-13- (1''H''-imidazol-5-yl)methyl9-hydroxy-5- 1''R'')-1-hydroxyethyl8,10-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 , chemical_formula = , C=55 , H=84 , N=17 , O=21 , S=3 , molecular_weight = 1415.551 , SMILES = CC1=C(N=C(N=C1N) @HCC(=O)N)NC @@HC(=O)N)N)C(=O)N @@HC(C2=CN=CN2)O @H @H @H @@H @@HO3)CO)O)O)O @@H @H @H @@H @HO4)CO)O)OC(=O)N)O)C(=O)N @HC) @H @HC)C(=O)N @@H @@HC)O)C(=O)NCCC5=NC(=CS5)C6=NC(=CS6)C(=O)NCCC +C)C)O , Jmol = , StdInChI_Ref = , 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 , StdInChI_comment = , StdInChIKey_Ref = , StdInChIKey = OYVAGSVQBOHSSS-UAPAGMARSA-O , density = , density_notes = , melting_point = , melting_high = , melting_notes = , boiling_point = , boiling_notes = , solubility = , sol_units = , specific_rotation = Bleomycin is a medication used to treat

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

. This includes

Hodgkin's lymphoma Hodgkin lymphoma (HL) is a type of lymphoma, in which cancer originates from a specific type of white blood cell called lymphocytes, where multinucleated Reed–Sternberg cells (RS cells) are present in the patient's lymph nodes. The condition w ...

non-Hodgkin's lymphoma Non-Hodgkin lymphoma (NHL), also known as non-Hodgkin's lymphoma, is a group of hematological malignancy, blood cancers that includes all types of lymphomas except Hodgkin lymphomas. Symptoms include lymphadenopathy, enlarged lymph nodes, fever ...

, testicular cancer, ovarian cancer, and cervical cancer among others. Typically used with other cancer medications, it can be given intravenously, by injection into a muscle or under the skin. It may also be administered inside the chest to help prevent the recurrence of a fluid around the lung due to cancer; however

talc Talc, or talcum, is a clay mineral, composed of hydrated magnesium silicate with the chemical formula Mg3Si4O10(OH)2. Talc in powdered form, often combined with corn starch, is used as baby powder. This mineral is used as a thickening agent a ...

is better for this. Common side effects include fever, weight loss, vomiting, and rash. A severe type of anaphylaxis may occur. It may also cause inflammation of the lungs that can result in lung scarring. Chest X-rays every couple of weeks are recommended to check for this. Bleomycin may cause harm to the baby if used during pregnancy. It is believed to primarily work by preventing the synthesis of DNA. Bleomycin was discovered in 1962. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

. It is available as a generic medication. It is made by the bacterium ''

Streptomyces verticillus ''Streptomyces verticillus'' is a species of Gram-positive bacteria in the genus ''Streptomyces''. Whilst screening fermentation broths of this species for bioactivity in the early 1960s, Hamao Umezawa and colleagues at the Institute of Microbi ...

''.

Medical uses

Cancer

Bleomycin is mostly used to treat

. This includes testicular cancer, ovarian cancer, and Hodgkin's disease, and less commonly non-Hodgkin's disease. It can be given intravenously, by intramuscular injection, or under the skin.

Other uses

It may also be put inside the chest to help prevent the recurrence of a

pleural effusion A pleural effusion is accumulation of excessive fluid in the pleural space, the potential space that surrounds each lung. Under normal conditions, pleural fluid is secreted by the parietal pleural capillaries at a rate of 0.6 millilitre per k ...

due to cancer. However, for scarring down the pleura, talc appears to be the better option although indwelling pleural catheters are at least as effective in reducing the symptoms of an effusion(such as dyspnea). While potentially effective against bacterial infections, its toxicity prevents its use for this purpose. It has been studied in the treatment of warts but is of unclear benefit.

Side effects

The most common side effects are flu-like symptoms and include fever, rash, dermatographism, hyperpigmentation,

alopecia Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scar ...

(hair loss), chills, and

Raynaud's phenomenon Raynaud syndrome, also known as Raynaud's phenomenon, eponymously named after the physician Auguste Gabriel Maurice Raynaud, who first described it in his doctoral thesis in 1862, is a medical condition in which the spasm of small arteries cau ...

(discoloration of fingers and toes). The most serious complication of bleomycin, occurring upon increasing dosage, is

pulmonary fibrosis Pulmonary fibrosis is a condition in which the lungs become scarred over time. Symptoms include shortness of breath, a dry cough, feeling tired, weight loss, and nail clubbing. Complications may include pulmonary hypertension, respiratory failu ...

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. Any previous 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. Bleomycin has also been found to disrupt the sense of taste.

Lifetime cumulative dose

Bleomycin should not exceed a lifetime cumulative dose greater than 400 units. Pulmonary toxicities, most commonly presenting as

, are associated with doses of bleomycin greater than 400 units.

Mechanism of action

Bleomycin, a non-heme iron protein, acts by induction of DNA strand breaks. Some studies suggest bleomycin also inhibits incorporation of

thymidine Thymidine (symbol dT or dThd), also known as deoxythymidine, deoxyribosylthymine, or thymine deoxyriboside, is a pyrimidine deoxynucleoside. Deoxythymidine is the DNA nucleoside T, which pairs with deoxyadenosine (A) in double-stranded DNA. ...

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. In addition, these complexes also mediate lipid peroxidation and oxidation of other cellular molecules. Therefore, bleomycin is used in combination with

doxorubicin Doxorubicin, sold under the brand name Adriamycin among others, is a chemotherapy medication used to treat cancer. This includes breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia. It is often used toge ...

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 Type II topoisomerases are topoisomerases that cut both strands of the DNA helix simultaneously in order to manage DNA tangles and supercoils. They use the hydrolysis of ATP, unlike Type I topoisomerase. In this process, these enzymes change th ...

enzyme thus relaxing the topoisomerase complexes.

Biosynthesis

Bleomycin is a nonribosomal peptide that is a hybrid peptide-

polyketide Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...

natural product. The peptide/

/ 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: #NRPS-mediated formation of P-3A from Ser, Asn, His, and Ala #PKS-mediated elongation of P-3A by malonyl CoA and AdoMet to yield P-4 #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. Biosynthesis of bleomycin is completed by glycosylation of the aglycones. Bleomycin naturally occurring-analogues have two to three sugar molecules, and DNA cleavage activities of these analogues have been assessed, primarily by the plasmid relaxation and break light assays.

History

Bleomycin was first discovered in 1962 when the Japanese scientist

Hamao Umezawa was a Japanese scientist who discovered several antimicrobial agents and enzyme inhibitors. Umezawa was born in Obama City, Fukui Prefecture, as the second son in a family of seven children. After graduating from Musashi Junior and Senior High ...

found anticancer activity while screening culture filtrates of ''

''. Umezawa published his discovery in 1966. The drug was launched in Japan by

Nippon Kayaku (Japan Pharmaceuticals) is a Japanese company that was founded in 1916 as the first industrial explosives manufacturer in Japan under the company name Nippon Kayaku Seizo Co., Ltd.. Its main business areas are functional chemicals, pharmaceutical ...

in 1969. In the US, bleomycin gained FDA approval in July 1973. It was initially marketed in the US by the

Bristol-Myers Squibb The Bristol Myers Squibb Company (BMS) is an American multinational pharmaceutical company. Headquartered in New York City, BMS is one of the world's largest pharmaceutical companies and consistently ranks on the ''Fortune'' 500 list of the lar ...

precursor, Bristol Laboratories, under the brand name Blenoxane.

Research

Bleomycin is used in research to induce

in mice.

References

External links

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