Bleomycin

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	CID 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 ancestors of structurally accompanying compounds. If acclimated as an anti-cancer agent, the chemotherapeutical forms are primarily bleomycin A₂ and B₂. It works by causing break in DNA. The biologic is acclimated in the analysis of Hodgkin lymphoma (as a basic of the ABVD regimen), squamous cell carcinomas, and testicular cancer, as able-bodied as in the analysis of plantar warts ¹ and as a agency of ability pleurodesis.²

History

Bleomycin was aboriginal apparent in 1966 if the Japanese scientist Hamao Umezawa begin anti-cancer action while screening ability filtrates of S. verticullus. Umezawa appear his analysis in 1966.³ The biologic was launched in Japan by Nippon Kayaku in 1969. In the US bleomycin acquired Food and Biologic Administration (FDA) approval in July 1973. It was initially marketed in the US by the Bristol-Myers Squibb forerunner Bristol Laboratories beneath the cast name Blenoxane.

Suppliers

Bristol-Myers Squibb still food Blenoxane. There are aswell all-encompassing versions of bleomycin accessible from APP Pharmaceuticals, Bedford, Sicor (Teva), Hospira and Cipla.

Mechanism of action

Bleomycin acts by consecration of DNA fiber breaks.⁴ Some studies advance that bleomycin aswell inhibits assimilation of thymidine into DNA strands. DNA break by bleomycin depends on oxygen and metal ions, at atomic in vitro. It is believed that bleomycin chelates metal ions (primarily iron) bearing a pseudoenzyme that reacts with oxygen to aftermath superoxide and hydroxide chargeless radicals that carve DNA. In addition, these complexes aswell arbitrate lipid peroxidation and blaze of added cellular molecules.

Biosynthesis

Bleomycin is a nonribosomal peptide that is a amalgam peptide-polyketide natural product. The peptide/polyketide/peptide courage of the bleomycin aglycon is accumulated by the bleomycin megasynthetase, which is fabricated of both nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) modules. Nonribosomal peptides and polyketides are actinic from amino acids and abbreviate carboxylic acids by NRPSs and PKSs, respectively. These NRPSs and PKSs use agnate strategies for the accumulation of these two audible classes of accustomed products. Both NRPs and blazon I PKSs are organized into modules. The structural variations of the consistent peptide and polyketide articles are bent by the amount and adjustment of modules on anniversary NRPS and PKS protein.

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

NRPS-mediated accumulation of P-3A from Ser, Asn, His, and Ala
PKS-mediated addendum of P-3A by malonyl CoA and AdoMet to crop P-4
NRPS-mediated addendum of P-4 by Thr to P-5 that is added continued by ß-Ala, Cys, and Cys to get P-6m.

On the base of the bleomycin anatomy and the deduced functions of alone NRPS and PKS domains and modules, a beeline archetypal for the bleomycin megasynthetase-templated accumulation of the bleomycin peptide/polyketide/peptide aglycon was proposed from nine amino acids and one acetate.

Side effects

The a lot of austere aggravation of bleomycin is pulmonary fibrosis and broken lung function. It has been appropriate that bleomycin induces acuteness to oxygen toxicity⁵ and contempo studies abutment the role of the proinflammatory cytokines IL-18 and IL-1beta in the apparatus of bleomycin-induced lung injury.⁶ Past history of analysis with bleomycin should accordingly consistently be appear to the anaesthetist above-mentioned to ability a action acute general anaesthesia.

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

References

^ PMID 16774100
^ PMID 14973997
^ Umenzawa, H. et al. J. Antibiot. (Tokyo) Ser. A 1966, 19, 200.
^ 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.
^ Dr Malcom Thompson (2003-07-25). "Bleomycin and Anaesthesia". http://ctec.uwa.edu.au/anaesthesiawa/bleomycin.pdf. Retrieved 2008-04-10.
^ 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 Abrasion in Humans and Mice". Am. J. Respir. Cell Mol. Biol.. doi:10.1165/rcmb.2008-0182OC. PMID 19265174.