-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 wa ...

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

testicular cancer Testicular cancer is cancer that develops in the testicles, a part of the male reproductive system. Symptoms may include a lump in the testicle, or swelling or pain in the scrotum. Treatment may result in infertility. Risk factors include an u ...

ovarian cancer Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different c ...

, and

cervical cancer Cervical cancer is a cancer arising from the cervix. It is due to the abnormal growth of cells that have the ability to invade or spread to other parts of the body. Early on, typically no symptoms are seen. Later symptoms may include abnormal ...

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 minerals, 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 thi ...

is better for this. Common

side effects In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

include

fever Fever, also referred to as pyrexia, is defined as having a body temperature, temperature above the human body temperature, normal range due to an increase in the body's temperature Human body temperature#Fever, set point. There is not a single ...

, weight loss, vomiting, and rash. A severe type of

anaphylaxis Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the follow ...

may occur. It may also cause inflammation of the lungs that can result in lung scarring.

Chest X-rays A chest radiograph, called a chest X-ray (CXR), or chest film, is a Projectional radiography, projection radiograph of the chest used to diagnose conditions affecting the chest, its contents, and nearby structures. Chest radiographs are the most ...

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 ...

. It is available as a

generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...

. It is made by the

bacterium Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...

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

, and

Hodgkin's disease 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 wa ...

, 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 kilog ...

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

are flu-like symptoms and include

, rash, dermatographism,

hyperpigmentation Hyperpigmentation is the darkening of an area of skin or nails caused by increased melanin. Causes Hyperpigmentation can be caused by sun damage, inflammation, or other skin injuries, including those related to acne vulgaris.James, William; Ber ...

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 scarri ...

(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 Oxygen toxicity is a condition resulting from the harmful effects of breathing molecular oxygen () at increased partial pressures. Severe cases can result in cell damage and death, with effects most often seen in the central nervous system, lu ...

and recent studies support the role of the

proinflammatory cytokine An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule (a cytokine) that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include inte ...

s IL-18 and

IL-1beta Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin" ...

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 General anaesthesia (UK) or general anesthesia (US) is a medically induced loss of consciousness that renders the patient unarousable even with painful stimuli. This effect is achieved by administering either intravenous or inhalational general ...

. 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 Scuba diving is a mode of underwater diving whereby divers use breathing equipment that is completely independent of a surface air supply. The name "scuba", an acronym for "Self-Contained Underwater Breathing Apparatus", was coined by Chris ...

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 In biochemistry, non-heme iron proteins describe families of enzymes that utilize iron at the active site but lack heme cofactors. Iron-sulfur proteins, including those that are enzymes, are not included in this definition. Some of non-heme iron p ...

, 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. I ...

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 Chelation is a type of bonding of ions and molecules to metal ions. It involves the formation or presence of two or more separate coordinate bonds between a polydentate (multiple bonded) ligand and a single central metal atom. These ligands are ...

metal ions (primarily iron), producing a pseudoenzyme that reacts with oxygen to produce superoxide and hydroxide

free radicals In chemistry, a radical, also known as a free radical, is an atom, molecule, or ion that has at least one unpaired valence electron. With some exceptions, these unpaired electrons make radicals highly chemically reactive. Many radicals spont ...

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 togeth ...

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 Nonribosomal peptides (NRP) are a class of peptide secondary metabolites, usually produced by microorganisms like bacteria and fungi. Nonribosomal peptides are also found in higher organisms, such as nudibranchs, but are thought to be made by bacter ...

that is a hybrid

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A ...

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 A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical syn ...

. The

backbone of the bleomycin

aglycon An aglycone (aglycon or genin) is the compound remaining after the glycosyl group on a glycoside is replaced by a hydrogen atom. For example, the aglycone of a cardiac glycoside would be a steroid molecule. Detection A way to identify aglycone ...

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 The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

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

* * {{portal bar, Medicine Cancer research DNA intercalaters DNA replication inhibitors Glycopeptide antibiotics IARC Group 2B carcinogens Sulfonium compounds World Health Organization essential medicines Wikipedia medicine articles ready to translate Eukaryotic selection compounds Hydroxymethyl compounds Japanese inventions