Bleomycin#Side effects

{{Short description|Glycopeptide antibiotic used to treat various cancers}}

{{Drugbox

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| verifiedrevid = 401932982

| image = Bleomycin A2.svg

| image_class = skin-invert-image

| caption = Bleomycin A2

| width = 350

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| pronounce =

| tradename = Blenoxane

| Drugs.com = {{drugs.com|monograph|bleomycin-sulfate}}

| MedlinePlus = a682125

| DailyMedID = Bleomycin

| pregnancy_AU = D

| pregnancy_AU_comment ={{cite web | title=Bleomycin Use During Pregnancy | website=Drugs.com | date=9 August 2019 |url=https://www.drugs.com/pregnancy/bleomycin.html | access-date=16 February 2020}}

| pregnancy_category =

| routes_of_administration = intravenous, intramuscular, subcutaneous, intrapleural

| class = Glycopeptide antibiotic

| ATC_prefix = L01

| ATC_suffix = DC01

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| legal_UK = POM

| legal_UK_comment ={{cite web | title=Bleo-Kyowa Powder for solution for injection - Summary of Product Characteristics (SmPC) | website=(emc) | date=31 August 2018 |url=https://www.medicines.org.uk/emc/medicine/26918 | access-date=16 February 2020 | archive-date=16 February 2020 | archive-url=https://web.archive.org/web/20200216055521/https://www.medicines.org.uk/emc/medicine/26918 | url-status=dead }}

| legal_US = Rx-only

| legal_US_comment =

| legal_EU = Rx-only

| legal_EU_comment ={{cite web | title=Bleomycin | website=European Medicines Agency (EMA) | date=18 March 2009 |url=https://www.ema.europa.eu/en/medicines/human/referrals/bleomycin }}

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| bioavailability = 100% and 70% following intramuscular and subcutaneous administrations, respectively, and 45% following both intraperitoneal and intrapleural administrations{{cite web | title=Bleomycin- bleomycin sulfate injection, powder, lyophilized, for solution | website=DailyMed | date=31 December 2019 |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b5806c40-12ce-48e3-8abd-9f8997ef4428 | access-date=16 February 2020}}

| protein_bound =

| metabolism =

| metabolites =

| onset =

| elimination_half-life = two hours

| duration_of_action =

| excretion = Kidney (60–70%)

| index_label =

| index2_label = sulfate

| CAS_number_Ref = {{cascite|correct|CAS}}

| CAS_number = 11056-06-7

| CAS_number2_Ref = {{cascite|correct|CAS}}

| CAS_number2 = 9041-93-4

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 40S1VHN69B

| PubChem = 5460769

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| DrugBank_Ref = {{drugbankcite|changed|drugbank}}

| DrugBank = DB00290

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 4574226

| UNII2_Ref = {{fdacite|correct|FDA}}

| UNII2 = 7DP3NTV15T

| KEGG_Ref = {{keggcite|changed|kegg}}

| KEGG = D07535

| KEGG2_Ref = {{keggcite|changed|kegg}}

| KEGG2 = C15773

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 22907

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 403664

| NIAID_ChemDB =

| PDB_ligand =

| synonyms =

| IUPAC_name = (3-{{(}}[(2'-{{(}}(5S,8S,9S,10R,13S)-15-{{(}}6-amino-2- [(1S)-3-amino-1-{{(}}[(2S)-2,3-diamino-3-oxopropyl]amino}-3-oxopropyl] -5-methylpyrimidin-4-yl}-13-[{[(2R,3S,4S,5S,6S)-3- {[(2R,3S,4S,5R,6R)-4-(carbamoyloxy)-3,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy} -4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy} (1H-imidazol-5-yl)methyl]-9-hydroxy-5-[(1R)-1-hydroxyethyl]-8,10-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)[C@H](CC(=O)N)NC[C@@H](C(=O)N)N)C(=O)N[C@@H](C(C2=CN=CN2)O[C@H]3[C@H]([C@H]([C@@H]([C@@H](O3)CO)O)O)O[C@@H]4[C@H]([C@H]([C@@H]([C@H](O4)CO)O)OC(=O)N)O)C(=O)N[C@H](C)[C@H]([C@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCCC5=NC(=CS5)C6=NC(=CS6)C(=O)NCCC[S+](C)C)O

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| 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 = {{stdinchicite|changed|chemspider}}

| StdInChIKey = OYVAGSVQBOHSSS-UAPAGMARSA-O

| density =

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Bleomycin is a medication primarily used to treat cancer.{{cite web|title=Bleomycin Sulfate|url=https://www.drugs.com/monograph/bleomycin-sulfate.html|publisher=The American Society of Health-System Pharmacists|access-date=1 August 2015|url-status=live|archive-url=https://web.archive.org/web/20150908071131/http://www.drugs.com/monograph/bleomycin-sulfate.html|archive-date=8 September 2015}} This includes Hodgkin's lymphoma, non-Hodgkin's lymphoma, 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 pleural effusion due to cancer; however talc is better for this.{{cite journal | vauthors = Dipper A, Jones HE, Bhatnagar R, Preston NJ, Maskell N, Clive AO | title = Interventions for the management of malignant pleural effusions: a network meta-analysis | journal = The Cochrane Database of Systematic Reviews | volume = 2020 | issue = 4 | pages = CD010529 | date = April 2020 | pmid = 32315458 | pmc = 7173736 | doi = 10.1002/14651858.CD010529.pub3 }} It may sometimes be used to treat other difficult-to-treat skin lesions such as plantar warts in immunocompromised patients.

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.{{cite book| vauthors = Sneader W |title=Drug discovery : a history|date=2005|publisher=Wiley|location=Chichester|isbn=9780471899792|page=312|edition=Rev. and updated|url=https://books.google.com/books?id=Cb6BOkj9fK4C&pg=PA312|url-status=live|archive-url=https://web.archive.org/web/20160305013634/https://books.google.ca/books?id=Cb6BOkj9fK4C&pg=PA312|archive-date=5 March 2016}}{{cite book | vauthors = Phillips GO |title=Innovation and Technology Transfer in Japan and Europe: Industry-Academic Interactions |date=2018 |publisher=Routledge |isbn=9780429774546 |page=PT155 |url=https://books.google.com/books?id=Jfl0DwAAQBAJ&pg=PT155 |language=en}} It is on the World Health Organization's List of Essential Medicines.{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }} It is available as a generic medication. It is made by the bacterium Streptomyces verticillus.

Medical uses

=Cancer=

Bleomycin is mostly used to treat cancer. 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 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).{{cite journal | vauthors = Shaw P, Agarwal R | title = Pleurodesis for malignant pleural effusions | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD002916 | date = 2004 | pmid = 14973997 | doi = 10.1002/14651858.CD002916.pub2 | veditors = Shaw PH }} {{Retracted|doi=10.1002/14651858.CD002916.pub3|pmid=24259053|intentional=yes}}{{cite journal | vauthors = Thomas R, Murray K, Lee YC | title = Treatment Approaches for Malignant Pleural Effusion | journal = JAMA | volume = 319 | issue = 14 | pages = 1507–1508 | date = April 2018 | pmid = 29634827 | doi = 10.1001/jama.2018.1323 }}

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.{{cite journal | vauthors = Kwok CS, Gibbs S, Bennett C, Holland R, Abbott R | title = Topical treatments for cutaneous warts | journal = The Cochrane Database of Systematic Reviews | volume = 9 | issue = 9 | pages = CD001781 | date = September 2012 | pmid = 22972052 | pmc = 8101088 | doi = 10.1002/14651858.CD001781.pub3 }}

Side effects

The most common side effects are flu-like symptoms and include fever, rash, dermatographism, hyperpigmentation, alopecia (hair loss), chills, and Raynaud's phenomenon (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{{Cite web|url=http://www.anaesthesiawa.org/bleomycin.pdf |title=Bleomycin and Anaesthesia| vauthors = Thompson M | website=Anaesthesia Western Australia|access-date=8 September 2017|archive-url=https://web.archive.org/web/20170908202217/http://www.anaesthesiawa.org/bleomycin.pdf|archive-date=8 September 2017|url-status=dead}} and recent studies support the role of the proinflammatory cytokines IL-18 and IL-1beta in the mechanism of bleomycin-induced lung injury.{{cite journal | vauthors = Hoshino T, Okamoto M, Sakazaki Y, Kato S, Young HA, Aizawa H | title = Role of proinflammatory cytokines IL-18 and IL-1beta in bleomycin-induced lung injury in humans and mice | journal = American Journal of Respiratory Cell and Molecular Biology | volume = 41 | issue = 6 | pages = 661–670 | date = December 2009 | pmid = 19265174 | doi = 10.1165/rcmb.2008-0182OC | pmc = 10283344 }} 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.{{cite journal | vauthors = Huls G, ten Bokkel Huinink D | title = Bleomycin and scuba diving: to dive or not to dive? | journal = The Netherlands Journal of Medicine | volume = 61 | issue = 2 | pages = 50–53 | date = February 2003 | pmid = 12735422 }} Bleomycin has also been found to disrupt the sense of taste.{{cite journal | vauthors = Ackerman BH, Kasbekar N | title = Disturbances of taste and smell induced by drugs | journal = Pharmacotherapy | volume = 17 | issue = 3 | pages = 482–496 | date = 1997 | pmid = 9165552 | doi = 10.1002/j.1875-9114.1997.tb03058.x | s2cid = 12671326 }}

= Lifetime cumulative dose =

Bleomycin should not exceed a lifetime cumulative dose greater than 400 units.{{Cite web|title=bleomycin [TUSOM {{!}} Pharmwiki]|url=https://tmedweb.tulane.edu/pharmwiki/doku.php/bleomycin|access-date=2 February 2022|website=tmedweb.tulane.edu}} 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 DNA strand breaks.{{cite book | vauthors = Takimoto CH, Calvo E | chapter-url=http://www.cancernetwork.com/cancer-management-11/chapter03/article/10165/1402628 | chapter = Principles of Oncologic Pharmacotherapy | archive-url=https://web.archive.org/web/20090515221337/http://www.cancernetwork.com/cancer-management-11/chapter03/article/10165/1402628 | archive-date=15 May 2009 | veditors = Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ | title = Cancer Management: A Multidisciplinary Approach | volume = 3 | edition = 11th | date = 2008 | publisher = UBM Medica LLC }} Some studies suggest bleomycin also inhibits incorporation of thymidine 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.{{cite journal | vauthors = Hecht SM | title = Bleomycin: new perspectives on the mechanism of action | journal = Journal of Natural Products | volume = 63 | issue = 1 | pages = 158–168 | date = January 2000 | pmid = 10650103 | doi = 10.1021/np990549f | bibcode = 2000JNAtP..63..158H }}

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,{{cite journal | vauthors = Hindra, Yang D, Teng Q, Dong LB, Crnovčić I, Huang T, Ge H, Shen B | title = Genome Mining of Streptomyces mobaraensis DSM40847 as a Bleomycin Producer Providing a Biotechnology Platform To Engineer Designer Bleomycin Analogues | journal = Organic Letters | volume = 19 | issue = 6 | pages = 1386–1389 | date = March 2017 | pmid = 28256838 | doi = 10.1021/acs.orglett.7b00283 }}{{cite journal | vauthors = Yang D, Hindra, Dong LB, Crnovcic I, Shen B | title = Engineered production and evaluation of 6'-deoxy-tallysomycin H-1 revealing new insights into the structure-activity relationship of the anticancer drug bleomycin | journal = The Journal of Antibiotics | volume = 71 | pages = 97–103 | date = August 2017 | pmid = 28831149 | doi = 10.1038/ja.2017.93 | s2cid = 33531845 }} primarily by the plasmid relaxation and break light assays.

History

Bleomycin was first discovered in 1962 when the Japanese scientist Hamao Umezawa found anticancer activity while screening culture filtrates of Streptomyces verticillus. Umezawa published his discovery in 1966.{{cite journal | vauthors = Umezawa H, Maeda K, Takeuchi T, Okami Y | title = New antibiotics, bleomycin A and B | journal = The Journal of Antibiotics | volume = 19 | issue = 5 | pages = 200–9 | date = September 1966 | pmid = 5953301 | doi = |url=}} The drug was launched in Japan by Nippon Kayaku in 1969. In the US, bleomycin gained FDA approval in July 1973. It was initially marketed in the US by the Bristol-Myers Squibb precursor, Bristol Laboratories, under the brand name Blenoxane.

Research

Bleomycin is used in research to induce pulmonary fibrosis in mice.{{cite journal | vauthors = Song N, Liu J, Shaheen S, Du L, Proctor M, Roman J, Yu J | title = Vagotomy attenuates bleomycin-induced pulmonary fibrosis in mice | journal = Scientific Reports | volume = 5 | pages = 13419 | date = August 2015 | pmid = 26289670 | pmc = 4542162 | doi = 10.1038/srep13419 | quote = In our studies, mice developed classic PF with structural alteration of the lung following intravenous bleomycin treatment | bibcode = 2015NatSR...513419S }} It accomplishes this by preventing alveolar cell proliferation, which in turn leads to cellular senescence.