Chlorambucil

Chemical compound

Chlorambucil, sold under the brand name Leukeran among others, is a chemotherapy medication used to treat chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, and non Hodgkin lymphoma. For CLL it is a preferred treatment. It was originally made from nitrogen mustard.

Chlorambucil's current use is mainly in chronic lymphocytic leukemia, as it is well tolerated by most patients, though chlorambucil has been largely replaced by fludarabine as first line treatment in younger patients. It can be used for treating some types of non Hodgkin lymphoma, Waldenström macroglobulinemia, polycythemia vera, trophoblastic neoplasms, and ovarian carcinoma. Moreover, it also has been used as an immunosuppressive drug for various autoimmune and inflammatory conditions, such as nephrotic syndrome.

A recent study has shown Chlorambucil to be detoxified by human glutathione transferase Pi (GST P1 1), an enzyme that is often found over expressed in cancer tissues. This is important since Chlorambucil, as an electrophile, is made less reactive by conjugation with glutathione, thereby making the drug less toxic to the cell. Shown above, Chlorambucil reacts with glutathione as catalyzed by hGSTA 1 1 leading to the formation of the monoglutathionyl derivative of Chlorambucil.

Chlorambucil is a white to pale beige crystalline or granular powder with a slight odor. When heated to decomposition it emits very toxic fumes of hydrogen chloride and nitrogen oxides Since the sulphur mustard gas was too toxic to be used in humans, Gilman hypothesized that by reducing the electrophilicity of the agent, which made it highly chemically reactive towards electron rich groups, then less toxic drugs could be obtained. To this end, he made analogues that were less electrophilic by exchanging the sulphur with a nitrogen, leading to the nitrogen mustards. With an acceptable therapeutic index in humans, nitrogen mustards were first introduced in the clinic in 1946. Aliphatic mustards were developed first, such as mechlorethamine hydrochloride (mustine hydrochloride), which is still used in the clinic today. In the 1950s, aromatic mustards like chlorambucil were introduced as less toxic alkylating agents than the aliphatic nitrogen mustards, proving to be less electrophilic and react with DNA more slowly. Additionally, these agent can be administered orally, a significant advantage. Chlorambucil was first synthesized by Everett et al.