-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 , C=55 , H=84 , N=17 , O=21 , S=3 , 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 , 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 primarily used to treat

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

. 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 lymph nodes. The condition was named a ...

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 enlarged lymph nodes, fever, night sweats, weight loss, and tire ...

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 c ...

, ovarian cancer, and

cervical cancer Cervical cancer is a cancer arising from the cervix or in any layer of the wall of the cervix. It is due to the abnormal growth of cells that can invade or spread to other parts of the body. Early on, typically no symptoms are seen. Later sympt ...

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

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

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

is better for this. It may sometimes be used to treat other difficult-to-treat skin lesions such as plantar warts in immunocompromised patients. Common

side effects In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually used ...

include

fever Fever or pyrexia in humans is a symptom of an anti-infection defense mechanism that appears with Human body temperature, body temperature exceeding the normal range caused by an increase in the body's temperature Human body temperature#Fever, s ...

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

anaphylaxis Anaphylaxis (Greek: 'up' + 'guarding') is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of the use of emergency medication on site. It typicall ...

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 Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...

. 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 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 (; : 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 the ...

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

, ovarian cancer, 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 lymph nodes. The condition was named a ...

, 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

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, also known as the dark spots or circles on the skin, is the darkening of an area of Human skin, skin or nail (anatomy), nails caused by increased melanin. Causes Hyperpigmentation can be caused by sun damage, inflammation, or ...

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 scarring ...

(hair loss), chills, and

Raynaud's phenomenon Raynaud syndrome, also known as Raynaud's phenomenon, is a medical condition in which the spasm of small arteries causes episodes of reduced blood flow to end arterioles. Typically the fingers, and, less commonly, the toes, are involved. Rare ...

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

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 General anaesthesia (UK) or general anesthesia (US) is medically induced loss of consciousness that renders a patient unarousable even by painful stimuli. It is achieved through medications, which can be injected or inhaled, often with an analges ...

. 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 Diving mode, mode of underwater diving whereby divers use Scuba set, breathing equipment that is completely independent of a surface breathing gas supply, and therefore has a limited but variable endurance. The word ''scub ...

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

Mechanism of action

Bleomycin acts by induction of

strand breaks. Some studies suggest bleomycin also inhibits incorporation of

thymidine Thymidine (nucleoside#List of nucleosides and corresponding nucleobases, symbol dT or dThd), also known as deoxythymidine, deoxyribosylthymine, or thymine deoxyriboside, is a pyrimidine nucleoside, deoxynucleoside. Deoxythymidine is the DNA nuc ...

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

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.

Biosynthesis

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 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, doing business as Bristol Myers Squibb (BMS), is an American multinational pharmaceutical company. Headquartered in Princeton, New Jersey, BMS is one of the world's largest pharmaceutical companies and consist ...

precursor, Bristol Laboratories, under the brand name Blenoxane.

Research

Bleomycin is used in research to induce pulmonary fibrosis in mice. It accomplishes this by preventing alveolar cell proliferation, which in turn leads to

cellular senescence Cellular senescence is a phenomenon characterized by the cessation of cell division. In their experiments during the early 1960s, Leonard Hayflick and Paul Moorhead found that normal human fetal fibroblasts in culture reach a maximum of appro ...