Busulfan

Busulfan
Systematic (IUPAC) name
butane-1,4-diyl dimethanesulfonate
Clinical data
Trade names Myleran
AHFS/Drugs.com monograph
MedlinePlus a682248
Licence data EMA:Link, US FDA:link
Pregnancy cat. D(US)
Legal status ℞ Prescription only
Routes Oral, parenteral
Pharmacokinetic data
Bioavailability 80% (oral)
Protein binding 32.4%
Metabolism Hepatic
Half-life 2.5 hours
Excretion  ?
Identifiers
CAS number 55-98-1 Y
ATC code L01AB01
PubChem CID 2478
DrugBank APRD00664
ChemSpider 2384 Y
UNII G1LN9045DK Y
KEGG D00248 Y
ChEBI CHEBI:28901 Y
ChEMBL CHEMBL820 Y
Synonyms 1,4-butanediol dimethanesulfonate
Chemical data
Formula C6H14O6S2 
Mol. mass 246.304 g/mol
SMILES eMolecules & PubChem
 N(what is this?)  (verify)

Busulfan (Myleran, GlaxoSmithKline, Busulfex IV, PDL BioPharma, Inc.) 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.

Contents

History

Busulfan was the mainstay of the chemotherapeutic 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.

Indications

Currently, its main uses are in bone marrow transplantation, especially in chronic myelogenous leukemia (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.[1]

Availability

Myleran is supplied in white film coated tablets with 2 mg of busulfan per tablet.

Side effects

Toxicity may include interstitial pulmonary fibrosis, 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.[2]

Busulfan is listed by the IARC as a Group 1 carcinogen.

Pharmacology

Its mechanism of action through alkylation produces guanine-adenine intrastrand crosslinks.[3] 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.[4]

Complexation

The molecular recognition of ureido-cyclodextrin with busulfan was investigated.[5] 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.[6]

References

  1. ^ Lesurtel M, Graf R, Aleil B, Walther D, Tian Y, Jochum W, Gachet C, Bader M, Clavien P (2006). "Platelet-derived serotonin mediates liver regeneration". Science 312 (5770): 104–7. doi:10.1126/science.1123842. PMID 16601191. 
  2. ^ Eberly, AL.; Anderson, GD.; Bubalo, JS.; McCune, JS. (Dec 2008). "Optimal prevention of seizures induced by high-dose busulfan.". Pharmacotherapy 28 (12): 1502–10. doi:10.1592/phco.28.12.1502. PMID 19025431. 
  3. ^ Iwamoto T, Hiraku Y, Oikawa S, Mizutani H, Kojima M, Kawanishi S (May 2004). "DNA intrastrand cross-link at the 5'-GA-3' sequence formed by busulfan and its role in the cytotoxic effect". Cancer Sci. 95 (5): 454–8. doi:10.1111/j.1349-7006.2004.tb03231.x. PMID 15132775. http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=1347-9032&date=2004&volume=95&issue=5&spage=454. 
  4. ^ Karstens A, Kramer I (2007). "Chemical and physical stability of diluted busulfan infusion solutions". EJHP Science 13: 40–7. 
  5. ^ Menuel S, Joly JP, Courcot B, Elysee J, Ghermani NE, Marsura A (2007). "Synthesis and inclusion ability of a bis-beta-cyclodextrin pseudo-cryptand towards Busulfan anticancer agent". Tetrahedron 63 (7): 1706–14. doi:10.1016/j.tet.2006.10.070. 
  6. ^ Porwanski S, Florence DCB, Menuel S, Joly JP, Bulach V, Marsura A (2009). "Bis-beta-cyclodextrinyl- and bis-cellobiosyl-diazacrowns: synthesis and molecular complexation behaviors toward Busulfan anticancer agent and two basic aminoacids". Tetrahedron 65 (31): 6196–6203. doi:10.1016/j.tet.2009.05.057. 

External links