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Bleomycin
Systematic (IUPAC) name
(3-{[(2'-{(5S,8S,9S,10R,13S)-15-{6-amino-2- [(1S)-3-amino-1-{[(2S)-2,3-diamino-3-oxopropyl]amino}-3-oxopropyl] -5-methylpyrimidin-4-yl}-13-[{[(2R,3S,4S,5S,6S)-3- {[(2R,3S,4S,5R,6R)-4-(carbamoyloxy)-3,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy} -4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy} (1H-imidazol-5-yl)methyl]-9-hydroxy-5-[(1R)-1-hydroxyethyl]-8,10-dimethyl-4,7,12,15-

tetraoxo-3,6,11,14-tetraazapentadec-1-yl}-2,4'-bi-1,3- thiazol-4-yl)carbonyl]amino}propyl)(dimethyl)sulfonium

Identifiers
CAS number 11056-06-7
ATC code L01DC01
PubChem 456190
DrugBank APRD00453
ChemSpider 401687
Chemical data
Formula C55H84N17O21S3 
Mol. mass 1415.551
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability well absorbed
Metabolism  ?
Half life 2 hours
Excretion renal (60-70%)
Therapeutic considerations
Pregnancy cat. D(US)
Legal status  ?
Routes intramuscular and subcutaneous
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Bleomycin is a glycopeptide antibiotic produced by the bacterium Streptomyces verticillus. Bleomycin refers to a family of structurally related compounds. When used as an anti-cancer agent, the chemotherapeutical forms are primarily bleomycin A2 and B2. Bleomycin A2 is shown in the image. The drug is used in the treatment of Hodgkin lymphoma (as a component of the ABVD regimen), squamous cell carcinomas, and testicular cancer, as well as in the treatment of pleurodesis[1] and plantar warts. [2]

Contents

History

Bleomycin was first discovered in 1966 when the Japanese scientist Hamao Umezawa found anti-cancer activity while screening culture filtrates of S. verticullus. Umezawa published his discovery in 1966.[3] The drug was launched in Japan by Nippon Kayaku in 1969. In the US bleomycin gained Food and Drug Administration (FDA) approval in July 1973. It was initially marketed in the US by the Bristol-Myers Squibb precursor Bristol Laboratories under the brand name Blenoxane.

Suppliers

Bristol-Myers Squibb still supplies Blenoxane. There are also generic versions of bleomycin available from APP Pharmaceuticals, Bedford, Sicor (Teva) and Hospira. (Cipla as well has longtime provided Bleocip).

Mechanism of action

Bleomycin acts by induction of DNA strand breaks.[4] Some studies suggest that bleomycin also inhibits incorporation of thymidine into DNA strands. DNA cleavage by bleomycin depends on oxygen and metal ions, at least in vitro. It is believed that bleomycin chelates metal ions (primarily iron) producing a pseudoenzyme that reacts with oxygen to produce superoxide and hydroxide free radicals that cleave DNA. In addition, these complexes also mediate lipid peroxidation and oxidation of other cellular molecules.

Biosynthesis

Bleomycin is a nonribosomal peptide that is a hybrid peptide-polyketide natural product. The peptide/polyketide/peptide backbone of the bleomycin aglycon is assembled by the bleomycin megasynthetase, which is made of both nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) modules. Nonribosomal peptides and polyketides are synthesized from amino acids and short carboxylic acids by NRPSs and PKSs, respectively. These NRPSs and PKSs use similar strategies for the assembly of these two distinct classes of natural products. Both NRPs and type I PKSs are organized into modules. The structural variations of the resulting peptide and polyketide products are determined by the number and order of modules on each NRPS and PKS protein.


The biosynthesis of the bleomycin aglycon can be easily visualized in three stages (see Figure 2):

  1. NRPS-mediated formation of P-3A from Ser, Asn, His, and Ala
  2. PKS-mediated elongation of P-3A by malonyl CoA and AdoMet to yield P-4
  3. NRPS-mediated elongation of P-4 by Thr to P-5 that is further elongated by ß-Ala, Cys, and Cys to get P-6m.


On the basis of the bleomycin structure and the deduced functions of individual NRPS and PKS domains and modules, a linear model for the bleomycin megasynthetase-templated assembly of the bleomycin peptide/polyketide/peptide aglycon was proposed from nine amino acids and one acetate.

Side effects

The most serious complication of bleomycin is pulmonary fibrosis and impaired lung function. It has been suggested that bleomycin induces sensitivity to oxygen toxicity[5] and recent studies support the role of the proinflammatory cytokines IL-18 and IL-1beta in the mechanism of bleomycin-induced lung injury.[6] Past history of treatment with bleomycin should therefore always be disclosed to the anaesthetist prior to undergoing a procedure requiring general anaesthesia.

Other side effects include fever, rash, dermatographism, hyperpigmentation, alopecia (hair loss) and Raynaud's phenomenon (discoloration of fingers and toes).

See also

References

  1. ^ PMID 14973997
  2. ^ PMID 16774100
  3. ^ Umenzawa, H. et al. J. Antibiot. (Tokyo) Ser. A 1966, 19, 200.
  4. ^ Takimoto CH, Calvo E. "Principles of Oncologic Pharmacotherapy" in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach. 11 ed. 2008.
  5. ^ Dr Malcom Thompson (2003-07-25). "Bleomycin and Anaesthesia". http://ctec.uwa.edu.au/anaesthesiawa/bleomycin.pdf. Retrieved 2008-04-10. 
  6. ^ Hoshino T, Okamoto M, Sakazaki Y, Kato S, Young HA, Aizawa H (March 2009). "Role of Proinflammatory Cytokine IL-18 and IL-1{beta} in Bleomycin-induced Lung Injury in Humans and Mice". Am. J. Respir. Cell Mol. Biol.. doi:10.1165/rcmb.2008-0182OC. PMID 19265174. 

Further reading

  • Claussen, C.A.; Long, E.C. (1999). "Nucleic Acid Recognition by Metal Complexes of Bleomycin". Chem. Rev. 99: 2797–2816. doi:10.1021/cr980449z. PMID 11749501. 
  • Shen, B.; Du, L.C.; Sanchez, C.; Edwards, D.J.; Chen, M.; Murrell, J.M. (2001). "The biosynthetic gene cluster for the anticancer drug bleomycin from Streptomyces verticillus ATCC15003 as a model for hybrid peptide-polyketide natural product biosynthesis". Journal of Industrial Microbiology & Biotechnology 27: 378–385. doi:10.1038/sj.jim.7000194. 
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