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Nature Medicine Sep 2023Anthracycline-based chemotherapy is associated with increased subsequent breast cancer (SBC) risk in female childhood cancer survivors, but the current evidence is...
Anthracycline-based chemotherapy is associated with increased subsequent breast cancer (SBC) risk in female childhood cancer survivors, but the current evidence is insufficient to support early breast cancer screening recommendations for survivors treated with anthracyclines. In this study, we pooled individual patient data of 17,903 survivors from six well-established studies, of whom 782 (4.4%) developed a SBC, and analyzed dose-dependent effects of individual anthracycline agents on developing SBC and interactions with chest radiotherapy. A dose-dependent increased SBC risk was seen for doxorubicin (hazard ratio (HR) per 100 mg m: 1.24, 95% confidence interval (CI): 1.18-1.31), with more than twofold increased risk for survivors treated with ≥200 mg m cumulative doxorubicin dose versus no doxorubicin (HR: 2.50 for 200-299 mg m, HR: 2.33 for 300-399 mg m and HR: 2.78 for ≥400 mg m). For daunorubicin, the associations were not statistically significant. Epirubicin was associated with increased SBC risk (yes/no, HR: 3.25, 95% CI: 1.59-6.63). For patients treated with or without chest irradiation, HRs per 100 mg m of doxorubicin were 1.11 (95% CI: 1.02-1.21) and 1.26 (95% CI: 1.17-1.36), respectively. Our findings support that early initiation of SBC surveillance may be reasonable for survivors who received ≥200 mg m cumulative doxorubicin dose and should be considered in SBC surveillance guidelines for survivors and future treatment protocols.
Topics: Child; Female; Humans; Breast Neoplasms; Anthracyclines; Doxorubicin; Breast; Daunorubicin; Polyketides
PubMed: 37696934
DOI: 10.1038/s41591-023-02514-1 -
Expert Opinion on Pharmacotherapy Sep 2019: Topoisomerase II inhibitors have long been used in the frontline and as salvage therapy for AML, with daunorubicin and idarubicin being prototypical agents in this... (Review)
Review
: Topoisomerase II inhibitors have long been used in the frontline and as salvage therapy for AML, with daunorubicin and idarubicin being prototypical agents in this therapeutic class, classically in combination with nucleoside analogs, e.g. cytarabine. Most recently, several other compounds from this drug class have or are being investigated. : The current paper reviews older and newer topoisomerase II inhibitors in clinical development for the treatment of AML. The authors discuss the clinical use of these agents, current trials involving them as well as their safety profile. Important side effects of these medications including therapy-related AML (t-AML) are also covered. : Topoisomerase II inhibitors have helped improve outcomes in AML. Recently, the FDA approved several agents including CPX-351 for the treatment of secondary and t-AML. CPX-351 may have applicability in other high-risk myeloid diseases. Future directions include a combination of these agents with other targeted therapies. Finally, the authors believe that small molecule inhibitors, such as venetoclax and possibly immunotherapy options could also be incorporated to our treatment paradigm in selected patients.
Topics: Antineoplastic Combined Chemotherapy Protocols; Daunorubicin; Humans; Idarubicin; Leukemia, Myeloid, Acute; Salvage Therapy; Topoisomerase II Inhibitors
PubMed: 31136213
DOI: 10.1080/14656566.2019.1621292 -
Best Practice & Research. Clinical... Mar 2019Patients with AML that develops after cytotoxic therapy (tAML) have overall inferior outcomes relative to de novo AML due to both patient-related factors and the... (Review)
Review
Patients with AML that develops after cytotoxic therapy (tAML) have overall inferior outcomes relative to de novo AML due to both patient-related factors and the intrinsic biology of the disease. Treatment of patients with tAML is challenging. The key initial clinical decision is whether a patient is a candidate for or likely to benefit from intensive induction chemotherapy, a determination which we argue should not be predicated on chronologic age alone. For those determined likely to tolerate intensive induction chemotherapy, CPX-351 is likely superior to conventional induction with cytarabine and daunorubicin. For those deemed inappropriate for intensive induction, hypomethylating agents have the strongest evidence base in elderly adults with AML, and are an attractive option in tAML. This is particularly true in patients with TP53 mutations who are less likely to respond to conventional induction chemotherapy. Exciting options on the therapeutic horizon for tAML include combination therapies incorporating BCL2 inhibitors, Hedgehog pathway inhibitors, and isocitrate dehydrogenase inhibitors.
Topics: Cytarabine; Daunorubicin; Enzyme Inhibitors; Humans; Induction Chemotherapy; Leukemia, Myeloid, Acute; Mutation; Neoplasms, Second Primary
PubMed: 30927979
DOI: 10.1016/j.beha.2019.02.013 -
Leukemia Jan 2024Prior experience indicated that use of higher doses of cytarabine during induction for acute myeloid leukemia (AML) with a histone deacetylase inhibitor resulted in high... (Randomized Controlled Trial)
Randomized Controlled Trial
Prior experience indicated that use of higher doses of cytarabine during induction for acute myeloid leukemia (AML) with a histone deacetylase inhibitor resulted in high response rates. S1203 was a randomized multicenter trial for previously untreated patients aged 18-60 with AML which compared daunorubicin and cytarabine (DA), idarubicin with higher dose cytarabine (IA) and IA with vorinostat (IA + V). The primary endpoint was event free survival (EFS). 738 patients were randomized: 261 to each DA and IA arms and 216 to the IA + V arm. 96, 456, and 150 patients had favorable-, intermediate-, and unfavorable-risk cytogenetics, respectively. 152 were NPM1 and 158 FLT3 mutated. The overall remission rate was 77.5% including 62.5% CR and 15.0% CRi. No differences in remission, EFS, or overall survival were observed among the 3 arms except for the favorable cytogenetics subset who had improved outcomes with DA and postremission high dose cytarabine. A trend towards increased toxicity was observed with the IA and IA + V arms. The use of higher dose cytarabine during induction therapy in younger patients with AML, with or without vorinostat, does not result in improved outcomes. (Funded by the US National Institutes of Health and others, ClinicalTrials.gov number, NCT01802333.).
Topics: Humans; Cytarabine; Vorinostat; Leukemia, Myeloid, Acute; Daunorubicin; Idarubicin; Remission Induction; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37935977
DOI: 10.1038/s41375-023-02073-x -
Acta Pharmacologica Sinica Nov 2023Current therapy for acute myeloid leukemia (AML) is largely hindered by the development of drug resistance of commonly used chemotherapy drugs, including cytarabine,...
Current therapy for acute myeloid leukemia (AML) is largely hindered by the development of drug resistance of commonly used chemotherapy drugs, including cytarabine, daunorubicin, and idarubicin. In this study, we investigated the molecular mechanisms underlying the chemotherapy drug resistance and potential strategy to improve the efficacy of these drugs against AML. By analyzing data from ex vivo drug-response and multi-omics profiling public data for AML, we identified autophagy activation as a potential target in chemotherapy-resistant patients. In THP-1 and MV-4-11 cell lines, knockdown of autophagy-regulated genes ATG5 or MAP1LC3B significantly enhanced AML cell sensitivity to the chemotherapy drugs cytarabine, daunorubicin, and idarubicin. In silico screening, we found that chloroquine phosphate mimicked autophagy inactivation. We showed that chloroquine phosphate dose-dependently down-regulated the autophagy pathway in MV-4-11 cells. Furthermore, chloroquine phosphate exerted a synergistic antitumor effect with the chemotherapy drugs in vitro and in vivo. These results highlight autophagy activation as a drug resistance mechanism and the combination therapy of chloroquine phosphate and chemotherapy drugs can enhance anti-AML efficacy.
Topics: Humans; Idarubicin; Leukemia, Myeloid, Acute; Daunorubicin; Cytarabine; Autophagy; Chloroquine; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37316630
DOI: 10.1038/s41401-023-01112-8 -
Nucleic Acids Research Sep 2023Genotoxicants have been used for decades as front-line therapies against cancer on the basis of their DNA-damaging actions. However, some of their non-DNA-damaging...
Genotoxicants have been used for decades as front-line therapies against cancer on the basis of their DNA-damaging actions. However, some of their non-DNA-damaging effects are also instrumental for killing dividing cells. We report here that the anthracycline Daunorubicin (DNR), one of the main drugs used to treat Acute Myeloid Leukemia (AML), induces rapid (3 h) and broad transcriptional changes in AML cells. The regulated genes are particularly enriched in genes controlling cell proliferation and death, as well as inflammation and immunity. These transcriptional changes are preceded by DNR-dependent deSUMOylation of chromatin proteins, in particular at active promoters and enhancers. Surprisingly, inhibition of SUMOylation with ML-792 (SUMO E1 inhibitor), dampens DNR-induced transcriptional reprogramming. Quantitative proteomics shows that the proteins deSUMOylated in response to DNR are mostly transcription factors, transcriptional co-regulators and chromatin organizers. Among them, the CCCTC-binding factor CTCF is highly enriched at SUMO-binding sites found in cis-regulatory regions. This is notably the case at the promoter of the DNR-induced NFKB2 gene. DNR leads to a reconfiguration of chromatin loops engaging CTCF- and SUMO-bound NFKB2 promoter with a distal cis-regulatory region and inhibition of SUMOylation with ML-792 prevents these changes.
Topics: Humans; Daunorubicin; Leukemia, Myeloid, Acute; Esters; Chromatin
PubMed: 37462077
DOI: 10.1093/nar/gkad581 -
Journal of Drug Targeting Mar 2020Conventional treatment fails to completely eliminate highly invasive breast cancer cells, and most surviving breast cancer cells tend to reproliferate and metastasize by... (Review)
Review
Conventional treatment fails to completely eliminate highly invasive breast cancer cells, and most surviving breast cancer cells tend to reproliferate and metastasize by forming vasculogenic mimicry (VM) channels. Thus, a type of targeted liposomes was developed by modification with arginine-glycine-aspartic acid (RGD) to encapsulate daunorubicin and emodin separately. A combination of the two targeted liposomes was then developed to destroy VM channels and inhibit tumour metastasis. MDA-MB-435S cells, a highly invasive breast cancer, were then evaluated and in mice. The experiments indicated that RGD modified daunorubicin liposomes plus RGD modified emodin liposomes had small particle size, uniform particle size distribution and high drug encapsulation rate. The combination of the two targeted liposomes exerted strong toxicity on the MDA-MB-435S cells and effectively inhibited the formation of VM channels and the metastasis of tumour cells. Action mechanism studies showed that the RGD modified daunorubicin liposomes plus RGD modified emodin liposomes could downregulate some metastasis-related proteins, including MMP-2, VE-cad, TGF-β1 and HIF-1α. These studies also demonstrated that the targeted liposomes allowed the chemotherapeutic drug to selectively accumulate at tumour site, thus exhibiting a distinct antitumor effect. Therefore, the combination of targeted daunorubicin liposomes and targeted emodin liposomes can provide a potential treatment for invasive breast cancer.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Daunorubicin; Drug Delivery Systems; Emodin; Female; Humans; Liposomes; Mice; Neoplasm Invasiveness; Particle Size
PubMed: 31462111
DOI: 10.1080/1061186X.2019.1656725 -
The Annals of Pharmacotherapy Aug 2018To evaluate the efficacy and safety of daunorubicin and cytarabine liposome in older adults with newly diagnosed therapy-related acute myeloid leukemia (t-AML) or AML... (Review)
Review
OBJECTIVE
To evaluate the efficacy and safety of daunorubicin and cytarabine liposome in older adults with newly diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC).
DATA SOURCE
A literature search of PubMed and MEDLINE (January 2017 to January 2018) was performed using the terms CPX-351, Vyxeos, daunorubicin and cytarabine liposome, and acute myeloid leukemia.
STUDY SELECTION/DATA EXTRACTION
Phase I, II, and III clinical trials evaluating the efficacy and safety of daunorubicin and cytarabine liposome were reviewed with a specific focus on its use in older patients with newly diagnosed AML. All peer-reviewed articles with clinically relevant information were evaluated for inclusion.
DATA SYNTHESIS
The phase II trial demonstrated that daunorubicin and cytarabine liposome improved response rates (RR), but there was no difference in event-free survival and overall survival in the overall patient population. However, clinical benefit was most pronounced in secondary AML with an increased RR and survival. The phase III trial illustrated that daunorubicin and cytarabine liposome improved survival and RR with tolerable toxicity compared with standard 7 plus 3 (daunorubicin and cytarabine) in patients 60 to 75 years of age with t-AML or AML-MRC. More patients proceeded to a stem cell transplant, and 30-day and 60-day mortality was lower with daunorubicin and cytarabine liposome. Grade 3 to 5 toxicities were similar between the 2 groups, except daunorubicin and cytarabine liposome had prolonged cytopenia and a higher risk of hemorrhage.
CONCLUSIONS
Daunorubicin and cytarabine liposome improves RR and survival, with tolerable toxicity in older patients with t-AML or AML-MRC.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Drug Combinations; Drug Interactions; Humans; Leukemia, Myeloid, Acute; Liposomes; Myelodysplastic Syndromes
PubMed: 29532662
DOI: 10.1177/1060028018764923 -
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 -
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