Vinblastine: Difference between revisions

{{Short description|Chemotherapy medication}}

{{Distinguish|vincristine}}

{{Use dmy dates|date=March 2024}}

| verifiedrevid = 460778829

| IUPAC_name = dimethyl (2β,3β,4β,5α,12β,19α)-15-[(5''S'',9''S'')-5-ethyl-5-hydroxy-9-(methoxycarbonyl)-1,4,5,6,7,8,9,10-octahydro-2''H''-3,7-methanoazacycloundecino[5,4-b]indol- 9-yl]-3-hydroxy-16-methoxy-1-methyl-6,7-didehydroaspidospermidine-3,4-dicarboxylate

| image = Vinblastine2DCSD.svg

| alt =

| image2 = Vinblastine ball-and-stick.png

| alt2 =

| tradename = Velban, Velbe, others

| DailyMedID = Vinblastine

| routes_of_administration = [[Intravenous therapy|intravenous]]

| ATC_prefix = L01

| ATC_suffix = CA01

| legal_AU =S4

| legal_CA = Rx-only

| legal_status = Rx-only

| metabolism = [[Liver]] ([[CYP3A4]]-mediated)

| excretion = [[Bile duct]] and [[kidney]]

| NIAID_ChemDB = 002673

| KEGG_Ref = {{keggcite|correct|kegg}}

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 159

| synonyms = vincaleukoblastine

<!--Chemical data-->

| C=46 | H=58 | N=4 | O=9

| smiles = [H][C@]89CN(CCc1c([nH]c2ccccc12)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@@]5([H])[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]7(CC)C=CCN6CC[C@]45[C@@]67[H])C8)C[C@](O)(CC)C9

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

<!-- Definition and medical uses -->

'''Vinblastine''' ('''VBL'''), sold under the brand name '''Velban''' among others, is a [[chemotherapy medication]], typically used with other medications, to treat a number of types of [[cancer]].<ref name=AHFS2015/> This includes [[Hodgkin's lymphoma]], [[non-small-cell lung cancer]], [[bladder cancer]], [[brain cancer]], [[melanoma]], and [[testicular cancer]].<ref name=AHFS2015/> It is given by [[intravenous|injection into a vein]].<ref name=AHFS2015>{{cite web|title=Vinblastine Sulfate|url=https://www.drugs.com/monograph/vinblastine-sulfate.html|publisher=The American Society of Health-System Pharmacists|access-date=2 January 2015|url-status=live|archive-url=https://web.archive.org/web/20150102140150/http://www.drugs.com/monograph/vinblastine-sulfate.html|archive-date=2 January 2015}}</ref>

<!-- Side effects and mechanism -->

Most people experience some side effects.<ref name=AHFS2015/> Commonly it causes a change in sensation, [[constipation]], weakness, loss of appetite, and [[headaches]].<ref name=AHFS2015/> Severe side effects include [[cytopenia|low blood cell counts]] and [[shortness of breath]].<ref name=AHFS2015/> It should not be given to people who have a current [[bacterial infection]].<ref name=AHFS2015/> Use during [[pregnancy]] will likely harm the baby.<ref name=AHFS2015/> Vinblastine works by [[mitotic inhibitor|blocking cell division]].<ref name=AHFS2015/>

<!-- Society and culture -->

Vinblastine was isolated in 1958.<ref name = "Ravina_2011">{{cite book| vauthors = Ravina E |title=The evolution of drug discovery : from traditional medicines to modern drugs|date=2011|publisher=Wiley-VCH|location=Weinheim|isbn=9783527326693|page=157|edition=1. Aufl.|url=https://books.google.com/books?id=iDNy0XxGqT8C&pg=PA157|url-status=live|archive-url=https://web.archive.org/web/20170801200844/https://books.google.ca/books?id=iDNy0XxGqT8C&pg=PA157|archive-date=1 August 2017}}</ref> An example of a [[Herbal remedy|natural herbal remedy]] that has since been developed into a conventional medicine, vinblastine was originally obtained from the [[Madagascar periwinkle]].<ref>{{cite book | vauthors = Liljefors T, Krogsgaard-Larsen P, Madsen U |title=Textbook of Drug Design and Discovery | edition = Third |date=2002 |publisher=CRC Press |isbn=9780415282888 |page=550 |url=https://books.google.com/books?id=EL-UI6t8omQC&pg=PA550 |url-status=live|archive-url=https://web.archive.org/web/20161220164328/https://books.google.ca/books?id=EL-UI6t8omQC&pg=PA550|archive-date=20 December 2016}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO23rd">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}</ref>

== Medical uses ==

Vinblastine is a component of a number of [[chemotherapy regimen]]s, including [[ABVD]] for [[Hodgkin lymphoma]].<ref>{{cite journal | vauthors = Rueda Domínguez A, Márquez A, Gumá J, Llanos M, Herrero J, de Las Nieves MA, Miramón J, Alba E | display-authors = 6 | title = Treatment of stage I and II Hodgkin's lymphoma with ABVD chemotherapy: results after 7 years of a prospective study | journal = Annals of Oncology | volume = 15 | issue = 12 | pages = 1798–1804 | date = December 2004 | pmid = 15550585 | doi = 10.1093/annonc/mdh465 | doi-access = free }}</ref> It is also used to treat [[histiocytosis]] according to the established protocols of the Histiocytosis Association.

==Side effects==

Adverse effects of vinblastine include hair loss, loss of white blood cells and blood platelets, gastrointestinal problems, high blood pressure, excessive sweating, depression, muscle cramps, vertigo and headaches.<ref>{{cite web | title=Vinblastine sulfate- vinblastine sulfate injection | website=DailyMed | date=31 December 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f073b58e-56d6-4c8d-a2ce-b37719402d77 | access-date=15 April 2020}}</ref><ref name=AHFS2015/> As a [[vesicant]], vinblastine can cause extensive tissue damage and blistering if it escapes from the vein from improper administration.<ref>{{cite web |title=Vinblastine |url=https://chemocare.com/chemotherapy/drug-info/vinblastine.aspx |website=Chemocare |access-date=12 November 2021}}</ref>

==Pharmacology==

Vinblastine is a [[vinca alkaloid|''vinca'' alkaloid]]<ref>{{cite journal | vauthors = van Der Heijden R, Jacobs DI, Snoeijer W, Hallard D, Verpoorte R | title = The Catharanthus alkaloids: pharmacognosy and biotechnology | journal = Current Medicinal Chemistry | volume = 11 | issue = 5 | pages = 607–628 | date = March 2004 | pmid = 15032608 | doi = 10.2174/0929867043455846 }}</ref><ref name = "Ravina_2011" /><ref>{{cite book|chapter = Africa's gift to the world|pages = 46–51|chapter-url = https://books.google.com/books?id=aXGmCwAAQBAJ&pg=PA46|title = Botanical Miracles: Chemistry of Plants That Changed the World| vauthors = Cooper R, Deakin JJ |publisher = [[CRC Press]]|year = 2016|isbn = 9781498704304|url-status = live|archive-url = https://web.archive.org/web/20170801195333/https://books.google.com.au/books?id=aXGmCwAAQBAJ&pg=PA46|archive-date = 1 August 2017}}</ref> and a chemical analogue of [[vincristine]].<ref name=MoleculesReview>{{cite journal | vauthors = Keglevich P, Hazai L, Kalaus G, Szántay C | title = Modifications on the basic skeletons of vinblastine and vincristine | journal = Molecules | volume = 17 | issue = 5 | pages = 5893–5914 | date = May 2012 | pmid = 22609781 | pmc = 6268133 | doi = 10.3390/molecules17055893 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Sears JE, Boger DL | title = Total synthesis of vinblastine, related natural products, and key analogues and development of inspired methodology suitable for the systematic study of their structure-function properties | journal = Accounts of Chemical Research | volume = 48 | issue = 3 | pages = 653–662 | date = March 2015 | pmid = 25586069 | pmc = 4363169 | doi = 10.1021/ar500400w | author-link2 = Dale L. Boger }}</ref> It binds [[tubulin]], thereby inhibiting the assembly of [[microtubules]].<ref name="altmann">{{cite book|chapter-url = https://books.google.com/books?id=FfCfFgWenSAC&pg=PA158|title = The Epothilones: An Outstanding Family of Anti-Tumor Agents: From Soil to the Clinic| veditors = Mulzer JH |editor-link = Johann Mulzer|publisher = [[Springer Science & Business Media]]|year = 2009|isbn = 9783211782071|chapter = Preclinical Pharmacology and Structure-Activity Studies of Epothilones|pages = 157–220| vauthors = Altmann KH |url-status = live|archive-url = https://web.archive.org/web/20170911002758/https://books.google.com.au/books?id=FfCfFgWenSAC&pg=PA158|archive-date = 11 September 2017}}</ref> Vinblastine treatment causes M phase specific [[cell cycle]] arrest by disrupting microtubule assembly and proper formation of the [[mitotic spindle]] and the [[kinetochore]], each of which are necessary for the separation of chromosomes during [[anaphase]] of mitosis. Toxicities include [[bone marrow suppression]] (which is dose-limiting), [[gastrointestinal tract|gastrointestinal]] toxicity, potent [[blister agent|vesicant]] (blister-forming) activity, and [[extravasation]] injury (forms deep ulcers). Vinblastine paracrystals may be composed of tightly packed unpolymerized tubulin or microtubules.<ref>{{cite journal | vauthors = Starling D | title = Two ultrastructurally distinct tubulin paracrystals induced in sea-urchin eggs by vinblastine sulphate | journal = Journal of Cell Science | volume = 20 | issue = 1 | pages = 79–89 | date = January 1976 | pmid = 942954 | doi = 10.1242/jcs.20.1.79 | url = http://jcs.biologists.org/content/20/1/79.full.pdf | url-status = live | archive-url = https://web.archive.org/web/20140113033809/http://jcs.biologists.org/content/20/1/79.full.pdf | archive-date = 13 January 2014 }}</ref>

Vinblastine is reported to be an effective component of certain chemotherapy regimens, particularly when used with [[bleomycin]] and [[methotrexate]] in VBM chemotherapy for Stage IA or IIA Hodgkin lymphomas.

The inclusion of vinblastine allows for lower doses of bleomycin and reduced overall toxicity with larger resting periods between chemotherapy cycles.<ref>{{cite journal | vauthors = Gobbi PG, Broglia C, Merli F, Dell'Olio M, Stelitano C, Iannitto E, Federico M, Bertè R, Luisi D, Molica S, Cavalli C, Dezza L, Ascari E | display-authors = 6 | title = Vinblastine, bleomycin, and methotrexate chemotherapy plus irradiation for patients with early-stage, favorable Hodgkin lymphoma: the experience of the Gruppo Italiano Studio Linfomi | journal = Cancer | volume = 98 | issue = 11 | pages = 2393–2401 | date = December 2003 | pmid = 14635074 | doi = 10.1002/cncr.11807 | hdl-access = free | s2cid = 21376280 | hdl = 11380/4847 }}</ref>

===Mechanism of action===

[[Image:Tublin&vinblastin-1Z2B.png|thumb|left|The complex of tubulin and vinblastine. Vinblastine is shown in yellow.]]

Microtubule-disruptive drugs like vinblastine, [[colcemid]], and [[nocodazole]] have been reported to act by two mechanisms.<ref>{{cite journal | vauthors = Jordan MA, Wilson L | title = Microtubules as a target for anticancer drugs | journal = Nature Reviews. Cancer | volume = 4 | issue = 4 | pages = 253–265 | date = April 2004 | pmid = 15057285 | doi = 10.1038/nrc1317 | s2cid = 10228718 }}</ref> At very low concentrations they suppress microtubule dynamics and at higher concentrations they reduce microtubule polymer mass. Recent findings indicate that they also produce microtubule fragments by stimulating microtubule minus-end detachment from their organizing centers. Dose-response studies further indicate that enhanced microtubule detachment from spindle poles correlate best with cytotoxicity.<ref>{{cite journal | vauthors = Yang H, Ganguly A, Cabral F | title = Inhibition of cell migration and cell division correlates with distinct effects of microtubule inhibiting drugs | journal = The Journal of Biological Chemistry | volume = 285 | issue = 42 | pages = 32242–32250 | date = October 2010 | pmid = 20696757 | pmc = 2952225 | doi = 10.1074/jbc.M110.160820 | doi-access = free }}</ref> But research into the mechanism is still ongoing as recent studies also show vinblastine inducing apoptosis that is phase-independent in certain leukemias.<ref>{{cite journal | vauthors = Salerni BL, Bates DJ, Albershardt TC, Lowrey CH, Eastman A | title = Vinblastine induces acute, cell cycle phase-independent apoptosis in some leukemias and lymphomas and can induce acute apoptosis in others when Mcl-1 is suppressed | journal = Molecular Cancer Therapeutics | volume = 9 | issue = 4 | pages = 791–802 | date = April 2010 | pmid = 20371726 | pmc = 2852489 | doi = 10.1158/1535-7163.MCT-10-0028 }}</ref>

===Pharmacokinetics===

Vinblastine appears to be a [[peripherally selective drug]] due to limited [[brain]] uptake caused by binding to [[P-glycoprotein]].<ref name="pmid10837715">{{cite journal | vauthors = Schinkel AH | title = P-Glycoprotein, a gatekeeper in the blood-brain barrier | journal = Adv Drug Deliv Rev | volume = 36 | issue = 2–3 | pages = 179–194 | date = April 1999 | pmid = 10837715 | doi = 10.1016/s0169-409x(98)00085-4 | url = }}</ref><ref name="pmid9780140">{{cite journal | vauthors = Tsuji A | title = P-glycoprotein-mediated efflux transport of anticancer drugs at the blood-brain barrier | journal = Ther Drug Monit | volume = 20 | issue = 5 | pages = 588–90 | date = October 1998 | pmid = 9780140 | doi = 10.1097/00007691-199810000-00024 | url = }}</ref>

==Isolation and synthesis==

Vinblastine may be isolated from the Madagascar Periwinkle (''[[Catharanthus roseus]]''), its only known biological producer,<ref name="Zhu 2015">{{cite journal | vauthors = Zhu J, Wang M, Wen W, Yu R | title = Biosynthesis and regulation of terpenoid indole alkaloids in Catharanthus roseus | journal = Pharmacognosy Reviews | volume = 9 | issue = 17 | pages = 24–28 | date = January 2015 | pmid = 26009689 | doi = 10.4103/0973-7847.156323| pmc=4441158 | doi-access = free }}</ref> along with several of its precursors, [[catharanthine]] and [[vindoline]]. Extraction is costly and yields of vinblastine and its precursors are low, although procedures for rapid isolation with improved yields avoiding auto-oxidation have been developed. Enantioselective synthesis has been of considerable interest in recent years, as the natural mixture of isomers is not an economical source for the required C16'S, C14'R stereochemistry of biologically active vinblastine. Initially, the approach depends upon an enantioselective [[Sharpless epoxidation]], which sets the stereochemistry at C20. The desired configuration around C16 and C14 can then be fixed during the ensuing steps. In this pathway, vinblastine is constructed by a series of cyclization and coupling reactions which create the required stereochemistry. The overall yield may be as great as 22%, which makes this synthetic approach more attractive than extraction from natural sources, whose overall yield is about 10%.<ref>{{ cite journal | vauthors = Kuehne ME, Matson PA, Bornmann WG | title = Enantioselective Syntheses of Vinblastine, Leurosidine, Vincovaline, and 20'-''epi''-Vincovaline | journal = Journal of Organic Chemistry | year = 1991 | volume = 56 | issue = 2 | pages = 513–528 | doi = 10.1021/jo00002a008 }}</ref> Stereochemistry is controlled through a mixture of chiral agents (Sharpless catalysts), and reaction conditions (temperature, and selected enantiopure starting materials).<ref>{{ cite journal | vauthors = Yokoshima S, Tokuyama H, Fukuyama T | title = Total Synthesis of (+)-Vinblastine: Control of the Stereochemistry at C18′ | journal = The Chemical Record | year = 2009 | volume = 10 | issue = 2 | pages = 101–118 | doi = 10.1002/tcr.200900025 | pmid = 20394103 }}</ref> Due to difficulty of stereochemical restraints in total synthetic processes, other [[semisynthesis|semi-synthetic]] methods from precursors, [[catharanthine]] and [[vindoline]], continue to be developed.<ref>{{cite journal | vauthors = Verma A, Laakso I, Seppänen-Laakso T, Huhtikangas A, Riekkola ML | title = A simplified procedure for indole alkaloid extraction from Catharanthus roseus combined with a semi-synthetic production process for vinblastine | journal = Molecules | volume = 12 | issue = 7 | pages = 1307–1315 | date = July 2007 | pmid = 17909486 | pmc=6149338| doi = 10.3390/12071307 | doi-access = free }}</ref>

== History ==

Vinblastine was first isolated by [[Robert Noble (physician)|Robert Noble]] and [[Charles Thomas Beer]] at the [[University of Western Ontario]] from the [[Madagascar periwinkle]] plant. Vinblastine's utility as a chemotherapeutic agent was first suggested by its effect on the body when an extract of the plant was injected in rabbits to study the plant's supposed anti-diabetic effect. (A tea made from the plant was a folk-remedy for diabetes.) The rabbits died from a bacterial infection, due to a [[leukopenia|decreased number of white blood cells]], so it was hypothesized that vinblastine might be effective against cancers of the [[white blood cell]]s such as [[lymphoma]].<ref name="pmid13627916">{{cite journal | vauthors = Noble RL, Beer CT, Cutts JH | title = Role of chance observations in chemotherapy: Vinca rosea | journal = Annals of the New York Academy of Sciences | volume = 76 | issue = 3 | pages = 882–894 | date = December 1958 | pmid = 13627916 | doi = 10.1111/j.1749-6632.1958.tb54906.x | s2cid = 34879726 | bibcode = 1958NYASA..76..882N }}</ref> It was approved by FDA in 1965.<ref name="altmann"/>

== References ==

{{Portal bar|Medicine}}

[[Category:Vinca alkaloids]]

[[Category:World Health Organization essential medicines]]

[[Category:Wikipedia medicine articles ready to translate]]