Alkylating Agents

An overview of alkylating agents used in medicine

Alkylating agents are a class of chemotherapy drugs that work by adding an alkyl group (CnH2n+1) to the DNA molecule, which can lead to the disruption of DNA function and cell death. These agents are used primarily in the treatment of various types of cancer.

Mechanism of Action

Alkylating agents exert their effects by forming covalent bonds with DNA. This process involves the transfer of an alkyl group to the DNA, which can result in:

• Cross-linking of DNA strands: This prevents the DNA from being separated for replication or transcription.
• Mis-pairing of nucleotides: Alkylation can lead to incorrect base pairing, which can cause mutations.
• DNA strand breaks: The structural changes can lead to breaks in the DNA strands, triggering cell death.

The ability of alkylating agents to damage DNA makes them effective against rapidly dividing cancer cells, which are more susceptible to DNA damage than normal cells.

Types of Alkylating Agents

Alkylating agents can be classified into several categories based on their chemical structure and mechanism of action:

• Nitrogen mustards: These include cyclophosphamide, ifosfamide, and chlorambucil. They are among the oldest and most widely used alkylating agents.
• Nitrosoureas: Such as carmustine and lomustine, which can cross the blood-brain barrier and are used to treat brain tumors.
• Alkyl sulfonates: Busulfan is a well-known example, used primarily in chronic myelogenous leukemia.
• Triazines: Dacarbazine and temozolomide are used in the treatment of melanoma and brain tumors.
• Ethylenimines: Thiotepa is used in the treatment of breast cancer and ovarian cancer.

Clinical Uses

Alkylating agents are used in the treatment of a variety of cancers, including:

• Leukemia: Particularly effective in chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML).
• Lymphoma: Used in both Hodgkin's and non-Hodgkin's lymphoma.
• Breast cancer: Often used in combination with other chemotherapy agents.
• Ovarian cancer: Used as part of combination chemotherapy regimens.
• Brain tumors: Especially nitrosoureas, due to their ability to penetrate the blood-brain barrier.

Side Effects

The use of alkylating agents is associated with several side effects, which can vary depending on the specific drug and dosage. Common side effects include:

• Myelosuppression: Decreased production of blood cells, leading to anemia, increased risk of infection, and bleeding.
• Nausea and vomiting: Often managed with antiemetic medications.
• Alopecia: Hair loss, which is usually temporary.
• Secondary malignancies: Long-term use can increase the risk of developing a second cancer, such as acute myeloid leukemia (AML).

Resistance

Cancer cells can develop resistance to alkylating agents through various mechanisms, such as increased DNA repair capabilities, increased drug efflux, and alterations in drug targets. Overcoming resistance is a significant challenge in cancer treatment.

Also see

• Chemotherapy
• DNA repair
• Cancer treatment
• Pharmacology