LGM Pharma

Clofarabine

CAS No: 123318-82-1

Clofarabine

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Product Details:

CAS No: 123318-82-1
ATC code: L01BB06
Molecular Weight: 303.677 g/mol
PubChem: 119182
Chemical Formula: C6332H9808N1678O1989S42
DrugBank: DB00631 (APRD00878, DB07554)
Assay/Purity: Typically NLT 98%
IUPAC Name: (2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)oxolan-3-ol
SMILES: NC1=C2N=CN([C,,H]3O[C,H](CO)[C,,H](O)[C,,H]3F)C2=NC(Cl)=N1
InChl: WDDPHFBMKLOVOX-AYQXTPAHSA-N

Additional Details: [+]

Indication:

For the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphocytic (lymphoblastic) leukemia after at least two prior regimens. It is designated as an orphan drug by the FDA for this use.

Pharmacodynamics:

Clofarabine is a purine nucleoside antimetabolite that differs from other puring nucleoside analogs by the presence of a chlorine in the purine ring and a flourine in the ribose moiety. Clofarabine seems to interfere with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells may also be affected by clofarabine, other effects also occur. Clofarabine prevents cells from making DNA and RNA by interfering with the synthesis of nucleic acids, thus stopping the growth of cancer cells.

Mode of Action:

Clofarabine is metabolized intracellularly to the active 5'-monophosphate metabolite by deoxycytidine kinase and 5'-triphosphate metabolite by mono- and di-phospho-kinases. This metabolite inhibits DNA synthesis through an inhibitory action on ribonucleotide reductase, and by terminating DNA chain elongation and inhibiting repair through competitive inhibition of DNA polymerases. This leads to the depletion of the intracellular deoxynucleotide triphosphate pool and the self-potentiation of clofarabine triphosphate incorporation into DNA, thereby intensifying the effectiveness of DNA synthesis inhibition. The affinity of clofarabine triphosphate for these enzymes is similar to or greater than that of deoxyadenosine triphosphate. In preclinical models, clofarabine has demonstrated the ability to inhibit DNA repair by incorporation into the DNA chain during the repair process. Clofarabine 5'-triphosphate also disrupts the integrity of mitochondrial membrane, leading to the release of the pro-apoptotic mitochondrial proteins, cytochrome C and apoptosis-inducing factor, leading to programmed cell death.

Metabolism:

Clofarabine is sequentially metabolized intracellularly to the 5ê-monophosphate metabolite by deoxycytidine kinase and mono- and di-phosphokinases to the active 5ê-triphosphate metabolite. Clofarabine has high affinity for the activating phosphorylating enzyme, deoxycytidine kinase, equal to or greater than that of the natural substrate, deoxycytidine.

Toxicity:

There were no known overdoses of clofarabine. The highest daily dose administered to a human to date (on a mg/m2 basis) has been 70 mg/m2/day _ 5 days (2 pediatric ALL patients). The toxicities included in these 2 patients included grade 4 hyperbilirubinemia, grade 2 and 3 vomiting, and grade 3 maculopapular rash.

General Reference:

  1. Pession A, Masetti R, Kleinschmidt K, Martoni A: Use of clofarabine for acute childhood leukemia. Biologics. 2010 Jun 24;4:111-8. Pubmed
  2. Harned TM, Gaynon PS: Treating refractory leukemias in childhood, role of clofarabine. Ther Clin Risk Manag. 2008 Apr;4(2):327-36. Pubmed
  3. Lech-Maranda E, Korycka A, Robak T: Clofarabine as a novel nucleoside analogue approved to treat patients with haematological malignancies: mechanism of action and clinical activity. Mini Rev Med Chem. 2009 Jun;9(7):805-12. Pubmed
  4. 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
  5. 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


Clofarabine News:

  • Clofarabine is also known as the brand name Clolar, and is an injectable medication used to treat relapsed or refractory acute lymphoblastic leukemia.
  • Clofarabine is indicated for the pediatric population, or for children ages 1-21.
  • One particular study of clofarabine showed roughly one-third of pediatric patients experiencing remission after several treatment regimens.

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