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Pixantrone

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Pixantrone
Names
IUPAC name
6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione
Identifiers
3D model (JSmol)
  • C1=CC(=C2C(=C1NCCN)C(=O)C3=C(C2=O)C=NC=C3)NCCN
Properties
C17H19N5O2
Molar mass 325.365 g/mol
Pharmacology
Intravenous
Pharmacokinetics:
9.5–17.5 hours
Fecal (main route of excretion) and renal (4–9%)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Pixantrone (6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione dimaleate; rINN, codenamed BBR 2778.[1]) is an experimental antineoplastic drug, an analogue of mitoxantrone with less toxic effects on cardiac tissue.[2] It acts as a topoisomerase II poison and intercalating agent.[3]

History

Anthracyclines are important chemotherapy agents; however, their use is associated with irreversible and cumulative heart damage. Investigators have attempted to design related drugs which maintain the biological activity, but do not possess the cardiotoxicity of the anthracyclines.[4] Pixantrone was developed to reduce heart damage related to treatment while retaining efficacy.[5]

Random screening at the US National Cancer Institute of a vast number of compounds provided by the Allied Chemical Company led to the discovery of ametantrone as having significant antitumor activity. Further investigation regarding the rational development of analogs of ametantrone led to the synthesis of mitoxantrone which also exhibited marked antitumor activity[4] Mitoxantrone was considered as an analog of doxorubicin with less structural complexity but with a similar mode of action. In clinical studies, mitoxantrone was shown to be effective against numerous types of tumors with less toxic side effects than those resulting from doxorubicin therapy. However, mitoxantrone was not totally free of cardiotoxicity. A number of structurally modified analogs of mitoxantrone were synthesized and structure-activity relationship studies made.[4]

BBR2778 was characterized in vitro for tumor cell cytotoxicity and mechanism of action by studies at the University of Vermont, Burlington, the University of Texas M. D. Anderson Cancer Center, Houston, and the Istituto Nazionale Tumori, Milan.[6][7][8] In the search for novel heteroanalogs of anthracenediones, it was selected as the most promising compound. Toxicological studies indicated that BBR 2778 was not cardiotoxic, and a US patent application was completed in June 1995 by Boehringer Mannheim, Italy.[4]

Novuspharma, an Italian company, was established in 1998 following the merger of Boehringer Mannheim and Hoffmann-La Roche, and BBR 2778 was developed as Novuspharma's leading anti-cancer drug, pixantrone.[9] A patent application for the injectable preparation was filed in May 2003.[1] In 2003 Cell Therapeutics, a Seattle biotechnology company, acquired pixantrone through a merger with Novuspharma. [10]

Uses

Pixantrone is a substance that is being studied in the treatment of cancer. It belongs to the family of drugs called antitumor antibiotics.[11] As of 2009, phase III clinical trials of pixantrone are underway.[12][13] Pixantrone is being studied as an antineoplastic for different kinds of cancer, including solid tumors and hematological malignancies such as non-Hodgkin lymphomas.

Animal studies demonstrated that pixantrone does not worsen pre-existing heart muscle damage, suggesting that pixantrone may be useful in patients pretreated with anthracyclines. While only minimal cardiac changes are observed in mice given repeated cycles of pixantrone, 2 cycles of traditional anthracyclines doxorubicin or mitoxantrone result in marked or severe heart muscle degeneragion. [5]

Clinical trials substituting pixantrone for doxorubicin in standard first-line treatment of patients with aggressive non-Hodgkin's lymphoma, had a reduction in severe side effects when compared to patients treated with standard doxorubicin-based therapy. Despite pixantrone patients receiving more treatment cycles, a three-fold reduction in the incidence of severe heart damage was seen as well as clinically significant reductions in infections and thrombocytopenia, and a significant reduction in febrile neutropenia. These findings could have major implications for treating patients with breast cancer, lymphoma, and leukemia, where debilitating cardiac damage from doxorubicin might be prevented. [14] Previous treatment options for multiply relapsed aggressive non-Hodgkin lymphoma had disappointing response rates.[15] The completed phase II RAPID trial compared the CHOP-R regimen of Cyclophosphamide, Doxorubicin, Vincristine, Prednisone, and Rituximab to the same regimen, but substituting Doxorubicin with Pixantrone. The objective was to show that Pixantrone was not inferior to CHOP-R and less toxic to the heart.[16] Pixantrone was shown to have potentially reduced cardiotoxicity and demonstrated promising clinical activity in these phase II studies in heavily pretreated non-Hodgkin lymphoma patients. [15] The pivotal phase III EXTEND (PIX301) randomized clinical trial studied pixantrone to see how well it works compared to other chemotherapy drugs in treating patients with relapsed non-Hodgkin's lymphoma. [17] The complete response rate in patients treated with pixantrone has been significantly higher than in those receiving other chemotherapeutic agents for treatment of relapsed/refractory aggressive non-Hodgkin lymphoma.[15]

Administration

It can be administered through a peripheral vein rather than a central implanted catheter as required for other similar drugs.[1][18].

Regulatory Approval Process

U.S. Food and Drug Administration

The FDA granted fast track designation for pixantrone in patients who had previously been treated two or more times for relapsed or refractory aggressive NHL. Study sponsor Cell Therapeutics announced that Pixantrone achieved the primary efficacy endpoint, and in April 2009 began a rolling submission of a New Drug Application to the U.S. Food and Drug Administration for Pixantrone to treat relapsed or refractory aggressive NHL. They will request priority review by the FDA. [19].

European Medicines Evaluation Agency

On May 5, 2009, Pixantrone became available in Europe on a Named-Patient Basis. A named-patient program is a compassionate use drug supply program under which physicians can legally supply investigational drugs to qualifying patients. Under a named-patient program, investigational drugs can be administered to patients who are suffering from serious illnesses prior to the drug being approved by the European Medicines Evaluation Agency. "Named-patient" distribution refers to the distribution or sale of a product to a specific healthcare professional for the treatment of an individual patient. In Europe, under the named-patient program the drug is most often purchased through the national health system[20].

Research

Pixantrone is as potent as mitoxantrone in animal models of multiple sclerosis. [21] Pixantrone has a similar mechanism of action as mitoxantrone on the effector function of lymphomonocyte B and T cells in experimental allergic encephalomyelitis but with lower cardiotoxicity. Pixantrone inhibits antigen specific and mitogen induced lymphomononuclear cell proliferation, as well as IFN-gamma production[2].

Pixantrone also reduces the severity of experimental autoimmune myasthenia gravis in Lewis rats,[22] and in vitro cell viability experiments indicated that Pixantrone significantly reduces amyloid beta (A beta(1-42)) neurotoxicity, a mechanism implicated in Alzheimer's disease. [23]

References

  1. ^ a b c http://www.freepatentsonline.com/EP1503797.html Injectable Pharmaceutical Compositions of an Anthracenedione Derivative with Anti-Tumoral Activity.
  2. ^ a b Mazzanti B, Biagioli T, Aldinucci A; et al. (2005). "Effects of pixantrone on immune-cell function in the course of acute rat experimental allergic encephalomyelitis". J. Neuroimmunol. 168 (1–2): 111–7. doi:10.1016/j.jneuroim.2005.07.010. PMID 16120465. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) Cite error: The named reference "pmid16120465" was defined multiple times with different content (see the help page).
  3. ^ Evison BJ, Mansour OC, Menta E, Phillips DR, Cutts SM (2007). "Pixantrone can be activated by formaldehyde to generate a potent DNA adduct forming agent". Nucleic Acids Res. 35 (11): 3581–9. doi:10.1093/nar/gkm285. PMC 1920253. PMID 17483512.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ a b c d http://www.freepatentsonline.com/5587382.html United States Patent 5587382 6,9-bis[(2-aminoethyl) amino]benzo [g]isoquinoline-5,10- dione dimaleate; an aza-anthracenedione with reduced cardiotoxicity
  5. ^ a b Cavalletti E, Crippa L, Mainardi P, Oggioni N, Cavagnoli R, Bellini O, Sala F. (2007). "Pixantrone (BBR 2778) has reduced cardiotoxic potential in mice pretreated with doxorubicin: comparative studies against doxorubicin and mitoxantrone". Invest New Drugs. 25 (3): 187–95. doi:10.1007/s10637-007-9037-8. PMID 17285358.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ De Isabella P, Palumbo M, Sissi C, Capranico G, Carenini N, Menta E, Oliva A, Spinelli S, Krapcho AP, Giuliani FC; et al. (1995). "Topoisomerase II DNA cleavage stimulation, DNA binding activity, cytotoxicity, and physico-chemical properties of 2-aza- and 2-aza-oxide-anthracenedione derivatives". Mol Pharmacol. 48 (1): 30–8. PMID 7623772. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  7. ^ Zwelling LA, Mayes J, Altschuler E, Satitpunwaycha P, Tritton TR, Hacker MP. (1993). "Activity of two novel anthracene-9,10-diones against human leukemia cells containing intercalator-sensitive or -resistant forms of topoisomerase II". Biochem Pharmacol. 46 (2): 265–71. doi:10.1016/0006-2952(93)90413-Q. PMID 8394077.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ Krapcho AP, Petry ME, Getahun Z, Landi JJ Jr, Stallman J, Polsenberg JF, Gallagher CE, Maresch MJ, Hacker MP, Giuliani FC; et al. (1994). "6,9-Bis[(aminoalkyl)amino]benzo[g]isoquinoline-5,10-diones. A novel class of chromophore-modified antitumor anthracene-9,10-diones: synthesis and antitumor evaluations". J Med Chem. 37 (6): 828–37. doi:10.1021/jm00032a018. PMID 8145234. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  9. ^ http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/06-24-2002/0001752386
  10. ^ http://www.nytimes.com/2003/06/17/business/company-news-cell-therapeutics-announces-plan-to-buy-novuspharma.html?sec=health
  11. ^ http://www.survivorship.cancer.gov/Templates/db_alpha.aspx?CdrID=322132
  12. ^ BBR 2778 for Relapsed, Aggressive Non-Hodgkin's Lymphoma (NHL). ClinicalTrials.gov (2007-08-30). Retrieved on 2007-11-06.
  13. ^ Fludarabine and Rituximab With or Without Pixantrone in Treating Patients With Relapsed or Refractory Indolent Non-Hodgkin Lymphoma. ClinicalTrials.gov (2007-10-25). Retrieved on 2007-11-06.
  14. ^ http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/07-11-2007/0004623260 Pixantrone Combination Therapy for First-line Treatment of Aggressive Non-Hodgkin's Lymphoma Results in Reduction in Severe Toxicities Including Heart Damage When Compared to Doxorubicin-based Therapy
  15. ^ a b c http://www.abstract.asco.org/AbstView_65_35306.html Randomized phase III trial of pixantrone compared with other chemotherapeutic agents for third-line single-agent treatment of relapsed aggressive non-Hodgkin's lymphoma. J Clin Oncol 27:15s, 2009 (suppl; abstr 8523)
  16. ^ http://clinicaltrials.gov/ct2/show/NCT00268853 A Trial in Patients With Diffuse Large-B-Cell Lymphoma Comparing Pixantrone Against Doxorubicin (RAPID) Retrieved on 2009-05-16
  17. ^ Pixantrone or Other Chemotherapy Drugs in Treating Patients With Relapsed Non-Hodgkin's Lymphoma. ClinicalTrials.gov (2007-10-25). Retrieved on 2007-11-06.
  18. ^ http://news.prnewswire.com/DisplayReleaseContent.aspx?ACCT=104&STORY=/www/story/05-15-2009/0005026831
  19. ^ http://www.celltherapeutics.com/pixantrone
  20. ^ http://news.prnewswire.com/DisplayReleaseContent.aspx?ACCT=104&STORY=/www/story/05-05-2009/0005019037
  21. ^ Gonsette RE, Dubois B (2004). "Pixantrone (BBR2778): a new immunosuppressant in multiple sclerosis with a low cardiotoxicity". J. Neurol. Sci. 223 (1): 81–6. doi:10.1016/j.jns.2004.04.024. PMID 15261566.
  22. ^ Ubiali F, Nava S, Nessi V, et al. Pixantrone (BBR2778) reduces the severity of experimental autoimmune myasthenia gravis in Lewis rats. J Immunol. 2008 Feb 15;180(4):2696-703.
  23. ^ Electrophoresis. 2009 Apr;30(8):1418-29. CE can identify small molecules that selectively target soluble oligomers of amyloid beta protein and display antifibrillogenic activity. Colombo R, Carotti A, Catto M, Racchi M, Lanni C, Verga L, Caccialanza G, De Lorenzi E.
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