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Pixantrone (formerly known as BBR 2778), is a novel, potent aza-anthracenedione analog with anticancer activity with little cardiotoxicity. It functions as a weak inhibitor of topoisomerase II and a DNA intercalator, selectively forming stable DNA adducts at sites of hypermethylation through alkylation. DNA replication is inhibited and tumor cell cytotoxicity is caused when it intercalates into DNA and creates topoisomerase II-mediated DNA strand crosslinks. Despite their importance as oncotherapeutics, anthracene and anthracene derivatives are linked to cumulative and irreversible cardiotoxicity. Pixantrone was created to decrease treatment-related cardiotoxicity without compromising effectiveness. For patients with aggressive non-Hodgkin lymphoma (aNHL), Pixantrone is a less cardiotoxic and more effective treatment than doxorubicin.
| Targets |
Topoisomerase II
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| Cell Assay |
Following seeding into 96-well plates, cells are exposed to escalating doses of either doxorubicin or pixantrone for a full 72 hours. Subsequently, the cells are treated with MTS reagent and allowed to incubate for an additional 4 hours at 37°C. The absorbance at 490 nm is then used to calculate the rate of cell proliferation. Every data point is compared to untreated cells for normalcy. Every treatment is administered in triplicate and at least three times.
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| Animal Protocol |
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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Intravenous administration results in a rapid distribution followed by a slow elimination. [2] In ex vivo myocardial strips, pixantrone is taken up to a higher degree than mitoxantrone. In myocardial strips which are doxorubicin naive pixantrone displays higher uptake than in DOX-loaded myocardial strips. DOX clearance causes membrane effects which may be responsible for this observation. DOX clearance involves rapid passive diffusion through one side of the membrane followed by "flip flop" reorientation of the lipid bilayer. This disorganization of lipids is believed to impair membrane penetration by pixantrone. [3] Fecally and renally excreted. Urinary elimination of unchanged drug is less than 10%. [2] 9.7-29.7 L/kg. [2] Plasma clearance is 0.75 - 1.31 L/h/kg. [2] Metabolism / Metabolites Pixantrone does not form secondary alcohol metabolites. [2] Pixantrone hydrolyzes extensively to CT-45886 which is believed to inhibit doxol formation by displacing DOX from the active site of reductases. CT4889 and CT-45890 are also formed.[3] Biological Half-Life Half life ranges from 14.7 to 31.9 hours. |
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| Toxicity/Toxicokinetics |
Protein Binding
Anthracyclines, which may be effective second line treatments for NHL have limited use in therapy because of cumulative cardiotoxicity which may result in irreversible damage to cardiac tissue. [2] |
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| Additional Infomation |
Pharmacodynamics
Pixantrone has a wide range of antitumor activity, especially in terms of treating leukemias and lymphomas [3]. Pixantrone lacks cardio-toxic effects. It has postulated that his is because of its redox inactivity and lack and inhibition of doxorubicinol formation in human myocardium. [3] |
| Molecular Formula |
C17H19N5O2
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| Molecular Weight |
325.37
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| Exact Mass |
325.153
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| CAS # |
144510-96-3
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| Related CAS # |
144510-96-3;144675-97-8 (dimaleate); 175989-38-5 (HCl)
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| PubChem CID |
134019
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| Appearance |
Solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
650.0±55.0 °C at 760 mmHg
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| Flash Point |
346.9±31.5 °C
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| Vapour Pressure |
0.0±1.9 mmHg at 25°C
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| Index of Refraction |
1.729
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| LogP |
-1.13
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
24
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| Complexity |
472
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
PEZPMAYDXJQYRV-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H19N5O2/c18-4-7-21-12-1-2-13(22-8-5-19)15-14(12)16(23)10-3-6-20-9-11(10)17(15)24/h1-3,6,9,21-22H,4-5,7-8,18-19H2
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| Chemical Name |
6,9-bis(2-aminoethylamino)benzo[g]isoquinoline-5,10-dione
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.0734 mL | 15.3671 mL | 30.7342 mL | |
| 5 mM | 0.6147 mL | 3.0734 mL | 6.1468 mL | |
| 10 mM | 0.3073 mL | 1.5367 mL | 3.0734 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.
Calculation results
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.
(2) Be sure to add the solvent(s) in order.
Comparative Trial for Pixantrone in Combination With Rituximab in Indolent Non-Hodgkin's Lymphoma
CTID: NCT00060671
Phase: Phase 3 Status: Terminated
Date: 2015-01-19
Comparison of the preventive and therapeutic PIX treatments on EAMG manifestation.J Immunol.2008 Feb 15;180(4):2696-703. |
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Variations in clinical score and body weight in EAMG rats.J Immunol.2008 Feb 15;180(4):2696-703. |
Immunological evaluation of the therapeutic PIX and MTX treatments in EAMG rats.J Immunol.2008 Feb 15;180(4):2696-703. |
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