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BMC Infectious Diseases Nov 2016Bacillus anthracis, the causative agent of anthrax, is a spore forming and toxin producing rod-shaped bacterium that is classified as a category A bioterror agent. This... (Review)
Review
BACKGROUND
Bacillus anthracis, the causative agent of anthrax, is a spore forming and toxin producing rod-shaped bacterium that is classified as a category A bioterror agent. This pathogenic microbe can be transmitted to both animals and humans. Clinical presentation depends on the route of entry (direct contact, ingestion, injection or aerosolization) with symptoms ranging from isolated skin infections to more severe manifestations such as cardiac or pulmonary shock, meningitis, and death. To date, anthrax is treatable if antibiotics are administered promptly and continued for 60 days. However, if treatment is delayed or administered improperly, the patient's chances of survival are decreased drastically. In addition, antibiotics are ineffective against the harmful anthrax toxins and spores. Therefore, alternative therapeutics are essential. In this review article, we explore and discuss advances that have been made in anthrax therapy with a primary focus on alternative pre-approved and novel antibiotics as well as anti-toxin therapies.
METHODS
A literature search was conducted using the University of Manitoba search engine. Using this search engine allowed access to a greater variety of journals/articles that would have otherwise been restricted for general use. In order to be considered for discussion for this review, all articles must have been published later than 2009.
RESULTS
The alternative pre-approved antibiotics demonstrated high efficacy against B. anthracis both in vitro and in vivo. In addition, the safety profile and clinical pharmacology of these drugs were already known. Compounds that targeted underexploited bacterial processes (DNA replication, RNA synthesis, and cell division) were also very effective in combatting B. anthracis. In addition, these novel compounds prevented bacterial resistance. Targeting B. anthracis virulence, more specifically the anthrax toxins, increased the length of which treatment could be administered.
CONCLUSIONS
Several novel and pre-existing antibiotics, as well as toxin inhibitors, have shown increasing promise. A combination treatment that targets both bacterial growth and toxin production would be ideal and probably necessary for effectively combatting this armed bacterium.
Topics: Alpha-Globulins; Anthrax; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, Bacterial; Antitoxins; Bacillus anthracis; Bacterial Toxins; DNA Helicases; Daunorubicin; Doxorubicin; Drug Discovery; Fluoroquinolones; Humans; Interferon Inducers; Levofloxacin; Linezolid; Moxifloxacin; Ofloxacin; Polyketides; Serine Proteinase Inhibitors; Tilorone; Virulence
PubMed: 27809794
DOI: 10.1186/s12879-016-1951-y -
BMC Cancer Apr 2021Daunorubicin is used clinically in the treatment of myeloma, acute lymphatic and myelocytic leukaemia. The toxic lesions caused by daunorubicin induce various modes of...
BACKGROUND
Daunorubicin is used clinically in the treatment of myeloma, acute lymphatic and myelocytic leukaemia. The toxic lesions caused by daunorubicin induce various modes of cell death, including apoptosis. Apoptosis is highly regulated programmed cell death that can be initiated mainly via two pathways, through death receptors (extrinsic) or involvement of the mitochondria (intrinsic). Induction of apoptosis via these pathways has been alluded following treatment with daunorubicin, but never compared in acute lymphoblastic leukaemia over a time course.
METHODS
This study investigated the mechanisms of daunorubicin induced apoptosis in the treatment of CCRF-CEM, MOLT-4 (acute T-lymphoblastic leukaemia) and SUP-B15 (acute B-lymphoblastic leukaemia) cells. Cells were treated with daunorubicin for 4 h, and then placed in recovery medium (without daunorubicin) for 4 h, 12 h and 24 h. Apoptotic response was analysing using annexin-V expression, caspase activity, mitochondrial membrane potential change and an array to detect 43 apoptotic proteins.
RESULTS
Daunorubicin induced apoptosis in all leukemic cell lines, but with different levels and duration of response. Both apoptosis levels and caspase activity increased after four hours recovery then declined in CCRF-CEM and MOLT-4 cells. However, SUP-B15 cells displayed initially comparable levels but remained elevated over the 24 h assessment period. Changes in mitochondrial membrane potential occurred in both MOLT-4 and CCRF-CEM cells but not in SUP-B15 cells. Expression of apoptotic proteins, including Bcl-2, Bax, caspase 3 and FADD, indicated that daunorubicin potentially induced both extrinsic and intrinsic apoptosis in both CCRF-CEM and MOLT-4 cells, but only extrinsic apoptosis in SUP-B15 cells.
CONCLUSIONS
This study describes variations in sensitivities and timing of apoptotic responses in different leukaemia cell lines. These differences could be attributed to the lack of functional p53 in coordinating the cells response following cytotoxic treatment with daunorubicin, which appears to delay apoptosis and utilises alternative signalling mechanisms that need to be further explored.
Topics: Annexin A5; Antibiotics, Antineoplastic; Apoptosis; Apoptosis Regulatory Proteins; Caspases; Cell Line, Tumor; Daunorubicin; Humans; Leukemia; Membrane Potential, Mitochondrial
PubMed: 33879127
DOI: 10.1186/s12885-021-08167-y -
Scientific Reports Jan 2020Unexpectedly, the widely used anticancer agents Cisplatin (Cis-Pt) and Daunorubicin (Dauno) exhibited cell type- and concentration-dependent synergy or antagonism in...
Unexpectedly, the widely used anticancer agents Cisplatin (Cis-Pt) and Daunorubicin (Dauno) exhibited cell type- and concentration-dependent synergy or antagonism in vitro. We attempted to interpret these effects in terms of the changes elicited by the drugs in the chromatin, the target held primarily responsible for the cytotoxicity of both agents. We measured the effect of Cis-Pt on the levels of Dauno in different cell compartments, the effect of Cis-Pt on Dauno-induced nucleosome eviction, and assessed the influence of Dauno on DNA platination in flow- and laser scanning cytometry as well as in laser ablation-inductively coupled plasma-mass spectrometry assays. We show that the two drugs antagonize each other through a decrease of interstrand crosslinks upon co-treatment with Dauno, and also via the diminished Dauno uptake in the presence of Cis-Pt, and both effects are observed already at low Dauno concentrations. At high Dauno concentrations synergy becomes dominant because histone eviction by Dauno intercalation into the DNA is enhanced in the presence of co-treatment with Cis-Pt. These interactions may have an impact on the efficacy of combination treatment protocols, considering the long retention time of DNA adducts formed by both agents.
Topics: Antineoplastic Agents; Cell Line, Tumor; Chromatin; Cisplatin; DNA Adducts; DNA, Neoplasm; Daunorubicin; Dose-Response Relationship, Drug; Drug Interactions; Humans
PubMed: 31980698
DOI: 10.1038/s41598-020-57702-7 -
Clinical Lymphoma, Myeloma & Leukemia Jan 2021To investigate the effects of mitoxantrone and daunorubicin in induced chemotherapy on complete remission (CR), death during induction therapy, overall survival (OS),... (Meta-Analysis)
Meta-Analysis
PURPOSE
To investigate the effects of mitoxantrone and daunorubicin in induced chemotherapy on complete remission (CR), death during induction therapy, overall survival (OS), disease-free survival (DFS), and relapse in patients of all ages with acute myeloid leukemia (AML).
METHODS
We searched published reports at the Medline, Embase, and Cochrane Databases as well as other databases from inception through July 2019. There was no restriction on date of publication or language (PROSPERO registration CRD42018095843).
RESULTS
We enrolled 12 randomized controlled trials that included data of 4583 AML patients whose disease was untreated or relapsed/refractory, and compared the CR, death during induction therapy, DFS, and OS between mitoxantrone and daunorubicin. Mitoxantrone significantly increased the CR rate (relative risk = 1.07; 95% confidence interval [CI], 1.01, 1.14; P = .03) and DFS (hazard ratio = 0.87; 95% CI, 0.79, 0.96; P = .005) compared to daunorubicin. However, there was no significant difference in death during induction therapy (relative risk = 1.00; 95% CI, 0.81, 1.24; P = .99) and OS (hazard ratio = 0.94; 95% CI, 0.87, 1.01; P = .077) between the two drugs.
CONCLUSION
Although more studies are needed to compare mitoxantrone with higher-dose daunorubicin, the results showed that compared to daunorubicin, mitoxantrone can significantly improve CR and DFS in patients of all ages. These findings suggest that mitoxantrone may be a better choice than daunorubicin as an induction chemotherapy agent for AML patients, especially in developing countries.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Daunorubicin; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Mitoxantrone; Randomized Controlled Trials as Topic
PubMed: 32863193
DOI: 10.1016/j.clml.2020.08.001 -
Best Practice & Research. Clinical... 2014A common occurrence in management of acute myeloid leukemia (AML) is persistence of disease in the first post-treatment marrow, typically obtained 14-21 days after... (Review)
Review
A common occurrence in management of acute myeloid leukemia (AML) is persistence of disease in the first post-treatment marrow, typically obtained 14-21 days after initiation of therapy. Here we will briefly discuss the prognostic significance of this finding and the relative values of morphology and multiparameter flow cytometry (MPFC) in assessing persistent AML. We will then consider the therapeutic options for persistent AML: (a) repetition of the first course of therapy, most frequently 3 days of daunorubicin or idarubicin followed by 7 days of cytarabine (ara-C) (hereafter "3 + 7"), (b) change to different chemotherapy, often "high-dose ara-C" (HiDAC) +/- other agents, (c) immediate allogeneic hematopoietic cell transplantation (HCT), or (d) HiDAC with HCT done in HiDAC-induced aplasia and using a conditioning regimen other than HiDAC. Since it is generally accepted that response to azacitidine or decitabine requires several months, the remarks here principally apply to patients not given these drugs, but rather given ara-C-containing therapy.
Topics: Allografts; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Cytarabine; Daunorubicin; Decitabine; Disease-Free Survival; Hematopoietic Stem Cell Transplantation; Humans; Idarubicin; Leukemia, Myeloid, Acute; Survival Rate; Time Factors; Transplantation Conditioning
PubMed: 25455272
DOI: 10.1016/j.beha.2014.10.004 -
International Journal of Molecular... Aug 2023Unlike genomic alterations, gene expression profiles have not been widely used to refine cancer therapies. We analyzed transcriptional changes in acute myeloid leukemia...
Unlike genomic alterations, gene expression profiles have not been widely used to refine cancer therapies. We analyzed transcriptional changes in acute myeloid leukemia (AML) cell lines in response to standard first-line AML drugs cytarabine and daunorubicin by means of RNA sequencing. Those changes were highly cell- and treatment-specific. By comparing the changes unique to treatment-sensitive and treatment-resistant AML cells, we enriched for treatment-relevant genes. Those genes were associated with drug response-specific pathways, including calcium ion-dependent exocytosis and chromatin remodeling. Pharmacological mimicking of those changes using EGFR and MEK inhibitors enhanced the response to daunorubicin with minimum standalone cytotoxicity. The synergistic response was observed even in the cell lines beyond those used for the discovery, including a primary AML sample. Additionally, publicly available cytotoxicity data confirmed the synergistic effect of EGFR inhibitors in combination with daunorubicin in all 60 investigated cancer cell lines. In conclusion, we demonstrate the utility of treatment-evoked gene expression changes to formulate rational drug combinations. This approach could improve the standard AML therapy, especially in older patients.
Topics: Humans; Aged; Leukemia, Myeloid, Acute; Daunorubicin; Cell Line; Chromatin Assembly and Disassembly; ErbB Receptors
PubMed: 37629110
DOI: 10.3390/ijms241612926 -
Drug Design, Development and Therapy 2023This study aimed to develop a binary nanodrug-delivery system decorated with aptamers (APs) and transferrin (Tf) and loaded with daunorubicin (Drn) and luteolin (Lut)...
OBJECTIVE
This study aimed to develop a binary nanodrug-delivery system decorated with aptamers (APs) and transferrin (Tf) and loaded with daunorubicin (Drn) and luteolin (Lut) for the treatment of leukemia.
METHODS
Oligonucleotide AP- and Tf-contaiing ligands were designed and synthesized separately. AP-decorated Drn-loaded nanoparticles (AP-Drn NPs) and Tf-Lut NPs were prepared by self-assembly. An AP- and Tf-codecorated Drn- and Lut-coloaded nanodrug-delivery system (AP/Tf-Drn/Lut NPs) was prepared by self-assembly of AP-Drn NPs and Tf-Lut NPs. In vitro and in vivo efficiency of the system was evaluated on leukemia cell line and cell-bearing mouse model in comparison with single ligand-decorated, single drug-loaded and free-drug formulations.
RESULTS
AP/Tf-Drn/Lut NPs were spherical and nanosized (187.3±5.3 nm) and loaded with about 85% of drugs. In vitro cytotoxicity of AP/Tf-Drn/Lut NPs was remarkably higher than single ligand-decorated ones. Double drug-loaded AP/Tf-Drn/Lut NPs exhibited higher tumor-cell inhibition than single drug-loaded ones, which showed a synergic effect of the two drugs. AP/Tf-Drn/Lut NPs achieved the most efficient antileukemic activity and absence of toxicity in vivo.
CONCLUSION
The present study showed that AP/Tf-Drn/Lut NPs are a promising drug-delivery system for targeted treatment of leukemia, due to the synergic effect of the two drugs in this system. The limitations of this system include stability during large-scale production and application from bench to bedside.
Topics: Mice; Animals; Daunorubicin; Luteolin; Transferrin; Ligands; Drug Delivery Systems; Leukemia; Nanoparticles; Oligonucleotides; Cell Line, Tumor
PubMed: 36636745
DOI: 10.2147/DDDT.S387246 -
Current Oncology Reports Aug 2021With the recent approval of multiple new drugs for the treatment of acute myeloid leukemia (AML), the relevance of conventional treatment approaches, such as... (Review)
Review
PURPOSE OF REVIEW
With the recent approval of multiple new drugs for the treatment of acute myeloid leukemia (AML), the relevance of conventional treatment approaches, such as daunorubicin and cytarabine ("3+7") induction chemotherapy, has been challenged. We review the AML risk stratification, the efficacy of the newly approved drugs, and the role of "3+7".
RECENT FINDINGS
Treatment of AML is becoming more niched with specific subtypes more appropriately treated with gemtuzumab, midostaurin, and CPX-351. Although lower intensity therapies can yield high response rates, they are less efficient at preventing relapses. The only curative potential for poor-risk AML is still an allogeneic stem cell transplant. The number of AML subtypes where 3+7 alone is an appropriate therapeutic option is shrinking. However, it remains the backbone for combination therapy with newer agents in patients suitable for intensive chemotherapy.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Gemtuzumab; Hematopoietic Stem Cell Transplantation; Humans; Induction Chemotherapy; Leukemia, Myeloid, Acute; Risk Assessment; Staurosporine
PubMed: 34350512
DOI: 10.1007/s11912-021-01108-9 -
European Journal of Medicinal Chemistry Oct 2023Nowadays, with the advent of cutting-edge technologies in the field of biotechnology, some highly advanced medical methods are introduced to treat cancers more... (Review)
Review
Nowadays, with the advent of cutting-edge technologies in the field of biotechnology, some highly advanced medical methods are introduced to treat cancers more efficiently. In the chemotherapy processes, anti-cancer drugs can be encapsulated in a stimuli-responsive coating which is capable of being functionalized by diverse ligands to increase the biocompatibility and control drug release behavior in a targeted drug delivery system. Nanoparticles (NPs) are playing an important role as nanocarriers in chemotherapy procedures, recently, numerous novel drug delivery systems have been studied which employed diverse types of NPs with remarkable structural features like porous nanocarriers with active and extended surface areas to enhance the drug loading and delivery efficacy. In this study, Daunorubicin (DAU) as an effective anti-cancer drug for treating various cancers introduced, and its application for novel drug delivery systems either as a single chemotherapy agent or co-delivery alongside other drugs with diverse NPs has been reviewed.
Topics: Humans; Daunorubicin; Antineoplastic Agents; Nanoparticles; Drug Delivery Systems; Neoplasms; Drug Carriers
PubMed: 37327678
DOI: 10.1016/j.ejmech.2023.115547 -
Cancer Chemotherapy and Pharmacology Jun 2019In the treatment of acute myeloid leukemia (AML), the "7 + 3"-based strategy, combining cytarabine 100-200 mg/m for 7 days with an anthracycline for 3 days,... (Meta-Analysis)
Meta-Analysis Review
In the treatment of acute myeloid leukemia (AML), the "7 + 3"-based strategy, combining cytarabine 100-200 mg/m for 7 days with an anthracycline for 3 days, remains the standard of care for younger and medically fit patients. Daunorubicin (DNR) and idarubicin (IDA) are the two anthracyclines most commonly used. DNR and IDA are used interchangeably with different conversion factors, as there is no high-level evidence on the equipotency of these two agents for AML treatment. To determine the equipotent doses of DNR and IDA, we first systematically reviewed studies directly comparing the clinical outcomes of AML induction therapy utilizing DNR and IDA. We found 15 articles that met our inclusion criteria and compared time-to-event survival end points as well as complete remission rates post-induction. The DNR:IDA equipotency ratio was estimated at 5.90 with 95% confidence interval (CI) 1.7-20.7. To validate the estimate from our meta-analysis biologically, we conducted in vitro tests comparing anti-AML activity of DNR and IDA against six AML cell lines and two primary AML cells from patients with different cytogenetic and molecular characteristics. Based on these in vitro data, the equipotency dose ratio between DNR and IDA was 4.06 with 95% CI 3.64-4.49. Combining the estimates from the meta-analysis and the in vitro data using inverse-variance weighting, the current best estimate of the DNR:IDA equipotent ratio is 4.1 with 95% CI 3.9-4.3. This estimate, however, is largely driven by the in vitro chemo-sensitivity data. Given clinical studies demonstrating the safety of IDA at higher doses, our work implies that dose intensification of IDA could be investigated in future clinical trials in AML.
Topics: Antineoplastic Combined Chemotherapy Protocols; Daunorubicin; Dose-Response Relationship, Drug; Humans; Idarubicin; Leukemia, Myeloid, Acute
PubMed: 30968179
DOI: 10.1007/s00280-019-03825-2