Vincristine

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Vincristine
Systematic (IUPAC) name
(3aR,3a1R,4R,5S,5aR,10bR)-methyl 4-acetoxy-3a-ethyl-9-((5S,7S,9S)-5-ethyl-5-hydroxy-9-(methoxycarbonyl)-2,4,5,6,7,8,9,10-octahydro-1H-3,7-methano[1]azacycloundecino[5,4-b]indol-9-yl)-6-formyl-5-hydroxy-8-methoxy-3a,3a1,4,5,5a,6,11,12-octahydro-1H-indolizino[8,1-cd]carbazole-5-carboxylate
Clinical data
AHFS/Drugs.commonograph
MedlinePlusa682822
Pregnancy cat.D (AU) D (US)
Legal status Prescription only
RoutesExclusively intravenous
Pharmacokinetic data
Bioavailabilityn/a
Protein binding~75%
MetabolismHepatic
Half-life19 to 155 hours
ExcretionMostly biliary, 10% in urine
Identifiers
CAS number57-22-7 YesY
ATC codeL01CA02
PubChemCID 5978
DrugBankDB00541
ChemSpider5758 YesY
UNII5J49Q6B70F YesY
KEGGD08679 YesY
ChEBICHEBI:28445 YesY
ChEMBLCHEMBL303560 N
Chemical data
FormulaC46H56N4O10 
Mol. mass824.958 g/mol
 N (what is this?)  (verify)
 
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Vincristine
Systematic (IUPAC) name
(3aR,3a1R,4R,5S,5aR,10bR)-methyl 4-acetoxy-3a-ethyl-9-((5S,7S,9S)-5-ethyl-5-hydroxy-9-(methoxycarbonyl)-2,4,5,6,7,8,9,10-octahydro-1H-3,7-methano[1]azacycloundecino[5,4-b]indol-9-yl)-6-formyl-5-hydroxy-8-methoxy-3a,3a1,4,5,5a,6,11,12-octahydro-1H-indolizino[8,1-cd]carbazole-5-carboxylate
Clinical data
AHFS/Drugs.commonograph
MedlinePlusa682822
Pregnancy cat.D (AU) D (US)
Legal status Prescription only
RoutesExclusively intravenous
Pharmacokinetic data
Bioavailabilityn/a
Protein binding~75%
MetabolismHepatic
Half-life19 to 155 hours
ExcretionMostly biliary, 10% in urine
Identifiers
CAS number57-22-7 YesY
ATC codeL01CA02
PubChemCID 5978
DrugBankDB00541
ChemSpider5758 YesY
UNII5J49Q6B70F YesY
KEGGD08679 YesY
ChEBICHEBI:28445 YesY
ChEMBLCHEMBL303560 N
Chemical data
FormulaC46H56N4O10 
Mol. mass824.958 g/mol
 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. Vincristine is created by the coupling of indole alkaloids vindoline and catharanthine in the vinca plant.[1]

Contents

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.[2]

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.[3] 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.[4]

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.[5]

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, 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

References

  1. ^ "Pharmacognosy of Vinca Alkaloids". http://pharmaxchange.info/press/2012/01/pharmacognosy-of-vinca-alkaloids-periwinkle/. 
  2. ^ Graf, W. D.; Chance, P. F.; Lensch, M. W.; Eng, L. J.; Lipe, H. P.; Bird, T. D. (1996). "Severe Vincristine Neuropathy in Charcot-Marie-Tooth Disease Type 1A". Cancer 77 (7): 1356–1362. doi:10.1002/(SICI)1097-0142(19960401)77:7<1356::AID-CNCR20>3.0.CO;2-#. PMID 8608515. 
  3. ^ Qweider, M.; Gilsbach, J. M.; Rohde, V. (2007). "Inadvertent Intrathecal Vincristine Administration: A Neurosurgical Emergency. Case Report". Journal of Neurosurgery: Spine 6 (3): 280–283. doi:10.3171/spi.2007.6.3.280. PMID 17355029. 
  4. ^ Jake Hooker and Walt Bogdanich (January 31, 2008). "Tainted Drugs Tied to Maker of Abortion Pill". New York Times. http://www.nytimes.com/2008/01/31/world/asia/31pharma.html?_r=1&ref=health. 
  5. ^ Johnson, I. S.; Armstrong, J. G.; Gorman, M.; Burnett, J. P. (1963). "The Vinca Alkaloids: A New Class of Oncolytic Agents" (pdf). Cancer Research 23 (8 Part 1): 1390–1427. PMID 14070392. http://cancerres.aacrjournals.org/content/23/8_Part_1/1390.full.pdf. 

External links