Chlorambucil

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Chlorambucil
Chlorambucil.svg
Chlorambucil ball-and-stick.png
Clinical data
Trade names Leukeran
AHFS/Drugs.com Monograph
MedlinePlus a682899
Pregnancy
category
  • US: D (Evidence of risk)
Routes of
administration
Oral
ATC code L01AA02 (WHO)
Legal status
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability ?
Metabolism Hepatic
Biological half-life 1.5 hours
Excretion N/A
Identifiers
Systematic (IUPAC) name: 4-[bis(2-chlorethyl)amino]benzenebutanoic acid
CAS Number 305-03-3 YesY
PubChem (CID) 2708
IUPHAR/BPS 7143
DrugBank DB00291 YesY
ChemSpider 2607 YesY
UNII 18D0SL7309 YesY
KEGG D00266 YesY
ChEBI CHEBI:28830 YesY
ChEMBL CHEMBL515 YesY
Chemical and physical data
Formula C14H19Cl2NO2
Molar mass 304.212 g/mol
3D model (Jmol) Interactive image
  (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]

Medical uses[edit]

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.[3] 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[edit]

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 Withdrawn from the drug, this side effect is typically reversible.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:

Pharmacology[edit]

Mechanism of action[edit]

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.[4][5][6]

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:[7][8][9]

  1. 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.
  2. DNA damage via the formation of cross-links which prevents DNA from being separated for synthesis or transcription.
  3. 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[edit]

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.[10]

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.

REACTION.PNG

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

Chemistry[edit]

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.[11]

History[edit]

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.[12] 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.[13]

With an acceptable therapeutic index in humans, nitrogen mustards were first introduced in the clinic in 1946.[14] 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.[4]

References[edit]

  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. ^ 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. 
  4. ^ a b "Leukeran (Chlorambucil) Drug Information: Description, User Reviews, Drug Side Effects, Interactions - Prescribing Information at RxList". RxList. Retrieved 2015-12-21. 
  5. ^ "chlorambucil - CancerConnect News". CancerConnect News. Retrieved 2015-12-21. 
  6. ^ "Leukeran" (PDF). 
  7. ^ "Chlorambucil". 
  8. ^ "Chlorambucil". 
  9. ^ "chlorambucil | C14H19Cl2NO2 - PubChem". pubchem.ncbi.nlm.nih.gov. Retrieved 2015-12-21. 
  10. ^ 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. 
  11. ^ "chlorambucil | C14H19Cl2NO2 - PubChem". pubchem.ncbi.nlm.nih.gov. Retrieved 2015-12-21. 
  12. ^ http://www.medscape.com/viewarticle/502816_2
  13. ^ Gilman, A.G.; Rall, T.W.; Nies, A.S.; Taylor, P. (1990). Goodman and Gilman's The Pharmacological Basis of Therapeutics. New York: Pergamon. 
  14. ^ Anslow, W. P. (1948). "The intravenous, subcutaneous and cutaneous toxicity of bis(-chloroethyl) sulfide (mustard gas) and of various derivatives.". J. Pharmacol. Exp. Ther. 

External links[edit]