Not to be confused with vincristine.
Vinblastine
|
|
| Clinical data |
| AHFS/Drugs.com |
Monograph |
| MedlinePlus |
a682848 |
Pregnancy
category |
- AU: D
- US: D (Evidence of risk)
|
Routes of
administration |
intravenous |
| ATC code |
L01CA01 (WHO) |
| Legal status |
| Legal status |
- UK: POM (Prescription only)
- US: ℞-only
- ℞ (Prescription only)
|
| Pharmacokinetic data |
| Bioavailability |
n/a |
| Metabolism |
Hepatic (CYP3A4-mediated) |
| Biological half-life |
24.8 hours (terminal) |
| Excretion |
Biliary and renal |
| Identifiers |
| CAS Number |
865-21-4 Y |
| PubChem |
CID 241903 |
| DrugBank |
DB00570 Y |
| ChemSpider |
211446 Y |
| UNII |
5V9KLZ54CY Y |
| KEGG |
D08675 Y |
| ChEBI |
CHEBI:27375 Y |
| ChEMBL |
CHEMBL159 N |
| NIAID ChemDB |
002673 |
| Synonyms |
vincaleukoblastine |
| Chemical and physical data |
|
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
|
| 3D model (Jmol) |
Interactive image |
| Formula |
C46H58N4O9 |
| Molar mass |
810.975 g/mol |
SMILES
-
O=C(OC)[C@]4(c2c(c1ccccc1n2)CCN3C[C@](O)(CC)C[C@@H](C3)C4)c5c(OC)cc6c(c5)[C@@]89[C@@H](N6C)[C@@](O)(C(=O)OC)[C@H](OC(=O)C)[C@@]7(/C=C\CN([C@@H]78)CC9)CC
|
InChI
-
InChI=1S/C46H58N4O9/c1-8-42(54)23-28-24-45(40(52)57-6,36-30(15-19-49(25-28)26-42)29-13-10-11-14-33(29)47-36)32-21-31-34(22-35(32)56-5)48(4)38-44(31)17-20-50-18-12-16-43(9-2,37(44)50)39(59-27(3)51)46(38,55)41(53)58-7/h10-14,16,21-22,28,37-39,47,54-55H,8-9,15,17-20,23-26H2,1-7H3/t28-,37+,38-,39-,42+,43-,44-,45+,46+/m1/s1 Y
-
Key:JXLYSJRDGCGARV-XQKSVPLYSA-N Y
|
| NY (what is this?) (verify) |
Vinblastine is a medication used to treat a number of types of cancer including: Hodgkin's lymphoma, non-small cell lung cancer, bladder cancer, brain cancer, and testicular cancer among others.[1] It is used intravenously and works by inhibiting mitosis.[1]
Most people experience some side effects.[1] Commonly it causes a change in sensation, constipation, weakness, loss of appetite, and headaches among other symptoms.[1] It will likely cause harm to an infant if given during pregnancy.[1]
The isolation of vinblastine was first reported in 1958.[2] It is on the World Health Organization's List of Essential Medicines, the most important medication needed in a basic health system.[3] As of 2014 the wholesale cost is between 7.70 and 31.70 USD per dose.[4] 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.[5]
Contents
- 1 Medical uses
- 2 Side effects
- 3 Pharmacology
- 4 Mechanism of action
- 5 Isolation and synthesis
- 6 History
- 7 Footnotes
Medical uses
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
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.[6]
Pharmacology
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.[7]
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.[8]
Mechanism of action
The complex of tubulin and vinblastine. Vinblastine is shown in yellow.
Microtubule-disruptive drugs like vinblastine, colcemid, nocodazole have been reported to act by two mechanisms.[9] 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.[10]
Isolation and synthesis
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, 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%.[11] Stereochemistry is controlled through a mixture of chiral agents (Sharpless catalysts), and reaction conditions (temperature, and selected enantiopure starting materials).[12]
History
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.[13]
- ^ a b c d e "Vinblastine Sulfate". The American Society of Health-System Pharmacists. Retrieved Jan 2, 2015.
- ^ Ravina, Enrique (2011). The evolution of drug discovery : from traditional medicines to modern drugs (1. Aufl. ed.). Weinheim: Wiley-VCH. p. 157. ISBN 9783527326693.
- ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
- ^ "Vinblastine". Retrieved 28 November 2015.
- ^ "Pharmacognosy of Vinca Alkaloids".
- ^ "FASS" (in Swedish). Retrieved 28 February 2013.
- ^ 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.
- ^ Goppi, P. G.; Broglia, C.; Merli, F.; Dell'Olio, M.; Stelitano, C.; Iannitto, E.; Federico, M.; Berté 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ R.C. Noble, C.T. Beer, and J.H. Cutts (5 December 1958) "Role of chance observations in chemotherapy: Vinca rosea," Annals of the New York Academy of Sciences, 76 (3): 882-894.
