Busulfan
Encyclopedia
Busulfan is a cancer drug, in use since 1959.
Busulfan is a cell cycle non-specific alkylating antineoplastic agent
, in the class of alkyl sulfonates. Its chemical designation is 1,4-butanediol dimethanesulfonate.
treatment of chronic myeloid leukemia (CML) until it was displaced by the new gold standard, imatinib
, though it is still in use to a degree as a result of the drug's relative low cost.
(CML), where it is used as a conditioning drug. Busulfan can control tumor burden but cannot prevent transformation or correct cytogenic abnormalities.
The drug was recently used in a study to examine the role of platelet-transported serotonin
in liver
regeneration.
, hyperpigmentation
, seizures, hepatic (veno-occlusive disease) and wasting syndrome. Busulfan also induces thrombocytopenia
, a condition of lowered blood platelet
count and activity.
Phenytoin
may be used concurrently to prevent the seizures. Levetiracetam, has shown efficacy for the prophylaxis against busulfan-induced seizures. Benzodiazepines can also be used for busulfan-induced seizures.
Busulfan is listed by the IARC
as a Group 1 carcinogen
.
produces guanine
-adenine
intrastrand crosslinks. This occurs through an SN2 reaction in which the relatively nucleophilic guanine N7 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
.
with busulfan was investigated. The formation of complexes was observed with electrostatic interactions between urea and the sulfonate
part of busulfan.
Another structure was used for this complextation type, two disaccharidyl units connected by urea linkers to a diazacrown ether organizing platform.
Busulfan is a cell cycle non-specific alkylating antineoplastic agent
Alkylating antineoplastic agent
An alkylating antineoplastic agent is an alkylating agent used in cancer treatment that attaches an alkyl group to DNA.The alkyl group is attached to the guanine base of DNA, at the number 7 nitrogen atom of the purine ring....
, in the class of alkyl sulfonates. Its chemical designation is 1,4-butanediol dimethanesulfonate.
History
Busulfan was the mainstay of the chemotherapeuticChemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
treatment of chronic myeloid leukemia (CML) until it was displaced by the new gold standard, imatinib
Imatinib
Imatinib is a drug used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec or Glivec as its mesylate salt, imatinib mesilate . It is used in treating chronic myelogenous leukemia , gastrointestinal stromal tumors and some other diseases...
, though it is still in use to a degree as a result of the drug's relative low cost.
Indications
Currently, its main uses are in bone marrow transplantation, especially in chronic myelogenous leukemiaChronic myelogenous leukemia
Chronic myelogenous leukemia , also known as chronic granulocytic leukemia , is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood...
(CML), where it is used as a conditioning drug. Busulfan can control tumor burden but cannot prevent transformation or correct cytogenic abnormalities.
The drug was recently used in a study to examine the role of platelet-transported serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
in liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
regeneration.
Availability
Myleran is supplied in white film coated tablets with 2 mg of busulfan per tablet.Side effects
Toxicity may include interstitial pulmonary fibrosisPulmonary fibrosis
Pulmonary fibrosis is the formation or development of excess fibrous connective tissue in the lungs. It is also described as "scarring of the lung".-Symptoms:Symptoms of pulmonary fibrosis are mainly:...
, hyperpigmentation
Hyperpigmentation
In dermatology, hyperpigmentation is the darkening of an area of skin or nails caused by increased melanin.-Causes:Hyperpigmentation may be caused by sun damage, inflammation, or other skin injuries, including those related to acne vulgaris...
, seizures, hepatic (veno-occlusive disease) and wasting syndrome. Busulfan also induces thrombocytopenia
Thrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
, a condition of lowered blood platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
count and activity.
Phenytoin
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
may be used concurrently to prevent the seizures. Levetiracetam, has shown efficacy for the prophylaxis against busulfan-induced seizures. Benzodiazepines can also be used for busulfan-induced seizures.
Busulfan is listed by the IARC
International Agency for Research on Cancer
The International Agency for Research on Cancer is an intergovernmental agency forming part of the World Health Organisation of the United Nations....
as a Group 1 carcinogen
Carcinogen
A carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in causing cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes...
.
Pharmacology
Its mechanism of action through alkylationAlkylation
Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion or a carbene . Alkylating agents are widely used in chemistry because the alkyl group is probably the most common group encountered in...
produces guanine
Guanine
Guanine is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine . In DNA, guanine is paired with cytosine. With the formula C5H5N5O, guanine is a derivative of purine, consisting of a fused pyrimidine-imidazole ring system with...
-adenine
Adenine
Adenine is a nucleobase with a variety of roles in biochemistry including cellular respiration, in the form of both the energy-rich adenosine triphosphate and the cofactors nicotinamide adenine dinucleotide and flavin adenine dinucleotide , and protein synthesis, as a chemical component of DNA...
intrastrand crosslinks. This occurs through an SN2 reaction in which the relatively nucleophilic guanine N7 attacks the carbon adjacent to the mesylate
Mesylate
In chemistry, a mesylate is any salt or ester of methanesulfonic acid . In salts, the mesylate is present as the CH3SO3− anion. When modifying the International Nonproprietary Name of a pharmaceutical substance containing the group or anion, the correct spelling is mesilate .Mesylate esters are a...
leaving group. This kind of damage cannot be repaired by cellular machinery and thus the cell undergoes apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
.
Complexation
The molecular recognition of ureido-cyclodextrinCyclodextrin
Cyclodextrins are a family of compounds made up of sugar molecules bound together in a ring ....
with busulfan was investigated. The formation of complexes was observed with electrostatic interactions between urea and the sulfonate
Sulfonate
A sulfonate is a salt or ester of a sulfonic acid. It contains the functional group R-SO2O-.- Sulfonate salts:Anions with the general formula RSO2O− are called sulfonates. They are the conjugate bases of sulfonic acids with formula RSO2OH. As sulfonic acids tend to be strong acids, the...
part of busulfan.
Another structure was used for this complextation type, two disaccharidyl units connected by urea linkers to a diazacrown ether organizing platform.
External links
- Myleran (PDF prescribing information)
- Busulfex (PDF prescribing information)
- Detailed information