Bleomycin
Encyclopedia
Bleomycin is a glycopeptide antibiotic
Glycopeptide antibiotic
Glycopeptide antibiotics are a class of antibiotic drugs. The class is composed of glycosylated cyclic or polycyclic nonribosomal peptides. Significant glycopeptide antibiotics include vancomycin, teicoplanin, telavancin, bleomycin, ramoplanin, and decaplanin....

 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. As with the other Actinobacteria, streptomycetes are gram-positive, and have genomes with high guanine and cytosine content...

 verticillus
. Bleomycin refers to a family of structurally related compounds. When used as an anticancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

 agent, the chemotherapeutical forms are primarily bleomycin A2 and B2. It works by causing breaks in DNA. The drug is used in the treatment of Hodgkin's lymphoma
Hodgkin's lymphoma
Hodgkin's lymphoma, previously known as Hodgkin's disease, is a type of lymphoma, which is a cancer originating from white blood cells called lymphocytes...

 (as a component of the ABVD
ABVD
ABVD is a chemotherapy regimen used in the first-line treatment of Hodgkin lymphoma, supplanting the older MOPP protocol. It consists of concurrent treatment with the chemotherapy drugs:*Adriamycin *bleomycin...

 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. In the UK, approximately 2,000 men are diagnosed each year. Over his lifetime, a man's risk of...

, as well as in the treatment of plantar warts  and as a means of effecting pleurodesis
Pleurodesis
Pleurodesis is a medical procedure in which the pleural space is artificially obliterated. It involves the adhesion of the two pleura.- Uses :Pleurodesis is done to prevent recurrence of pneumothorax or recurrent pleural effusion...

.

History

Bleomycin was first discovered in 1966 when the Japanese scientist Hamao Umezawa
Hamao Umezawa
was a Japanese scientist who discovered several antimicrobial agents and enzyme inhibitors.After graduating from the Musashi Junior and Senior High School, Umezawa completed his medical degree in 1937. After serving in Japanese army during World War II Umezawa did work on tuberculosis which led to...

 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
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

 approval in July 1973. It was initially marketed in the US by the Bristol-Myers Squibb
Bristol-Myers Squibb
Bristol-Myers Squibb , often referred to as BMS, is a pharmaceutical company, headquartered in New York City. The company was formed in 1989, following the merger of its predecessors Bristol-Myers and the Squibb Corporation...

 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 and proprietary pharmaceuticals and active pharmaceutical ingredients...

), Hospira and Cipla.

Mechanism of action

Bleomycin acts by induction of DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...

 strand breaks. Some studies suggest bleomycin also inhibits incorporation of thymidine
Thymidine
Thymidine is a 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 bleomycin chelates
Chelation
Chelation is the formation or presence of two or more separate coordinate bonds between apolydentate ligand and a single central atom....

 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 constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...

 peroxidation and oxidation of other cellular molecules. Therefore bleomycin is used in combination with doxorubicin
Doxorubicin
Doxorubicin INN is a drug used in cancer chemotherapy. It is an anthracycline antibiotic, closely related to the natural product daunomycin, and like all anthracyclines, it works by intercalating DNA....

 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
Topoisomerase
Topoisomerases are enzymes that regulate the overwinding or underwinding of DNA. The winding problem of DNA arises due to the intertwined nature of its double helical structure. For example, during DNA replication, DNA becomes overwound ahead of a replication fork...

 enzyme thus relaxing the topoisomerase complexes.

Biosynthesis

Bleomycin is a nonribosomal peptide
Nonribosomal peptide
Nonribosomal peptides 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 bacteria inside these organisms...

 that is a hybrid peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...

-polyketide
Polyketide
Polyketides are secondary metabolites from bacteria, fungi, plants, and animals. Polyketides are usually biosynthesized through the decarboxylative condensation of malonyl-CoA derived extender units in a similar process to fatty acid 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
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...

/polyketide
Polyketide
Polyketides are secondary metabolites from bacteria, fungi, plants, and animals. Polyketides are usually biosynthesized through the decarboxylative condensation of malonyl-CoA derived extender units in a similar process to fatty acid synthesis...

/peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...

 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
Pulmonary fibrosis
Pulmonary fibrosis is the formation or development of excess fibrous connective tissue in the lungs. It is also described as "scarring of the lung".-Symptoms:Symptoms of pulmonary fibrosis are mainly:...

 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, and oxygen poisoning...

 and recent studies support the role of the proinflammatory cytokines IL-18
IL-18
IL-18, IL 18 or IL18 may refer to:* Interleukin 18, a protein encoded in humans by the IL18 gene* Ilyushin Il-18, a Cold War–era Soviet airliner and military transport* Illinois's 18th congressional district...

 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
General anaesthesia
General anaesthesia is a state of unconsciousness and loss of protective reflexes resulting from the administration of one or more general anaesthetic agents...

.

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 surgery.An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or...

 include fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...

, rash, dermatographism, hyperpigmentation
Hyperpigmentation
In dermatology, hyperpigmentation is the darkening of an area of skin or nails caused by increased melanin.-Causes:Hyperpigmentation may be caused by sun damage, inflammation, or other skin injuries, including those related to acne vulgaris...

, alopecia
Alopecia
Alopecia means loss of hair from the head or body. Alopecia can mean baldness, a term generally reserved for pattern alopecia or androgenic alopecia. Compulsive pulling of hair can also produce hair loss. Hairstyling routines such as tight ponytails or braids may induce Traction alopecia. Both...

 (hair loss) and Raynaud's phenomenon
Raynaud's phenomenon
In medicine, Raynaud's phenomenon is a vasospastic disorder causing discoloration of the fingers, toes, and occasionally other areas. This condition can also cause nails to become brittle with longitudinal ridges. Named for French physician Maurice Raynaud , the phenomenon is believed to be the...

 (discoloration of fingers and toes).

See also

  • Flagellate pigmentation from bleomycin
  • 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. In the UK, approximately 2,000 men are diagnosed each year. Over his lifetime, a man's risk of...

  • Hodgkin lymphoma
  • Chemotherapy regimen
  • History of cancer chemotherapy
    History of cancer chemotherapy
    The era of cancer chemotherapy began in the 1940s with the first use of nitrogen mustards and folic acid antagonist drugs. Cancer drug development has exploded since then into a multi-billion dollar industry...

  • ABVD
    ABVD
    ABVD is a chemotherapy regimen used in the first-line treatment of Hodgkin lymphoma, supplanting the older MOPP protocol. It consists of concurrent treatment with the chemotherapy drugs:*Adriamycin *bleomycin...

  • Pleurodesis
    Pleurodesis
    Pleurodesis is a medical procedure in which the pleural space is artificially obliterated. It involves the adhesion of the two pleura.- Uses :Pleurodesis is done to prevent recurrence of pneumothorax or recurrent pleural effusion...

  • Esperamicin
    Esperamicin
    The esperamicins are a class of bacteria-derived chromoprotein enediyne antibiotics, of which esperamicin A1 is the most well studied. Esperamcin A1 and the related enediyne calicheamicin are the two most potent antitumor agents known. The esperamicins are extremely toxic DNA splicing...

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