Vincristine

Vincristine

Systematic (IUPAC) name
methyl (1R,9R,10S,11R,12R,19R)- 11-(acetyloxy)
Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a682822
Pregnancy cat.	D(AU) D(US)
Legal status	℞ Prescription only
Routes	Exclusively intravenous
Pharmacokinetic data
Bioavailability	n/a
Protein binding	~75%
Metabolism	Hepatic
Half-life	19 to 155 hours
Excretion	Mostly biliary, 10% in urine
Identifiers
CAS number	57-22-7 Y
ATC code	L01CA02
PubChem	CID 5978
DrugBank	APRD00495
ChemSpider	5758 Y
UNII	5J49Q6B70F N
KEGG	D08679 N
ChEBI	CHEBI:28445 N
ChEMBL	CHEMBL303560 N
Chemical data
Formula	C46H56N4O10
Mol. mass	824.958 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C46H56N4O10/c1-7-42(55)22-28-23-45(40(53)58-5,36-30(14-18-48(24-28) N Key:OGWKCGZFUXNPDA-XQKSVPLYSA-N Y
N(what is this?)  (verify)

Vincristine (brand name, Oncovin), formally known as leurocristine, sometimes abbreviated "VCR", is a vinca alkaloid from the Catharanthus roseus (Madagascar periwinkle), formerly Vinca rosea and hence its name. It is a mitotic inhibitor, and is used in cancer chemotherapy.

Mechanism

Tubulin is a structural protein that polymerizes to microtubules. The cell cytoskeleton and mitotic spindle, among other things, are made of microtubules. Vincristine binds to tubulin dimers, inhibiting assembly of microtubule structures. Disruption of the microtubules arrests mitosis in metaphase. Therefore, the vinca alkaloids affect all rapidly dividing cell types including cancer cells, but also those of intestinal epithelium and bone marrow.

Uses

Vincristine is delivered via intravenous infusion for use in various types of chemotherapy regimens. Its main uses are in non-Hodgkin's lymphoma as part of the chemotherapy regimen CHOP, Hodgkin's lymphoma as part of MOPP, COPP, BEACOPP, or the less popular Stanford V chemotherapy regimen, in acute lymphoblastic leukemia, and in treatment for nephroblastoma (Wilms tumor, a kidney tumor most common in young children). It is also used to induce remission in ALL with Dexamethasone and L-Asparaginase. Vincristine is occasionally used as an immunosuppressant, for example, in treating thrombotic thrombocytopenic purpura (TTP) or chronic idiopathic thrombocytopenic purpura (ITP). It is used in combination with prednisone to treat childhood leukemia.

Side-effects

The main side-effects of vincristine are peripheral neuropathy, hyponatremia, constipation, and hair loss.

Peripheral neuropathy can be severe, and hence a reason to avoid, reduce, or stop the use of vincristine. One of the first symptoms of peripheral neuropathy is foot drop: A person with a family history of foot drop and/or Charcot-Marie-Tooth disease (CMT) may benefit from genetic testing for CMT before taking vincristine.^[1]

Accidental injection of vinca alkaloids into the spinal canal (intrathecal administration) is highly dangerous, with a mortality rate approaching 100 percent. The medical literature documents cases of ascending paralysis due to massive encephalopathy and spinal nerve demyelination, accompanied by intractable pain, almost uniformly leading to death; a handful of survivors were left with devastating neurological damage with no hope of recovery. Rescue treatments consist of washout of the cerebrospinal fluid and administration of protective medications.^[2] A significant series of inadvertent intrathecal vincristine administration occurred in China in 2007 when batches of cytarabine and methotrexate (both often used intrathecally) manufactured by the company Shanghai Hualian were found to be contaminated with vincristine.^[3]

History

Having been used as a folk remedy for centuries, studies in the 1950s revealed that C. roseus contained 70 alkaloids, many of which are biologically active. While initial studies for its use in diabetes mellitus were disappointing, the discovery that it caused myelosuppression (decreased activity of the bone marrow) led to its study in mice with leukemia, whose lifespan was prolonged by the use of a vinca preparation. Treatment of the ground plant with Skelly-B defatting agent and an acid benzene extract led to a fraction termed "fraction A". This fraction was further treated with aluminium oxide, chromatography, trichloromethane, benz-dichloromethane, and separation by pH to yield vincristine.^[4]

Vincristine was approved by the United States Food and Drug Administration (FDA) in July 1963 as Oncovin. The drug was initially discovered by a team led by Dr. J.G. Armstrong; it was then marketed by Eli Lilly and Company.

Suppliers

Three generic drug makers supply vincristine in the United States - APP, Mayne, and Sicor (Teva).

See also

• Rosy Periwinkle

References

1. ^ Graf WD, Chance PF, Lensch MW, Eng LJ, Lipe HP, Bird TD (1996). "Severe vincristine neuropathy in Charcot-Marie-Tooth disease type 1A". Cancer 77 (7): 1356–62. doi:10.1002/(SICI)1097-0142(19960401)77:7<1356::AID-CNCR20>3.0.CO;2-#. PMID 8608515. 
2. ^ Qweider M, Gilsbach JM, Rohde V (2007). "Inadvertent intrathecal vincristine administration: a neurosurgical emergency. Case report". J Neurosurg Spine 6 (3): 280–3. doi:10.3171/spi.2007.6.3.280. PMID 17355029. 
3. ^ Tainted Drugs Tied to Maker of Abortion Pill, Jake Hooker and Walt Bogdanich, New York Times, January 31, 2008
4. ^ Johnson IS, Armstrong JG, Gorman M, Burnett JP (1 September 1963). "The vinca alkaloids: a new class of oncolytic agents". Cancer Res 23 (8 Part 1): 1390–427. PMID 14070392. http://cancerres.aacrjournals.org/cgi/reprint/23/8_Part_1/1390. 

External links

• Vincristine chemotherapy
• Vincristine and vinblastine
• Description and Natural History of the Periwinkle
• The Boger Route to (-)-Vindoline
• U.S. National Library of Medicine: Drug Information Portal - Vincristine