-
Nucleic Acids Research Dec 2023DNA i-motifs (iMs) are non-canonical C-rich secondary structures implicated in numerous cellular processes. Though iMs exist throughout the genome, our understanding of...
DNA i-motifs (iMs) are non-canonical C-rich secondary structures implicated in numerous cellular processes. Though iMs exist throughout the genome, our understanding of iM recognition by proteins or small molecules is limited to a few examples. We designed a DNA microarray containing 10976 genomic iM sequences to examine the binding profiles of four iM-binding proteins, mitoxantrone and the iMab antibody. iMab microarray screens demonstrated that pH 6.5, 5% BSA buffer was optimal, and fluorescence was correlated with iM C-tract length. hnRNP K broadly recognizes diverse iM sequences, favoring 3-5 cytosine repeats flanked by thymine-rich loops of 1-3 nucleotides. Array binding mirrored public ChIP-Seq datasets, in which 35% of well-bound array iMs are enriched in hnRNP K peaks. In contrast, other reported iM-binding proteins had weaker binding or preferred G-quadruplex (G4) sequences instead. Mitoxantrone broadly binds both shorter iMs and G4s, consistent with an intercalation mechanism. These results suggest that hnRNP K may play a role in iM-mediated regulation of gene expression in vivo, whereas hnRNP A1 and ASF/SF2 are possibly more selective in their binding preferences. This powerful approach represents the most comprehensive investigation of how biomolecules selectively recognize genomic iMs to date.
Topics: DNA; G-Quadruplexes; Heterogeneous-Nuclear Ribonucleoprotein K; Mitoxantrone; Nucleotide Motifs; Humans; Oligonucleotide Array Sequence Analysis
PubMed: 37962331
DOI: 10.1093/nar/gkad981 -
Multiple Sclerosis and Related Disorders Oct 2017Aggressive, highly active, or rapidly evolving severe relapsing-remitting multiple sclerosis (RRMS) is characterized by frequent relapses and active disease on magnetic... (Review)
Review
BACKGROUND
Aggressive, highly active, or rapidly evolving severe relapsing-remitting multiple sclerosis (RRMS) is characterized by frequent relapses and active disease on magnetic resonance imaging, ultimately leading to a high risk for rapid disability accumulation. The treatment approach for high-risk patients is evolving into a model of individualized therapy in which early initiation of high-efficacy disease-modifying therapy (DMT), which I refer to as "early and strong" therapy, is viewed as a rational strategy to prevent the irreversible damage that occurs at disease onset and early in the disease course. This approach uses an individualized benefit-risk assessment to match the level of DMT efficacy with the patient's risk of disease progression and balances it against the risk of drug-related adverse events. It also includes consideration of the patient's risk tolerance and desire for a high-efficacy treatment. This paper discusses the rationale for early treatment, and summarizes the available clinical data on high-efficacy and moderately-high efficacy DMTs in patients with high-risk RRMS.
METHODS
Literature searches were conducted using search terms "aggressive RRMS", "highly active RRMS", and "severe RRMS" alone and in conjunction with the terms "natalizumab", "fingolimod", "alemtuzumab", "mitoxantrone", and "cyclophosphamide". Studies of drug efficacy in these high-risk populations were reviewed.
RESULTS
Subgroup analyses of pivotal trials of natalizumab, fingolimod, and alemtuzumab were available, as well as an independent study of mitoxantrone and a pilot study of cyclophosphamide. In each study, DMT reduced relapses versus either placebo, active comparator, or baseline relapse rate.
CONCLUSION
Data for the high-efficacy DMTs natalizumab and alemtuzumab, and the moderately high-efficacy DMT fingolimod, suggest they are effective in this patient population. Further studies are warranted, and clinical trial data to inform treatment decisions for this high-risk group represent a significant unmet need.
Topics: Alemtuzumab; Antineoplastic Agents; Clinical Trials as Topic; Cyclophosphamide; Disease Progression; Fingolimod Hydrochloride; Humans; Immunologic Factors; Immunosuppressive Agents; Mitoxantrone; Multiple Sclerosis, Relapsing-Remitting; Natalizumab; Precision Medicine; Risk Assessment; Risk Factors; Treatment Outcome
PubMed: 29055479
DOI: 10.1016/j.msard.2017.07.003 -
Chemistry & Biology May 2010DNA topoisomerases are the targets of important anticancer and antibacterial drugs. Camptothecins and novel noncamptothecins in clinical development (indenoisoquinolines... (Review)
Review
DNA topoisomerases are the targets of important anticancer and antibacterial drugs. Camptothecins and novel noncamptothecins in clinical development (indenoisoquinolines and ARC-111) target eukaryotic type IB topoisomerases (Top1), whereas human type IIA topoisomerases (Top2alpha and Top2beta) are the targets of the widely used anticancer agents etoposide, anthracyclines (doxorubicin, daunorubicin), and mitoxantrone. Bacterial type II topoisomerases (gyrase and Topo IV) are the targets of quinolones and aminocoumarin antibiotics. This review focuses on the molecular and biochemical characteristics of topoisomerases and their inhibitors. We also discuss the common mechanism of action of topoisomerase poisons by interfacial inhibition and trapping of topoisomerase cleavage complexes.
Topics: Anti-Bacterial Agents; Antineoplastic Agents; Camptothecin; DNA Topoisomerases; Doxorubicin; Enzyme Inhibitors; Etoposide; Humans; Mitoxantrone; Quinolones; Topoisomerase Inhibitors
PubMed: 20534341
DOI: 10.1016/j.chembiol.2010.04.012 -
The Cochrane Database of Systematic... May 2013This is an updated Cochrane review of the previous published version.Mitoxantrone (MX) has been shown to be moderately effective in reducing the clinical outcome... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This is an updated Cochrane review of the previous published version.Mitoxantrone (MX) has been shown to be moderately effective in reducing the clinical outcome measures of disease activity in multiple sclerosis (MS) patients.
OBJECTIVES
The main objective was to assess the efficacy and safety of MX compared to a control group in relapsing-remitting (RRMS), progressive relapsing (PRMS) and secondary progressive (SPMS) MS participants.
SEARCH METHODS
We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (June 2012) and reference lists of articles. We also undertook handsearching and contacted trialists and pharmaceutical companies.
SELECTION CRITERIA
Randomised, double-blinded, controlled trials (RCTs) comparing the administration of MX versus placebo or MX plus steroids treatment versus placebo plus steroids treatment were included.
DATA COLLECTION AND ANALYSIS
The review authors independently selected articles for inclusion. They independently extracted clinical, safety and magnetic resonance imaging (MRI) data, resolving disagreements by discussion. Risk of bias was evaluated to assess the quality of the studies. Treatment effect was measured using odds ratios (OR) with 95% confidence intervals (CI) for the binary outcomes and mean differences (MD) with 95% CI for the continuous outcomes. If heterogeneity was absent, a fixed-effect model was used.
MAIN RESULTS
Three trials were selected and 221 participants were included in the analyses. MX reduced the progression of disability at two years follow-up (proportion of participants with six months confirmed progression of disability (OR 0.30, 95% CI 0.09 to 0.99 and MD -0.36, 95% CI- 0.70 to -0.02; P = 0.04)). Significant results were found regarding the reduction in annualised relapse rate (MD -0.85, 95% CI -1.47 to -0.23; P = 0.007), the proportion of patients free from relapses at one year (OR 7.13, 95% CI 2.06 to 24.61; P = 0.002) and two years (OR 2.82, 95% CI 1.54 to 5.19; P = 0.0008), and the number of patients with active MRI lesions at six months or one year only (OR 0.24, 95% CI 0.10 to 0.57; P = 0.001). Side effects reported in the trials (amenorrhoea, nausea and vomiting, alopecia and urinary tract infections) were more frequent in treated patients than in controls, while no major adverse events have been reported. These results should be considered with caution because of the heterogeneous characteristics of included trials in term of drug dosage, inclusion criteria and quality of included trials. Moreover, it was not possible to estimate the long-term efficacy and safety of MX.
AUTHORS' CONCLUSIONS
MX shows a significant but partial efficacy in reducing the risk of MS progression and the frequency of relapses in patients affected by worsening RRMS, PRMS and SPMS in the short-term follow-up (two years). No major neoplastic events or symptomatic cardiotoxicity related to MX have been reported; however studies with longer follow-up (not included in this review) have raised concerns about the risk of systolic disfunction (˜12%) and therapy-related acute leukaemias (0.8%), which are increasingly reported in the literature.MX should be limited to treating patients with worsening RRMS and SPMS and with evidence of persistent inflammatory activity after a careful assessment of the individual patients' risk and benefit profiles. Assessment should also consider the present availability of alternative therapies with less severe adverse events.
Topics: Disease Progression; Humans; Immunosuppressive Agents; Mitoxantrone; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Randomized Controlled Trials as Topic
PubMed: 23728638
DOI: 10.1002/14651858.CD002127.pub3 -
Scientific Reports Dec 2016There are hundreds of ligands which can interact with G-quadruplex DNA, yet very few which target i-motif. To appreciate an understanding between the dynamics between...
There are hundreds of ligands which can interact with G-quadruplex DNA, yet very few which target i-motif. To appreciate an understanding between the dynamics between these structures and how they can be affected by intervention with small molecule ligands, more i-motif binding compounds are required. Herein we describe how the drug mitoxantrone can bind, induce folding of and stabilise i-motif forming DNA sequences, even at physiological pH. Additionally, mitoxantrone was found to bind i-motif forming sequences preferentially over double helical DNA. We also describe the stabilisation properties of analogues of mitoxantrone. This offers a new family of ligands with potential for use in experiments into the structure and function of i-motif forming DNA sequences.
Topics: Circular Dichroism; DNA; Fluorescence Resonance Energy Transfer; G-Quadruplexes; Humans; Hydrogen-Ion Concentration; Kinetics; Ligands; Magnetic Resonance Spectroscopy; Mitoxantrone; Nucleic Acid Conformation; Nucleotide Motifs; Oligonucleotides; Surface Plasmon Resonance; Telomere; Temperature; Thermodynamics
PubMed: 28004744
DOI: 10.1038/srep39456 -
The Canadian Veterinary Journal = La... Mar 2016Forty-four dogs with multicentric lymphoma were treated using a cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) induction protocol or treated using a... (Comparative Study)
Comparative Study Randomized Controlled Trial
Forty-four dogs with multicentric lymphoma were treated using a cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) induction protocol or treated using a cyclophosphamide, mitoxantrone, vincristine, and prednisolone (CMOP) induction protocol. There was no statistical difference in signalment and the presence of historical negative prognostic factors between the groups. The median progression-free survival (PFS) in the CHOP and CMOP groups were 222 d and 162 d, respectively (P = 0.75). The median survival time (MST) of dogs in CHOP and CMOP groups were 318 d and 242 d, respectively (P = 0.63). Anorexia and diarrhea episodes were significantly higher in the CHOP group than in the CMOP group (P = 0.02 and P = 0.01, respectively). These results suggest that the CMOP protocol provides similar PFS, MST and causes fewer side effects compared to the CHOP protocol. Therefore, the CMOP protocol may be another treatment choice for canine multicentric lymphoma.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Dog Diseases; Dogs; Doxorubicin; Female; Lymphoma; Male; Mitoxantrone; Prednisone; Prospective Studies; Vincristine
PubMed: 26933263
DOI: No ID Found -
Trials Sep 2023About 50% of older patients with acute myeloid leukemia (AML) fail to attain complete remission (CR) following cytarabine plus anthracycline-based induction therapy.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
About 50% of older patients with acute myeloid leukemia (AML) fail to attain complete remission (CR) following cytarabine plus anthracycline-based induction therapy. Salvage chemotherapy regimens are based on high-dose cytarabine (HiDAC), which is frequently combined with mitoxantrone (HAM regimen). However, CR rates remain low, with less than one-third of the patients achieving a CR. FLT3-ITD has consistently been identified as an unfavorable molecular marker in both relapsed and refractory (r/r)-AML. One-quarter of patients who received midostaurin are refractory to induction therapy and relapse rate at 2 years exceeds 40%. The oral second-generation bis-aryl urea tyrosine kinase inhibitor quizartinib is a very selective FLT3 inhibitor, has a high capacity for sustained FLT3 inhibition, and has an acceptable toxicity profile.
METHODS
In this multicenter, upfront randomized phase II trial, all patients receive quizartinib combined with HAM (cytarabine 3g/m bidaily day one to day three, mitoxantrone 10mg/m days two and three) during salvage therapy. Efficacy is assessed by comparison to historical controls based on the matched threshold crossing approach with achievement of CR, complete remission with incomplete hematologic recovery (CRi), or complete remission with partial recovery of peripheral blood counts (CRh) as primary endpoint. During consolidation therapy (chemotherapy and allogeneic hematopoietic cell transplantation), patients receive either prophylactic quizartinib therapy or measurable residual disease (MRD)-triggered preemptive continuation therapy with quizartinib according to up-front randomization. The matched threshold crossing approach is a novel study-design to enhance the classic single-arm trial design by including matched historical controls from previous clinical studies. It overcomes common disadvantages of single-armed and small randomized studies, since the expected outcome of the observed study population can be adjusted based on the matched controls with a comparable distribution of known prognostic and predictive factors. Furthermore, balanced treatment groups lead to stable statistical models. However, one of the limitations of our study is the inability to adjust for unobserved or unknown confounders. Addressing the primary endpoint, CR/CRi/CRh after salvage therapy, the maximal sample size of 80 patients is assessed generating a desirable power of the used adaptive design, assuming a logistic regression is performed at a one-sided significance level α=0.05, the aspired power is 0.8, and the number of matching partners per intervention patient is at least 1. After enrolling 20 patients, the trial sample size will be recalculated in an interim analysis based on a conditional power argument.
CONCLUSION
Currently, there is no commonly accepted standard for salvage chemotherapy treatment. The objective of the salvage therapy is to reduce leukemic burden, achieve the best possible remission, and perform a hemopoietic stem-cell transplantation. Thus, in patients with FLT3-ITD mutation, the comparison of quizartinib with intensive salvage therapy versus chemotherapy alone appears as a logical consequence in terms of efficacy and safety.
ETHICS AND DISSEMINATION
Ethical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings.
TRIAL REGISTRATION
ClinicalTrials.gov NCT03989713; EudraCT Number: 2018-002675-17.
Topics: Humans; Mitoxantrone; Leukemia, Myeloid, Acute; Phenylurea Compounds; Chronic Disease; Cytarabine; fms-Like Tyrosine Kinase 3
PubMed: 37715270
DOI: 10.1186/s13063-023-07421-x -
Journal of Biomolecular Structure &... Nov 2021The outbreak of novel coronavirus (COVID-19), which began from Wuhan City, Hubei, China, and declared as a Public Health Emergency of International Concern by World...
The outbreak of novel coronavirus (COVID-19), which began from Wuhan City, Hubei, China, and declared as a Public Health Emergency of International Concern by World Health Organization (WHO) on 30 January 2020. The present study describes how the available drug candidates can be used as a potential SARS-CoV-2 M inhibitor by molecular docking and molecular dynamic simulation studies. Drug repurposing strategy is applied by using the library of antiviral and FDA approved drugs retrieved from the Selleckchem Inc. (Houston, TX, http://www.selleckchem.com) and DrugBank database respectively. Computational methods like molecular docking and molecular dynamics simulation were used. The molecular docking calculations were performed using LeadIT FlexX software. The molecular dynamics simulations of 100 ns were performed to study conformational stability for all complex systems. Mitoxantrone and Leucovorin from FDA approved drug library and Birinapant and Dynasore from anti-viral drug libraries interact with SARS-CoV-2 M at higher efficiency as a result of the improved steric and hydrophobic environment in the binding cavity to make stable complex. Also, the molecular dynamics simulations of 100 ns revealed the mean RMSD value of 2.25 Å for all the complex systems. This shows that lead compounds bound tightly within the M cavity and thus having conformational stability. Glutamic acid (Glu166) of M is a key residue to hold and form a stable complex of reported lead compounds by forming hydrogen bonds and salt bridge. Our findings suggest that Mitoxantrone, Leucovorin, Birinapant, and Dynasore represents potential inhibitors of SARS-CoV-2 M.
Topics: Antiviral Agents; COVID-19; Dipeptides; Humans; Hydrazones; Indoles; Leucovorin; Mitoxantrone; Molecular Docking Simulation; Molecular Dynamics Simulation; Pharmaceutical Preparations; Protease Inhibitors; SARS-CoV-2
PubMed: 32815481
DOI: 10.1080/07391102.2020.1805019 -
Molecules (Basel, Switzerland) Sep 2015Major problems of cancer treatment using systemic chemotherapy are severe side effects. Magnetic drug targeting (MDT) employing superparamagnetic iron oxide...
Major problems of cancer treatment using systemic chemotherapy are severe side effects. Magnetic drug targeting (MDT) employing superparamagnetic iron oxide nanoparticles (SPION) loaded with chemotherapeutic agents may overcome this dilemma by increasing drug accumulation in the tumor and reducing toxic side effects in the healthy tissue. For translation of nanomedicine from bench to bedside, nanoparticle-mediated effects have to be studied carefully. In this study, we compare the effect of SPION, unloaded or loaded with the cytotoxic drug mitoxantrone (MTO) with the effect of free MTO, on the viability and proliferation of HT-29 cells within three-dimensional multicellular tumor spheroids. Fluorescence microscopy and flow cytometry showed that both free MTO, as well as SPION-loaded MTO (SPION(MTO)) are able to penetrate into tumor spheroids and thereby kill tumor cells, whereas unloaded SPION did not affect cellular viability. Since SPION(MTO) has herewith proven its effectivity also in complex multicellular tumor structures with its surrounding microenvironment, we conclude that it is a promising candidate for further use in magnetic drug targeting in vivo.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Humans; Magnetite Nanoparticles; Mitoxantrone; Spheroids, Cellular; Tumor Cells, Cultured
PubMed: 26437393
DOI: 10.3390/molecules201018016 -
Canadian Journal of Veterinary Research... Apr 2020The objective of this study was to evaluate taurolidine as a therapy for transitional cell carcinomas in canine patients. Transitional cell carcinoma (TCC) is the most...
The objective of this study was to evaluate taurolidine as a therapy for transitional cell carcinomas in canine patients. Transitional cell carcinoma (TCC) is the most common cancer of the urinary bladder in dogs and accounts for approximately 2% of reported malignancies in this species. There is no cure for this neoplasm and most dogs are lost from complications associated with progression of the local disease. Taurolidine has been shown to have anti-tumor and antiangiogenic effects against a variety of neoplasms in human and animal models. Four canine TCC cell lines were treated with various concentrations of taurolidine, mitoxantrone, and piroxicam alone. In addition, combinations of taurolidine/mitoxantrone, taurolidine/piroxicam, mitoxantrone/piroxicam, and taurolidine/mitoxantrone/piroxicam were assessed. Susceptibility of the TCC cell lines was based on a 72-hour growth inhibition assay using resazurin with absorbance measured at λ530/590. The ability of taurolidine to induce apoptosis was evaluated on 2 of the cell lines with an Annexin-V/propidium iodide assay. All cell lines were susceptible to treatment with taurolidine, mitoxantrone, and piroxicam alone. The results of the combination therapies of the 3 drugs were dependent on cell line and concentration and revealed no change in cell growth inhibition, a subadditive relationship, or a synergistic relationship. Taurolidine induced apoptosis in a concentration- and time-dependent fashion. Taurolidine alone showed significant effects on cell viability in canine TCC cell lines and these effects can be potentially enhanced with the addition of mitoxantrone and/or piroxicam.
Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Transitional Cell; Cell Line; Cell Survival; Dog Diseases; Dogs; Drug Synergism; Mitoxantrone; Piroxicam; Taurine; Thiadiazines
PubMed: 32255906
DOI: No ID Found