Pixantrone dimaleate for treating non-Hodgkin’s lymphoma

Pettengell, Ruth; Kaur, Jasvinder

doi:10.1517/21678707.2015.1042454

Cited by 12 publications

(11 citation statements)

References 29 publications

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“…1) used for the treatment of aggressive non-Hodgkin lymphoma (NHL) that was designed to minimize cardiotoxicity (Mukherji and Pettengell, 2010;Boyle and Morschhauser, 2015). Pixantrone was granted conditional marketing approval in the European Union in May 2012 as a monotherapy for the treatment of adult patients with multiply relapsed or refractory aggressive B cell NHLs (Pean et al, 2013;Pettengell and Kaur, 2015). Anthracyclines such as doxorubicin are highly active against NHL, but their use in relapsed patients is compromised by their well-known total dose-limiting cardiotoxicity.…”

Section: Introductionmentioning

confidence: 99%

“…Anthracyclines such as doxorubicin are highly active against NHL, but their use in relapsed patients is compromised by their well-known total dose-limiting cardiotoxicity. A phase III clinical trial in heavily pretreated patients with relapsed or refractory aggressive NHL showed that pixantrone is efficacious and tolerable (Pean et al, 2013;Pettengell and Kaur, 2015). The National Institutes of Health clinical trials website (www.clinicaltrials.gov) currently lists 14 clinical trials involving pixantrone.…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms of Action and Reduced Cardiotoxicity of Pixantrone; a Topoisomerase II Targeting Agent with Cellular Selectivity for the Topoisomerase II Isoform

Hasinoff

Patel

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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Pixantrone is a new noncardiotoxic aza-anthracenedione anticancer drug structurally related to anthracyclines and anthracenediones, such as doxorubicin and mitoxantrone. Pixantrone is approved in the European Union for the treatment of relapsed or refractory aggressive B cell non-Hodgkin lymphoma. This study was undertaken to investigate both the mechanism(s) of its anticancer activity and its relative lack of cardiotoxicity. Pixantrone targeted DNA topoisomerase IIa as evidenced by its ability to inhibit kinetoplast DNA decatenation; to produce linear double-strand DNA in a pBR322 DNA cleavage assay; to produce DNA double-strand breaks in a cellular phosphohistone gH2AX assay; to form covalent topoisomerase II-DNA complexes in a cellular immunodetection of complex of enzymeto-DNA assay; and to display cross-resistance in etoposideresistant K562 cells. Pixantrone produced semiquinone free radicals in an enzymatic reducing system, although not in a cellular system, most likely due to low cellular uptake. Pixantrone was 10-to 12-fold less damaging to neonatal rat myocytes than doxorubicin or mitoxantrone, as measured by lactate dehydrogenase release. Three factors potentially contribute to the reduced cardiotoxicity of pixantrone. First, its lack of binding to iron(III) makes it unable to induce iron-based oxidative stress. Second, its low cellular uptake may limit its ability to produce semiquinone free radicals and redox cycle. Finally, because the b isoform of topoisomerase II predominates in postmitotic cardiomyocytes, and pixantrone is demonstrated in this study to be selective for topoisomerase IIa in stabilizing enzyme-DNA covalent complexes, the attenuated cardiotoxicity of this agent may also be due to its selectivity for targeting topoisomerase IIa over topoisomerase IIb.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mechanisms of Action and Reduced Cardiotoxicity of Pixantrone; a Topoisomerase II Targeting Agent with Cellular Selectivity for the Topoisomerase II Isoform

Hasinoff

Patel

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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“…For this reason, a new therapy was started, this time using pixantrone dimaleate. This drug was chosen taking into account both the previous therapy lines and the recent approval by the European Medicines Agency for its usage in multiple relapsed/refractory aggressive non-Hodgkin lymphomas [3,4,5,6,7]. Pixantrone was administered on days +1, +8, and +15 of each 28-day cycle at a dose of 50 mg/m 2 (reduced by 20% because of the numerous previous lines of therapy and the high risk of hematologic toxicity), with the first infusion happening on August 10, 2015.…”

Section: Case Presentationmentioning

confidence: 99%

Impressive Response to Pixantrone after Allogeneic Transplant in a Multiple Relapsed Diffuse Large B-Cell Lymphoma

Malaspina

Pellegrini²,

Casadei³

et al. 2017

Acta Haematol

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Diffuse large B-cell lymphoma is the most frequent histology at diagnosis among non-Hodgkin B lymphomas and can be cured in 50-70% of cases after the first-line chemotherapy regimen. Patients who do not respond to first-line treatment can undergo numerous subsequent steps, culminating in allogeneic stem cell transplant (alloSCT). A relapse after alloSCT, however, carries an awful prognosis, seeing the demise of the patient usually in the following months. Here we present the case of a multiple relapsed patient who successfully underwent therapy with pixantrone after alloSCT, obtaining a complete remission without any considerable side effects.

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“…Pixantrone is an aza-athracenedione that alkylates DNA directly, forming stable DNA adducts and inducing double-strand DNA breaks, thereby inhibiting DNA replication, transcription and repair [21][22][23][24][25][26]; in addition, pixantrone-induced DNA damage also appears to impair mitosis [27,28]. Cardiotoxicity is an issue with anthracyclines, via iron-dependent formation of reactive oxygen species, and topoisomerase IIβ-mediated DNA damage response [25].…”

Section: • Pixantronementioning

confidence: 99%

The Servier oncology pipeline in 2017

et al. 2017

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Cancer is a complex, multifactorial disease that for years has been the focus of intensive research efforts to explore both the molecular and biological mechanisms involved and the development of novel agents to target these pathways. Servier is an independent French pharmaceutical company with a focus on oncology. Currently, Servier's commercial portfolio includes agents used to treat non-Hodgkin's lymphoma and metastatic colorectal cancer; Servier's oncology pipeline involves agents for the treatment of both solid and hematological tumors. The main areas of future research focus on the development of therapeutics targeting apoptosis or the active immune components involved in tumour development/maintenance. Servier intends to continue its focus on cutting-edge oncology innovation by collaborating with both industry and academia, and maintaining its strong patient-centered approach.

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Pixantrone dimaleate for treating non-Hodgkin’s lymphoma

Cited by 12 publications

References 29 publications

Mechanisms of Action and Reduced Cardiotoxicity of Pixantrone; a Topoisomerase II Targeting Agent with Cellular Selectivity for the Topoisomerase II Isoform

Mechanisms of Action and Reduced Cardiotoxicity of Pixantrone; a Topoisomerase II Targeting Agent with Cellular Selectivity for the Topoisomerase II Isoform

Impressive Response to Pixantrone after Allogeneic Transplant in a Multiple Relapsed Diffuse Large B-Cell Lymphoma

The Servier oncology pipeline in 2017

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