and subsequent DNA replication are processes that a cell must undergo before it can divide. Rapidly growing tumor cells are particularly susceptible to DNA and RNA replication interference. Further, inhibiting DNA and RNA replication triggers the activation of death-promoting pathways in these cells, causing the antimetabolite to decrease the tumor size.
Cancers treated: Many solid tumors, including breast, colon, lung (small-cell and non-small-cell), ovarian, and head and neck cancers; several leukemias and lymphomas, including acute lymphocytic leukemia, indolent B-cell lymphoma, and non-Hodgkin lymphoma
Subclasses of this group: Folic acid antagonists, pyrimidine antagonists, purine antagonists
Delivery routes: Intravenous (IV), oral, intra-arterial (into an artery), intrathecal (into the spinal canal)
How these drugs work: The development of antimetabolite therapy was based on understanding the importance of DNA replication in cell division and proliferation. Antimetabolites inhibit DNA replication through one or both of two mechanisms. First, these drugs can inhibit the synthesis of nucleotides, the structural molecules that make up the DNA strand. The four nucleotides used to replicate DNA are divided into two categories. The two purine nucleotides are adenine and guanine, while the two pyrimidines are cytosine and thymine. With the exception of thymine, these nucleotides also serve as the structural units for ribonucleic acid (RNA). In RNA, thymine is replaced with another nucleotide, uracil. When the synthesis of these molecules is inhibited, the cellular pool of nucleotides is reduced, limiting the ability of the cell to synthesize new DNA strands. The second mechanism of action is the actual incorporation of the antimetabolite into the DNA itself. The enzymes responsible for DNA replication can mistake the agents for DNA nucleotides, but the direct consequences of this mistaken identity are unknown. The main subclasses of antimetabolites used in cancer therapy are antifolates (folic acid antagonists), pyrimidine and purine antagonists (base analogs), and nucleoside analogs.
Antifolates or folic acid (folate) antagonists act primarily by inhibiting the dihydrofolate reductase (DHFR) enzyme. DHFR functions to change the structure of folic acid, also known as vitamin B9, allowing it to be used in various metabolic processes. These result in the formation of nucleotides. Inhibition of DHFR reduces the production of many of the nucleotides essential for DNA replication. Methotrexate is the prototypical folate antagonist and has been successfully used as an anticancer drug in the clinic for decades. One of the reasons that methotrexate is so efficacious is that once it enters the cell, it is chemically modified in such a way that it is unable to exit the cell. This causes the intracellular concentration of methotrexate to remain high.
Pyrimidine and purine antagonists target tumor cells via a dual mechanism of action-inhibition of nucleotide synthesis and incorporation into DNA. To inhibit nucleotide synthesis, pyrimidine antagonists can directly inhibit the thymidylate synthase protein, a critical enzyme in the formation of the thymine nucleotide. When thymidylate synthase mistakes pyrimidine antagonists for their natural substrate, the agent inhibits and traps the enzyme in the middle of the catalysis reaction. A stable complex of the enzyme and drug is formed, decreasing the number of enzymes available for the further formation of thymine. Because there is a relatively small concentration of thymine normally in the cell, reducing these pools can drastically inhibit DNA synthesis. The most common pyrimidine antagonists, fluoropyrimidines such as floxuridine and fluorouracil, have also been found to incorporate into DNA and RNA, replacing the nucleic acids thymine and uracil, respectively. This incorporation occurs at a relatively low level, however, and is not believed to be the primary cause of cell death. Fluoropyrimidines, especially 5-fluorouracil, are used to treat many commonly occurring cancers, including colorectal, breast, gastric, pancreatic, and head and neck tumors.
Compared with pyrimidine antagonists, purine antagonists incorporate more readily into nucleic acids. Purine antagonists also inhibit the synthesis of nucleic acids. Each purine antagonist may inhibit purine synthesis at different points along the metabolic pathway, but their effects are perhaps most notable on the enzymes PRPP amidotransferase and IMP dehydrogenase. Purine antagonists are self-limiting, meaning that the biochemical effects produced by the agents can antagonize each other. For example, when purine synthesis is inhibited, total DNA replication is reduced, thereby diminishing the potential for drug incorporation into the DNA. The main purine antagonists are pentostatin, fludarabine, mercaptopurine, and thioguanine, and they are used primarily to treat leukemia, especially in children.
Nucleoside analogs such as gemcitabine are principally used in the treatment of breast cancer, non-small cell lung cancer, pancreatic cancer, bladder cancer, ovarian cancer, and biliary tract cancer. Gemcitabine is a synthetic pyrimidine nucleoside that acts primarily in the S phase of the cell cycle. The combined actions of diphosphate and triphosphate metabolites lead to the inhibition of DNA synthesis. Gemcitabine diphosphate interferes with subsequent de novo nucleotide production by inhibiting ribonucleotide reductase, which catalyzes the formation of deoxynucleoside triphosphates critical to DNA synthesis.
Side effects: In general, antimetabolites are more toxic to cells that are actively dividing compared to cells that are not. Because tumor cells rapidly proliferate, antimetabolites can target these cells quite effectively. The drugs cannot differentiate between cancer cells and rapidly dividing healthy cells, such as those that occur in the bone marrow, the lining of the gastrointestinal tract, and hair follicles. Therefore, most side effects induced by these drugs depend on which normal cells are affected. Methotrexate toxicity is mainly confined to the bone marrow and the gastrointestinal tissue lining. The side effects that can result in systemic therapy with pyrimidine and purine antagonists are mainly bone marrow suppression, although gastrointestinal toxicity can occur. Fluoropyrimidines, in particular, induce nausea, vomiting, anorexia, and diarrhea.
Despite the efficacies of antimetabolite treatments, their use causes great physical and mental impacts on patients. Although efforts to therapeutically target specific cancerous cells have progressed relatively slowly, research efforts are ongoing.
Bibliography
"Chemotherapy Drugs." The Cleveland Clinic, 20 Oct. 2022, my.clevelandclinic.org/health/treatments/24323-chemotherapy-drugs. Accessed 20 June 2024.
Jackman, Ann L. Antifolate Drugs in Cancer Therapy. Totowa, Humana, 1999. Print.
Kantarjian, Hagop M., et. al. The MD Anderson Manual of Medical Oncology. 2nd ed. New York, McGraw-Hill, 2011.
Hong, Waun Ki, et al., Holland-Frei Cancer Medicine. 8th ed. Shelton, BC Decker, 2010.
Perez, Alexandra. "Antimetabolite Drugs for Cancer: Options, Effects, Benefits, and More." Healthline, 19 Sept. 2021, www.healthline.com/health/cancer/antimetabolites. Accessed 20 June 2024.
Peters, Godefridus J. "Novel Development in the Use of Antimetabolites." Nucleosides, Nucleotides, and Nucleic Acids, vol. 334, no. 6, 2014, pp. 358–74.
Rustum, Youcef M., Fluoropyrimidines in Cancer Therapy. Totowa, Humana, 2003.
Skeel, Roland T., and Samir N. Khleif. Handbook of Cancer Chemotherapy. 8th ed. Philadelphia, Lippincott, 2011.
Stine, Zachary, et. al. "Targeting Cancer Metabolism in the Era of Precision Oncology." Nature, 3 Dec. 2021, www.nature.com/articles/s41573-021-00339-6. Accessed 20 June 204.
Tilsed, Caitlin, et. al. "Cancer Chemotherapy: Insights into Cellular and Tumor Microenvironmental Mechanisms of Action." Frontiers in Oncology, 29 July 2022, www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.960317/full. Accessed 20 June 2024.
Tiwari, Manjul. "Antimetabolites: Established Cancer Therapy." Journal of Cancer Research and Therapeutics, vol. 8, no.4, 2012, pp. 510–19.