The inception of chemotherapy as a therapeutic agent is built on the foundation of biochemical warfare. The synthesis of mustard gas in 1854 and its subsequent use during World War I highlighted its gastrointestinal and myelosuppressive toxicity. After swapping out the sulfide group in favor of an amino group, chlormethine (mechlorethamine) became the first evaluated chemotherapeutic agent of the modern age. It became the prototype medication for alkylating agents.

An alkyl (e.g., methyl, ethyl, propyl) is an alkane (e.g., methane, ethane, propane) with one hydrogen missing. Alkyls are highly active radicals that form covalent bonds with different molecules; hence, they are always attached to other molecular fragments. MOPP (a combination of mechlorethamine, vincristine [oncovin], procarbazine, and prednisone) is one of the first regimens that was used with curative intent in oncology.

Alkylating agents directly damage the DNA via DNA intra- and interstrand covalent crosslinking, preventing the cells from reproducing. Generally, they are cell cycle–dependent but not cell cycle phase-specific. Bone marrow suppression, including leukopenia, neutropenia, lymphopenia, anemia, and thrombocytopenia, is a common adverse event of all alkylating agents. Other common adverse events include gonadal toxicity/failure, carcinogenicity, and nausea and vomiting. All alkylating agents can cause therapy-related myeloid neoplasms (t-MN), including acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs), that usually occur 5 to 7 years after treatment and involve abnormalities of chromosome 5 and /or 7.

There are different types of alkylating agents based on the chemical structures:

• Nitrogen mustard: cyclophosphamide, ifosfamide, chlorambucil, melphalan, bendamustine, mechlorethamine
• Nitrosourea: streptozocin, carmustine (BCNU), lomustine (CCNU)
• Triazine:dacarbazine, temozolomide
• Alkyl sulfonate: busulfan
  • Busulfan is used as part of conditioning regimens for allogeneic stem cell transplant and causes pulmonary fibrosis (busulfan lung), hepatic veno-occlusive disease (VOD), skin hyperpigmentation, and seizure. Prophylactic anticonvulsants should be used with busulfan-containing conditioning regimens.
• Ethylenimine: thiotepa
• Platinum agents: cisplatin, carboplatin, oxaliplatin

Most of these alkylating agents are metabolized hepatically and excreted in the urine; dose adjustment for renal dysfunction and severe hepatic dysfunction is often required.

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Alkylating agents have been a mainstay of cancer chemotherapy for over 60 years and continue to play formative roles in diverse cytotoxic regimens for a broad spectrum of hematologic and epithelial malignancies as well as cytoreductive regimens for bone marrow transplantation. There are several different types of alkylating agents that are used in daily oncology clinical practice. These agents exert their cytotoxic effects by directly damaging DNA through intra- and interstrand covalent crosslinking. Although not phase-specific, alkylating agents are cell cycle–dependent and exert their toxicities predominantly on organs with actively cycling cells, such as bone marrow and gastrointestinal mucosal cells. All alkylating agents are capable of inducing t-MDS and t-AML, which are associated with losses of parts or all of chromosome 5 and /or 7, often with complex cytogenetic abnormalities. These myeloid malignancies emerge at a median 5 to 7 years (but as late as 20+ years) after alkylating agent therapy, often have complex cytogenetic abnormalities involving multiple chromosomes, exhibit refractoriness to multiple classes of chemotherapeutic agents, and carry a poor prognosis. Understand ing the clinical indications and special adverse event profile and the management of those related to each agent is imperative for hematologists and oncologists.

• To prevent hemorrhagic cystitis, MESNA must be used after administration of intermediate-dose to high-dose cyclophosphamide and ifosfamide.
• High-dose ifosfamide can cause encephalopathy, which can be treated/prevented with methylene blue.
• Hypermethylation of the O⁶-methylguanine-DNA-methyltransferase (MGMT) gene is associated with improved outcome in glioblastoma and is a predictive marker of sensitivity to alkylating agents such as temozolomide.
• Thiotepa is the only alkylating agent that can be given intrathecally. The other cytotoxic agents that can be given intrathecally are cytarabine (see Chapter 3, Antimetabolites: Hydroxyurea, Pyrimidine and Purine Analogs, and L-Asparaginase) and methotrexate (see Chapter 4, Antimetabolites: Antifolates). Steroids and rituximab can be used for intrathecal injection.

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