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Eribulin is an anticancer drug marketed by Eisai Co. under the trade name Halaven. Eribulin is also known as E7389 and ER-086526, and also carries the US NCI designation NSC-707389. It is used to treat certain patients with breast cancer and liposarcoma.

Approvals and indications

Breast cancer

The mesylate salt was approved by the U.S. Food and Drug Administration on November 15, 2010, to treat patients with metastatic breast cancer who have received at least two prior chemotherapy regimens for late-stage disease, including both anthracycline- and taxane-based chemotherapies.^[1] It was approved by Health Canada on December 14, 2011, for treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease.^[2]

Liposarcoma

On January 28, 2016 the US FDA approved Halaven for the treatment of inoperable liposarcoma in patients who received prior chemotherapy that contained an anthracycline drug.^[3] A phase III trial reported: With Halaven the median overall survival for patients with liposarcoma was 15.6 months, compared to 8.4 months for patients treated with dacarbazine.^[3]

Clinical trials

Eribulin is also being investigated by Eisai Co. for use in a variety of other solid tumors, including non-small cell lung cancer, prostate cancer and sarcoma.^[4]

Structure and mechanism

Eribulin is a fully synthetic macrocyclic ketone analogue of the marine natural product halichondrin B,^[5]^[6] the parent molecule being a potent naturally occurring mitotic inhibitor with a unique mechanism of action found in the Halichondria genus of sponges.^[7]^[8]

Eribulin is a mechanistically unique inhibitor of microtubule dynamics,^[9]^[10] binding predominantly to a small number of high affinity sites at the plus ends of existing microtubules.^[11]^[12] Eribulin has both cytotoxic and non-cytotoxic mechanisms of action. Its cytotoxic effects are related to its antimitotic activities, wherein apoptosis of cancer cells is induced following prolonged and irreversible mitotic blockade.^[13]^[14] In addition to its cytotoxic, antimitotic-based mechanisms, preclinical studies in human breast cancer models have shown that eribulin also exerts complex effects on the biology of surviving cancer cells and residual tumors that appear unrelated to its antimitotic effects. These non-mitotic mechanisms include vascular remodeling that leads to increased tumor perfusion and mitigation of tumor hypoxia, phenotypic changes consistent with reversal of epithelial-mesenchymal transition (EMT), and decreased capacity for migration and invasion leading to reduced metastatic capacity as measured in a preclinical experimental metastasis model.^[15]^[16] In other studies, eribulin treatment of leiomyosarcoma and liposarcoma cells leads to increased expression of smooth muscle and adipocyte differentiation antigens, respectively.^[17]

A new synthetic route to the drug was published in 2009.^[18]

References

^ "FDA approves new treatment option for late-stage breast cancer" (Press release). USFDA. 2010-11-15. Retrieved November 15, 2010.
^ Notice of Decision for HALAVEN^{[permanent dead link]}
^ ^a ^b FDA approves first drug to show survival benefit in liposarcoma. Jan 2016
^ http://www.clinicaltrials.gov/ct2/results?term=eribulin+OR+E7389
^ Towle MJ, Salvato KA, Budrow J, Wels BF, Kuznetsov G, Aalfs KK, Welsh S, Zheng W, Seletsky BM, Palme MH, Habgood GJ, Singer LA, Dipietro LV, Wang Y, Chen JJ, Quincy DA, Davis A, Yoshimatsu K, Kishi Y, Yu MJ, Littlefield BA (February 2001). "In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B". Cancer Res. 61 (3): 1013–21. PMID 11221827.
^ Yu MJ, Kishi Y, Littlefield BA (2005). "Discovery of E7389, a fully synthetic macrocyclic ketone analogue of halichondrin B". In Newman DJ, Kingston DGI, Cragg, GM. Anticancer agents from natural products. Washington, DC: Taylor & Francis. ISBN 0-8493-1863-7.
^ Hirata Y, Uemura D (1986). "Halichondrins - antitumor polyether macrolides from a marine sponge". Pure Appl. Chem. 58 (5): 701–710. doi:10.1351/pac198658050701.
^ Bai RL, Paull KD, Herald CL, Malspeis L, Pettit GR, Hamel E (August 1991). "Halichondrin B and homohalichondrin B, marine natural products binding in the vinca domain of tubulin. Discovery of tubulin-based mechanism of action by analysis of differential cytotoxicity data". J. Biol. Chem. 266 (24): 15882–9. PMID 1874739.
^ Jordan MA, Kamath K, Manna T, Okouneva T, Miller HP, Davis C, Littlefield BA, Wilson L (July 2005). "The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth". Mol. Cancer Ther. 4 (7): 1086–95. PMID 16020666. doi:10.1158/1535-7163.MCT-04-0345.
^ Okouneva T, Azarenko O, Wilson L, Littlefield BA, Jordan MA (July 2008). "Inhibition of Centromere Dynamics by Eribulin (E7389) during Mitotic Metaphase". Mol. Cancer Ther. 7 (7): 2003–11. PMC 2562299 . PMID 18645010. doi:10.1158/1535-7163.MCT-08-0095.
^ Smith JA, Wilson L, Azarenko O, Zhu X, Lewis BM, Littlefield BA, Jordan MA (February 2010). "Eribulin Binds at Microtubule Ends to a Single Site on Tubulin to Suppress Dynamic Instability". Biochemistry. 49 (6): 1331–7. PMC 2846717 . PMID 20030375. doi:10.1021/bi901810u.
^ Wilson, L; Lopus, M; Miller, HP; Azarenko, O; Riffle, S; Smith, JA; Jordan, MA (2015). "Effects of eribulin on microtubule binding and dynamic instability are strengthened in the absence of the βIII tubulin isotype". Biochemistry. 54: 6482–9. PMID 26435331. doi:10.1021/acs.biochem.5b00745.
^ Kuznetsov G, Towle MJ, Cheng H, Kawamura T, TenDyke K, Liu D, Kishi Y, Yu MJ, Littlefield BA (August 2004). "Induction of morphological and biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389". Cancer Res. 64 (16): 5760–6. PMID 15313917. doi:10.1158/0008-5472.CAN-04-1169.
^ Towle MJ, Salvato KA, Wels BF, Aalfs KK, Zheng W, Seletsky BM, Zhu X, Lewis BM, Kishi Y, Yu MJ, Littlefield BA (January 2011). "Eribulin induces irreversible mitotic blockade: implications of cell-based pharmacodynamics for in vivo efficacy under intermittent dosing conditions". Cancer Res. 71 (2): 496–505. PMID 21127197. doi:10.1158/0008-5472.CAN-10-1874.
^ Funahashi Y, Okamoto K, Adachi Y, Semba T, Uesugi M, Ozawa Y, Tohyama O, Uehara T, Kimura T, Watanabe H, Asano M, Kawano S, Tizon X, McCracken PJ, Matsui J, Aoshima K, Nomoto K, Oda Y (October 2014). "Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models". Cancer Sci. 105 (10): 1334–42. PMID 25060424. doi:10.1111/cas.12488.
^ Yoshida T, Ozawa Y, Kimura T, Sato Y, Kuznetsov G, Xu S, Uesugi M, Agoulnik S, Taylor N, Funahashi Y, Matsui J (March 2014). "Eribulin mesilate suppresses experimental metastasis of breast cancer cells by reversing phenotype from epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET) states". Br. J. Cancer. 110 (6): 1497–505. PMID 24569463. doi:10.1038/bjc.2014.80.
^ Kawano S, Asano M, Adachi Y, Matsui J (April 2016). "Antimitotic and non-mitotic effects of eribulin mesilate in soft tissue sarcoma.". Anticancer Res. 36 (4): 1553–61. PMID 27069131.
^ Kim DS, Dong CG, Kim JT, Guo H, Huang J, Tiseni PS, Kishi Y (November 2009). "New syntheses of E7389 C14-C35 and halichondrin C14-C38 building blocks: double-inversion approach". J. Am. Chem. Soc. 131 (43): 15636–41. PMID 19807076. doi:10.1021/ja9058475.

External links

UpToDate Contents

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1. 非プラチナ製剤ベースの癌化学療法の神経学的合併症の概要 overview of neurologic complications of non platinum cancer chemotherapy
2. 女性の転移性乳癌に対する全身療法：化学療法 systemic treatment of metastatic breast cancer in women chemotherapy
3. 転移性軟部組織肉腫の全身治療 systemic treatment of metastatic soft tissue sarcoma
4. アントラサイクリン系以外の癌化学療法剤の心毒性 cardiotoxicity of nonanthracycline cancer chemotherapy agents
5. 化学療法関連腎毒性および腎不全患者における用量調整 chemotherapy related nephrotoxicity and dose modification in patients with renal insufficiency

English Journal

Eribulin in non-small cell lung cancer: challenges and potential strategies.

Swami U1, Shah U2, Goel S2.
Expert opinion on investigational drugs.Expert Opin Investig Drugs.2017 Feb 6. doi: 10.1080/13543784.2017.1292250. [Epub ahead of print]
INTRODUCTION: Eribulin is a non-taxane, macrocyclic, synthetic, ketone analog of Halichondrin B with a microtubule inhibitory action specific towards plus ends. It is approved by United States Food and Drug Administration (USFDA) for the treatment of patients with unresectable or metastatic liposarc
PMID 28161993

Newer medical therapies for metastatic soft tissue sarcoma.

Tiwari A1, Gupta VG1, Bakhshi S1.
Expert review of anticancer therapy.Expert Rev Anticancer Ther.2017 Feb 6:1-14. doi: 10.1080/14737140.2017.1285229. [Epub ahead of print]
INTRODUCTION: Metastatic/advanced soft tissue sarcoma has a poor prognosis conventionally, treatment options have been limited. In recent years, this area has been a rich ground for research with many new drugs being approved and several more in the pipeline. With multiple new treatment options avai
PMID 28103739

Use of Tumor-infiltrating lymphocytes (TILs) to predict the treatment response to eribulin chemotherapy in breast cancer.

Kashiwagi S1, Asano Y1, Goto W1, Takada K1, Takahashi K2, Noda S1, Takashima T1, Onoda N1, Tomita S2, Ohsawa M3, Hirakawa K1, Ohira M1.
PloS one.PLoS One.2017 Feb 6;12(2):e0170634. doi: 10.1371/journal.pone.0170634. eCollection 2017.
BACKGROUND: Eribulin mesylate (eribulin) is currently indicated for treatment of locally advanced or metastatic breast cancer (MBC). It is a cytotoxic agent with unique mechanisms that suppress epithelial-mesenchymal transition (EMT) of cancer cells. On the other hand, Tumor-infiltrating lymphocytes
PMID 28166544

Japanese Journal

悪性軟部腫瘍に対するエリブリンメシル酸塩（ハラヴェン<sup>®</sup>静注1 mg）の臨床効果と抗腫瘍メカニズムについて

日本薬理学雑誌 148(6), 329-333, 2016
NAID 130005170824

エリブリンによる転移・再発乳がん治療のパラダイムシフト

腫瘍内科 11(4), 495-502, 2013-04
NAID 40019686437

エリブリン(ハラヴェン) : 海洋天然物からの創薬展開 (特集アカデミアの創薬スクリーニング : 分子標的からリード化合物発見への戦略)

細胞工学 32(6), 675-681, 2013
NAID 40019689894

Related Pictures

Image of halaven soln for inj 0.5 mg/ml 0 Halaven, due to concerns over its safety Eisai’s Halaven® Approved In Israel Halaven Dosage & Drug Information | MIMS The FDA approved Eisai’s Halaven of halaven from sea to patients halaven Halaven intravenous : Uses, Side Effects Halaven | Bad Drug

★リンクテーブル★

リンク元

「エリブリン」

Eribulin
Clinical data
Trade names	Halaven
AHFS/Drugs.com	Consumer Drug Information
MedlinePlus	a611007
License data	US FDA: Eribulin;
Pregnancy; category	US: D (Evidence of risk); ;
Routes of; administration	Intravenous
ATC code	L01XX41 (WHO);
Legal status
Legal status	US: ℞-only;
Identifiers
	IUPAC name 2-(3-Amino-2-hydroxypropyl)hexacosahydro-3-methoxy- 26-methyl-20,27-bis(methylene)11,15-18,21-24,28-triepoxy- 7,9-ethano-12,15-methano-9H,15H-furo(3,2-i)furo(2',3'-5,6) pyrano(4,3-b)(1,4)dioxacyclopentacosin-5-(4H)-one;
CAS Number	253128-41-5 ;
PubChem CID	17755248;
ChemSpider	21396142 ;
UNII	LR24G6354G;
ChEMBL	CHEMBL1237028 ;
ECHA InfoCard	100.230.372
Chemical and physical data
Formula	C40H59NO11
Molar mass	729.90 g/mol
3D model (JSmol)	Interactive image;
	SMILES O=C1C[C@@H]2[C@H]([C@H](O[C@H]2C[C@H]3O[C@H](C[C@H](C3=C)C)CC[C@H]4C(C[C@@H](O4)CC[C@]5(O6)C[C@@H]([C@@H]7O5)O[C@H]([C@H]7O[C@]8(CC9)[H])[C@@H]6[C@@]8([H])O[C@H]9C1)=C)C[C@@H](CN)O)OC ;
	InChI InChI=1S/C41H61NO11/c1-20-12-26-7-9-29-21(2)13-25(46-29)6-5-11-41-18-34-37(52-41)38-39(51-34)40(53-41)36-30(50-38)10-8-27(48-36)14-23(43)15-28-32(17-31(47-26)22(20)3)49-33(35(28)45-4)16-24(44)19-42/h20,24-40,44H,2-3,5-19,42H2,1,4H3/t20-,24+,25+,26+,27-,28+,29+,30+,31-,32+,33-,34-,35-,36+,37+,38+,39-,40+,41+/m1/s1 ; Key:IGHZKAIPGTYWLF-FAXVPLPQSA-N ;
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　　[★]

英: eribulin
商: ハラヴェン Halaven
化: エリブリンメシル酸塩 eribulin mesilate
関: その他の腫瘍用薬

[1] "FDA approves new treatment option for late-stage breast cancer" (Press release). USFDA. 2010-11-15. Retrieved November 15, 2010.

[2] Notice of Decision for HALAVEN^{[permanent dead link]}

[FDA-lipo2016-3] FDA approves first drug to show survival benefit in liposarcoma. Jan 2016

[4] ttp://www.clinicaltrials.gov/ct2/results?term=eribulin+OR+E7389

[pmid11221827-5] Towle MJ, Salvato KA, Budrow J, Wels BF, Kuznetsov G, Aalfs KK, Welsh S, Zheng W, Seletsky BM, Palme MH, Habgood GJ, Singer LA, Dipietro LV, Wang Y, Chen JJ, Quincy DA, Davis A, Yoshimatsu K, Kishi Y, Yu MJ, Littlefield BA (February 2001). "In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B". Cancer Res. 61 (3): 1013–21. PMID 11221827.

[isbn0-8493-1863-7-6] Yu MJ, Kishi Y, Littlefield BA (2005). "Discovery of E7389, a fully synthetic macrocyclic ketone analogue of halichondrin B". In Newman DJ, Kingston DGI, Cragg, GM. Anticancer agents from natural products. Washington, DC: Taylor & Francis. ISBN 0-8493-1863-7.

[Hirata_1986-7] Hirata Y, Uemura D (1986). "Halichondrins - antitumor polyether macrolides from a marine sponge". Pure Appl. Chem. 58 (5): 701–710. doi:10.1351/pac198658050701.

[pmid1874739-8] Bai RL, Paull KD, Herald CL, Malspeis L, Pettit GR, Hamel E (August 1991). "Halichondrin B and homohalichondrin B, marine natural products binding in the vinca domain of tubulin. Discovery of tubulin-based mechanism of action by analysis of differential cytotoxicity data". J. Biol. Chem. 266 (24): 15882–9. PMID 1874739.

[pmid16020666-9] Jordan MA, Kamath K, Manna T, Okouneva T, Miller HP, Davis C, Littlefield BA, Wilson L (July 2005). "The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth". Mol. Cancer Ther. 4 (7): 1086–95. PMID 16020666. doi:10.1158/1535-7163.MCT-04-0345.

[pmid18645010-10] Okouneva T, Azarenko O, Wilson L, Littlefield BA, Jordan MA (July 2008). "Inhibition of Centromere Dynamics by Eribulin (E7389) during Mitotic Metaphase". Mol. Cancer Ther. 7 (7): 2003–11. PMC 2562299 . PMID 18645010. doi:10.1158/1535-7163.MCT-08-0095.

[pmid20030375-11] Smith JA, Wilson L, Azarenko O, Zhu X, Lewis BM, Littlefield BA, Jordan MA (February 2010). "Eribulin Binds at Microtubule Ends to a Single Site on Tubulin to Suppress Dynamic Instability". Biochemistry. 49 (6): 1331–7. PMC 2846717 . PMID 20030375. doi:10.1021/bi901810u.

[12] Wilson, L; Lopus, M; Miller, HP; Azarenko, O; Riffle, S; Smith, JA; Jordan, MA (2015). "Effects of eribulin on microtubule binding and dynamic instability are strengthened in the absence of the βIII tubulin isotype". Biochemistry. 54: 6482–9. PMID 26435331. doi:10.1021/acs.biochem.5b00745.

[pmid15313917-13] Kuznetsov G, Towle MJ, Cheng H, Kawamura T, TenDyke K, Liu D, Kishi Y, Yu MJ, Littlefield BA (August 2004). "Induction of morphological and biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389". Cancer Res. 64 (16): 5760–6. PMID 15313917. doi:10.1158/0008-5472.CAN-04-1169.

[pmid21127197-14] Towle MJ, Salvato KA, Wels BF, Aalfs KK, Zheng W, Seletsky BM, Zhu X, Lewis BM, Kishi Y, Yu MJ, Littlefield BA (January 2011). "Eribulin induces irreversible mitotic blockade: implications of cell-based pharmacodynamics for in vivo efficacy under intermittent dosing conditions". Cancer Res. 71 (2): 496–505. PMID 21127197. doi:10.1158/0008-5472.CAN-10-1874.

[pmid25060424-15] Funahashi Y, Okamoto K, Adachi Y, Semba T, Uesugi M, Ozawa Y, Tohyama O, Uehara T, Kimura T, Watanabe H, Asano M, Kawano S, Tizon X, McCracken PJ, Matsui J, Aoshima K, Nomoto K, Oda Y (October 2014). "Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models". Cancer Sci. 105 (10): 1334–42. PMID 25060424. doi:10.1111/cas.12488.

[pmid24569463-16] Yoshida T, Ozawa Y, Kimura T, Sato Y, Kuznetsov G, Xu S, Uesugi M, Agoulnik S, Taylor N, Funahashi Y, Matsui J (March 2014). "Eribulin mesilate suppresses experimental metastasis of breast cancer cells by reversing phenotype from epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET) states". Br. J. Cancer. 110 (6): 1497–505. PMID 24569463. doi:10.1038/bjc.2014.80.

[pmid27069131-17] Kawano S, Asano M, Adachi Y, Matsui J (April 2016). "Antimitotic and non-mitotic effects of eribulin mesilate in soft tissue sarcoma.". Anticancer Res. 36 (4): 1553–61. PMID 27069131.

[pmid19807076-18] Kim DS, Dong CG, Kim JT, Guo H, Huang J, Tiseni PS, Kishi Y (November 2009). "New syntheses of E7389 C14-C35 and halichondrin C14-C38 building blocks: double-inversion approach". J. Am. Chem. Soc. 131 (43): 15636–41. PMID 19807076. doi:10.1021/ja9058475.

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Halaven