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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 -
Effect of cumulative daunorubicin dose on cardiotoxicity after allogeneic stem cell transplantation.Leukemia Research Oct 2022Cardiotoxicity after allogeneic stem cell transplantation (SCT) is associated with a high rate of mortality and worsening quality of life. The relation between...
Cardiotoxicity after allogeneic stem cell transplantation (SCT) is associated with a high rate of mortality and worsening quality of life. The relation between daunorubicin dose and post- allogeneic stem cell transplantation (SCT) cardiotoxicity remains unclear. We retrospectively evaluated 171 patients with acute myeloid leukemia (AML) who underwent their first allogeneic SCT at our institution between 2005 and 2021. High-dose daunorubicin (50 mg/m/day for 5 days) and cytarabine were usually used as induction therapy for AML. The median cumulative daunorubicin dose was 310 mg/m (range, 0-950 mg/m), and 43 patients received two courses of induction therapy with high-dose daunorubicin (daunorubicin doses of ≥500 mg/m). Cardiotoxicity developed in 12 patients, and the cumulative incidence at 2 years after SCT was 7.1%. Univariable analysis revealed that female sex, left ventricular ejection fraction (LVEF) of < 60% before SCT, and daunorubicin doses of ≥ 500 mg/m were associated with cardiotoxicity. Multivariable analysis showed that a daunorubicin dose of ≥ 500 mg/m was an independent risk factor for cardiotoxicity. LVEF decline during the study was observed with an increase in the daunorubicin dose, and only a daunorubicin dose of ≥ 500 mg/m2 was associated with a pre-SCT decreased LVEF. Second induction therapy with high-dose daunorubicin is a risk factor for cardiotoxicity after SCT. This should be taken into consideration when determining reinduction therapies for SCT-eligible patients with relapsed or refractory AML.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cardiotoxicity; Cytarabine; Daunorubicin; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Quality of Life; Remission Induction; Retrospective Studies; Stem Cell Transplantation; Stroke Volume; Ventricular Function, Left
PubMed: 36115066
DOI: 10.1016/j.leukres.2022.106951 -
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 -
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 -
Bioconjugate Chemistry Dec 2023Bioorthogonal prodrug therapies offer an intriguing two-component system that features enhanced circulating stability and controlled activation on demand. Current...
Bioorthogonal prodrug therapies offer an intriguing two-component system that features enhanced circulating stability and controlled activation on demand. Current strategies often deliver either the prodrug or its complementary activator to the tumor with a monomechanism targeted mechanism, which cannot achieve the desired antitumor efficacy and safety profile. The orchestration of two distinct and orthogonal mechanisms should overcome the hierarchical heterogeneity of solid tumors to improve the delivery efficiency of both components simultaneously for bio-orthogonal prodrug therapies. We herein developed a dual-mechanism targeted bioorthogonal prodrug therapy by integrating two orthogonal, receptor-independent tumor-targeting strategies. We first employed the endogenous albumin transport system to generate the albumin-bound, bioorthogonal-caged doxorubicin prodrug with extended plasma circulation and selective accumulation at the tumor site. We then employed enzyme-instructed self-assembly (EISA) to specifically enrich the bioorthogonal activators within tumor cells. As each targeted delivery mode induced an intrinsic pharmacokinetic profile, further optimization of the administration sequence according to their pharmacokinetics allowed the spatiotemporally controlled prodrug activation on-target and on-demand. Taken together, by orchestrating two discrete and receptor-independent targeting strategies, we developed an all-small-molecule based bioorthogonal prodrug system for dual-mechanism targeted anticancer therapies to maximize therapeutic efficacy and minimize adverse drug reactions for chemotherapeutic agents.
Topics: Humans; Prodrugs; Doxorubicin; Neoplasms; Albumins; Cell Line, Tumor
PubMed: 37955377
DOI: 10.1021/acs.bioconjchem.3c00404 -
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 -
Molecules (Basel, Switzerland) Jul 2022The scarcity of novel and effective therapeutics for the treatment of cancer is a pressing and alarming issue that needs to be prioritized. The number of cancer cases... (Review)
Review
The scarcity of novel and effective therapeutics for the treatment of cancer is a pressing and alarming issue that needs to be prioritized. The number of cancer cases and deaths are increasing at a rapid rate worldwide. Doxorubicin, an anticancer agent, is currently used to treat several types of cancer. It disrupts myriad processes such as histone eviction, ceramide overproduction, DNA-adduct formation, reactive oxygen species generation, Ca, and iron hemostasis regulation. However, its use is limited by factors such as drug resistance, toxicity, and congestive heart failure reported in some patients. The combination of doxorubicin with other chemotherapeutic agents has been reported as an effective treatment option for cancer with few side effects. Thus, the hybridization of doxorubicin and other chemotherapeutic drugs is regarded as a promising approach that can lead to effective anticancer agents. This review gives an update on hybrid compounds containing the scaffolds of doxorubicin and its derivatives with potent chemotherapeutic effects.
Topics: Antineoplastic Agents; DNA Damage; Doxorubicin; Histones; Humans
PubMed: 35889350
DOI: 10.3390/molecules27144478 -
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