Product Name

Cladribine

CAS Number

4291-63-8

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Product Name:
Cladribine
CAS Number:
4291-63-8
Indication:
For the treatment of active hairy cell leukemia (leukemic reticuloendotheliosis) as defined by clinically significant anemia, neutropenia, thrombocytopenia, or disease-related symptoms. Also used as an alternative agent for the treatment of chronic lymphocytic leukemia (CLL), low-grade non-Hodgkin's lymphoma, and cutaneous T-cell lymphoma.
Mode of Action:

Cladribine is structurally related to fludarabine and pentostatin but has a different mechanism of action. Although the exact mechanism of action has not been fully determined, evidence shows that cladribine is phosphorylated by deoxycytidine kinase to the nucleotidecladribine triphosphate (CdATP; 2-chloro-2_-deoxyadenosine 5_-triphosphate), which accumulates and is incorporated into DNA in cells such as lymphocytes that contain high levels of deoxycytidine kinase and low levels of deoxynucleotidase, resulting in DNA strand breakage and inhibition of DNA synthesis and repair. High levels of CdATP also appear to inhibit ribonucleotide reductase, which leads to an imbalance in triphosphorylated deoxynucleotide (dNTP) pools and subsequent DNA strand breaks, inhibition of DNA synthesis and repair, nicotinamide adenine dinucleotide (NAD) and ATP depletion, and cell death. Unlike other antimetabolite drugs, cladribine has cytotoxic effects on resting as well as proliferating lymphocytes. However, it does cause cells to accumulate at the G1/S phase junction, suggesting that cytotoxicity is associated with events critical to cell entry into S phase. It also binds purine nucleoside phosphorylase (PNP), however no relationship between this binding and a mechanism of action has been established.

Pharmacodynamics:

Cladribine is a synthetic purine nucleoside that acts as an antineoplastic agent with immunosuppressive effects. Cladribine differs structurally from deoxyadenosine only by the presence of a chlorine atom at position 2 of the purine ring, which results in resistance to enzymatic degradation by adenosine deaminase. Due to this resistance, cladribine exhibits a more prolonged cytotoxic effect than deoxyadenosine against resting and proliferating lymphocytes. Cladribine is one of a group of chemotherapy drugs known as the anti-metabolites. Anti-metabolites stop cells from making and repairing DNA, which are processes that are necessary for cancer cells to grow and multiply.

Metabolism:

Metabolized in all cells with deoxycytidine kinase activity to 2-chloro-2'-deoxyadenosine-5'-triphosphate

Toxicity:

Symptoms of overdose include irreversible neurologic toxicity (paraparesis/quadriparesis), acute nephrotoxicity, and severe bone marrow suppression resulting in neutropenia, anemia and thrombocytopenia.

IUPAC:
(2R, 3S, 5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-2-(hydroxymethyl)oxolan-3-ol
ATC:
L01BB04
PubChem:
20279
DrugBank:
DB00242 (APRD00260)
Formula:
C21H21N
Molecular Mass:
285.687
Synonyms:
2-CdA 2-Chloro-2'-deoxy-beta-adenosine 2-Chloro-2'-deoxyadenosine 2-Chlorodeoxyadenosine Chlorodeoxyadenosine
SMILES:
NC1=C2N=CN([C@H]3C[C@H](O)[C@@H](CO)O3)C2=NC(Cl)=N1
AHFS Code:
10:00.0
InChi:
PTOAARAWEBMLNO-KVQBGUIXSA-N
General Reference:
General Reference:

  1. Warnke C, Wiendl H, Hartung HP, Stuve O, Kieseier BC: Identification of targets and new developments in the treatment of multiple sclerosis _ focus on cladribine. Drug Des Devel Ther. 2010 Jul 21;4:117-26. Pubmed
  2. Sigal DS, Miller HJ, Schram ED, Saven A: Beyond hairy cell: the activity of cladribine in other hematologic malignancies. Blood. 2010 Jul 15. Pubmed
  3. Khalid BA, Hamilton NT, Cauchi MN: Binding of thyroid microsomes by lymphocytes from patients with thyroid disease and normal subjects. Clin Exp Immunol. 1976 Jan;23(1):28-32. Pubmed
  4. Sampat K, Kantarjian H, Borthakur G: Clofarabine: emerging role in leukemias. Expert Opin Investig Drugs. 2009 Oct;18(10):1559-64. Pubmed
  5. Kantarjian HM, Jeha S, Gandhi V, Wess M, Faderl S: Clofarabine: past, present, and future. Leuk Lymphoma. 2007 Oct;48(10):1922-30. Pubmed
  6. Zhenchuk A, Lotfi K, Juliusson G, Albertioni F: Mechanisms of anti-cancer action and pharmacology of clofarabine. Biochem Pharmacol. 2009 Dec 1;78(11):1351-9. Epub 2009 Jul 1. Pubmed
  7. Larson ML, Venugopal P: Clofarabine: a new treatment option for patients with acute myeloid leukemia. Expert Opin Pharmacother. 2009 Jun;10(8):1353-7. Pubmed

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