Alkylating Agents: Nitrogen mustard derivatives

Several alkylating agents are used in clinical practice. They all share the same mechanism of action; they introduce alkyl groups into nucleophilic sites on other molecules, DNA being the principal target in cancers.  Alkylating agents can be subdivided into chemical classes, one of which is the nitrogen mustard derivatives.

Nitrogen mustard derivatives include cyclophosphamide, melphalan, chlorambucil, and others. They are not derived from mustard plants but they do have an interesting and grim history. These compounds were initially developed for trench warfare in World War I ('mustard gases') and they were dropped on enemy troops from planes. High doses were quickly lethal, but it was noticed that individuals who were exposed to lower doses downwind from the battlefield, developed severe low white blood counts. Two American pharmacologists, Louis Goodman and Alfred Gilman, decided to change the agents from gas to liquid formulations and administered them intravenously into a patient with malignant lymphoma. They found that the cancer cells disappeared within two weeks. Unfortunately, the cancer returned later and the patient died, but this was the first step in cancer chemotherapy. This was the birth of modern chemotherapy and a positive outcome of chemical warfare. Cyclophosphamide was identified through this research process, and it has become one of the most commonly used agents in a range of chemotherapy regimens. The nitrogen group in the molecule is extremely reactive and the majority of the cytotoxic effects come from the irreversible binding of these nitrogens to the DNA molecule at the N-7 position on the guanine base- this is the 'alkylation' reaction. This insertion of a chemical along the DNA molecule disrupts DNA replication and increases the likelihood of DNA breaks. In addition, the drugs can form cross-links between two DNA strands, further adding to the inability of the cell to repair or use the damaged DNA. So, all DNA is susceptible to these agents, but cells that are rapidly dividing and growing (e.g., cancer cells) are more susceptible than non-cancer somatic cells. Cells that have rapid turnover (skin, hair, and gastric mucosa) are inherently more susceptible to cancer chemotherapy, and collateral damage to these tissues manifests as skin hypersensitivities and rashes, alopecia, and GI upset/nausea and vomiting. 

Cyclophosphamide is discussed here, as the prototype alkylating agent. It is used for a variety of hematologic and solid organ tumors. Cyclophosphamide can be given orally without causing significant damage to the gastrointestinal epithelium because it is metabolized and activated in the liver.The toxicity profile includes a dose-limiting myelosuppression, delayed and acute nausea and vomiting, SIADH (syndrome of inappropriate antidiuretic hormone secretion), alopecia, and hemorrhagic cystitis. Hemorrhagic cystitis is rarely observed in practice since we know how to prevent it. Acrolein is the cyclophosphamide metabolite that is toxic to the urinary bladder. Its accumulation in the bladder results in severe damage to the bladder mucosa and presents with pain and discomfort, as well as blood in urine. To prevent this toxicity, vigorous hydration before administration of cyclophosphamide and ensuring urine output is over 100 mL/hour will assist in preventing hemorrhagic cystitis. Co-administration of MESNA (mercapto-ethane sulfonates) also helps to prevent hemorrhagic cystitis. MESNA acts as an acrolein scavenger, by binding to acrolein via its reactive sulfhydryl group. This reaction generates a stable, non-toxic byproduct. Ifosfamide (a second-generation agent) is more toxic than cyclophosphamide and must always be given with MESNA. Usually, vigorous hydration is sufficient to combat hemorrhagic cystitis with cyclophosphamide; however, MESNA may be given with higher doses of cyclophosphamide and especially with ifosfamide. N-acetyl-cysteine, a thiol agent, has also been used to reduce these side effects.

Other alkylating agents that are used in many chemotherapy regimens include the platinum-containing agents carboplatin and cisplatin. Like nitrogen mustards, these platinum compounds disrupt DNA replication and interfere with cancer cell growth.