Bbr 2778, an Aza-anthracenedione Endowed with Preclinical Anticancer Activity and Lack of Delayed Cardiotoxicity

Beggiolin, G.; Crippa, Luca; Menta, Ernesto; Manzotti, C.; Cavalletti, Ennio; Pezzoni, Gabriella; Torriani, Dante; Randisi, Eleonora; Cavagnoli, R.; Sala, Federica; Giuliani, F; Spinelli, Silvano

doi:10.1177/030089160108700611

Cited by 58 publications

(46 citation statements)

References 26 publications

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“…In preclinical models pixantrone, a novel aza-anthracenedione, was shown to have greater cytotoxicity against P388 and L1210 leukemia cell lines compared to mitoxantrone and doxorubicin, and an in vivo murine model. 39,40 These studies reported a more favorable therapeutic index with less cardiotoxicity. Recently, a very small Phase II experience in lymphoma was published on 33 patients with either DLCL-B (n = 24), MCL (n = 7), and 2 patients with transformed lymphoma.…”

Section: Other Promising Agentsmentioning

confidence: 99%

Diffuse Aggressive Lymphoma

Fisher¹,

Miller²,

O’Connor³

2004

Hematology

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The aggressive non-Hodgkin's lymphomas can be cured in more than half of the cases. However, there has been great variation in the results reported from individual clinical Phase II trials. This variation in result can be attributed to unrecognized heterogeneity in this group of diseases. Recent clinical and molecular studies have enabled us to define more homogenous population in which new therapies can be studied. For patients with advanced stages of diffuse large B cell lymphoma, a new standard of therapy exists. For patients with localized aggressive non-Hodgkin's lymphomas, heterogeneity in patient selection prevents us from defining a new standard of care. Finally, in mantle cell lymphoma, new opportunities in drug discovery may permit advances in the treatment of this uniformly fatal malignancy.In Section I, Dr. Richard Fisher reviews the development of combination chemotherapy for patients with advanced stage diffuse large B cell lymphoma. Because of great heterogeneity in patients enrolled in Phase II studies, large randomized Phase III studies were required in the 1980s to define CHOP has the standard of care. This heterogeneity has now been defined carefully in the international prognostic factor index and more recently by gene array studies. It will now need to be incorporated prospectively into studies or retrospectively analyzed to understand clinical trial results. The addition of rituximab to CHOP has now been demonstrated to improve survival in two large Phase III studies in elderly patients. A recently presented study in younger patients suggests a similar benefit. Thus CHOP/rituximab has become the established standard of care for all patients with advanced stage diffuse large B cell lymphoma. Other concepts being evaluated to further improve on these results include: dose intensification; initial treatment with chemotherapy plus allogeneic stem cell transplantation; and infusional chemotherapy. Finally, the status of the treatment for relapsed patients will be defined. In Section III, Dr. Owen O'Connor describes the pathology immunophenotype and natural history of mantle cell lymphoma. Conventional treatment strategies with combination chemotherapy achieved objective responses in approximately half of the patients but no significant impact on survival. The addition to rituximab to CHOP chemotherapy or other treatment strategies appears to improve the remission rate; however, no major changes in survival have also been reported. Excellent single institution results have been reported with HyperCVAD plus rituximab regimen, which is currently being tested in a national cooperative group trial. The most excitement in this field currently relates to the variety of new agents which appear to have significant activity in relapsed patients with mantle cell lymphoma. This includes the proteosome inhibitor, bortezomib, which is shown to have approximately a 50% response rate with some CRs and reasonable durability in early single institution Phase II studies. Larger national multi-center trials are ong...

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Section: Other Promising Agentsmentioning

confidence: 99%

Diffuse Aggressive Lymphoma

Fisher¹,

Miller²,

O’Connor³

2004

Hematology

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“…As far as cardiotoxicity is concerned, we performed a limited histopathological assessment on hearts from PIXand vehicle-treated animals, without detecting any signs of damage to cardiomyocytes. We did not analyze cardiotoxicity in PIX-vs MTX-treated rats; however, the lack of cardiotoxicity of PIX has been already reported (2,9,10).…”

Section: Discussionmentioning

confidence: 97%

“…injection in rats. This correspondence was chosen to compare drug effect and the cardiotoxicity of the two compounds (9). Treatment assignation was performed at day 4 after TAChR immunization (preventive schedule) in coincidence of the acute phase of EAMG, or at onset of clinical signs (therapeutic schedule), which occurs after 4 wk.…”

Section: Immunization and Treatment Protocolsmentioning

confidence: 99%

“…The doses of PIX and MTX used in this study were in both cases equal to one-fourth of the LD 10 for single i.v. injection in rats and this correspondence was chosen to compare drug effect and the cardiotoxicity of the two compounds (9). During the observation period we found that both PIX and MTX treatments improved EAMG symptoms as compared with vehicletreated EAMG rats.…”

Section: Comparison Of Pix Vs Mtx Treatment In Eamg Ratsmentioning

confidence: 99%

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Pixantrone (BBR2778) Reduces the Severity of Experimental Autoimmune Myasthenia Gravis in Lewis Rats

Ubiali¹,

Nava²,

Nessi³

et al. 2008

The Journal of Immunology

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Pixantrone (BBR2778) (PIX) and mitoxantrone share the same mechanism of action because both drugs act as DNA intercalants and inhibitors of topoisomerase II. PIX is an interesting candidate immunosuppressant for the treatment of autoimmune diseases because of its reduced cardiotoxicity compared with mitoxantrone. The clinical response to conventional immunosuppressive treatments is poor in some patients affected by myasthenia gravis (MG), and new but well-tolerated drugs are needed for treatment-resistant MG. PIX was tested in vitro on rat T cell lines specific for the immunodominant peptide 97–116 derived from rat acetylcholine receptor (AChR), and showed strong antiproliferative activity in the nanomolar range. We demonstrate in this study that PIX administration reduced the severity of experimental autoimmune MG in Lewis rats. Biological and immunological analysis confirmed the effect of PIX, compared with vehicle-treated as well as mitoxantrone-treated experimental autoimmune MG rats. Anti-rat AChR Abs were significantly reduced in PIX-treated rats, and AChR content in muscles were found increased. Torpedo AChR-induced T cell proliferation tests were found reduced in both in vitro and ex vivo experiments. The effectiveness and the reduced cardiotoxicity make PIX a promising immunosuppressant agent suitable for clinical investigation in MG, although additional experiments are needed to confirm its safety profile in prolonged treatments.

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“…Pixantrone showed in vitro and in vivo activity against lymphoid malignancies with a therapeutic range broader than that of mitoxantrone, from which it differs because of a lack of delayed cardiotoxicity [131].…”

Section: New Cytotoxicsmentioning

confidence: 99%

Beyond Monoclonal Antibodies: New Therapeutic Agents in Non-Hodgkin’s Lymphomas

2009

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1. Utilize new therapeutic agents with proven efficacy in the chemotherapy-and monoclonal antibody-refractory NHL setting.2. Analyze the study of these new agents in lymphoma subtypes and in relation to genetic aberrations of the lymphoma.3. Differentiate the toxicity of these new agents from that of chemotherapy.This article is available for continuing medical education credit at CME.TheOncologist.com. CME CME ABSTRACTThe availability of active monoclonal antibodies, either as single agents or in combination with cytotoxic agents, has improved treatment results in non-Hodgkin's lymphoma (NHL). Despite this and the increasing number of available active monoclonal antibodies, alone or conjugated with radioisotopes, not all types of lymphoma are sensitive to these biological agents and often they become resistant because of different molecular mechanisms.New molecular targets in neoplastic cells are emerging and provide the rationale for novel discovery initiatives. In fact, a greater knowledge of the biology of lymphoma and the identification of compounds selectively active against a potential therapeutic pathway have already improved the time to progression and survival time of patients with some subtypes of NHL. The growing list of new drugs provides the exciting prospect of developing disease-specific and even patient-specific therapies.The aim of this review is to identify and discuss nonmonoclonal antibody new therapeutic agents in terms of mechanism of action and clinical results. The preclinical and clinical features of proteasome inhibitors, histone deacetylase inhibitors, thalidomide and lenalidomide,

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Bbr 2778, an Aza-anthracenedione Endowed with Preclinical Anticancer Activity and Lack of Delayed Cardiotoxicity

Cited by 58 publications

References 26 publications

Diffuse Aggressive Lymphoma

Diffuse Aggressive Lymphoma

Pixantrone (BBR2778) Reduces the Severity of Experimental Autoimmune Myasthenia Gravis in Lewis Rats

Beyond Monoclonal Antibodies: New Therapeutic Agents in Non-Hodgkin’s Lymphomas

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