WordNet

the writing point of a pen (同)pen nib

PrepTutorEJDIC

ペン先 / (一般的に)とがった部分,先端(tip) / (鳥の)くちばし

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/02/23 22:19:01」(JST)

wiki en

Dasatinib, previously known as BMS-354825, is a cancer drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel. Dasatinib is an oral multi- BCR/Abl and Src family tyrosine kinase inhibitor approved for first line use in patients with chronic myelogenous leukemia (CML)^[1] and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). It is being evaluated for use in numerous other cancers, including advanced prostate cancer.

The drug is named after one of the inventor chemists, Jagabandhu Das, who was a member of the large discovery and development team at Bristol Myers Squibb.^[2]

Origin and development[edit]

Efficacy[edit]

In a Phase I dose escalation study published in June 2006, dasatinib was tested in patients who were resistant to or who could not tolerate imatinib.^[3] Complete hematological responses^[4] were seen in 37 of 40 patients with chronic-phase CML. Major hematologic responses^[5] were seen in 31 of 44 patients with accelerated-phase CML, CML in blast crisis, or Ph+ ALL.

Molecular targets[edit]

Crystal structure^[6] (PDB 2GQG) of Abl kinase domain (blue) in complex with dasatinib (red).

The main targets of dasatinib are BCR/Abl, Src, c-Kit, ephrin receptors, and several other tyrosine kinases, but not erbB kinases such as EGFR or Her2.

Duration of benefit[edit]

Responses were maintained in 95% of patients with chronic-phase CML, with a median follow-up time of >12 months. In patients with accelerated-phase CML, 82% remained in remission, although with a median follow-up of only 5 months. Nearly all patients with CML in blast crisis or Ph+ ALL relapsed within 6 months.

Susceptible genotypes[edit]

Responses were seen in patients with all BCR/Abl genotypes, with the exception of T315I mutation, which confers resistance to dasatinib, nilotinib and imatinib in vitro.

Toxicities[edit]

Neutropenia and myelosuppression were common toxic effects. Fifteen patients (of 84, i.e. 18%) in the above-mentioned study developed pleural effusions, which were felt to be a side effect of dasatinib. Some of these patients required thoracentesis or pleurodesis to treat the effusions. Other adverse events included mild to moderate diarrhea, peripheral edema, and headache. A small number of patients developed abnormal liver function tests which returned to normal without dose adjustments. Mild hypocalcemia was also noted, but did not appear to cause any significant problems.Several cases of pulmonary arterial hypertension (PAH) were found in patients treated with dasatinib.^[7]

Adverse effects[edit]

On October 11, 2011 the U.S. Food and Drug Administration (FDA) announced that dasatinib may increase the risk of a rare but serious condition in which there is abnormally high blood pressure in the arteries of the lungs (pulmonary hypertension, PAH). Symptoms of PAH may include shortness of breath, fatigue, and swelling of the body (such as the ankles and legs). In reported cases, patients developed PAH after starting dasatinib, including after more than one year of treatment.

And information about this risk has been added to the Warnings and Precautions section of the Sprycel drug label.^[8]

References[edit]

^ FDA. "FDA approves additional medical indication for Sprycel". www.fda.gov. FDA. Retrieved 22 March 2013.
^ Das J et al. (2006). "2-aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1- piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor". J Med Chem 49 (23): 6819–32. doi:10.1021/jm060727j. PMID 17154512.
^ Talpaz M, Shah NP, Kantarjian H, et al. (June 2006). "Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias". N. Engl. J. Med. 354 (24): 2531–41. doi:10.1056/NEJMoa055229. PMID 16775234.
^ Complete hematologic response was defined as normal white blood cell and platelet counts, no blasts in the peripheral blood, <5% myelocytes plus metamyelocytes in the peripheral blood, <20% basophils in the peripheral blood, and no extramedullary disease.
^ The definition of a major hematologic response was sufficiently abstruse that the reader is referred to the original article (Talpaz et al., 2006) for details.
^ Tokarski, J. S.; Newitt, J. A.; Chang, C. Y.; Cheng, J. D.; Wittekind, M.; Kiefer, S. E.; Kish, K.; Lee, F. Y.; Borzillerri, R.; Lombardo, L. J.; Xie, D.; Zhang, Y.; Klei, H. E. (2006). "The Structure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase Domain Elucidates Its Inhibitory Activity against Imatinib-Resistant ABL Mutants". Cancer Research 66 (11): 5790–5797. doi:10.1158/0008-5472.CAN-05-4187. PMID 16740718. edit
^ NHS - Healthcare News
^ FDA: Sprycel (dasatinib): Drug Safety Communication - Risk of Pulmonary Arterial Hypertension, 10/11/2011.

External links[edit]

Summary Basis for Approval from the U.S. Food and Drug Administration Freedom of Information homepage
Prescribing information from Bristol-Myers Squibb
Sprycel Summary of Product Characteristics (from the European Medicines Agency website)

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. 慢性期の慢性骨髄性白血病の初期治療 initial treatment of chronic myeloid leukemia in chronic phase
2. 初期治療不奏効後の慢性期における慢性骨髄性白血病の治療 treatment of chronic myeloid leukemia in chronic phase after failure of initial therapy
3. 抗腫瘍療法関連肺毒性：分子標的剤 pulmonary toxicity associated with antineoplastic therapy molecularly targeted agents
4. 移行期における慢性骨髄性白血病の治療 treatment of chronic myeloid leukemia in accelerated phase
5. 慢性骨髄性白血病に対するチロシンキナーゼ阻害剤の臨床使用 clinical use of tyrosine kinase inhibitors for chronic myeloid leukemia

English Journal

Managing inadequate responses to frontline treatment of chronic myeloid leukemia: a case-based review.

Bixby DL.SourceDepartment of Internal Medicine, University of Michigan Comprehensive Cancer Center, 1500 East Medical Center Drive, Room 4214 CC, Ann Arbor, MI 48109, United States. dbixby@umich.edu
Cancer treatment reviews.Cancer Treat Rev.2013 May;39(3):241-51. doi: 10.1016/j.ctrv.2012.04.010. Epub 2012 Jul 19.
The tyrosine kinase inhibitors (TKIs) imatinib, nilotinib, and dasatinib are the standard of care for treating patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML). Compared with interferon-based treatment, the previous standard of care, imatinib is associated with significantl
PMID 22818213

Method development and validation for the quantification of dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, sorafenib and sunitinib in human plasma by liquid chromatography coupled with tandem mass spectrometry.

Lankheet NA, Hillebrand MJ, Rosing H, Schellens JH, Beijnen JH, Huitema AD.SourceDepartment of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Louwesweg 6, 1066, EC, Amsterdam, The Netherlands.
Biomedical chromatography : BMC.Biomed Chromatogr.2013 Apr;27(4):466-76. doi: 10.1002/bmc.2814. Epub 2012 Sep 17.
To support pharmacokinetic-guided dosing in individual patients, a fast and accurate method for simultaneous determination of anticancer tyrosine kinase inhibitors (TKIs) dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, sorafenib and sunitinib in human plasma was developed using high
PMID 22987603

Japanese Journal

成人急性リンパ性白血病に対する化学療法の現況

薄井紀子
臨床血液 51(10), 229-237, 2010-10-30
NAID 10026728556

慢性骨髄性白血病と第二世代ABLチロシンキナーゼ阻害剤

松村到
臨床血液 51(10), 66-74, 2010-10-30
NAID 10026727759

Related Pictures

★リンクテーブル★

リンク元	「イマチニブ」「nib」「上皮成長因子受容体阻害薬」「ダサチニブ」「血小板由来成長因子受容体」

「イマチニブ」

Dasatinib
Systematic (IUPAC) name
	N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-; 1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole; carboxamide monohydrate
Clinical data
Trade names	Sprycel
AHFS/Drugs.com	monograph
MedlinePlus	a607063
Licence data	EMA:Link, US FDA:link
Pregnancy cat.	D (AU) D (US)
Legal status	℞-only (US)
Routes	Oral
Pharmacokinetic data
Protein binding	96%
Metabolism	Hepatic
Half-life	1.3 to 5 hours
Excretion	Faecal (85%), renal (4%)
Identifiers
CAS number	302962-49-8
ATC code	L01XE06
PubChem	CID 3062316
DrugBank	DB01254
ChemSpider	2323020
UNII	X78UG0A0RN
KEGG	D03658
ChEBI	CHEBI:49375
ChEMBL	CHEMBL1421
Chemical data
Formula	C22H26ClN7O2S
Mol. mass	488.01 g/mol
	SMILES Cc1cccc(c1NC(=O)c2cnc(s2)Nc3cc(nc(n3)C)N4CCN(CC4)CCO)Cl;
	InChI InChI=1S/C22H26ClN7O2S/c1-14-4-3-5-16(23)20(14)28-21(32)17-13-24-22(33-17)27-18-12-19(26-15(2)25-18)30-8-6-29(7-9-30)10-11-31/h3-5,12-13,31H,6-11H2,1-2H3,(H,28,32)(H,24,25,26,27) ; Key:ZBNZXTGUTAYRHI-UHFFFAOYSA-N = ;
(what is this?) (verify)

　　[★]

英: imatinib
化: imatinib mesylate
商: グリベック
関: nib; 分子標的薬剤

分類

その他

チロシンキナーゼ阻害薬

概念

低分子のチロシンキナーゼ阻害薬である。
最初はPDGFRに特異的な阻害薬である2-phenylaminopyrimidine誘導体として開発された。
t(9;22)の染色体転座を有する慢性骨髄性白血病でみられるBCR-ABL融合蛋白を含め、ABLキナーゼに対する強い阻害作用を持つことが明らかとなった。
また受容体チロシンキナーゼであるC-KITのキナーゼも阻害することが明らかとなった。
造血幹細胞因子(SCF)の受容体はC-KITであるが、C-KITの変異はGISTやsystemic mastocytosisでしばしば見られる。
FIPL1-PDGFRA融合蛋白質の発現が特徴的なidiopathic hypereosinophilic syndromeはイマチニブ投与によりPDGFRAで阻害することで治療が成功する。