Bleomycin

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Bleomycin
Bleomycin A2.svg
Bleomycin ball-and-stick.png
Bleomycin A2
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
Clinical data
Trade names Blenoxane
AHFS/Drugs.com monograph
MedlinePlus a682125
Pregnancy cat. D (US)
Legal status -only (US)
Routes intravenous, intramuscular, subcutaneous, intrapleural, intratumoral
Pharmacokinetic data
Bioavailability well absorbed
Metabolism ?
Half-life 2 hours
Excretion renal (60-70%)
Identifiers
CAS number 11056-06-7 YesY
ATC code L01DC01
PubChem CID 456190
DrugBank DB00290
ChemSpider 401687 YesY
UNII 40S1VHN69B YesY
KEGG D07535 N
ChEMBL CHEMBL403664 N
Chemical data
Formula C55H84N17O21S3 
Mol. mass 1415.551
 N (what is this?)  (verify)

Bleomycin is a glycopeptide antibiotic produced by the bacterium Streptomyces verticillus. Bleomycin refers to a family of structurally related compounds. When used as an anticancer agent, the chemotherapeutical forms are primarily bleomycin A2 and B2. The drug is used in the treatment of Hodgkin's lymphoma (as a component of the ABVD and BEACOPP regimen), squamous cell carcinomas, and testicular cancer, as well as in the treatment of plantar warts [1] and as a means of effecting pleurodesis.[2] The mechanism of action involves breaking DNA.

Bleomycin is on the World Health Organization's List of Essential Medicines that are needed for a basic health system.[3]

Side effects[edit]

The most serious complication of bleomycin is pulmonary fibrosis and impaired lung function. It has been suggested that bleomycin induces sensitivity to oxygen toxicity[4] and recent studies support the role of the proinflammatory cytokines IL-18 and IL-1beta in the mechanism of bleomycin-induced lung injury.[5] Past history of treatment with bleomycin should therefore always be disclosed to the anaesthetist prior to undergoing a procedure requiring general anaesthesia. Due to the oxygen sensitive nature of bleomycin, and the theorised increased likelihood of developing pulmonary fibrosis following supplemental oxygen therapy, it has been questioned whether patients should take part in scuba diving following treatment with the drug.[6]

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

Mechanism of action[edit]

Bleomycin acts by induction of DNA strand breaks.[7] Some studies suggest bleomycin also inhibits incorporation of thymidine into DNA strands. DNA cleavage by bleomycin depends on oxygen and metal ions, at least in vitro. The exact mechanism of DNA strand scission is unresolved, but it has been suggested that bleomycin chelates metal ions (primarily iron), producing a pseudoenzyme that reacts with oxygen to produce superoxide and hydroxide free radicals that cleave DNA. An alternative hypothesis states that bleomycin may bind at specific sites in the DNA strand and induce scission by abstracting the hydrogen atom from the base, resulting in strand cleavage as the base undergoes a Criegee-type rearrangement, or forms an alkali-labile lesion.[8] In addition, these complexes also mediate lipid peroxidation and oxidation of other cellular molecules. Therefore bleomycin is used in combination with doxorubicin in Hodgkins lymphoma, as they have additive and complementary effects on the DNA, since doxorubicin acts by intercalating between DNA strands, and also acts on topoisomerase II enzyme thus relaxing the topoisomerase complexes.

Biosynthesis[edit]

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 visualized in three stages:

  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 β-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.

History[edit]

Bleomycin was first discovered in 1966 when the Japanese scientist Hamao Umezawa found anticancer activity while screening culture filtrates of S. verticillus. Umezawa published his discovery in 1966.[9] The drug was launched in Japan by Nippon Kayaku in 1969. In the US, bleomycin gained 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[edit]

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

See also[edit]

References[edit]

  1. ^ Lewis, TG; Nydorf, ED (2006). "Intralesional bleomycin for warts: a review.". Journal of Drugs in Dermatology 5 (6): 499–504. PMID 16774100. 
  2. ^ Shaw, P; Agarwal, R (2004). "Pleurodesis for malignant pleural effusions". In Shaw, Paul HS. Cochrane Database of Systematic Reviews (1): CD002916. doi:10.1002/14651858.CD002916.pub2. PMID 14973997. 
  3. ^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014. 
  4. ^ Dr Malcom Thompson (2003-07-25). "Bleomycin and Anaesthesia". Retrieved 2008-04-10. 
  5. ^ 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. 41 (6): 661–70. doi:10.1165/rcmb.2008-0182OC. PMID 19265174. 
  6. ^ USA (2012-05-24). "Bleomycin and scuba diving: to dive or not to dive? [Neth J Med. 2003] - PubMed - NCBI". Ncbi.nlm.nih.gov. Retrieved 2012-10-29. 
  7. ^ 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.
  8. ^ Hecht, SM (2000). "Bleomycin: new perspectives on the mechanism of action". J. Nat. Prod. 63: 158–168. PMID 10650103. 
  9. ^ Umenzawa, H. et al. J. Antibiot. (Tokyo) Ser. A 1966, 19, 200.

Further reading[edit]

  • Claussen, C.A.; Long, E.C. (1999). "Nucleic Acid Recognition by Metal Complexes of Bleomycin". Chem. Rev. 99 (9): 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 (6): 378–385. doi:10.1038/sj.jim.7000194. PMID 11774003.