Fludarabine (NSC 118218)

Alias: FaraA; Fludarabinum; HSDB 6964; F-ara-A; HSDB6964; NSC118218; HSDB-6964; NSC 118218; F-ara A; NSC-118218
Cat No.:V1379 Purity: ≥98%
Fludarabine (also known as FaraA; Fludarabinum; NSC-118218; F-ara-A; HSDB6964; NSC118218; HSDB-6964)is a potent STAT1 activation inhibitor and a DNA synthesis inhibitor that has been approved as a chemotherapeutic drug for the treatment of leukemia and lymphoma.
Fludarabine (NSC 118218) Chemical Structure CAS No.: 21679-14-1
Product category: DNA(RNA) Synthesis
This product is for research use only, not for human use. We do not sell to patients.
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

Fludarabine (also known as FaraA, Fludarabinum; NSC-118218; F-ara-A, HSDB6964; NSC118218; HSDB-6964) is a potent STAT1 activation inhibitor and a DNA synthesis inhibitor that has been approved as a chemotherapeutic drug for the treatment of leukemia and lymphoma. In order to cause biological activity, the prodrug fludarabine must be phosphorylated in cells to produce nucleoside triphosphate, or F-ara-ATP. It had an impact on several enzymes needed for DNA synthesis, including ribonucleotide reductase, DNA primase, DNA polymerases, DNA ligase I, and the 3'–5' exonuclease activity of DNA polymerases δ and ΰ. Fludarabine decreased Akt phosphorylation and markedly slowed down the growth of human myeloma cell RPMI8226.

Biological Activity I Assay Protocols (From Reference)
Targets
STAT1
ln Vitro

In vitro activity: Fludarabine effectively prevents RPMI 8226 cell growth, with an IC50 of 1.54 μg/mL. When it comes to MM.1S and MM.1R cells, fludarabine's IC50 values are 13.48 μg/mL and 33.79 μg/mL, respectively. On the other hand, U266 cells exhibit fludarabine resistance, with an IC50 of 222.2 μg/mL. Treatment with fludarabine causes a time-dependent increase in the number of cells in the G1 phase of the cell cycle and a corresponding decrease in the number of cells at the S phase. In MM cells, fludarabine causes a block in the cell cycle and initiates apoptosis. Fludarabine causes caspase-8, -9, and -3, -7 to cleave in a time-dependent manner, which is followed by PARP cleavage. Bak expression remains unchanged while fludarabine increases Bax expression in a time-dependent manner. RPMI 8226 cells exhibit a loss of membrane potential following a 12-hour exposure to fludarabine; 61.05% of the cells express low fluorescence of rhodamine 123, compared to 8.62% of cells in the untreated control.[1] In order to improve solubility, fludarabine is synthesized as the monophosphate (F-ara-AMP, fudarabine), which, upon intravenous infusion, dephosphorylates instantly and quantitatively to the parent nucleoside. Fuoroadenine arabinoside triphosphate (F-ara-ATP), the primary cytotoxic metabolite of F-ara-A, is produced inside the cells as a result of rephosphorylation.[2] Increased expression of ICAM-1 and IL-8 release are two more indicators that fludarabine can stimulate monocytic cells in a pro-inflammatory manner.[3] Fludarabine causes a noticeable and dose-dependent inhibition of proliferation in melanoma cell lines, but it has no effect on the growth of ovarian cancer cell lines.[4] While fludarabine does not alter JAK2 activation, it does cause a notable decrease in STAT-1 phosphorylation. Interestingly, the phosphorylation of these three STAT proteins is not significantly affected by fludarabine. The administration of 1.5 mg of fludarabine not only lowers the elevated level of this protein but also effectively inhibits STAT-1 phosphorylation. At two days, there are no discernible changes in JAK2 phosphorylation; however, at seven days, fludarabine inhibits JAK2-increased expression. By selectively blocking STAT-1 activation while sparing other STAT proteins, fludarabine reduces the proliferation of VSMCs.[5]

ln Vivo
On the other hand, tumors treated with fludarabine at a dose of 40 mg/kg grow less than five times as quickly, taking 25 days to reach approximately 10-fold growth from their initial volume. RPMI8226 tumor growth is shown to be significantly inhibited by fludarabine at a dose of 40 mg/kg. When 40 mg/kg of fludarabine is administered to RPMI8226 tumors on day 10, more apoptotic nuclei are produced. The myeloma xenografts RPMI8226 can be effectively suppressed in SCID mice by fludarabine.[1]
Cell Assay
Fludarabine- or control-treated human MM cell lines, RPMI8226 and U266 (5 × 105 cells), that are dexamethasone-sensitive (MM.1S) and -resistant (MM.1R) are fixed with 70% ice-cold ethanol, centrifuged, and suspended in PBS containing 100 μg/mL RNase A. Sampling is done in 25 μg/mL propidium iodide after 30 minutes of incubation at 37 ºC. The FACSCalibur automated system is used to perform flow cytometry. As per the manufacturer's instructions, apoptosis is identified using the Annexin V-FITC apoptosis detection kit. In situ cell death detection kit-assisted flow cytometry is used to analyze cells for the TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling) assay.
Animal Protocol
Dissolved in PBS; 40 mg/kg; i.p. injection
Severe combined immunodeficient (SCID) mice bearing RPMI 8226 cells
References

[1]. Eur J Haematol . 2007 Dec;79(6):486-93.

[2]. Bioorg Med Chem . 1999 Jun;7(6):1195-200.

[3]. Int Immunopharmacol . 2006 May;6(5):715-23.

[4]. Eur J Cancer . 1996 Sep;32A(10):1766-73.

[5]. Am J Physiol Heart Circ Physiol . 2007 Jun;292(6):H2935-43.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C10H12FN5O4
Molecular Weight
285.23
Exact Mass
285.09
Elemental Analysis
C, 42.11; H, 4.24; F, 6.66; N, 24.55; O, 22.44
CAS #
21679-14-1
Appearance
Solid powder
SMILES
C1=NC2=C(N=C(N=C2N1[C@H]3[C@H]([C@@H]([C@H](O3)CO)O)O)F)N
InChi Key
HBUBKKRHXORPQB-FJFJXFQQSA-N
InChi Code
InChI=1S/C10H12FN5O4/c11-10-14-7(12)4-8(15-10)16(2-13-4)9-6(19)5(18)3(1-17)20-9/h2-3,5-6,9,17-19H,1H2,(H2,12,14,15)/t3-,5-,6+,9-/m1/s1
Chemical Name
(2R,3S,4S,5R)-2-(6-amino-2-fluoropurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol
Synonyms
FaraA; Fludarabinum; HSDB 6964; F-ara-A; HSDB6964; NSC118218; HSDB-6964; NSC 118218; F-ara A; NSC-118218
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: 25~57 mg/mL (87.7~199.8 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In Vivo)
30% propylene glycol, 5% Tween 80, 65% D5W: 30 mg/mL
 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 3.5059 mL 17.5297 mL 35.0594 mL
5 mM 0.7012 mL 3.5059 mL 7.0119 mL
10 mM 0.3506 mL 1.7530 mL 3.5059 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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g/mol

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Note: Chemical formula is case sensitive: C12H18N3O4  c12h18n3o4
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Working concentration mg/mL;

Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.

(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
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Clinical Trial Information
NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT03524235 Active
Recruiting
Drug: Fludarabine
Drug: Rituximab
CLL
Leukemia
Lymphoma
Noah Merin July 18, 2018 Phase 1
NCT00719888 Active
Recruiting
Drug: Fludarabine
Drug: Thiotepa
Burkitt Lymphoma
Myelofibrosis
Fred Hutchinson Cancer
Center
November 18, 2005 Phase 2
NCT03434769 Active
Recruiting
Drug: Fludarabine
Drug: Cyclophosphamide
Non-Hodgkin Lymphoma Benjamin Tomlinson July 9, 2018 Phase 1
NCT00577278 Active
Recruiting
Drug: fludarabine phosphate
Drug: melphalan
Leukemia
Lymphoma
City of Hope Medical Center October 3, 2007 Phase 2
NCT01163357 Active
Recruiting
Drug: fludarabine phosphate
Drug: bortezomib
Loss of Chromosome 17p
Plasma Cell Leukemia
City of Hope Medical Center January 28, 2011 Phase 1
Biological Data
  • Fludarabine


    Fludarabine

  • Fludarabine
    Effects of fludarabine on survival pathways.Eur J Haematol.2007 Dec;79(6):486-93.
  • Fludarabine
    Antitumoral efficacy of fludarabine in established RPMI8226 tumors in vivo.Eur J Haematol.2007 Dec;79(6):486-93.
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