Alkylating Agents

The alkylating agents exert their antineoplastic actions by generating highly reactive carbonium ion intermediates that form a covalent linkage with various nucleophilic components on both proteins and DNA. The 7 position of the purine base guanine is particularly susceptible to alkylation, resulting in miscoding, depurination, or ring cleavage. Bifunctional alkylating agents are able to cross-link either two nucleic acid molecules or one protein and one nucleic acid molecule. Although these agents are very active from a therapeutic perspective, they are also notorious for their tendency to cause carcinogenesis and mutagenesis. Alkylating agents that have a nonspecific effect on the cell-cycle phase are the most cytotoxic to rapidly proliferating tissues.

Nitrogen Mustards

The activity of nitrogen mustards depends on the presence of a bis-(2-chloroethyl) grouping:






This is present in mechlorethamine (Mustargen), which is used in patients with Hodgkin’s disease and other lymphomas, usually in combination with other drugs, such as in MOPP therapy (mechlorethamine, Oncovin [vincristine], procarbazine, andprednisone). It may cause bone marrow depression.


Chlorambucil (Leukeran) is the least toxic nitrogen mustard and is used as the drug of choice in the treatment of chronic lymphocytic leukemia. It is absorbed orally, is slow in its onset of action, and may cause bone marrow depression.


Cyclophosphamide (Cytoxan and Endoxan) is used in the treatment of Hodgkin’s disease, lymphosarcoma, and other lymphomas. It is employed as a secondary drug in patients with acute leukemia and in combination with doxorubicin in women with breast cancer. A drug combination effective in the treatment of breast cancer is cyclophosphamide, methotrexate, fluorouracil, and prednisone (CMFP). Cyclophosphamide is also an immunosuppressive agent. The toxicity of cyclophosphamide causes alopecia, bone marrow depression, nausea and vomiting, and hemorrhagic cystitis.

Alkyl Sulfonate

The alkyl sulfonate busulfan (Myleran) is metabolized to an alkylating agent. Because it produces selective myelosuppression, it is used in cases of chronic myelocytic leukemia. It causes pronounced hyperuricemia stemming from the catabolism of purine.


Carmustine (BCNU), lomustine (CCNU), and semustine (methyl-CCNU) generate alkyl carbonium ions and isocyanate molecules and hence are able to interact with DNA and other macromolecules. These agents, which are lipid soluble, cross the blood-brain barrier and are therefore effective in treating brain tumors. They are bone marrow depressants.


Dacarbazine (DTIC-Dome) is metabolized to an active alkylating substance. It is used in the treatment of malignant melanoma and causes myelosuppression.