Bleomycin

{{Drugbox
 * Verifiedfields = changed
 * Watchedfields = changed
 * verifiedrevid = 401932982
 * 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-
 * image = Bleomycin.png


 * tradename = Blenoxane
 * Drugs.com = {{drugs.com|monograph|bleomycin-sulfate}}
 * MedlinePlus = a682125
 * pregnancy_US = D
 * pregnancy_category =
 * legal_status = ?
 * routes_of_administration = intravenous, intramuscular, subcutaneous, intrapleural, intratumoral


 * bioavailability = well absorbed
 * metabolism = ?
 * elimination_half-life = 2 hours
 * excretion = renal (60-70%)


 * CASNo_Ref = {{cascite|correct|CAS}}
 * CAS_number = 11056-06-7
 * ATC_prefix = L01
 * ATC_suffix = DC01
 * PubChem = 456190
 * DrugBank_Ref = {{drugbankcite|correct|drugbank}}
 * DrugBank = APRD00453
 * ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
 * ChemSpiderID = 401687
 * UNII_Ref = {{fdacite|correct|FDA}}
 * UNII = 40S1VHN69B
 * KEGG_Ref = {{keggcite|changed|kegg}}
 * KEGG = D07535
 * ChEMBL_Ref = {{ebicite|changed|EBI}}
 * ChEMBL = 403664

}} 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 A{{sub|2}} and B{{sub|2}}. It works by causing breaks in DNA. The drug is used in the treatment of Hodgkin's lymphoma (as a component of the ABVD regimen), squamous cell carcinomas, and testicular cancer, as well as in the treatment of plantar warts and as a means of effecting pleurodesis.
 * C=55 | H=84 | N=17 | O=21 | S=3
 * molecular_weight = 1415.551
 * smiles = NC(=O)[C@@H](N)CN[C@@H](CC(N)=O)c1nc(N)c(C)c(n1)C(=O)N[C@@H](C(O[C@@H]3O[C@@H](CO)[C@@H](O)[C@H](O)[C@@H]3O[C@H]2O[C@H](CO)[C@@H](O)[C@H](OC(N)=O)[C@@H]2O)c4cncn4)C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N
 * InChI = 1/C55H83N17O21S3/c1-20-33(69-46(72-44(20)58)25(12-31(57)76)64-13-24(56)45(59)82)50(86)71-35(41(26-14-61-19-65-26)91-54-43(39(80)37(78)29(15-73)90-54)92-53-40(81)42(93-55(60)88)38(79)30(16-74)89-53)51(87)66-22(3)36(77)21(2)47(83)70-34(23(4)75)49(85)63-10-8-32-67-28(18-94-32)52-68-27(17-95-52)48(84)62-9-7-11-96(5)6/h14,17-19,21-25,29-30,34-43,53-54,64,73-75,77-81H,7-13,15-16,56H2,1-6H3,(H13-,57,58,59,60,61,62,63,65,66,69,70,71,72,76,82,83,84,85,86,87,88)/p+1/t21-,22+,23+,24-,25-,29-,30+,34-,35-,36-,37+,38+,39-,40-,41?,42-,43-,53+,54-/m0/s1
 * InChIKey = OYVAGSVQBOHSSS-CIKNJMRMBZ
 * StdInChI_Ref = {{stdinchicite|correct|chemspider}}
 * StdInChI = 1S/C55H83N17O21S3/c1-20-33(69-46(72-44(20)58)25(12-31(57)76)64-13-24(56)45(59)82)50(86)71-35(41(26-14-61-19-65-26)91-54-43(39(80)37(78)29(15-73)90-54)92-53-40(81)42(93-55(60)88)38(79)30(16-74)89-53)51(87)66-22(3)36(77)21(2)47(83)70-34(23(4)75)49(85)63-10-8-32-67-28(18-94-32)52-68-27(17-95-52)48(84)62-9-7-11-96(5)6/h14,17-19,21-25,29-30,34-43,53-54,64,73-75,77-81H,7-13,15-16,56H2,1-6H3,(H13-,57,58,59,60,61,62,63,65,66,69,70,71,72,76,82,83,84,85,86,87,88)/p+1/t21-,22+,23+,24-,25-,29-,30+,34-,35-,36-,37+,38+,39-,40-,41?,42-,43-,53+,54-/m0/s1
 * StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
 * StdInChIKey = OYVAGSVQBOHSSS-QRQYLRPSSA-O

History
Bleomycin was first discovered in 1966 when the Japanese scientist Hamao Umezawa found anticancer activity while screening culture filtrates of S. verticullus. Umezawa published his discovery in 1966. 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
Bristol-Myers Squibb still supplies Blenoxane. There are also generic versions of bleomycin available from APP Pharmaceuticals, Bedford, Sicor (Teva), Hospira and Cipla.

Mechanism of action
Bleomycin acts by induction of DNA strand breaks. 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. It is believed 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. 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
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.

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 and recent studies support the role of the proinflammatory cytokines IL-18 and IL-1beta in the mechanism of bleomycin-induced lung injury. 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).