Vinblastine

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Not to be confused with vincristine.
Vinblastine
Vinblastine-skeletal.svg
Vinblastine3Dan.gif
Systematic (IUPAC) name
dimethyl (2β,3β,4β,5α,12β,19α)-15-[(5S,9S)-5-ethyl-5-hydroxy-9-(methoxycarbonyl)-1,4,5,6,7,8,9,10-octahydro-2H-3,7-methanoazacycloundecino[5,4-b]indol- 9-yl]-3-hydroxy-16-methoxy-1-methyl-6,7-didehydroaspidospermidine-3,4-dicarboxylate
Clinical data
AHFS/Drugs.com monograph
MedlinePlus a682848
Pregnancy cat. D (AU) D (US)
Legal status POM (UK) -only (US)
Routes intravenous
Pharmacokinetic data
Bioavailability n/a
Metabolism Hepatic (CYP3A4-mediated)
Half-life 24.8 hours (terminal)
Excretion Biliary and renal
Identifiers
CAS number 865-21-4 YesY
ATC code L01CA01
PubChem CID 241903
DrugBank DB00570
ChemSpider 211446 YesY
UNII 5V9KLZ54CY YesY
KEGG D08675 YesY
ChEBI CHEBI:27375 YesY
ChEMBL CHEMBL159 N
NIAID ChemDB 002673
Synonyms vincaleukoblastine
Chemical data
Formula C46H58N4O9 
Mol. mass 810.975 g/mol
 N (what is this?)  (verify)

Vinblastine is an antimicrotubule drug used to treat certain kinds of cancer, including Hodgkin's lymphoma, non-small cell lung cancer, breast cancer, head and neck cancer, and testicular cancer. It is also used to treat Langerhans cell histiocytosis. Vinblastine was traditionally obtained from Catharanthus roseus, also known as Vinca rosea, a Madagascar Periwinkle. It is generated in the plant by the joining of two alkaloids catharanthine and vindoline.[1]

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[2]

Medical uses[edit]

Vinblastine is a component of a number of chemotherapy regimens, including ABVD for Hodgkin lymphoma. It is also used to treat histiocytosis according to the established protocols of the Histiocytosis Association.

Side effects[edit]

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.[3]

Pharmacology[edit]

Vinblastine is a vinca alkaloid and a chemical analogue of vincristine. It binds tubulin, thereby inhibiting the assembly of microtubules. 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 toxicity, potent vesicant (blister-forming) activity, and extravasation injury (forms deep ulcers). Vinblastine paracrystals may be composed of tightly-packed unpolymerized tubulin or microtubules.[4]

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.[5]

Mechanism of Action[edit]

The complex of tublin and vinblastine. Vinblastine is shown in yellow.

Microtubule-disruptive drugs like vinblastine, colcemid, nocodazole have been reported to act by two mechanisms.[6] 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.[7]

Isolation and synthesis[edit]

Vinblastine may be isolated from the Madagascar Periwinkle (Catharanthus roseus), along with several of its precursors- catharanthine and vindoline. Extraction is costly and yields of vinblastine and its precursors are low. 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%.[8] Stereochemistry is controlled through a mixture of chiral agents (Sharpless catalysts), and reaction conditions (temperature, and selected enantiopure starting materials).[9]

History[edit]

Vinblastine was first isolated by 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 succumbed to a bacterial infection, due to a decreased number of white blood cells, so it was hypothesized that vinblastine might be effective against cancers of the white blood cells such as lymphoma.

See also[edit]

Footnotes[edit]

  1. ^ "Pharmacognosy of Vinca Alkaloids". 
  2. ^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014. 
  3. ^ "FASS" (in Swedish). Retrieved 28 February 2013. 
  4. ^ Starling, D. (1976). "Two Ultrastructurally Distinct Tubulin Paracrystals Induced in Sea-Urchin Eggs by Vinblastine Sulphate" (pdf). Journal of Cell Science 20 (1): 79–89. PMID 942954. 
  5. ^ Goppi, P. G.; 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. (2003). "Vinblastine, Bleomycin, and Methotrexate Chemotherapy plus Irradiation for Patients with Early-Stage, Favorable Hodgkin Lymphoma" (pdf). Cancer 98 (11): 2393–2401. doi:10.1002/cncr.11807. PMID 14635074. 
  6. ^ Jordan, M. A.; Leslie, W. (2004). "Microtubules as a Target for Anticancer Drugs". Nature Reviews Cancer 4 (4): 253–265. doi:10.1038/nrc1317. PMID 15057285. 
  7. ^ Yang, H.; Ganguly, A.; Cabral, F. (2010). "Inhibition of Cell Migration and Cell Division Correlate with Distinct Effects of Microtubule Inhibiting Drugs" (pdf). Journal of Biological Chemistry 285 (42): 32242–32250. doi:10.1074/jbc.M110.160820. PMC 2952225. PMID 20696757. 
  8. ^ Kuehne, M. E.; Matson, P. A.; Bornmann, W. G. (1991). "Enantioselective Syntheses of Vinblastine, Leurosidine, Vincovaline, and 20'-epi-Vincovaline". Journal of Organic Chemistry 56 (2): 513–528. doi:10.1021/jo00002a008. 
  9. ^ Yokoshima, S; Tokuyama, H; Fukuyama, T. (2009). "Total Synthesis of (+)-Vinblastine: Control of the Stereochemistry at C18′ ". The Chemical Record 10 (2): 101–118. doi:10.1002/tcr.200900025.