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Best Practice & Research. Clinical... Dec 2021The traditional cytotoxic induction regimen for acute myeloid leukemia (AML) is seven days of standard-dose cytarabine and three days of an anthracycline antibiotic... (Review)
Review
The traditional cytotoxic induction regimen for acute myeloid leukemia (AML) is seven days of standard-dose cytarabine and three days of an anthracycline antibiotic (such as daunorubicin or idarubicin), commonly known as "7 + 3." Many studies have been conducted to find an additional agent that might improve efficacy. Data from select studies has shown, in certain populations, benefit to adding cladribine, clofarabine and lomustine to a traditional backbone. For mutation-based chemotherapy regimens, midostaurin with 7 + 3 is the current standard of care for FLT3-mutant, younger AML patients. As we learn more about the synergism of molecular agents and traditional anti-cancer treatments, we can hopefully develop novel regimens without abandoning some of the benefits of these mutation agnostic historical therapies.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Humans; Idarubicin; Induction Chemotherapy; Leukemia, Myeloid, Acute; Remission Induction
PubMed: 34865698
DOI: 10.1016/j.beha.2021.101326 -
Journal of Pharmaceutical and... Nov 2020This report presents improved analysis methods of daunorubicin (DAUN) and its metabolite daunorubicinol (DAUNOL) in small volumes of plasma, as total and unbound...
Analysis of daunorubicin and its metabolite daunorubicinol in plasma and urine with application in the evaluation of total, renal and metabolic formation clearances in patients with acute myeloid leukemia.
This report presents improved analysis methods of daunorubicin (DAUN) and its metabolite daunorubicinol (DAUNOL) in small volumes of plasma, as total and unbound concentrations, as well as in urine. This study also presents the pharmacokinetics of DAUN and DAUNOL in patients (n = 12) diagnosed with acute myeloid leukemia treated with intravenous DAUN (60 mg/m/day, for three days). Serial blood and urine samples were collected up to 144 h after the beginning of the first infusion. The analytical methods presented no significant matrix effect. The linear ranges were 0.1-1000 ng/mL in plasma, 0.05-40 ng/mL in ultrafiltrate and 0.5-3000 ng/ml in urine. The precision and accuracy presented coefficients of variation and standard errors lower than 15 % in the three matrices. The methods allowed for the quantification of samples up to 144 h after the beginning of the first infusion. Unbound fractions for DAUN and DAUNOL were 23.91 % (17.33-32.99) and 29.23 % (25.84-33.07), respectively. The fraction recovered in urine was 4.40 % (3.87-5.03) for DAUN and 7.91 % (6.86-9.19) for DAUNOL. Total 292.96 L/h (261.74-327.90), renal 13.01 L/h (11.44-14.88), and hepatic 280.26 L/h (248.40-317.91) clearances of DAUN, as well as the DAUNOL formation clearance 23.41 L/h (19.09-28.97), were evaluated.
Topics: Body Fluids; Daunorubicin; Humans; Kidney; Leukemia, Myeloid, Acute
PubMed: 32889347
DOI: 10.1016/j.jpba.2020.113576 -
Current Treatment Options in Oncology Jan 2017Daunorubicin dose intensification for induction in acute myeloid leukemia has been reported as an effective strategy in recent trials to improve patient outcomes without... (Review)
Review
Daunorubicin dose intensification for induction in acute myeloid leukemia has been reported as an effective strategy in recent trials to improve patient outcomes without worsening treatment-related toxicity. Based on available evidence, 90 mg/m of daunorubicin given for three consecutive days (cumulative dose 270 mg/m) as a part of the "7 + 3" induction regimen along with cytarabine is the most effective dose to achieve a complete remission as well as improve survival in patients who can tolerate it. This should be considered strongly in younger patients (less than 65 years of age and especially in those less than 50 years) irrespective of cytogenetic risk (likely more beneficial for favorable and intermediate risk) or molecular mutations (definitely in those with NPM1 or FLT3-ITD mutations). Among older acute myeloid leukemia (AML) patients (>65 years), using a higher dose of daunorubicin may not improve survival. It is unclear if daunorubicin at 60 mg/m for 3 days is as efficacious as the 90 mg/m dose but may be used when there are concerns about tolerability of the higher dose. Although 90 mg/m has no more adverse effects compared to 45 mg/m of daunorubicin, increasing dosage beyond a cumulative dose of 330 mg/m is detrimental due to increase in early mortality. Idarubicin 12 mg/m for 3 days is an alternative with the possibility of better long-term outcomes. Elderly patients with AML and those with unfavorable cytogenetics, secondary, or treatment-related disease remain challenging to treat. All patients should be treated on clinical trials when available.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Daunorubicin; Drug Administration Schedule; Humans; Leukemia, Myeloid, Acute; Nucleophosmin; Remission Induction; Topoisomerase II Inhibitors; Treatment Outcome
PubMed: 28154969
DOI: 10.1007/s11864-017-0446-4 -
Future Oncology (London, England) May 2018Multiple novel therapeutic agents against acute myeloid leukemia (AML) have been evaluated in the past several decades without meaningful clinical improvement in... (Review)
Review
Multiple novel therapeutic agents against acute myeloid leukemia (AML) have been evaluated in the past several decades without meaningful clinical improvement in outcomes, especially for AML patients age ≥60, where the overall incidence of AML is highest. Therapeutic options mainly consist of hypomethylating agents, ongoing clinical trials and, less commonly, intensive cytotoxic chemotherapy. CPX-351, a novel liposomal formulation which encapsulates cytarabine and daunorubicin in 5:1 molar ratio, has shown promising efficacy, leading to recent US FDA approval for front-line therapy for patients with therapy-related AML and AML with myelodysplasia-related changes based on a large multicenter Phase III clinical trial. This review summarizes the clinical development of CPX-351 as induction therapy.
Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cytarabine; Daunorubicin; Drug Carriers; Drug Synergism; Humans; Leukemia, Myeloid, Acute; Liposomes; Prognosis; Survival Rate; Treatment Outcome
PubMed: 29378418
DOI: 10.2217/fon-2017-0603 -
Clinical Lymphoma, Myeloma & Leukemia Aug 2022Acute myeloid leukemia (AML) treatment landscape had evolved over the last decades with better understanding of the disease genomics and the use of the targeted therapy,... (Review)
Review
Acute myeloid leukemia (AML) treatment landscape had evolved over the last decades with better understanding of the disease genomics and the use of the targeted therapy, despite this treatment evolution, 7 + 3 remains the mainstay treatment for most AML cases. Many attempts had been made to improve the treatment outcome with 7 + 3 like manipulating the doses or the duration, but with no significant change in the outcome. In 2017 FDA approved CPX-351,a liposomal formulation of cytarabine and daunorubicin at a fixed 5:1 molar ratio, for the treatment of adults with newly diagnosed AML with myelodysplasia-related changes and therapy-related AML (t-AML). Since the approval, many trials were conducted or still ongoing in assessing the role of CPX-351 in treating different patient populations, AML subcategories or when combined with different agents. In this review, we will summarize the current role of CPX-351 in treating this largely heterogeneous disease.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes
PubMed: 35418351
DOI: 10.1016/j.clml.2022.02.008 -
Minerva Medica Oct 2020Over the last few years, we assisted to an increasing knowledge about acute myeloid leukemia (AML) pathobiology. However, outcomes remain unsatisfactory particularly for... (Review)
Review
Over the last few years, we assisted to an increasing knowledge about acute myeloid leukemia (AML) pathobiology. However, outcomes remain unsatisfactory particularly for adult patients over 60 years old. Not surprisingly several cases of therapy-related AML (tAML) and secondary AML, both characterized by poorer prognosis, are more common in older population. For several decades initial therapy for AML remained unchanged and typically treatment consisted of an anthracycline combined with continuous infusion of cytarabine for 7 days, the so-called "7+3" standard regimen. The efforts made by the researchers to improve this standard schedule, have led to only modest improvement in the response rate (RR) but no change in overall survival (OS), until the recent evolution seen with new target specific mutation therapies. In 2017, a new liposomal-encapsulated formulation with daunorubicin and cytarabine (CPX-351) was approved by the US Food and Drug Administration for the treatment of newly diagnosed tAML or AML with myelodysplasia-related changes (AML-MRCs). Based on the findings that ratiometric delivery may be more effective than administration of either drug at their maximum tolerated dose (MTD), CPX-351 was designed to deliver a fixed 5:1 molar ratio of the two molecules historically used in the standard "7+3" regimen, cytarabine and daunorubicin respectively. CPX-351 did show improvements of overall survival compared to traditional "7+3" in newly diagnosed secondary and therapy-related AML in adult patients. However, questions remain regarding how to select across AML patient subgroups to maximize the clinical benefit. Possible future directions include evaluating CPX-351 dose intensification, combining this liposomal formulation with targeted therapies and not least important a better understanding about the mechanism of improved responses in tAML and AML-MRC, two entities recognized to be less chemo-sensitive than other hematologic malignancies. In summary, CPX-351 offers finally something new in the landscape of AML therapy. Herein we will review the rationale behind this new drug product development, the main pharmacological characteristics, and discuss the results of clinical trials that led to its FDA approval at first and by EMA in 2018.
Topics: Age Factors; Antimetabolites, Antineoplastic; Clinical Trials as Topic; Cytarabine; Daunorubicin; Humans; Leukemia, Myeloid, Acute; Liposomes; Middle Aged; Mutation; Myelodysplastic Syndromes
PubMed: 32955826
DOI: 10.23736/S0026-4806.20.07017-2 -
Anti-cancer Agents in Medicinal... 2022Cancer, a crucial global health problem, is characterized by abnormal cell division and uncontrolled growth. According to WHO, cancer is the second leading cause of...
Cancer, a crucial global health problem, is characterized by abnormal cell division and uncontrolled growth. According to WHO, cancer is the second leading cause of global deaths and accounted for approximately 9.6 million deaths or one in six deaths in 2018. The National Cancer Registry Programme Report 2020, released by the ICMRIndia, estimated that there would be 13,90,000 cases of cancer in India in 2020 and that this number is likely to rise to 15,70,000 by 2025. In spite of several anti-cancer drugs, cancer cannot be cured completely, especially at late stages. In the current era, almost every person is suffering from some kind of disease. Thus, it is the necessity of time to develop novel, potent bioactive molecules. Many researchers are working on the development of new lead molecules or finding a new biological target for the betterment of human beings. However, heterocycles are constantly being used for the discovery of new lead molecules. Many of the clinically approved drugs contain the heterocyclic core as these molecules show exhilarating pharmaceutical properties, including anti-cancer agents such as methotrexate, vinblastine, vincristine, daunorubicin, 5-fluorouracil, doxorubicin, etc. Thus, heterocyclic compounds provide a fascinating research area for the design and development of anti-cancer drug(s). Herein, we focused on the natural as well as synthetic anti-cancer heterocyclic compounds. Furthermore, efforts have been made toward the mechanism of action of selected heterocyclic anti-cancer compounds.
Topics: Antineoplastic Agents; Daunorubicin; Doxorubicin; Fluorouracil; Heterocyclic Compounds; Humans; Methotrexate; Neoplasms; Pharmaceutical Preparations; Vinblastine; Vincristine
PubMed: 35379130
DOI: 10.2174/1871520622666220404082648 -
Biochimica Et Biophysica Acta.... Jan 2024Acute myeloid leukemia (AML) presents ongoing therapeutic challenges due to its intricate molecular pathogenesis. This study aimed to elucidate the role of RNA binding...
BACKGROUND
Acute myeloid leukemia (AML) presents ongoing therapeutic challenges due to its intricate molecular pathogenesis. This study aimed to elucidate the role of RNA binding motif protein 39 (RBM39) in AML cell proliferation, apoptosis, and chemosensitivity, and its potential modulation of the PI3K/AKT pathway.
METHODS
In vitro and in vivo experiments were conducted using AML cell lines (K562 and U937) and bone marrow mononuclear cells (BM-MNCs) from AML patients and healthy donors. RBM39 mRNA and protein levels were measured using qRT-PCR and Western blotting. Cells were transfected with sh-RBM39 or sh-control, and then treated with daunorubicin (DNR) or homoharringtonine (HHT) at varied concentrations. Cell proliferation, chemosensitivity, and apoptosis were assessed through CCK-8 assay and Annexin V-APC/PI staining. RNA sequencing identified differentially expressed genes (DEGs) post RBM39 knockdown. An in vivo xenograft AML model using E7070, a selective RBM39 inhibitor, was employed to evaluate RBM39 modulation effects.
RESULTS
Elevated RBM39 levels were found in AML patients and cell lines compared to controls. RBM39 knockdown promoted apoptosis, curtailed cell proliferation, and enhanced chemosensitivity to DNR and HHT in vitro. Drug-resistant or relapsed AML patients displayed higher RBM39 levels. RNA sequencing after RBM39 knockdown revealed downregulated PI3K/AKT signaling. The xenograft model validated in vitro results, as E7070 treatment suppressed AML xenograft growth via RBM39-mediated PI3K/AKT pathway suppression.
CONCLUSION
RBM39 plays a pivotal role in AML progression through the PI3K/AKT signaling pathway. Targeting RBM39, potentially with E7070, could inhibit proliferation and induce apoptosis in AML cells, offering a promising avenue for future AML research and treatment.
Topics: Humans; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Cell Line, Tumor; Leukemia, Myeloid, Acute; Daunorubicin
PubMed: 37852323
DOI: 10.1016/j.bbamcr.2023.119607 -
International Journal of Biological... Dec 2021The binding of aminoxyls to polymers extends their potential use as antioxidants and EPR-reporting groups and opens up new horizons for tailoring new smart materials. In...
The binding of aminoxyls to polymers extends their potential use as antioxidants and EPR-reporting groups and opens up new horizons for tailoring new smart materials. In this work, we synthesized and characterized non-sulfated and N-sulfated water-soluble amphiphilic chitosans with a critical micelle concentration of 0.02-0.05 mg/mL that contain 13-18% of aminoglycosides bound with various aminoxyls. Chitosan-polyaminoxyls (CPAs) formed micelles with hydrodynamic radii R of ca. 100 nm. The EPR spectra of CPAs were found to depend on the rigidity of the aminoxyl-polymer bond and structural changes caused by sulfation. CPAs demonstrated antioxidant capacity/activity in three tests against reactive oxygen species (ROS) of various nature. The charge of micelles and structure of aminoxyls significantly affected their antioxidant properties. CPAs were low toxic against tumor (HepG2, HeLa, A-172) and non-cancerous (Vero) cells (IC > 0.8 mM of aminoglycosides). Sulfated CPAs showed better water solubility and the ability of binding and retaining the anti-tumor antibiotic daunorubicin (DAU). DAU-loaded micelles of CPAs (CPAs-DAU) demonstrated a 1.5-4-fold potentiation of DAU cytotoxicity against several cell lines. CPAs-DAU micelles were found to affect the cell cycle in a manner markedly different from that of free DAU. Our results demonstrated the ability of CPAs to act as bioactive drug delivery vehicles.
Topics: Antibiotics, Antineoplastic; Antioxidants; Cell Line, Tumor; Cell Survival; Chitosan; Daunorubicin; Drug Carriers; Humans; Micelles; Solubility
PubMed: 34751143
DOI: 10.1016/j.ijbiomac.2021.10.170 -
Leukemia Jun 2022Acute myeloid leukemia (AML) is characterized by poor clinical outcomes due to high rates of relapse following standard-of-care induction chemotherapy. While many...
Acute myeloid leukemia (AML) is characterized by poor clinical outcomes due to high rates of relapse following standard-of-care induction chemotherapy. While many pathogenic drivers have been described in AML, our understanding of the molecular mechanisms mediating chemotherapy resistance remains poor. Therefore, we sought to identify resistance genes to induction therapy in AML and elucidated ALOX5 as a novel mediator of resistance to anthracycline-based therapy. ALOX5 is transcriptionally upregulated in AML patient blasts in comparison to normal hematopoietic stem/progenitor cells (HSPCs) and ALOX5 mRNA, and protein expression is increased in response to induction therapy. In vitro, and in vivo genetic, and pharmacologic perturbation studies confirm that ALOX5 positively regulates the leukemogenic potential of AML LSCs, and its loss does not significantly affect the function of normal HSPCs. ALOX5 mediates resistance to daunorubicin (DNR) and promotes AML cell survival and maintenance through its leukotriene (LT) synthetic capacity, specifically via modulating the synthesis of LTB4 and its binding to LTB receptor (BLTR). Our study reveals a previously unrecognized role of LTs in AML pathogenesis and chemoresistance, whereby inhibition of ALOX5 mediated LTB4 synthesis and function could be combined with standard chemotherapy, to enhance the overall therapeutic efficacy in AML.
Topics: Antineoplastic Agents; Cell Self Renewal; Daunorubicin; Drug Resistance, Neoplasm; Humans; Leukemia, Myeloid, Acute; Leukotriene B4; Neoplastic Stem Cells
PubMed: 35461365
DOI: 10.1038/s41375-022-01579-0