Alkylating agents in chemotherapy
Alkylating agents are a class of chemotherapeutic drugs used primarily to treat various types of cancer, particularly slow-growing tumors and leukemia. These highly reactive compounds work by interfering with the DNA of cancer cells, preventing their division and promoting cell death. Discovered during World War II, alkylating agents substitute alkyl groups for hydrogen in DNA, leading to cross-linking of the DNA strands. This mechanism of action is particularly effective against rapidly dividing cancer cells, as they are more susceptible to DNA damage compared to normal cells.
Alkylating agents can be administered intravenously or orally, depending on the specific drug and the cancer being treated. Despite their effectiveness, these drugs are nonspecific and can also harm healthy cells, leading to a range of side effects such as fatigue, hair loss, nausea, and decreased blood cell counts. Long-term use may increase the risk of developing secondary cancers years after treatment, underscoring the importance of monitoring patients over time. Overall, while alkylating agents are a cornerstone of chemotherapy, their use requires careful consideration of potential risks and benefits.
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Alkylating agents in chemotherapy
ATC CODE: 101A
DEFINITION: Alkylating neoplastic agents form a class of chemotherapeutic drugs, which consist of highly reactive compounds containing alkyl groups. They are employed as antineoplastics, drugs that kill neoplasms (cancerous tumor cells) by interfering with their deoxyribonucleic acid (DNA) and cell division.
Cancers treated: Various, especially slow-growing cancers such as solid tumors and leukemia
Subclasses of this group: Alkyl sulfonates, ethyleneimines and methylmelamines, nitrogen mustards, nitrosoureas, platinum compounds, triazenes
Delivery routes: These drugs are administered both intravenously and orally in capsule and tablet form, on an inpatient, outpatient, and at-home basis, depending on the specific drug, type of cancer, and its location and aggressiveness. When possible, these drugs are best delivered to the tumor site to limit damage to normal cells.
How these drugs work: One of the oldest classes of chemotherapeutic drugs, alkylating agents were discovered during World War II when physician Cornelius P. Rhoads drew a connection between the lowered white blood cell counts in six hundred sailors who had been exposed to mustard gas during the sinking of the Liberty in 1943 and the possibility that the nitrous mustards could be adopted for use in leukemia patients.
It was later observed that alkylating agents substitute alkyl groups for the hydrogen groups in the DNA of tumor cells. The alkyl groups cross-link guanine nucleobases in the double-helix strands of DNA, which makes it impossible for the two DNA strands to uncoil and separate in preparation for replication. As a result, these drugs prevent tumor cells from dividing during mitosis, stopping the cells’ growth. They may also stimulate the natural process of cell death (apoptosis). Because DNA is more actively replicated and transcribed in rapidly dividing cancer cells than in normal cells, these drugs are more toxic to tumor tissue than to normal tissue. Alkylating agents are also known to add methyl or alkyl groups onto any of the four nitrogenous bases found in DNA (adenine, guanine, cytosine, thymine), frequently altering the base-pairing relationships and leading to new mutations.
Side effects: Although alkylating agents are more toxic to cancer cells than to normal cells, these drugs are nonspecific. That is, they target normal as well as cancerous tissue, so they exhibit the “Janus effect”: They kill both bad and good cells. Therefore, they have toxic side effects, depending on the specific drug, its dosage, the duration of administration, and the individual patient’s physical condition and attitude. Common side effects include depressed blood cell counts, tiredness and fatigue, diarrhea, alopecia (hair loss), nausea and vomiting, infertility (both amenorrhea in women and impaired spermatogenesis in men), damage to intestinal mucosa, exfoliation of the bladder epithelium resulting in fluid retention, and in extreme cases cardiotoxicity, which would mitigate the chemotherapy regimen. In addition, some alkylating agents increase the risk of future malignancies, which may emerge years after treatment. For example, increases have been known to occur in patients who have been treated for acute myeloid leukemia. Reoccurrence in the form of subsequent breast cancer (SBC) has been documented in a 2023 study published by Nature Medicine.
Bibliography
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Wang, Y., et al. "Subsequent Female Breast Cancer Risk Associated with Anthracycline Chemotherapy for Childhood Cancer." Nature Medicine 29 (2023): 2268–2277. doi.org/10.1038/s41591-023-02514-1.