Vosaroxin is a novel topoisomerase-II inhibitor with efficacy in relapsed and refractory acute myeloid leukaemia

Hotinski, Anya K.; Lewis, Ian D.; Ross, David M.

doi:10.1517/14656566.2015.1044437

Cited by 17 publications

(8 citation statements)

References 27 publications

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“…Anyhow, based on the very short median time to relapse, post-transplantation interventions should be given early as a prophylactic or maintenance strategy. Vosaroxin [44, 45] is a quinolone derivative reported to be TP53 independent and shows some clinical benefit in combination with high-dose cytarabine in relapsed patients. Currently, it is completely unknown if this agent, administered prior to allo-SCT, might result into improved outcome after allo-SCT, but it might constitute a model to bring abn(17p) AML with better response to allo-SCT.…”

Section: Discussionmentioning

confidence: 99%

Allogeneic stem cell transplantation in adult patients with acute myeloid leukaemia and 17p abnormalities in first complete remission: a study from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT)

et al. 2017

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BackgroundAcute myeloid leukaemia (AML) with 17p abnormalities (abn(17p)) carries a very poor prognosis due to high refractoriness to conventional chemotherapy, and allogeneic stem cell transplantation (allo-SCT) appears as the only potential curative option.MethodsTo address outcomes after allo-SCT in patients with abn(17p), we retrospectively analysed de novo or secondary AML undergoing SCT between 2000 and 2013 from the EBMT registry.ResultsOne hundred thirty-nine patients with confirmed abn(17p) have been selected. At the time of transplant, one hundred twenty-five were in first remission (CR1). Median age was 54 years old. Abn(17p) was associated with a monosomal karyotype in 83% of patients, complex karyotype in 91%, monosomy 5 or 5q deletion (-5/5q-) in 55%, monosomy 7 (-7) in 39% and both -5/5q and -7 in 27%. Seventy-three patients (59%) had a reduced-intensity conditioning regimen. The 2-year overall survival (OS) and leukaemia-free survival (LFS) were 28 and 24%, respectively. The 2-year non-relapse mortality (NRM) was 15%, and 2-year relapse incidence (RI) was 61%. The cumulative incidence of grade II to IV acute graft-versus-host disease (GvHD) was 24% and that of chronic GvHD was 21%. In multivariate analysis, the presence of a -5/5q- in addition to abn(17p) was significantly and independently associated with worse OS, LFS and higher RI. Age and donor types did not correlate with outcome. Conditioning intensity was not statistically associated with OS, LFS and NRM when adjusted for patients’ age.ConclusionsIn contrast to the dismal prognosis reported for AML patients harbouring abn(17p) undergoing conventional chemotherapy, allogeneic SCT provides responses in about 25% of those patients transplanted in CR1.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0393-3) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Allogeneic stem cell transplantation in adult patients with acute myeloid leukaemia and 17p abnormalities in first complete remission: a study from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT)

et al. 2017

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“…Among the antimicrobial FQs, moxifloxacin and ciprofloxacin have selectively shown apoptogenic antiproliferative propensities in pancreatic cancer cell lines (Kan et al, 2013;Yadav, Varshney, Sultana, Yadav, & Saini, 2015). Vosaroxin is a new quinolone derivative that has been developed as an anticancer agent inhibiting topoisomerase-II, thus triggering apoptosis (Abbas & Stuart, 2012;Hotinski, Lewis, & Ross, 2015). Recently, novel FQ derivatives were synthesized with appreciably promising antiproliferative activity against human CRC cell lines (Alabsi, 2018;Arabiyat, 2016;Arabiyat et al, 2016Arabiyat et al, , 2017.…”

Section: Obesity and Cancermentioning

confidence: 99%

Evaluation of selected commercial pharmacotherapeutic drugs as potential pancreatic lipase inhibitors and antiproliferative compounds

Mamdooh

Kasabri

Al‐Hiari

et al. 2018

Drug Development Research

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In this study, 15 commercial acidic drugs have been evaluated for pancreatic lipase (PL) inhibitory activity using an in vitro spectrophotometric method. The acidity was the basis of selection, since most PL inhibitors exhibit acidic groups and high lipophilicity. Orlistat was the robust reference agent for potency and efficacy determinations. In comparison to the cisplatin, the evaluation of the antineoplastic activities of selected drugs in a panel of colorectal cancer cell lines (HT‐29, HCT‐116, SW620, CACO‐2, and SW480) and normal periodontal ligament fibroblasts for safety examination was performed by using a sulforhodamine procuring ascorbic acid as a reference in diphenyl‐2‐picryl‐hydrazyl assay of radical scavenging properties was performed. This research revealed three highly acidic pharmacological classes with reasonable PL inhibitory activity in comparison to orlistat out of 15 selected drugs, namely sulfonylureas, fluoroquinolones, and proton pump inhibitors. Docking studies supported the hypothesis of a selection based on acidity, since it showed that the sulfonamide acid group (glyburide) is a remarkably potent interacting group with the enzyme. Failing to fulfill other structure‐activity relationship requirements (lipophilicity) led to weak activity. Since the drugs are of different chemical classes with unknown mechanisms, they showed diverse antiproliferative activity. Some drugs such as atorvastatin and gemifloxacin showed higher antiproliferative activity than cisplatin with high‐safety profiles against SW620 and SW480 cell lines, respectively, whereas lansoprazole and clopidogrel revealed comparable activity to cisplatin against HCT‐116 and SW480, respectively. Unfortunately, selected tested drugs exhibited negligible radical scavenging activity versus ascorbic acid. Hit, Lead & Candidate Discovery

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“…However, so far vosaroxin has mainly been seen to improve remission rates or overall survival in AML-patients older than 60 years (Hotinski et al, 2015). Therefore it has the potential of less cardiotoxicity than traditional topoisomerase inhibitors.…”

Section: Other Cardiotoxic Chemotherapeutic Agents Used In Aml Treatmentmentioning

confidence: 99%

“…Therefore it has the potential of less cardiotoxicity than traditional topoisomerase inhibitors. However, so far vosaroxin has mainly been seen to improve remission rates or overall survival in AML-patients older than 60 years (Hotinski et al, 2015).…”

Section: Other Cardiotoxic Chemotherapeutic Agents Used In Aml Treatmentmentioning

confidence: 99%

Is it possible to cure childhood acute myeloid leukaemia without significant cardiotoxicity?

2016

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Since cardiotoxicity is a life threatening late effect, a reduction of cardiotoxicity in the treatment of acute myeloid leukaemia (AML) is essential. This review is a compilation of the current knowledge about cardiotoxicity after AML treatment and of how future directions in treatment may affect its incidence. A total of six studies concerning AML and cardiotoxicity were identified. The incidence of late subclinical cardiotoxicity varied between 1·3 and 15·3%, and late clinical cardiotoxicity varied between 1·3 and 9·3%. Cumulative dose of anthracyclines (ACs) and history of relapse were the most common risk factors identified. No conclusions could be drawn about new, potentially less toxic ACs. Differences in treatment data and variations in study populations made comparisons uncertain. The echocardiographic techniques used in the majority of the studies are inferior to more modern echocardiographic methods. This decreases reproducibility and may increase the risk of overestimation of cardiotoxicity. In summary, AML cannot be cured today without ACs. However, some ACs may cause less cardiotoxicity than others. Furthermore there is currently no consensus on equipotent doses of ACs and risk factors for cardiotoxicity. Further research including randomized trials is needed to evaluate whether or not the potentially less cardiotoxic agents fulfil their promise.

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Vosaroxin is a novel topoisomerase-II inhibitor with efficacy in relapsed and refractory acute myeloid leukaemia

Cited by 17 publications

References 27 publications

Allogeneic stem cell transplantation in adult patients with acute myeloid leukaemia and 17p abnormalities in first complete remission: a study from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT)

Allogeneic stem cell transplantation in adult patients with acute myeloid leukaemia and 17p abnormalities in first complete remission: a study from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT)

Evaluation of selected commercial pharmacotherapeutic drugs as potential pancreatic lipase inhibitors and antiproliferative compounds

Is it possible to cure childhood acute myeloid leukaemia without significant cardiotoxicity?

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