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periwinkle plant derivative used as an antineoplastic drug (trade name Oncovin); used to treat cancer of the lymphatic system (同)Oncovin

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/02/18 12:53:30」(JST)

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Vincristine, also known as leurocristine and marketed under the brandname Oncovin among others, is a chemotherapy medication used to treat a number of types of cancer.^[5] This includes acute lymphocytic leukemia, acute myeloid leukemia, Hodgkin's disease, neuroblastoma, and small cell lung cancer among others. It is given intravenously.^[5]

Most people experience some side effects from vincristine treatment. Commonly it causes a change in sensation, hair loss, constipation, difficulty walking, and headaches. Serious side effects may include neuropathic pain, lung damage, or low blood white cells. It will likely cause harm to an infant if given during pregnancy. It works by stopping cells from dividing properly.^[5]

Vincristine was first isolated in 1961.^[6] It is on the World Health Organization's List of Essential Medicines, the most important medication needed in a basic health system.^[7] The wholesale cost is between 1.80 and 42.60 USD per dose.^[8] It is a vinca alkaloid that can be obtained from the Madagascar periwinkle Catharanthus roseus.^[6]

Medical uses

Vincristine is delivered via intravenous infusion for use in various types of chemotherapy regimens.^[3] 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 (ALL), and in treatment for nephroblastoma.^[3] It is also used to induce remission in ALL with dexamethasone and L-Asparaginase, and in combination with prednisone to treat childhood leukemia.^[3] Vincristine is occasionally used as an immunosuppressant, for example, in treating thrombotic thrombocytopenic purpura (TTP) or chronic idiopathic thrombocytopenic purpura (ITP).^[3]

Side effects

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

Chemotherapy-induced peripheral neuropathy can be severe, and may be a reason to reduce or avoid using vincristine. The symptoms of this are progressive and enduring tingling numbness, pain and hypersensitivity to cold, beginning in the hands and feet and sometimes affecting the arms and legs.^[9] 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) should avoid the taking of vincristine.^[10]

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. Several patients have survived after aggressive and immediate intervention. Rescue treatments consist of washout of the cerebrospinal fluid and administration of protective medications.^[11] Children may do better following this injury. One child, who was aggressively treated at the time of the injection, recovered almost completely with only mild neurological deficits.^[12] 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.^[13]

Mechanism of action

Vincristine works partly by binding to the tubulin protein, stopping the cell from separating its chromosomes during the metaphase; the cell then undergoes apoptosis.^[14]

Because vincristine's mechanism of action targets all rapidly dividing cell types, it not only inhibits cancerous cells but can also affect the intestinal epithelium and bone marrow.^{[citation needed]}

Pharmacology

Vincristine is created by the coupling of indole alkaloids vindoline and catharanthine in the vinca plant.^[15]

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.^[16]

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).

Research

In 2012 the FDA approved a Liposomal formulation of Vincristine.^[17] A novel nano-particle bound version of Vincristine is under development.^[18]

References

^ "NCI Drug Dictionary". NCI. Retrieved 28 November 2015.
^ "Vincristine". Dictionary.com. Random House, Inc. Retrieved 9 November 2014.
^ ^a ^b ^c ^d ^e ^f ^g ^h Brayfield, A, ed. (13 December 2013). "Vincristine". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 15 April 2014.
^ "Oncovin, Vincasar PFS (vincristine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 16 April 2014.
^ ^a ^b ^c "Vincristine Sulfate". The American Society of Health-System Pharmacists. Retrieved Jan 2, 2015.
^ ^a ^b Ravina, Enrique (2011). The evolution of drug discovery : from traditional medicines to modern drugs (1. Aufl. ed.). Weinheim: Wiley-VCH. pp. 157–159. ISBN 9783527326693.
^ "WHO Model List of Essential Medicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
^ "Vincristine". International Drug Price Indicator Guide. Retrieved 28 November 2015.
^ del Pino BM. Chemotherapy-induced Peripheral Neuropathy. NCI Cancer Bulletin. Feb 23, 2010;7(4):6.
^ 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.
^ 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.
^ Zaragosa, M.; Ritchey, M.; Walter, A. (1995). "Neurological Consequences of Accidental Intrathecal Vincristine: A Case Report.". Medial and Pediatric Oncology 24: 61–62. doi:10.1002/mpo.2950240114. PMID 7968797.
^ Jake Hooker and Walt Bogdanich (January 31, 2008). "Tainted Drugs Tied to Maker of Abortion Pill". New York Times.
^ Jordan, MA (January 2002). "Mechanism of action of antitumor drugs that interact with microtubules and tubulin.". Current medicinal chemistry. Anti-cancer agents 2 (1): 1–17. doi:10.2174/1568011023354290. PMID 12678749.
^ "Pharmacognosy of Vinca Alkaloids".
^ 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.
^ FDA press release Aug 9, 2012
^ Bind Therapeutics conference call of Nov 6, 2014

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

UpToDate Contents

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English Journal

Endophytes as in vitro production platforms of high value plant secondary metabolites.

Venugopalan A1, Srivastava S2.
Biotechnology advances.Biotechnol Adv.2015 Nov 1;33(6 Pt 1):873-87. doi: 10.1016/j.biotechadv.2015.07.004. Epub 2015 Jul 28.
Many reports have been published on bioprospecting of endophytic fungi capable of producing high value bioactive molecules like, paclitaxel, vincristine, vinblastine, camptothecin and podophyllotoxin. However, commercial exploitation of endophytes for high value-low volume plant secondary metabolite
PMID 26225453

Theoretical insight into the structural mechanism for the binding of vinblastine with tubulin.

Chi S1, Xie W, Zhang J, Xu S.
Journal of biomolecular structure & dynamics.J Biomol Struct Dyn.2015 Oct;33(10):2234-54. doi: 10.1080/07391102.2014.999256. Epub 2015 Jan 14.
Vinblastine (VLB) is one of vinca alkaloids with high cytotoxicity toward cancer cells approved for clinical use. However, because of drug resistance, toxicity, and other side effects caused from the use of VLB, new vinca alkaloids with higher cytotoxicity toward cancer cells and other good qualitie
PMID 25588192

Lack of vincristine infiltrates in patients with retinoblastoma receiving chemotherapy by peripheral intravenous lines.

DiDomenico C1, Clerico D1, Leahey A1.
Pediatric blood & cancer.Pediatr Blood Cancer.2015 Oct;62(10):1859-61. doi: 10.1002/pbc.25566. Epub 2015 Apr 30.
The delivery route of chemotherapy for intraocular retinoblastoma has become controversial. One objection to systemic delivery is the need for central venous access. We cross-referenced a hospital vascular access database with our tumor registry to determine the incidence of chemotherapy infiltrates
PMID 25929686

Japanese Journal

Sequential chemotherapy and myeloablative allogeneic hematopoietic stem cell transplantation for refractory acute lymphoblastic leukemia

Arita Kotaro,Kondo Takeshi,Sugita Junichi,Shigematsu Akio,Shiratori Souichi,Wakasa Kentaro,Yasumoto Atsushi,Ibata Makoto,Shono Yusuke,Kikuchi Misato,Goto Hideki,Takeda Yukari,Takahata Mutsumi,Kato Naoko,Nishio Mitsufumi,Ota Shuichi,Tanaka Junji,Imamura Masahiro
International Journal of Hematology 94(3), 291-295, 2011-09
… To improve survival rates, we attempted to intensify the conditioning regimen with daunorubicin, vincristine, prednisolone, medium-dose etoposide, cyclophosphamide, and total body irradiation (DNR/VCR/PSL plus medium-dose VP/CY/TBI). …
NAID 80022059922

胃病変を伴った消化管濾胞性リンパ腫の1例

荻原真之,堀田欣一,小山恒男,宮田佳典,友利彰寿,高橋亜紀子,北村陽子
日本消化器内視鏡学会雑誌 = Gastroenterological endoscopy 53(8), 2006-2011, 2011-08-20
症例は70歳，女性．上部消化管内視鏡検査にて胃角小彎に境界不明瞭な発赤調の平坦性病変を認め，十二指腸下行部に白色顆粒の集簇を認めた．生検の結果，両病変とも消化管濾胞性リンパ腫と診断した．経口的・経肛門的ダブルバルーン内視鏡検査を施行し，空腸，回腸にも濾胞性リンパ腫を認めた．治療はrituximab併用化学療法を選択し，寛解導入し得た．消化管瀘胞性リンパ腫に胃病変を合併することはまれであり，報告する …
NAID 10029562680

Related Pictures

★リンクテーブル★

リンク元	「ビンクリスチン」「絨毛癌」「ビンカアルカロイド」「oncovin」「VCR」
拡張検索	「vincristine sulfate」

「ビンクリスチン」

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
Pronunciation	i/ˈvɪnˈkrɪstiːn/
Trade names	Oncovin, Vincasar, others
AHFS/Drugs.com	monograph
MedlinePlus	a682822
Pregnancy; category	AU: D; US: D (Evidence of risk); ;
Legal status	AU: S4 (Prescription only); CA: ℞-only; UK: POM (Prescription only); US: ℞-only;
Routes of; administration	intravenous
Pharmacokinetic data
Bioavailability	n/a (not reliably absorbed by the GI tract)
Protein binding	~44%
Metabolism	Liver, mostly via CYP3A4 and CYP3A5
Biological half-life	19 to 155 hours (mean: 85 hours)
Excretion	Faeces (70-80%), urine (10-20%)
Identifiers
CAS Number	57-22-7
ATC code	L01CA02
PubChem	CID 5978
IUPHAR/BPS	6785
DrugBank	DB00541
ChemSpider	5758
UNII	5J49Q6B70F
KEGG	D08679
ChEBI	CHEBI:28445
ChEMBL	CHEMBL303560
Chemical data
Formula	C46H56N4O10
Molar mass	824.958 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=O)[C@@](O)(C(=O)OC)[C@H](OC(=O)C)[C@@]7(/C=C\CN([C@@H]78)CC9)CC ;
	InChI InChI=1S/C46H56N4O10/c1-7-42(55)22-28-23-45(40(53)58-5,36-30(14-18-48(24-28) ; Key:OGWKCGZFUXNPDA-XQKSVPLYSA-N ;
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　　[★]

英: vincristine, VCR
同: 硫酸リューロクリスチン leurocristine sulfate
化: 硫酸ビンクリスチン vincristine sulfate　
商: ONCO-TCS、ONCOVIN、VINCASAR PFS、オンコビン oncovin
関

first aid step1 2006 p.84,310

特徴

ビンカアルカロイドの一つで、チューブリンに結合して微小管の重合(紡錘体の形成を含む)を阻害して細胞増殖を抑制する。　⇔ (パクリタキセルは微小管の脱重合を阻害)

構造

ビンカアルカロイド

作用機序

M-phase-specific alkaloids that bind to tubulin and block polymerization of microtubules so that mitotic spindle cannot form (first aid step1 2006 p.310)

適応

part of the MOPP (Oncovin [vincristine]) regimen for lymphoma, Wilms' tumor, choriocarcinoma(first aid step1 2006 p.310)
MAPP regimen for Hodgkin disease, ALL lymphoma, CNS tumer, sarcoma, Wilms tumor