Chlorambucil: Difference between revisions

{{Short description|Chemical compound}}

| verifiedrevid = 460028777

| image2 = Chlorambucil ball-and-stick.png

| tradename = Leukeran, others

| pregnancy_AU =

| pregnancy_category =

| routes_of_administration = [[Oral administration|By mouth]]

| metabolism = [[Liver]]

| IUPHAR_ligand = 7143

| CAS_number_Ref = {{cascite|correct|??}}

| C=14 | H=19 | Cl=2 | N=1 | O=2

| smiles = ClCCN(CCCl)c1ccc(cc1)CCCC(=O)O

<!-- Definition and medical uses -->

'''Chlorambucil''', sold under the brand name '''Leukeran''' among others, is a [[chemotherapy medication]] used to treat [[chronic lymphocytic leukemia]] (CLL), [[Hodgkin lymphoma]], and [[non-Hodgkin lymphoma]].<ref>{{cite web|title=Chlorambucil|url=https://www.cancer.gov/about-cancer/treatment/drugs/chlorambucil|website=National Cancer Institute|access-date=19 December 2016|date=17 September 2014|url-status=live|archive-url=https://web.archive.org/web/20161221053738/https://www.cancer.gov/about-cancer/treatment/drugs/chlorambucil|archive-date=21 December 2016}}</ref> For CLL it is a preferred treatment.<ref name=AHFS2016/> It is given [[Oral administration|by mouth]].<ref name=AHFS2016/>

<!-- Side effects and mechanism -->

Common side effects include [[bone marrow suppression]].<ref name=AHFS2016/> Other serious side effects include an increased long term risk of further [[cancer]], [[infertility]], and [[allergic reactions]].<ref name=AHFS2016/> Use during [[pregnancy]] often results in harm to the baby.<ref name=AHFS2016/> Chlorambucil is in the [[alkylating antineoplastic agent|alkylating agent]] family of medications.<ref name=AHFS2016/> It works by blocking the formation of [[DNA]] and [[RNA]].<ref name=AHFS2016/>

<!-- History and culture -->

Chlorambucil was approved for medical use in the United States in 1957.<ref name=AHFS2016/> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref><ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref> It was originally made from [[nitrogen mustard]].<ref name=AHFS2016>{{cite web|title=Chlorambucil|url=https://www.drugs.com/monograph/chlorambucil.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161221013623/https://www.drugs.com/monograph/chlorambucil.html|archive-date=21 December 2016}}</ref>

==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.<ref>{{cite journal | vauthors = Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Shepherd L, Hines J, Threatte GA, Larson RA, Cheson BD, Schiffer CA | display-authors = 6 | title = Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia | journal = The New England Journal of Medicine | volume = 343 | issue = 24 | pages = 1750–1757 | date = December 2000 | pmid = 11114313 | doi = 10.1056/NEJM200012143432402 | doi-access = free }}</ref> 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==

* Hair Loss

==Pharmacology==

===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 [[Bcl-2-associated X protein]], an apoptosis promoter.<ref name=":0" /><ref>{{Cite web|title = chlorambucil – CancerConnect News|url = http://news.cancerconnect.com/chlorambucil/|website = CancerConnect News|access-date = 2015-12-21|language = en-US|url-status = live|archive-url = https://web.archive.org/web/20151222113358/http://news.cancerconnect.com/chlorambucil/|archive-date = 2015-12-22}}</ref><ref>{{Cite web|url = http://hemonc.org/w/images/0/06/Chlorambucil.pdf |title =Leukeran (chlorambucil) Tablets |url-status =live |archive-url = https://web.archive.org/web/20151222120613/http://hemonc.org/w/images/0/06/Chlorambucil.pdf|archive-date =2015-12-22 | work = GlaxoSmithKline | via = emOnc.org - A Free Hematology/Oncology Reference }}</ref>

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:<ref>{{Cite web |title = Chlorambucil|url = http://www.drugbank.ca/drugs/DB00291|url-status = live|archive-url = https://web.archive.org/web/20170103035818/https://www.drugbank.ca/drugs/DB00291|archive-date = 2017-01-03 | work = Drug Bank }}</ref><ref>{{cite journal | vauthors = Di Antonio M, McLuckie KI, Balasubramanian S | title = Reprogramming the mechanism of action of chlorambucil by coupling to a G-quadruplex ligand | journal = Journal of the American Chemical Society | volume = 136 | issue = 16 | pages = 5860–5863 | date = April 2014 | pmid = 24697838 | pmc = 4132976 | doi = 10.1021/ja5014344 }}</ref><ref name = "PubChem_chlorambucil">{{Cite web|title = Chlorambucil {{!}} C14H19Cl2NO2 | work = PubChem|url = https://pubchem.ncbi.nlm.nih.gov/compound/chlorambucil#section=Pharmacology-and-Biochemistry| publisher = U.S. National Library of Medicine |access-date = 2015-12-21|url-status = live|archive-url = https://web.archive.org/web/20151222121331/http://pubchem.ncbi.nlm.nih.gov/compound/chlorambucil#section=Pharmacology-and-Biochemistry|archive-date = 2015-12-22}}</ref>

# 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.<ref>{{cite journal | vauthors = Parker LJ, Ciccone S, Italiano LC, Primavera A, Oakley AJ, Morton CJ, Hancock NC, Bello ML, Parker MW | display-authors = 6 | title = 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 = Journal of Molecular Biology | volume = 380 | issue = 1 | pages = 131–144 | date = June 2008 | pmid = 18511072 | doi = 10.1016/j.jmb.2008.04.066 | hdl-access = free | hdl = 2108/101037 }}</ref>

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.

[[File:Chlorambucil_glutathione_reaction.png|centre|frameless|800x291px]]

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

==Chemistry==

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<ref name = "PubChem_chlorambucil" />

==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.<ref>{{cite web | vauthors = Neidle S, Thurston DE | date = 2006 | work = Medcape |url=http://www.medscape.com/viewarticle/502816_2 |title=Chemical Approaches to the Discovery and Development of Cancer: Serendipity and Chemistry |access-date=2016-11-24 |url-status=live |archive-url=https://web.archive.org/web/20140623174136/http://www.medscape.com/viewarticle/502816_2 |archive-date=2014-06-23 }}</ref> 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.<ref>{{Cite book|title = Goodman and Gilman's The Pharmacological Basis of Therapeutics| vauthors = Gilman AG, Rall TW, Nies AS, Taylor P |publisher = Pergamon|year = 1990|location = New York}}</ref>

With an acceptable therapeutic index in humans, nitrogen mustards were first introduced in the clinic in 1946.<ref>{{cite journal | vauthors = Anslow WP, Karnofsky DA | title = The intravenous, subcutaneous and cutaneous toxicity of bis (beta-chloroethyl) sulfide (mustard gas) and of various derivatives | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 93 | issue = 1 | pages = 1–9 | date = May 1948 | pmid = 18865181 }}</ref> 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.<ref name=":0">{{Cite web|title = Leukeran (Chlorambucil) Drug Information: Description, User Reviews, Drug Side Effects, Interactions – Prescribing Information at RxList |url=http://www.rxlist.com/leukeran-drug.htm |website = RxList|access-date = 2015-12-21|url-status = live|archive-url = https://web.archive.org/web/20151222100307/http://www.rxlist.com/leukeran-drug.htm |archive-date = 2015-12-22}}</ref>

== References ==

{{reflist}}

== External links ==

* [https://web.archive.org/web/20060314141756/http://us.gsk.com/products/assets/us_leukeran.pdf Leukeran] (manufacturer's website)

* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/chlorambucil | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Chlorambucil }}

{{portal bar|Medicine}}

[[Category:Chloroethyl compounds]]

[[Category:World Health Organization essential medicines]]

[[Category:Wikipedia medicine articles ready to translate]]

[[Category:Carboxylic acids]]