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Current Oncology Reports Apr 2018The goal of this review is to summarize current understanding of pharmacogenetics and pharmacogenomics in chemotherapy-induced cardiotoxicity. (Review)
Review
PURPOSE OF REVIEW
The goal of this review is to summarize current understanding of pharmacogenetics and pharmacogenomics in chemotherapy-induced cardiotoxicity.
RECENT FINDINGS
Most of the studies rely on in vitro cytotoxic assays. There have been several smaller scale candidate gene approaches and a handful of genome-wide studies linking genetic variation to susceptibility to chemotherapy-induced cardiotoxicity. Currently, pharmacogenomic testing of all childhood cancer patients with an indication for doxorubicin or daunorubicin therapy for RARG rs2229774, SLC28A3 rs7853758, and UGT1A6*4 rs17863783 variants is recommended. There is no recommendation regarding testing in adults. There is clear evidence pointing to the role of pharmacogenetics and pharmacogenomics in cardiotoxicity susceptibility to chemotherapeutic agents. Larger scale studies are needed to further identify susceptibility markers and to develop pharmacogenomics-based risk profiling to improve quality of life and life expectancy in cancer survivors.
Topics: Animals; Antineoplastic Agents; Cardiotoxicity; Daunorubicin; Doxorubicin; Genetic Testing; Humans; Mice; Pharmacogenetics; Polymorphism, Single Nucleotide; Receptors, Retinoic Acid; Retinoic Acid Receptor gamma
PubMed: 29713898
DOI: 10.1007/s11912-018-0696-8 -
Hematology. American Society of... Dec 2022Acute myeloid leukemia (AML) secondary to antecedent hematologic disorder or prior therapeutics for cancer represent a diverse group of leukemias often associated with...
Acute myeloid leukemia (AML) secondary to antecedent hematologic disorder or prior therapeutics for cancer represent a diverse group of leukemias often associated with inferior outcomes. Conventional therapy with cytarabine-based chemotherapy has been the mainstay of care for the past 30 years with disappointing overall outcomes. Novel therapies, including liposomal cytarabine/daunorubicin, and venetoclax-based therapies have emerged as options in recent years based on studies showing improvement in outcomes over standard-of-care therapies. Despite these advances, mutations in TP53 are associated with inferior response to both therapies and represent an area of unmet clinical need. Novel strategies with immune-targeted therapies such as CD47 monoclonal antibodies appear active in early-phase studies, but randomized studies have yet to report outcomes leading to approval. Allogeneic transplant remains the only known curative therapy for many of these cases. Nonetheless, pretransplant high-risk molecular features of secondary AML are associated with inferior outcome despite transplantation. An optimal approach to secondary AML is yet to be determined.
Topics: Humans; Daunorubicin; Antineoplastic Combined Chemotherapy Protocols; Leukemia, Myeloid, Acute; Cytarabine; Neoplasms, Second Primary
PubMed: 36485116
DOI: 10.1182/hematology.2022000324 -
Critical Reviews in Oncology/hematology May 2023CPX-351, a dual-drug liposomal encapsulation of daunorubicin/cytarabine, was approved for newly diagnosed therapy-related acute myeloid leukemia (AML) and AML with... (Review)
Review
CPX-351, a dual-drug liposomal encapsulation of daunorubicin/cytarabine, was approved for newly diagnosed therapy-related acute myeloid leukemia (AML) and AML with myelodysplasia-related changes in adults in 2017 (US; updated to patients aged ≥1 year in 2021) and 2018 (EU/UK) based on improved survival and remission and comparable safety versus 7 + 3 chemotherapy in a randomized trial in older adults. Real-world studies have since evaluated CPX-351 in routine practice across several countries and addressed important data gaps (e.g., use in younger adults, measurable residual disease negativity, outcomes by mutation). This review discusses real-world studies of CPX-351 as AML treatment, with the aim of helping prescribers make informed treatment decisions.
Topics: Humans; Aged; Daunorubicin; Leukemia, Myeloid, Acute; Cytarabine; Liposomes; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37028531
DOI: 10.1016/j.critrevonc.2023.103984 -
British Journal of Cancer Sep 1974Seventy-eight adult patients with acute leukaemia were classified cytologically into 3 categories: acute lymphoblastic leukaemia (ALL), acute myelogenous leukaemia (AML)...
Seventy-eight adult patients with acute leukaemia were classified cytologically into 3 categories: acute lymphoblastic leukaemia (ALL), acute myelogenous leukaemia (AML) or acute undifferentiated leukaemia (AUL). The periodic acid-Schiff stain was of little value in differentiating the 3 groups. The treatment response in each group was different: 94% of patients with ALL (16/17) achieved complete remission with prednisone, vincristine and other drugs in standard use in childhood ALL; 59% of patients with AML (27/46) achieved complete remission with cytosine arabinoside and daunorubicin (22 patients), or 6-thioguanine and cyclophosphamide (2 patients), 6-thioguanine, cyclophosphamide and Adriamycin (1 patient), and cytosine and Adriamycin (1 patient); only 2 out of 14 patients (14%) with acute undifferentiated leukaemia achieved complete remission using cytosine and daunorubicin after an initial trial of prednisone and vincristine had failed. Prednisone and vincristine would seem to be of no value in acute undifferentiated leukaemia. It would seem also that no benefit is obtained by classifying all patients with acute leukaemia over 20 years of age as "adult acute leukaemia" and treating them with the same polypharmaceutical regimen. The problems posed by each disease are different and such a policy serves only to obscure them.
Topics: Acute Disease; Administration, Oral; Adult; Aged; Antineoplastic Agents; Cyclophosphamide; Cytarabine; Cytosine; Daunorubicin; Doxorubicin; Drug Therapy, Combination; Humans; Injections, Intravenous; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Middle Aged; Prednisone; Remission, Spontaneous; Staining and Labeling; Thioguanine; Vincristine
PubMed: 4141625
DOI: 10.1038/bjc.1974.191 -
International Journal of Nanomedicine 2019Combination regimens are a standard of care for many cancers. However, components of such regimens are typically first developed individually and subsequently combined... (Review)
Review
Combination regimens are a standard of care for many cancers. However, components of such regimens are typically first developed individually and subsequently combined using strategies to minimize toxicity. Little or no consideration is given to strategies that potentially maximize efficacy. In contrast, CPX-351 (Vyxeos®) is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that was rationally designed to improve efficacy over the traditional 7+3 cytarabine/daunorubicin chemotherapy regimen for patients with acute myeloid leukemia (AML). The notable clinical efficacy of CPX-351 is achieved through maintenance of a synergistic 5:1 molar ratio of cytarabine and daunorubicin within the liposome after intravenous injection. The CPX-351 liposome, which is formulated to contain bilayers of distearoylphosphatidylcholine, distearoylphosphatidylglycerol, and cholesterol at a 7:2:1 molar ratio and remains in a gel phase at body temperature, provides stability without polyethylene glycol, controlled release of cytarabine and daunorubicin, limited systemic drug distribution, and preferential internalization within malignant myeloblasts in the bone marrow via active uptake of liposomes into cytoplasmic vacuoles. Thus, the CPX-351 liposome protects cytarabine and daunorubicin from metabolism and elimination, while overcoming pharmacokinetic differences between the two agents. In clinical studies, these liposome properties markedly increased the elimination half-life of CPX-351 versus free cytarabine and daunorubicin and maintained a synergistic drug ratio for over 24 hrs after administration. Preferential uptake of liposomes by leukemia cells suggests that relatively large amounts of cytarabine and daunorubicin enter malignant cells via liposomes, potentially bypassing P-glycoprotein-based efflux pumps, which are important mediators of chemotherapy resistance, and contribute to the rapid clearance of leukemia cells from the circulation and bone marrow. These pharmacologic advantages, a direct consequence of properties of the encapsulating liposome, may explain the efficacy of CPX-351 in patients with newly diagnosed high-risk/secondary AML and the reduced drug exposure in off-target tissues that contribute to a manageable safety profile.
Topics: Cytarabine; Daunorubicin; Drug Compounding; Endocytosis; Humans; Liposomes; Neoplasms; Tissue Distribution
PubMed: 31213803
DOI: 10.2147/IJN.S139450 -
Oxidative Medicine and Cellular... 2022Cardiotoxicity is the major side effect of anthracyclines (doxorubicin, daunorubicin, epirubicin, and idarubicin), though being the most commonly used chemotherapy drugs... (Review)
Review
Cardiotoxicity is the major side effect of anthracyclines (doxorubicin, daunorubicin, epirubicin, and idarubicin), though being the most commonly used chemotherapy drugs and the mainstay of therapy in solid and hematological neoplasms. Advances in the field of cardio-oncology have expanded our understanding of the molecular mechanisms underlying anthracycline-induced cardiotoxicity (AIC). AIC has a complex pathogenesis that includes a variety of aspects such as oxidative stress, autophagy, and inflammation. Emerging evidence has strongly suggested that the loss of mitochondrial quality control (MQC) plays an important role in the progression of AIC. Mitochondria are vital organelles in the cardiomyocytes that serve as the key regulators of reactive oxygen species (ROS) production, energy metabolism, cell death, and calcium buffering. However, as mitochondria are susceptible to damage, the MQC system, including mitochondrial dynamics (fusion/fission), mitophagy, mitochondrial biogenesis, and mitochondrial protein quality control, appears to be crucial in maintaining mitochondrial homeostasis. In this review, we summarize current evidence on the role of MQC in the pathogenesis of AIC and highlight the therapeutic potential of restoring the cardiomyocyte MQC system in the prevention and intervention of AIC.
Topics: Anthracyclines; Antibiotics, Antineoplastic; Calcium; Cardiotoxicity; Daunorubicin; Doxorubicin; Epirubicin; Humans; Idarubicin; Mitochondria; Mitochondrial Proteins; Myocytes, Cardiac; Reactive Oxygen Species
PubMed: 36187332
DOI: 10.1155/2022/3659278 -
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 -
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 -
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 -
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