mutations. The precise mechanisms by which chlorambucil acts to kill tumor cells are not yet completely understood. Limitations to bioavailability 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. Chemistry 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. History Nitrogen mustards arose from the derivatization of sulphur mustard gas after military personnel exposed to it during World War I were observed to have decreased white blood cell counts. 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. References External links Leukeran (manufacturer's website) IARC Group 1 carcinogens Anilines Organochlorides Nitrogen mustards Chloroethyl compounds World Health Organization essential medicines Wikipedia medicine articles ready to translate