MYLERAN

Indications

• Chronic myeloid leukaemia (CML)

Mechanism of action

Busulfan acts as an alkylating agent, forming carbonium ions that alkylate DNA, specifically targeting guanine residues. This results in the formation of intrastrand crosslinks between guanine bases within the DNA double helix. Such crosslinking inhibits DNA replication and transcription by preventing the strands from uncoiling and separating, leading to apoptosis in affected cells. The drug disrupts nucleic acid function and has been shown to cause misreading of the DNA code and single-strand breakage. The cytotoxic effects of busulfan are dose-dependent, with increased crosslinking correlating with enhanced cytotoxicity.

Pharmacodynamics

As an antineoplastic agent, busulfan belongs to the class of alkylating agents known for their capacity to add alkyl groups to nucleophilic sites on DNA, leading to tumor growth inhibition. Its mechanism encompasses cross-linking of DNA strands, which halts cell division by preventing the necessary uncoiling during replication. Busulfan is considered cell cycle-nonspecific, affecting cells at any stage of the cell cycle. Resistance to busulfan may be associated with the overexpression of MGST2, although its specific role in busulfan metabolism remains unclear.

Pharmacokinetics

Busulfan is absorbed following oral administration, with its bioavailability influenced by factors such as food intake. It is metabolized predominantly in the liver through alkylation and conjugation pathways. The elimination half-life of busulfan varies among individuals but generally ranges from 2 to 3 hours. The drug is excreted primarily in the urine, both as unchanged drug and metabolites. Variability in pharmacokinetics may impact dosing and therapeutic outcomes, necessitating monitoring of drug levels in some cases.

Adverse effects

• Myelosuppression
• Nausea
• Vomiting
• Mucositis
• Pulmonary toxicity
• Hepatotoxicity
• Secondary malignancies

Interactions

• Increased risk of toxicity with other myelosuppressive agents
• Potential interactions with drugs that affect hepatic metabolism

Precautions

• Monitor blood counts regularly due to risk of myelosuppression
• Use caution in patients with a history of pulmonary disease
• Assess liver function prior to and during treatment

Pregnancy

Busulfan is not recommended during pregnancy due to potential teratogenic effects.

Breast-feeding

Breastfeeding is not advised during busulfan treatment as it may be excreted in breast milk.

Storage

Store at room temperature, protect from light and moisture.

Formulations

• Tablets
• Injection

Mechanism of action

Busulfan is an alkylating agent that contains 2 labile methanesulfonate groups attached to opposite ends of a 4-carbon alkyl chain. Once busulfan is hydrolyzed, the methanesulfonate groups are released and carbonium ions are produced. These carbonium ions alkylate DNA, which results in the interference of DNA replication and RNA transcription, ultimately leading to the disruption of nucleic acid function. Specifically, its mechanism of action through alkylation produces guanine-adenine intrastrand crosslinks. These crosslinks occur through a SN2 reaction guanine N7 nucleophilically attacks the carbon adjacent to the mesylate leaving group. This kind of damage cannot be repaired by cellular machinery and thus the cell undergoes apoptosis. The primary molecular action of busulfan is alkylation of intracellular nucleophiles. Both proteins and nucleic acids are affected. With regard to DNA, busulfan reacts with guanine residues to form a fourcarbon di-guanine DNA cross-linkage with release of methylsulfonate. The DNA cross-linkage causes misreading of the DNA code and single-strand breakage. The degree of DNA cross-linkage has been shown to be proportional to the dose and cytotoxicity of the compound. Busulfan-induced crosslinkages of DNA to nuclear proteins may also occur and is considered a cytotoxic mechanism. Busulfan has also been reported to esterify phosphate groups of chromosomal DNA, accounting for the fragmentation of chromosomes seen in various cell types after treatment. Chromosomal damage further contributes to the overall cytotoxic effect. Studies of cloned tumour and normal cells indicate that busulfan interrupts certain parts of the cell mitotic cycle. While busulfan can act on cells at any stage of mitosis, similar to other alkylating agents, in vitro studies with tumour cell lines indicate that replicating cells are most sensitive to busulfan in the late G1 phase and that progression through the cell cycle is blocked in the G2 phase. Cultured cells in the S-phase, which involves DNA synthesis, are not as affected because the DNA repair systems are active at this stage. Clinically, busulfan is cytotoxic to proliferating tissues, especially granulopoietic cells in the bone marrow.

Pharmacodynamics

Busulfan is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn leads to a miscoding of DNA. Alkylating agents are cell cycle-nonspecific and work by three different mechanisms, all of which achieve the same end result - disruption of DNA function and cell death. Overexpression of MGST2, a glutathione s-transferase, is thought to confer resistance to busulfan. The role of MGST2 in the metabolism of busulfan is unknown however.