Busulfan is an orally administered anticancer alkylating agent used in the treatment of chronic myelogenous leukemia, as well as a parenterally administered myeloablative agent used in the preparation of hematopoietic cell transplantation (HCT). Busulfan has been linked to transient serum enzyme elevations during therapy, to rare cases of cholestatic hepatitis, instances of nodular regenerative hyperplasia, and, when given in high doses, to sinusoidal obstruction syndrome which can be severe and fatal.
Busulfan is a synthetic derivative of dimethane-sulfonate with antineoplastic and cytotoxic properties. Although its mechanism of action is not fully understood, busulfan appears to act through the alkylation of DNA. Following systemic absorption of busulfan, carbonium ions are formed, resulting in DNA alkylation and DNA breaks and inhibition of DNA replication and RNA transcription. (NCI04)
Busulfan is a methanesulfonate ester that is butane-1,4-diol in which the hydrogens of the hydroxy groups are replaced by methanesulfonyl groups. An alkylating antineoplastic agent, it is used for the treatment of chronic myeloid leukemia (although it has been largely replaced by newer drugs). It is also used as an insect sterilant. It has a role as an insect sterilant, an antineoplastic agent, a teratogenic agent, a carcinogenic agent, and an alkylating agent. It is functionally related to a butane-1,4-diol.
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 an 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 the alkylation of intracellular nucleophiles. Both proteins and nucleic acids are affected. With regard to DNA, busulfan reacts with guanine residues to form a four-carbon di-guanine DNA cross-linkage with the release of methyl sulfonate. 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 cross-linkages of DNA to nuclear proteins may also occur and are 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.
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 for 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.
- For use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous (myeloid, myelocytic, granulocytic) leukemia (FDA has designated busulfan as an orphan drug for this use). It is also used as a component of pretransplant conditioning regimens in patients undergoing bone marrow transplantation for acute myeloid leukemia and nonmalignant diseases.
- Busulfan Fresenius Kabi followed by cyclophosphamide (BuCy2) is indicated as conditioning treatment prior to conventional hematopoietic progenitor cell transplantation (HPCT) in adult patients when the combination is considered the best available option.
- Busulfan Fresenius Kabi followed by cyclophosphamide (BuCy4) or melphalan (BuMel) is indicated as conditioning treatment prior to conventional hematopoietic progenitor cell transplantation in pediatric patients.
- Busilvex followed by cyclophosphamide (BuCy2) is indicated as conditioning treatment prior to conventional hematopoietic progenitor cell transplantation (HPCT) in adult patients when the combination is considered the best available option.
- Busilvex following fludarabine (FB) is indicated as conditioning treatment prior to hematopoietic progenitor cell transplantation (HPCT) in adult patients who are candidates for a reduced-intensity conditioning (RIC) regimen.
- Busilvex followed by cyclophosphamide (BuCy4) or melphalan (BuMel) is indicated as conditioning treatment prior to conventional hematopoietic progenitor cell transplantation in pediatric patients.
- Busulfan is used in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation in patients with chronic myelogenous leukemia (CML) and is designated an orphan drug by the US Food and Drug Administration (FDA) for the treatment of this disease.
- Busulfan is an alkylating agent with myeloablative properties and activity against non-dividing marrow cells and, possibly, non-dividing malignant cells. Its use has been well-established in the treatment of hematological malignancies, particularly in patients with chronic myeloid leukemia and other myeloproliferative syndromes.
Use in Cancer
Busulfan is approved to treat:
- Chronic myelogenous leukemia (CML).
- It is used as palliative treatment. This use is approved for the Myleran brand of busulfan.
- It is also used with other drugs to prepare patients with CML for a stem cell transplant. This use is approved for the Busulfex brand of busulfan.
Busulfan is also being studied in the treatment of other types of cancer.