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an alkalating agent (trade name Leukeran) used to treat some kinds of cancer (同)Leukeran

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/07/08 15:44:46」(JST)

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Chlorambucil (marketed as Leukeran by GlaxoSmithKline) is a chemotherapy drug that has been mainly used in the treatment of chronic lymphocytic leukemia. It is a nitrogen mustard alkylating agent^[1] and can be given orally.

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.^[2]

History

Nitrogen mustards arose from the derivatization of sulphur mustard gas after military personnel exposed to it during World War I were observed to have decreased white blood cell counts.^[3] Since the sulphur mustard gas was too toxic to be used in humans, Gilman hypothesized that by reducing the electrophilicity of the agent, which made it highly chemically reactive towards electron-rich groups, then less toxic drugs could be obtained. To this end, he made analogues that were less electrophilic by exchanging the sulphur with a nitrogen, leading to the nitrogen mustards.^[4]

With an acceptable therapeutic index in humans, nitrogen mustards were first introduced in the clinic in 1946.^[5] Aliphatic mustards were developed first, such as mechlorethamine hydrochloride (mustine hydrochloride) which is still used in the clinic today.

In the 1950s, aromatic mustards like chlorambucil were introduced as less toxic alkylating agents than the aliphatic nitrogen mustards, proving to be less electrophilic and react with DNA more slowly. Additionally, these agent can be administered orally, a significant advantage.

Chlorambucil was first synthesized by Everett et al.^[6]

Physical and Chemical Properties

Chlorambucil is a white to pale beige crystalline or granular powder with a slight odor. When heated to decomposition it emits very toxic fumes of hydrogen chloride and nitrogen oxides.^[7]

Mechanism of action

Chlorambucil produces its anti-cancer effects by interfering with DNA replication and damaging the DNA in a cell. The DNA damage induces cell cycle arrest and cellular apoptosis via the accumulation of cytosolic p53 and subsequent activation of Bax, an apoptosis promoter.^[6]^[8]^[9]

Chlorambucil alkylates and cross-links DNA during all phases of the cell cycle, inducing DNA damage via three different methods of covalent adduct generation with double-helical DNA:^[10]^[11]^[12]

Attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA.
DNA damage via the formation of cross-links which prevents DNA from being separated for synthesis or transcription.
Induction of mispairing of the nucleotides leading to mutations.

The precise mechanisms by which Chlorambucil acts to kill tumor cells are not yet completely understood.

Limitations to bioavailability

A recent study has shown Chlorambucil to be detoxified by human glutathione transferase Pi (GST P1-1), an enzyme that is often found over-expressed in cancer tissues.^[13]

This is important since chlorambucil, as an electrophile, is made less reactive by conjugation with glutathione, thereby making the drug less toxic to the cell.

Shown above, chlorambucil reacts with glutathione as catalyzed by hGSTA 1-1 leading to the formation of the monoglutathionyl derivative of chlorambucil.

Medical uses

Chlorambucil's current use is mainly in chronic lymphocytic leukemia, as it is well tolerated by most patients, though chlorambucil has been largely replaced by fludarabine as first-line treatment in younger patients.^[14] It can be used for treating some types of non-Hodgkin lymphoma, Waldenström macroglobulinemia, polycythemia vera, trophoblastic neoplasms, and ovarian carcinoma. Moreover, it also has been used as an immunosuppressive drug for various autoimmune and inflammatory conditions, such as nephrotic syndrome.

Side effects

Bone marrow suppression (anemia, neutropenia, thrombocytopenia) is the most commonly occurring side effect of chlorambucil. Withdrawn from the drug, this side effect is typically reversible. Like many alkylating agents, chlorambucil has been associated with the development of other forms of cancer.

Less commonly occurring side effects include:

Gastrointestinal Distress (nausea, vomiting, diarrhea, and oral ulcerations).
Central Nervous System: Seizures, tremors, muscular twitching, confusion, agitation, ataxia, and hallucinations.
Skin reactions
Hepatotoxicity
Infertility
Hair Loss

References

^ Takimoto CH, Calvo E. "Principles of Oncologic Pharmacotherapy" in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach. 11 ed. 2008.
^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
^ "Medscape Log In". www.medscape.com. Retrieved 2015-12-21.
^ Gilman, A.G.; Rall, T.W.; Nies, A.S.; Taylor, P. (1990). Goodman and Gilman's The Pharmacological Basis of Therapeutics. New York: Pergamon.
^ Anslow, W. P. (1948). "The intravenous, subcutaneous and cutaneous toxicity of bis(-chloroethyl) sulfide (mustard gas) and of various derivatives.". J. Pharmacol. Exp. Ther.
^ ^a ^b "Leukeran (Chlorambucil) Drug Information: Description, User Reviews, Drug Side Effects, Interactions - Prescribing Information at RxList". RxList. Retrieved 2015-12-21.
^ "chlorambucil | C14H19Cl2NO2 - PubChem". pubchem.ncbi.nlm.nih.gov. Retrieved 2015-12-21.
^ "chlorambucil - CancerConnect News". CancerConnect News. Retrieved 2015-12-21.
^ "Leukeran" (PDF).
^ "Chlorambucil".
^ "Chlorambucil".
^ "chlorambucil | C14H19Cl2NO2 - PubChem". pubchem.ncbi.nlm.nih.gov. Retrieved 2015-12-21.
^ Parker, Lorien J.; Ciccone, Sarah; Italiano, Louis C.; Primavera, Alessandra; Oakley, Aaron J.; Morton, Craig J.; Hancock, Nancy C.; Bello, Mario Lo; Parker, Michael W. (2008-06-27). "The anti-cancer drug chlorambucil as a substrate for the human polymorphic enzyme glutathione transferase P1-1: kinetic properties and crystallographic characterisation of allelic variants". Journal of Molecular Biology 380 (1): 131–144. doi:10.1016/j.jmb.2008.04.066. ISSN 1089-8638. PMID 18511072.
^ Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Shepherd L, Hines J, Threatte GA, Larson RA, Cheson BD, Schiffer CA (2000). "Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia.". N Engl J Med 343 (24): 1750–7. doi:10.1056/NEJM200012143432402. PMID 11114313.

External links

Leukeran (manufacturer's website)
MedlinePlus's Drug Information

UpToDate Contents

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1. クロラムブシル誘発性肺損傷 chlorambucil induced pulmonary injury
2. 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
3. 症候性または進行した慢性リンパ性白血病に対する初期治療の選択 selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia
4. Practice Changing UpDates
5. 小児における特発性ネフローゼ症候群の治療 treatment of idiopathic nephrotic syndrome in children

English Journal

Comparative efficacy of first-line therapies for advanced-stage chronic lymphocytic leukemia: A multiple-treatment meta-analysis.

Terasawa T, Trikalinos NA, Djulbegovic B, Trikalinos TA.SourceDepartment of Internal Medicine, Nanakuri Sanatorium, Fujita Health University School of Medicine, Tsu, Japan; Center for Clinical Evidence Synthesis, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA, USA; Clinical Research Center for Blood Diseases, National Hospital Organization Nagoya Medical Center, Nagoya, Japan. Electronic address: tterasawa@tuftsmedicalcenter.org.
Cancer treatment reviews.Cancer Treat Rev.2013 Jun;39(4):340-9. doi: 10.1016/j.ctrv.2012.05.007. Epub 2012 Jun 14.
Since the introduction of chlorambucil as a treatment for chronic lymphocytic leukemia (CLL) in the 1960s, several alternative treatment regimens have been explored. We performed a multiple-treatment meta-analysis using direct and indirect data based on all available head-to-head randomized controll
PMID 22703832

Immune thrombocytopenia in patients with chronic lymphocytic leukemia treated with cladribine-based regiments or chlorambucil - follow-up of PALG-CLL randomized trials.

Blonski JZ, Robak T, Chojnowski K, Gora-Tybor J, Warzocha K, Ceglarek B, Seferynska I, Calbecka M, Kostyra A, Stella-Holowiecka B, Kloczko J, Dmoszynska A, Kowal M, Lewandowski K, Dwilewicz-Trojaczek J, Wiater E, Kuliczkowski K, Potoczek S, Hellmann A, Mital A, Skotnicki A, Nowak W, Sulek K, Zawilska K, Trelinski J.SourceDepartment of Hematology, Medical University of Lodz, Lodz.
European journal of haematology.Eur J Haematol.2013 Mar 23. doi: 10.1111/ejh.12112. [Epub ahead of print]
OBJECTIVES: The relationship between treatment of Chronic lymphocytic leukemia (CLL) with cladribine (2 - CdA) or chlorambucil and immune thrombocytopenia (IT) have not been yet determined. Methods:The records of 777 patients in two randomized PALG (Polish Adult Leukemia Group) CLL programs treated
PMID 23521128

Immunosuppression for progressive membranous nephropathy: a UK randomised controlled trial.

Howman A, Chapman TL, Langdon MM, Ferguson C, Adu D, Feehally J, Gaskin GJ, Jayne DR, O'Donoghue D, Boulton-Jones M, Mathieson PW.SourceBirmingham Clinical Trials Unit, University of Birmingham, Birmingham, UK.
Lancet.Lancet.2013 Mar 2;381(9868):744-51. doi: 10.1016/S0140-6736(12)61566-9. Epub 2013 Jan 9.
BACKGROUND: Membranous nephropathy leads to end-stage renal disease in more than 20% of patients. Although immunosuppressive therapy benefits some patients, trial evidence for the subset of patients with declining renal function is not available. We aimed to assess whether immunosuppression preserve
PMID 23312808

Japanese Journal

Long Term Management of Vaccine-Induced Refractory Ischemic Dermatopathy in a Miniature Pinscher Puppy

KIM Ha-Jung,KANG Min-Hee,KIM Ju-Won,KIM DaeYoung,PARK Hee-Myung
Journal of Veterinary Medical Science advpub(0), 1105090511, 2011
… Chlorambucil plus cyclosporine therapy was initiated for vigorous immune suppression after rush therapy using intravenous immunoglobulin. …
NAID 130000677294

Comparative analysis of DNA alkylation by conjugates between pyrrole-imidazole hairpin polyamides and chlorambucil or seco-CBI.

Minoshima Masafumi,Bando Toshikazu,Shinohara Ken-Ichi,Kashiwazaki Gengo,Nishijima Shigeki,Sugiyama Hiroshi
Bioorganic & medicinal chemistry 18(3), 1236-1243, 2010-02-01
… We investigated sequence-specific DNA alkylation using conjugates between the N-methylpyrrole (Py)-N-methylimidazole (Im) polyamide and the DNA alkylating agent, chlorambucil, or 1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (seco-CBI). … Polyamide-chlorambucil conjugates 1-4 differed in the position at which the DNA alkylating chlorambucil moiety was bound to the Py-Im polyamide. …
NAID 120001887644

Related Pictures

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★リンクテーブル★

リンク元	「MALTリンパ腫」「ナイトロジェンマスタード」「クロランブシル」「leukeran」

「MALTリンパ腫」

Chlorambucil
Systematic (IUPAC) name
	4-[bis(2-chlorethyl)amino]benzenebutanoic acid
Clinical data
Trade names	Leukeran
AHFS/Drugs.com	Monograph
MedlinePlus	a682899
Pregnancy; category	US: D (Evidence of risk); ;
Routes of; administration	Oral
Legal status
Legal status	℞ (Prescription only);
Pharmacokinetic data
Bioavailability	?
Metabolism	Hepatic
Biological half-life	1.5 hours
Excretion	N/A
Identifiers
CAS Number	305-03-3
ATC code	L01AA02 (WHO)
PubChem	CID 2708
IUPHAR/BPS	7143
DrugBank	DB00291
ChemSpider	2607
UNII	18D0SL7309
KEGG	D00266
ChEBI	CHEBI:28830
ChEMBL	CHEMBL515
Chemical data
Formula	C14H19Cl2NO2
Molar mass	304.212 g/mol
	SMILES c1cc(ccc1CCCC(=O)O)N(CCCl)CCCl ;
	InChI InChI=1S/C14H19Cl2NO2/c15-8-10-17(11-9-16)13-6-4-12(5-7-13)2-1-3-14(18)19/h4-7H,1-3,8-11H2,(H,18,19) ; Key:JCKYGMPEJWAADB-UHFFFAOYSA-N ;
(verify)

　　[★]

英: mucosa-associated lymphoid tissue lymphoma MALToma
同: 粘膜関連リンパ組織リンパ腫
関: 胃MALTリンパ腫、悪性リンパ腫

概念

比較的緩徐な経過をたどる低悪性度リンパ腫

リンパ濾胞(リンパ小節)の胚中心：{被膜側}頂部明調域(生存を許された分化したB細胞がとどまる。記憶細胞か形質細胞になってリンパ小節を去る)～基底側明調域(sIgを発現しクラススイッチを起こして中心細胞となる。中心細胞は濾胞樹状細胞から抗原提示をうける。)～暗調域(sIgを持たないB細胞(中心芽細胞)が密集。増殖盛ん)～帽状域{中心側})

リンパ濾胞外側領域(おそらく胚中心の頂部明調領域であろう)のB細胞層にある記憶B細胞に由来する。
形態は小型胚中心細胞に似ており、広く明調な細胞質と切れ込みを認める。

原因

胃MALTリンパ腫

Helicobacter pyloriの感染
染色体異常：t(11;18)(q21;q21)

病理

胃MALTリンパ腫の場合、胃癌0-IIc型(表面感凹型)に似ている。
胃炎型の粘膜は萎縮性胃炎像、多発びらん、顆粒状、敷石状粘膜

細胞表面マーカー

CD5 -、CD10 -、CD19 +、CD23 -、CD43 -/+、sIgG -、sIgM +

特徴 YN.A-46

胚中心細胞に類似したcentrocyte-like cellの浸潤
粘膜上皮の破壊像
単クローン性免疫グロブリンを有する形質細胞の浸潤
リンパ濾胞の残存

検査

染色体

t(11;18)(q21;q21)

API2(11q21)、MALT1(18q21)

診断

胃生検

治療

ヘリコバクター・ピロリ菌の除菌により消失することがある

薬物療法：

抗菌薬：ヘリコバクターの除菌　→　第一選択とすることが推奨されている(参考1)

除菌治療の有効性予測因子：　H. pylori感染の有無、臨床病期、深達度、API2-MALT1 染色体転座　(参考1)

抗悪性腫瘍薬：(病変が広範囲に及んでいる場合 more extensive disease)chlorambucil単剤。rituximabを加えて使用するレジメンもある。(HIM.694)
放射線療法
リツキシマブ

手術療法：

(病変が限局している場合)有効

up2date

Management of gastrointestinal lymphomas (This topic last updated: 6月 2, 2010)

(Lugano I/II)

H. pylori陽性：H.pylori除菌を行う
H. pylori陰性 or t(11;18)転座：局所放射線療法

(Lugano IV)

H. pylori陽性：H.pylori除菌を行う。免疫療法や化学療法が必要になるまで症状が進むまで経過観察。

消化管の切除は消化管穿孔や消化管閉塞を合併するまでreserveされる。

予後

リンパ節転移は少なく、臨床的進行は遅い。
中間～良好 (LAB.1219)

参考

1. Helicobacter pylori 感染の診断と治療のガイドライン2009改訂版 - 日本ヘリコバクター学会

http://www.jshr.jp/pdf/journal/guideline2009-2.pdf

2. 写真

http://pathol.ncc.go.jp/matsuno/images/matsuno-43.htm

3. 写真

http://user.shikoku.ne.jp/hirata/geca/sub48.html

「ナイトロジェンマスタード」

　　[★]

英: nitrogen mustard
同: 窒素マスタード、窒素イペリット nitrogen yperite、メクロルエタミン mechlorethamine
関: [[]]

「クロランブシル」

　　[★]

英: chlorambucil
同: クロラムブシル
商: Leukeran

[show details]

クロラムブシル : 約 6,260 件
クロランブシル : 96 件

「leukeran」

　　[★]

同: chlorambucil

関: chlorambucil

[1] Takimoto CH, Calvo E. "Principles of Oncologic Pharmacotherapy" in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach. 11 ed. 2008.

[2] "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.

[3] "Medscape Log In". www.medscape.com. Retrieved 2015-12-21.

[4] Gilman, A.G.; Rall, T.W.; Nies, A.S.; Taylor, P. (1990). Goodman and Gilman's The Pharmacological Basis of Therapeutics. New York: Pergamon.

[5] Anslow, W. P. (1948). "The intravenous, subcutaneous and cutaneous toxicity of bis(-chloroethyl) sulfide (mustard gas) and of various derivatives.". J. Pharmacol. Exp. Ther.

[:0-6] "Leukeran (Chlorambucil) Drug Information: Description, User Reviews, Drug Side Effects, Interactions - Prescribing Information at RxList". RxList. Retrieved 2015-12-21.

[7] "chlorambucil | C14H19Cl2NO2 - PubChem". pubchem.ncbi.nlm.nih.gov. Retrieved 2015-12-21.

[8] "chlorambucil - CancerConnect News". CancerConnect News. Retrieved 2015-12-21.

[9] "Leukeran" (PDF).

[10] "Chlorambucil".

[11] "Chlorambucil".

[12] "chlorambucil | C14H19Cl2NO2 - PubChem". pubchem.ncbi.nlm.nih.gov. Retrieved 2015-12-21.

[13] Parker, Lorien J.; Ciccone, Sarah; Italiano, Louis C.; Primavera, Alessandra; Oakley, Aaron J.; Morton, Craig J.; Hancock, Nancy C.; Bello, Mario Lo; Parker, Michael W. (2008-06-27). "The anti-cancer drug chlorambucil as a substrate for the human polymorphic enzyme glutathione transferase P1-1: kinetic properties and crystallographic characterisation of allelic variants". Journal of Molecular Biology 380 (1): 131–144. doi:10.1016/j.jmb.2008.04.066. ISSN 1089-8638. PMID 18511072.

[14] Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Shepherd L, Hines J, Threatte GA, Larson RA, Cheson BD, Schiffer CA (2000). "Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia.". N Engl J Med 343 (24): 1750–7. doi:10.1056/NEJM200012143432402. PMID 11114313.

匿名

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案内

案内

chlorambucil