Alkylating Agents

No items found.



Alkylating agents are a class of cytotoxic drugs that disrupt DNA structure and function by transferring alkyl groups to DNA molecules, leading to crosslinks and inhibition of DNA replication and transcription.

Cyclophosphamide, a widely-used alkylating agent, works by transferring an alkyl group to the guanine base of DNA, and specifically targets the nitrogen atom at position 7. This then forms intrastrand and interstrand DNA crosslinks, which disrupt DNA replication. The alkylating action of cyclophosphamide is cell cycle phase non-specific; cell division is brought to a halt, and the cell undergoes apoptosis. However, before it takes effect, cyclophosphamide must be metabolized into its active form by the cytochrome P450 enzyme system in the liver.

Cyclophosphamide is used to treat different types of cancers, including leukemias, lymphomas, and solid tumors such as breast and ovarian cancer. Besides being cytotoxic to neoplastic cells, cyclophosphamide also effectively inhibits the proliferation of immune cells, and thus can be used to treat severe autoimmune and inflammatory conditions. However, cyclophosphamide does come with potential short and long-term toxicities. Notably, it may cause cytopenias secondary to myelosuppression, and hemorrhagic cystitis due to the formation of the toxic metabolite acrolein. The latter can be prevented through aggressive hydration and the co-administration of 2-mercaptoethanesulfonate or MESNA. Another serious risk is the development of bladder cancer and hyponatremia due to the syndrome of inappropriate antidiuretic hormone or SIADH. Prolonged use and higher doses of cyclophosphamide can also result in irreversible azoospermia in males and premature menopause in females.

Other alkylating agents discussed include busulfan, which is used as a conditioning agent prior to bone marrow transplantation, and nitrosoureas like carmustine and lomustine, all of which--- like cyclophosphamide--- form DNA crosslinks. Nitrosoureas are useful in treating brain tumors since they can cross the blood-brain barrier, but they may cause CNS side effects such as convulsions, dizziness, and ataxia.

Lesson Outline

Don't stop here!

Get access to 133 more Pharmacology lessons & 13 more medical school learning courses with one subscription!

Try 7 Days Free


What is the mechanism of action of cyclophosphamide and other alkylating agents?

Alkylating agents like cyclophosphamide work by donating an alkyl group to the guanine base of DNA (specifically at the number 7 nitrogen atom), which leads to the creation of DNA cross-links. The cross-links cause cell division to be brought to a halt, which in turn leads to apoptosis. This is considered a cell cycle NON-specific action, meaning it affects cells in all stages of the cell cycle.

How is cyclophosphamide activated in the body?

Cyclophosphamide is a prodrug, which means that it needs to be activated in the body in order to function. It is activated by hepatic cytochrome P450 enzymes in the liver, after which it can interact with DNA and interfere with its replication and transcription, leading to cell death.

What types of cancer can cyclophosphamide be used to treat?

Cyclophosphamide is used to treat both hematologic and solid malignancies. These include leukemias and lymphomas, breast cancer, and ovarian cancer. Due to its potent immunosuppressive properties, it is also used in the treatment of other conditions such as nephrotic syndrome, nephritic syndrome, vasculitis, and autoimmune hemolytic anemia.

What are some of the side effects and risks associated with cyclophosphamide?

Cyclophosphamide can cause various side effects including myelosuppression, hemorrhagic cystitis, hyponatremia due to SIADH, infertility, and premature menopause. It also increases the risk of bladder cancer, specifically high-grade transitional cell carcinoma. Coadministration of 2-mercaptoethanesulfonate (MESNA) is often used to prevent hemorrhagic cystitis.

What is the role of nitrosoureas like carmustine and lomustine in cancer treatment?

Nitrosoureas such as carmustine and lomustine are cytotoxic alkylating agents. They are highly lipophilic, which allows them to cross the blood-brain barrier and be used in the treatment of brain tumors such as glioblastoma multiforme. However, their use can result in CNS side effects, including convulsions, dizziness, and ataxia.