Bleomycin

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Bleomycin

Bleomycin is a glycopeptide antibiotic

Glycopeptide antibiotic

Glycopeptide antibiotics are a class of antibiotic medication. The class is composed of glycosylation cyclic or polycyclic nonribosomal peptides....
produced by the bacterium Streptomyces
Streptomyces

Streptomyces is the largest genus of Actinobacteria and the type genus of the family Streptomycetaceae. Over 500 species of Streptomyces bacteria have been described....
verticillus. Bleomycin refers to a family of structurally related compounds. When used as an anti-cancer

Cancer

Cancer is a class of diseases in which a group of cell display uncontrolled growth , invasion , and sometimes metastasis . These three malignant properties of cancers differentiate them from benign tumors, which are self-limited, do not invade or metastasize....
agent, the chemotherapeutical forms are primarily bleomycin A₂ and B₂. Bleomycin A₂ is shown in the image. The drug is used in the treatment of Hodgkin lymphoma (as a component of the ABVD

ABVD

ABVD is a chemotherapy regimen used in the first-line treatment of Hodgkin lymphoma. It consists of concurrent treatment with the chemotherapy drugs adriamycin , bleomycin, vinblastine and dacarbazine....
regimen), squamous cell carcinomas, and testicular cancer

Testicular cancer

Testicular cancer is cancer that develops in the testicles, a part of the male reproductive system.In the United States, between 7,500 and 8,000 diagnoses of testicular cancer are made each year....
, as well as in the treatment of pleurodesis

Pleurodesis

Pleurodesis is the artificial obliteration of the pleural cavity....
and plantar warts.

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Encyclopedia

Bleomycin is a glycopeptide antibiotic

Glycopeptide antibiotic

Cancer

ABVD

Testicular cancer

Pleurodesis

Pleurodesis is the artificial obliteration of the pleural cavity....
and plantar warts.

History

Bleomycin was first discovered in 1966 when the Japanese scientist Hamao Umezawa

Hamao Umezawa

Hamao Umezawa was a Japanese scientist famous for his discovery of various antimicrobial agents as well as enzyme inhibitor drugs.Umezawa completed his medical degree in 1937....
found anti-cancer 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 Food and Drug Administration

Food and Drug Administration

The U.S. Food and Drug Administration is an Government agency of the United States Department of Health and Human Services and is responsible for regulating and supervising the safety of foods, dietary supplements, Medications, vaccines, Biopharmaceutical, blood transfusion, medical devices, Electromagnetic radiation-emitting devices, veteri...
(FDA) approval in July 1973. It was initially marketed in the US by the Bristol-Myers Squibb

Bristol-Myers Squibb

Bristol-Myers Squibb , colloquially referred to as BMS, is a pharmaceutical corporation, formed by a 1989 merger between pharmaceutical companies Bristol-Myers Company, founded in 1887 by William McLaren Bristol and John Ripley Myers in Clinton, NY , and E.R....
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

Teva Pharmaceutical Industries

Teva Pharmaceutical Industries Ltd. , is an international pharmaceutical company headquartered in Petah Tikva, Israel. It specializes in generic drug and proprietary pharmaceuticals and active pharmaceutical ingredients....
) and Mayne Pharma.

Mechanism of action

Bleomycin acts by induction of DNA

DNA

Deoxyribonucleic acid is a nucleic acid that contains the genetics instructions used in the development and functioning of all known living organisms and some viruses....
strand breaks. Some studies suggest that bleomycin also inhibits incorporation of thymidine

Thymidine

Thymidine is a chemical Chemical compound, more precisely a pyrimidine deoxynucleoside. Deoxythymidine is the DNA nucleoside T, which pairs with deoxyadenosine in double-stranded DNA....
into DNA strands. DNA cleavage by bleomycin depends on oxygen and metal ions, at least in vitro. It is believed that bleomycin chelates

Chelation

Chelation is the binding or complex of a bi- or multidentate ligand. These ligands, which are often organic compounds, are called chelants, chelators, chelating agents, or sequestration....
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

Lipid

Lipids are broadly defined as any fat-soluble , naturally-occurring molecule, such as fats, oils, waxes, cholesterol, sterols, fat-soluble vitamins , monoglycerides, diglycerides, phospholipids, and others....
peroxidation and oxidation of other cellular molecules.

=Biosynthesis= Bleomycin is a nonribosomal peptide

Nonribosomal peptide

Nonribosomal peptides are a class of peptide secondary metabolites, usually produced by microorganisms like bacterium and fungi. Nonribosomal peptides are also found in higher organisms, such as nudibranchs, but are thought to be made by bacteria commensurism these organisms....
that is a hybrid peptide

Peptide

Peptides are short polymers formed from the linking, in a defined order, of a-amino acids. The link between one amino acid residue and the next is known as an amide chemical bond or a peptide bond....
-polyketide

Polyketide

Polyketides are secondary metabolites from bacterium, fungi, plants, and animals. Polyketides are biosynthesis by the polymerization of acetyl and propionyl subunits in a similar process to fatty acid metabolism#Synthesis ....
natural product

Natural product

A natural product is a chemical compound or substance produced by a living organism - found in nature that usually has a pharmacological or biological activity for use in pharmaceutical drug discovery and drug design....
. The peptide

Peptide

Polyketide

Peptide

Aglycon

A aglycon or aglycone is the non-sugar compound remaining after replacement of the glycosyl group from a glycoside by a hydrogen atom....
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 easily visualized in three stages (see Figure 2):

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 ß-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

Oxygen toxicity

Oxygen toxicity is a condition resulting from the harmful effects of breathing molecular oxygen at elevated partial pressures. It is also known as oxygen toxicity syndrome, oxygen intoxication, hyperoxia, or the Paul Bert effect and Lorrain Smith effect, after the researchers who pioneered its discovery and desc...
, recent studies support the role of the proinflammatory cytokines IL-18

Il-18

IL18 or IL-18 may be:* Ilyushin Il-18, a Cold War era Soviet Union airliner and military transport* Interleukin 18, a cytokine for stimulating the growth of T cell lymphocytes...
and IL-1beta in the mechanism of bleomycin-induced lung injury. and past history of treatment with bleomycin should therefore always be disclosed to the anaesthetist prior to undergoing a procedure requiring general anaesthesia

General anaesthesia

In modern medical practice, general anaesthesia is a state of total unconsciousness resulting from general anaesthetic drugs. A variety of drugs are given to the patient that have different effects with the overall aim of ensuring unconsciousness, amnesia and analgesia....
.

Other side effects

Adverse effect (medicine)

In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as chemotherapy or surgery....
include fever

Fever

Fever is a frequent medical sign that describes an increase in internal body temperature to levels above normal. Fever is most accurately characterized as a temporary elevation in the body's thermoregulatory set-point, usually by about 1?2 ?C ....
, rash, dermatographism, hyperpigmentation

Hyperpigmentation

In dermatology, hyperpigmentation is the darkening of an area of skin or nail caused by increased melanin....
, alopecia

Alopecia

Alopecia or hair loss is the medical description of the loss of hair from the head or body, sometimes to the extent of baldness. Unlike the common cosmetic depilation of body hair, alopecia tends to be involuntary and unwelcome, e.g., androgenic alopecia....
and Raynaud's phenomenon

Raynaud's phenomenon

Raynaud's phenomenon , in medicine, is a vasospasm disorder causing discoloration of the fingers, toes, and occasionally other extremities. This condition can also cause nails to become brittle with longitudinal ridges....
.

Bleomycin

History

Suppliers

Mechanism of action

Side effects

See also

Further reading