Chlorambucil
|
|
| Systematic (IUPAC) name |
|
4-[bis(2-chlorethyl)amino]benzenebutanoic acid
|
| Clinical data |
| Trade names |
Leukeran |
| AHFS/Drugs.com |
monograph |
| MedlinePlus |
a682899 |
Pregnancy
category |
|
Routes of
administration |
Oral |
| Legal status |
| Legal status |
|
| Pharmacokinetic data |
| Bioavailability |
? |
| Metabolism |
Hepatic |
| Biological half-life |
1.5 hours |
| Excretion |
N/A |
| Identifiers |
| CAS Number |
305-03-3 Y |
| ATC code |
L01AA02 (WHO) |
| PubChem |
CID 2708 |
| IUPHAR/BPS |
7143 |
| DrugBank |
DB00291 Y |
| ChemSpider |
2607 Y |
| UNII |
18D0SL7309 Y |
| KEGG |
D00266 Y |
| ChEBI |
CHEBI:28830 Y |
| ChEMBL |
CHEMBL515 Y |
| 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) Y
-
Key:JCKYGMPEJWAADB-UHFFFAOYSA-N Y
|
| (verify) |
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]
Contents
- 1 History
- 2 Physical and Chemical Properties
- 3 Mechanism of action
- 4 Limitations to bioavailability
- 5 Medical uses
- 6 Side effects
- 7 References
- 8 External links
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
