同: Abbokinase

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/08/07 23:00:22」(JST)

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Urokinase (trade name Abbokinase), also called urokinase-type plasminogen activator (uPA), is a serine protease (EC 3.4.21.73). It was discovered in 1947 by McFarlane.^[1] Urokinase was originally isolated from human urine, but is present in several physiological locations, such as blood stream and the extracellular matrix. The primary physiological substrate is plasminogen, which is an inactive form (zymogen) of the serine protease plasmin. Activation of plasmin triggers a proteolysis cascade that, depending on the physiological environment, participates in thrombolysis or extracellular matrix degradation. This links urokinase to vascular diseases and cancer.

Molecular characteristics

Urokinase is a 411-residue protein, consisting of three domains: the serine protease domain, the kringle domain, and the growth factor domain. Urokinase is synthesized as a zymogen form (prourokinase or single-chain urokinase), and is activated by proteolytic cleavage between Lys158 and Ile159. The two resulting chains are kept together by a disulfide bond.

Interaction partners

The most important inhibitors of urokinase are the serpins plasminogen activator inhibitor-1 (PAI-1) and plasminogen activator inhibitor-2 (PAI-2), which inhibit the protease activity irreversibly. In the extracellular matrix, urokinase is tethered to the cell membrane by its interaction to the urokinase receptor.

Fibrinolysis (simplified). Blue arrows denote stimulation, and red arrows inhibition.

The molecular weight of (high molecular weight) urokinase is about 54000 Daltons. Only the Abbokinase = low molecular weight urokinase has a molecular weight of about 31000 Daltons.

Urokinase and cancer

Elevated expression levels of urokinase and several other components of the plasminogen activation system are found to be correlated with tumor malignancy. It is believed that the tissue degradation following plasminogen activation facilitates tissue invasion and, thus, contributes to metastasis. This makes urokinase an attractive drug target, and, so, inhibitors have been sought to be used as anticancer agents.^[2]^[3] However, incompatibilities between the human and murine systems hamper clinical evaluation of these agents. Through its interaction with the urokinase receptor, urokinase affects several other aspects of cancer biology such as cells adhesion, migration, and cellular mitotic pathways.

As of December 7, 2012 Mesupron®, a small molecule serine protease inhibitor developed by the WILEX pharmaceutical company, has completed phase II trials.^[4] Mesupron appears to be safe when combined with chemotherapeutic drug Capecitabine for the progression-free survival in human breast cancer.^[5]

Clinical applications

Urokinase is used clinically as a thrombolytic agent in the treatment of severe or massive deep venous thrombosis, pulmonary embolism, myocardial infarction, and occluded intravenous or dialysis cannulas. It is also administered intrapleurally to improve the drainage of complicated pleural effusions and empyemas. Urokinase is marketed as Kinlytic^TM, and competes with Alteplase^TM as a thrombolytic drug in infarction. It is the most effective drug in myocardial infarction.^{[citation needed]} In contrast to TPA tissue plasminogen activator, it immediately removes the clot. Its injection is very costly.^[vague]

References

^ Nursing grand rounds pdfs.journals.lww.com/.../Nursing_grand_rounds.8.pdf J Vitello-Cicciu - 1987
^ Jankun J, Skrzypczak-Jankun E (July 1999). "Molecular basis of specific inhibition of urokinase plasminogen activator by amiloride". Cancer Biochem. Biophys. 17 (1-2): 109–23. PMID 10738907.
^ Matthews H, Ranson M, Kelso MJ (November 2011). "Anti-tumour/metastasis effects of the potassium-sparing diuretic amiloride: an orally active anti-cancer drug waiting for its call-of-duty?". Int. J. Cancer 129 (9): 2051–61. doi:10.1002/ijc.26156. PMID 21544803.
^ "Gemcitabine With or Without WX-671 in Treating Patients With Locally Advanced Pancreatic Cancer That Cannot Be Removed By Surgery". ClinicalTrials.gov.
^ "Fox Chase Cancer Center : New Small Molecule Inhibitor Could be a Safe and First-Line Treatment for Metastatic Breast Cancer". Press Release. Temple University Health System.

UpToDate Contents

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1. 急性肺塞栓症および下肢深部静脈血栓症における線溶（血栓溶解）療法 fibrinolytic thrombolytic therapy in acute pulmonary embolism and lower extremity deep vein thrombosis
2. 長期血液透析でのブラッドアクセスに関連した血栓症：カテーテル thrombosis associated with chronic hemodialysis vascular access catheters
3. 止血の概要 overview of hemostasis
4. 成人における肺炎随伴性胸水および膿胸 parapneumonic effusion and empyema in adults
5. 幼児および小児における静脈血栓症および血栓塞栓症の診断および治療 diagnosis and treatment of venous thrombosis and thromboembolism in infants and children

English Journal

Tissue and urokinase plasminogen activators instigate the degeneration of retinal ganglion cells in a mouse model of glaucoma.

Chintala SK1.
Experimental eye research.Exp Eye Res.2016 Feb;143:17-27. doi: 10.1016/j.exer.2015.10.003. Epub 2015 Oct 22.
Elevated intraocular pressure (IOP) promotes the degeneration of retinal ganglion cells (RGCs) during the progression of Primary Open-Angle Glaucoma (POAG). However, the molecular mechanisms underpinning IOP-mediated degeneration of RGCs remain unclear. Therefore, by employing a mouse model of POAG,
PMID 26474495

Decreased expression of the plasminogen activator inhibitor type 1 is involved in degradation of extracellular matrix surrounding cervical cancer stem cells.

Sato M1, Kawana K1, Adachi K1, Fujimoto A1, Yoshida M1, Nakamura H1, Nishida H1, Inoue T1, Taguchi A1, Takahashi J1, Kojima S1, Yamashita A1, Tomio K1, Nagamatsu T1, Wada-Hiraike O1, Oda K1, Osuga Y1, Fujii T1.
International journal of oncology.Int J Oncol.2016 Feb;48(2):829-35. doi: 10.3892/ijo.2015.3283. Epub 2015 Dec 9.
The plasminogen activator (PA) system consists of plasminogen activator inhibitor type 1 (PAI-1), urokinase-type plasminogen activator and its receptor (uPA and uPAR). PAI-1 inhibits the activation of uPA (which converts plasminogen to plasmin), and is involved in cancer invasion and metastasis, by
PMID 26676222

Hypoxia inducible factor-1 mediates upregulation of urokinase-type plasminogen activator receptor gene transcription during hypoxia in cervical cancer cells.

Nishi H1, Sasaki T1, Nagamitsu Y1, Terauchi F1, Nagai T2, Nagao T2, Isaka K1.
Oncology reports.Oncol Rep.2016 Feb;35(2):992-8. doi: 10.3892/or.2015.4449. Epub 2015 Nov 25.
Hypoxia occurs during development of cervical cancer and is considered to correlate with its invasion. Hypoxia mediates tumor cells to have more invasive property in a variety of cancers. Urokinase plasminogen activator receptor (uPAR) which mediates invasion is considered to be induced by hypoxia.
PMID 26718775

Japanese Journal

症例報告 Streptococcus intermediusとBacillus circulansを起炎菌とした膿胸に対しウロキナーゼによる胸腔内注入が有効であった1例

藤原清宏,大田正秀,小林真也 [他]
救急医学 = The Japanese journal of acute medicine 39(8), 1006-1011, 2015-08
NAID 40020560255

内視鏡下脊柱管拡大術におけるウロキナーゼ固定化抗血栓性ドレーンの効果とドレーン設置法の工夫 (日本脊椎・脊髄神経手術手技学会特集号) -- (合併症)

中村周
Journal of spine research : official journal of the Japanese Society for Spine Surgery and Related Research 6(7), 1215-1219, 2015-07
NAID 40020546274

急性期脳梗塞における，治療別に見た急性期血行再建術の成績の比較

竹中朋文,芝野克彦,梅垣昌士,佐々木学,鶴薗浩一郎,松本勝美
脳卒中 advpub(0), 2015
要旨：急性期脳梗塞への治療は，血管内治療併用や閉塞血管別の治療方針など未確定な部分が多い．我々は2005 年4 月～2014 年10 月の間に急性期脳梗塞にてrt-PA 静注療法および血管内治療，あるいはその双方を施行した急性期脳梗塞患者191 例に対し，A 群（rt-PA 静注），B 群（ウロキナーゼ動注），C 群（機械的血栓除去），D 群（failed rt-PA 患者に血管内治療を追加）に分 …
NAID 130005101624

Related Pictures

★リンクテーブル★

リンク元	「ウロキナーゼ」「u-PA」「urinary plasminogen activator」「uPA」
拡張検索	「urokinase-type plasminogen activator」

「ウロキナーゼ」

plasminogen activator, urokinase
Identifiers
Symbol	PLAU
Entrez	5328
HUGO	9052
OMIM	191840
RefSeq	NM_002658
UniProt	P00749
Other data
EC number	3.4.21.31
Locus	Chr. 10 q24

Urokinase
Clinical data
AHFS/Drugs.com	monograph
Identifiers
CAS Registry Number	9039-53-6
ATC code	B01AD04
DrugBank	DB00013
UNII	83G67E21XI
KEGG	D03341
ChEMBL	CHEMBL1201420
Chemical data
Formula	C1376H2145N383O406S18
Molecular mass	31126.5 g/mol
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