Biological Activity

• DescriptionPixantrone, a Mitoxantrone analogue with low cardiotoxicity, is a topoisomerase II inhibitor, usually used in study of non-Hodgkin's lymphomas as well as an immunosuppressant in multiple sclerosis. Pixantrone may preferentially target on topoisomerase IIα. Incubation with Pixantrone at concentration ranging in 0-100μM (especially 50-100μM) for 1h induced a dose-dependent increase of topoisomerase II-mediated DNA-protein cross-links in HL-60 cells. Pixantrone at concentration of 50μM led to inhibition of topoisomerase II (purified from HL-60 cells)-mediated DNA strand passage. Pixantrone can produce linear double-strand DNA in a pBR322 DNA cleavage assay (10-100μM) and cellular DNA double strand breaks (5-50μM) in K562 cells. Pixantrone can also be used as an immunosuppressive drug. Administration of pixantrone (8, 12, 16.25mg/kg, i.v) reduced the severity of acute and decreased the relapse rate of chronic relapsing EAE rat model, with a marked and long-lasting decrease in CD3+, CD4+, CD8+ and CD45RA+ blood cells and reduced anti-MBP titers observed. Compared with Mitoxantrone, Pixantrone showed much lower cardiotoxicity due to three factors: 1. Its lack of binding to iron(III) makes the inability to induce iron-based oxidative stress; 2. Its lower cellular uptake may limit the production of semiquinone free radicals and redox cycle; 3. Its less potency to topoisomerase IIβ attenuated cardiotoxicity due to topoisomerase IIβ predominates in post-mitotic cardiomyocytes.
• MechanismPixantrone could stabilize a covalent complex between DNA and topoisomerase II.^[1]

• Animal Study
  Dose	CD1 female mice: 27 mg/kg[2] (i.v.)
  Administration	i.v.

• Clinical Study

• NCT Number	Condition or disease	Phase	Recruitment Status	Estimated Study Completion Date	Locations
  NCT01321541	Diffuse Large B-cell Lymphoma ... more >> de Novo DLBCL DLBCL Transformed From Indolent Lymphoma Follicular Grade 3 Lymphoma Collapse <<	Phase 3	Completed	-	-
  NCT00069966	Lymphoma	Phase 2	Unknown	-	-
  NCT00551239	Leukemia Lymp... more >>homa Collapse <<	Phase 3	Unknown	-	United States, Washington ... more >> Cell Therapeutics, Incorporated Seattle, Washington, United States, 98119 Collapse <<

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• References

• [1] Evison BJ, Mansour OC, et al. Pixantrone can be activated by formaldehyde to generate a potent DNA adduct forming agent. Nucleic Acids Res. 2007;35(11):3581-9.

  [2] Cavalletti E, Crippa L, et al. Pixantrone (BBR 2778) has reduced cardiotoxic potential in mice pretreated with doxorubicin: comparative studies against doxorubicin and mitoxantrone. Invest New Drugs. 2007 Jun;25(3):187-95.