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Japanese Journal of Medicine 1989The present communication describes a patient with paraganglioma found in the retroperitoneum and neck. She was treated with the combination chemotherapy employing... (Review)
Review
The present communication describes a patient with paraganglioma found in the retroperitoneum and neck. She was treated with the combination chemotherapy employing cyclophosphamide, doxorubicin, and cisplatin (CAP therapy), and resulted in remarkable regression of the tumor in size. We reviewed the literature about the therapy of paraganglioma and the nature of retroperitoneal paraganglioma in relation with this case.
Topics: Aclarubicin; Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cisplatin; Female; Head and Neck Neoplasms; Humans; Paraganglioma; Peplomycin; Retroperitoneal Neoplasms; Tomography, X-Ray Computed; Ultrasonography
PubMed: 2483851
DOI: 10.2169/internalmedicine1962.28.772 -
RSC Advances Jan 2021[This retracts the article DOI: 10.1039/C9RA05572J.].
[This retracts the article DOI: 10.1039/C9RA05572J.].
PubMed: 35427023
DOI: 10.1039/d1ra90038b -
Cancers May 2022Cancer-related fatigue (CRF) is the most devastating long-term side effect of many cancer survivors that confounds the quality of life for months to years after...
Cancer-related fatigue (CRF) is the most devastating long-term side effect of many cancer survivors that confounds the quality of life for months to years after treatment. However, the cause of CRF is poorly understood. As a result, cancer survivors, at best, receive psychological support. Chemotherapy has been shown to increase the risk of CRF. Here, we study therapy-induced fatigue in a non-tumor-bearing mouse model with three different topoisomerase II-poisoning cancer drugs. These drugs either induce DNA damage and/or chromatin damage. Shortly before and several weeks after treatment, running wheel activity and electroencephalographic sleep were recorded. We show that doxorubicin, combining DNA damage with chromatin damage, unlike aclarubicin or etoposide, induces sustained CRF in this model. Surprisingly, this was not related to changes in sleep. In contrast, our data indicate that the therapy-induced CRF is associated with a disrupted circadian clock. The data suggest that CRF is probably a circadian clock disorder that influences the quality of waking and that the development of CRF depends on the type of chemotherapy provided. These findings could have implications for selecting and improving chemotherapy for the treatment of cancer in order to prevent the development of CRF.
PubMed: 35626030
DOI: 10.3390/cancers14102421 -
Oncotarget Oct 2015In this study, we investigated the effect of pre-treatment with demethylating agent decitabine on susceptibility to chemotherapeutic drugs in HL60/ADR, Kasumi-1 and...
In this study, we investigated the effect of pre-treatment with demethylating agent decitabine on susceptibility to chemotherapeutic drugs in HL60/ADR, Kasumi-1 and primary AML cells. Cytotoxic effect was increased by decitabine through activation of p53 and inhibition of c-Myc, Survivin and Bcl-2. We demonstrated in clinic that combination of decitabine and HAA consisting of harringtonine, aclarubicin and cytarabine was effective and safe to treat patients with refractory, relapsed or high-risk AML. Decitabine prior to HAA regimen improved the first induction complete response rate, and significantly prolonged overall survival and disease-free survival in these patients compared with HAA alone. These findings support clinic protocols based on decitabine prior to chemotherapy to overcome resistance and improve therapeutic efficacy in AML patients.
Topics: Aclarubicin; Adolescent; Adult; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Cell Line, Tumor; Cytarabine; Decitabine; Disease-Free Survival; Female; HL-60 Cells; Harringtonines; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Neoplasm Recurrence, Local; Treatment Outcome; Young Adult
PubMed: 26384351
DOI: 10.18632/oncotarget.5600 -
Molecular Biology of the Cell Mar 2012Defects in DNA replication and chromosome condensation are common phenotypes in cancer cells. A link between replication and condensation has been established, but...
Defects in DNA replication and chromosome condensation are common phenotypes in cancer cells. A link between replication and condensation has been established, but little is known about the role of checkpoints in monitoring chromosome condensation. We investigate this function by live analysis, using the rapid division cycles in the early Drosophila embryo. We find that S-phase and topoisomerase inhibitors delay both the initiation and the rate of chromosome condensation. These cell cycle delays are mediated by the cell cycle kinases chk1 and wee1. Inhibitors that cause severe defects in chromosome condensation and congression on the metaphase plate result in delayed anaphase entry. These delays are mediated by wee1 and are not the result of spindle assembly checkpoint activation. In addition, we provide the first detailed live analysis of the direct effect of widely used anticancer agents (aclarubicin, ICRF-193, VM26, doxorubicin, camptothecin, aphidicolin, hydroxyurea, cisplatin, mechlorethamine and x-rays) on key nuclear and cytoplasmic cell cycle events.
Topics: Anaphase; Animals; Cell Cycle Proteins; Checkpoint Kinase 1; Chromosomes; DNA Replication; Drosophila melanogaster; Nuclear Envelope; Nuclear Proteins; Protein Kinases; Protein-Tyrosine Kinases; S Phase; Topoisomerase Inhibitors
PubMed: 22262459
DOI: 10.1091/mbc.E11-10-0832 -
Current Biology : CB May 2013Doxorubicin is an anthracycline DNA intercalator that is among the most commonly used anticancer drugs. Doxorubicin causes DNA double-strand breaks in rapidly dividing...
Doxorubicin is an anthracycline DNA intercalator that is among the most commonly used anticancer drugs. Doxorubicin causes DNA double-strand breaks in rapidly dividing cells, although whether it also affects general chromatin properties is unknown. Here, we use a metabolic labeling strategy to directly measure nucleosome turnover to examine the effect of doxorubicin on chromatin dynamics in squamous cell carcinoma cell lines derived from genetically defined mice. We find that doxorubicin enhances nucleosome turnover around gene promoters and that turnover correlates with gene expression level. Consistent with a direct action of doxorubicin, enhancement of nucleosome turnover around promoters gradually increases with time of exposure to the drug. Interestingly, enhancement occurs both in wild-type cells and in cells lacking either the p53 tumor suppressor gene or the master regulator of the DNA damage response, ATM, suggesting that doxorubicin action on nucleosome dynamics is independent of the DNA damage checkpoint. In addition, another anthracycline drug, aclarubicin, shows similar effects on enhancing nucleosome turnover around promoters. Our results suggest that anthracycline intercalation promotes nucleosome turnover around promoters by its effect on DNA topology, with possible implications for mechanisms of cell killing during cancer chemotherapy.
Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Ataxia Telangiectasia Mutated Proteins; Doxorubicin; Mice; Microarray Analysis; Nucleosomes; Polymerase Chain Reaction; Promoter Regions, Genetic; Tumor Cells, Cultured; Tumor Suppressor Protein p53
PubMed: 23602475
DOI: 10.1016/j.cub.2013.03.043 -
BMC Cancer Dec 2018Definite prognostic clinical factors of benefit for decitabine-based induction chemotherapy in elderly patients newly diagnosed with acute myeloid leukaemia (AML) are... (Clinical Trial)
Clinical Trial
Early recovery of the platelet count after decitabine-based induction chemotherapy is a prognostic marker of superior response in elderly patients with newly diagnosed acute myeloid leukaemia.
BACKGROUND
Definite prognostic clinical factors of benefit for decitabine-based induction chemotherapy in elderly patients newly diagnosed with acute myeloid leukaemia (AML) are not identified. This study was designed to explore the potential biomarker, especially regeneration of haematopoiesis, of treatment response and survival in elderly patients with newly diagnosed AML.
METHOD
We analysed the clinical data of 117 elderly AML patients who were treated with a decitabine dose of 15 mg/m for 5 days, granulocyte colony-stimulating factor of 300 μg/d for priming, plus cytarabine 10 mg/m q12h for 7 days and aclarubicin 10 mg/d for 4 days (D-CAG).
RESULTS
After initial induction chemotherapy, the overall response rate and complete remission (CR) were 71.8% and 58.1%, respectively. Patients responding to the D-CAG regimen achieved higher platelet counts on day 14 after initial treatment (p < 0.001). Median counts were 59.5 × 10/L in the CR group, 37 × 10/L in the partial remission group and 28 × 10/L in the non-responsive group. We then classified patients into those who achieved platelet counts≥60 × 10/L or 100 × 10/L on day 14 after D-CAG vs. those who did not. Platelet counts≥60 × 10/L or 100 × 10/L on day 14 were significantly associated with superior CR, overall survival and disease-free survival (80.9% vs. 45.3% p < 0.001,16.5 vs. 9.1 months p = 0.009 and 16.3 vs. 7.4 months p = 0.024; 85.2% vs. 50% p = 0.001, 31 vs. 10.1 months p = 0.003 and 16.9 vs. 8.9 months p = 0.006). Multivariate analysis confirmed that poor cytogenetics (p = 0.010) and FLT3-ITD mutation (p = 0.007) were identified as independent factors of OS, but not platelet count (p = 0.091). However, platelet count≥100 × 10/L on day 14 was an independent prognostic factor of CR and DFS.
CONCLUSION
Platelet count recovery on day 14 after D-CAG induction chemotherapy is associated with response.
TRIAL REGISTRATION
D-CAG regimen was registered on ChicTR with number 11001700 .
Topics: Aclarubicin; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Blood Platelets; China; Cytarabine; Decitabine; Disease-Free Survival; Female; Granulocyte Colony-Stimulating Factor; Humans; Induction Chemotherapy; Leukemia, Myeloid, Acute; Male; Middle Aged; Platelet Count; Prognosis; Remission Induction
PubMed: 30567513
DOI: 10.1186/s12885-018-5160-5 -
Mutation Research. Genetic Toxicology... May 2019Topoisomerase II (topo II) inhibitors are commonly used as chemotherapy to treat multiple types of cancer, though their use is also associated with the development of...
Topoisomerase II (topo II) inhibitors are commonly used as chemotherapy to treat multiple types of cancer, though their use is also associated with the development of therapy related acute leukemias. While the chromosome-damaging effects of etoposide, a topo II poison, have been proposed to act through a threshold mechanism, little is known about the chromosome damaging effects and dose responses for the catalytic inhibitors of the enzyme. The current study was designed to further investigate the potencies and concentration-response relationships of several topoisomerase II inhibitors, including the topoisomerase II poison etoposide, as well as catalytic inhibitors aclarubicin, merbarone, ICRF-154 and ICRF-187 using both a traditional in vitro micronucleus assay as well as a flow-cytometry based version of the assay. Benchmark dose (BMD) analysis was used to identify models that best fit the data and estimate a BMD, in this case the concentration at which a one standard deviation increase above the control frequency would be expected. All of the agents tested were potent in inducing micronuclei in human lymphoblastoid TK6 cells, with significant increases seen at low micromolar, and in the cases of aclarubicin and etoposide, at low nanomolar concentrations. Use of the anti-kinetochore CREST antibody with the microscopy-based assay demonstrated that the vast majority of the micronuclei originated from chromosome breakage. In comparing the two versions of the micronucleus assay, significant increases in micronucleated cells were observed at similar or lower concentrations using the traditional microscopy-based assay. BMD modeling of the data exhibited several advantages and proved to be a valuable alternative for concentration-response analysis, producing points of departure comparable to those derived using traditional no-observed or lowest-observed genotoxic effect level (NOGEL or LOGEL) approaches.
Topics: Cell Line; Chromosome Aberrations; DNA Topoisomerases, Type II; Etoposide; Humans; Kinetochores; Micronucleus Tests; Topoisomerase II Inhibitors
PubMed: 31138411
DOI: 10.1016/j.mrgentox.2019.05.006 -
PloS One 2014Proteins can switch between different conformations in response to stimuli, such as pH or temperature variations, or to the binding of ligands. Such plasticity and its...
Proteins can switch between different conformations in response to stimuli, such as pH or temperature variations, or to the binding of ligands. Such plasticity and its kinetics can have a crucial functional role, and their characterization has taken center stage in protein research. As an example, Topoisomerases are particularly interesting enzymes capable of managing tangled and supercoiled double-stranded DNA, thus facilitating many physiological processes. In this work, we describe the use of a cantilever-based nanomotion sensor to characterize the dynamics of human topoisomerase II (Topo II) enzymes and their response to different kinds of ligands, such as ATP, which enhance the conformational dynamics. The sensitivity and time resolution of this sensor allow determining quantitatively the correlation between the ATP concentration and the rate of Topo II conformational changes. Furthermore, we show how to rationalize the experimental results in a comprehensive model that takes into account both the physics of the cantilever and the dynamics of the ATPase cycle of the enzyme, shedding light on the kinetics of the process. Finally, we study the effect of aclarubicin, an anticancer drug, demonstrating that it affects directly the Topo II molecule inhibiting its conformational changes. These results pave the way to a new way of studying the intrinsic dynamics of proteins and of protein complexes allowing new applications ranging from fundamental proteomics to drug discovery and development and possibly to clinical practice.
Topics: Adenosine Triphosphate; Antigens, Neoplasm; Biosensing Techniques; DNA Topoisomerases, Type II; DNA-Binding Proteins; Enzymes, Immobilized; Humans; Microscopy, Atomic Force; Nanotechnology; Protein Conformation
PubMed: 25077809
DOI: 10.1371/journal.pone.0103674 -
The Journal of Organic Chemistry Apr 2021Anthracyclines are effective drugs in the treatment of various cancers, but their use comes with severe side effects. The archetypal anthracycline drug, doxorubicin,...
Anthracyclines are effective drugs in the treatment of various cancers, but their use comes with severe side effects. The archetypal anthracycline drug, doxorubicin, displays two molecular modes of action: DNA double-strand break formation (through topoisomerase IIα poisoning) and chromatin damage (via eviction of histones). These biological activities can be modulated and toxic side effects can be reduced by separating these two modes of action through alteration of the aminoglycoside moiety of doxorubicin. We herein report on the design, synthesis, and evaluation of a coherent set of configurational doxorubicin analogues featuring all possible stereoisomers of the 1,2-amino-alcohol characteristic for the doxorubicin 3-amino-2,3-dideoxyfucoside, each in nonsubstituted and N,N-dimethylated forms. The set of doxorubicin analogues was synthesized using appropriately protected 2,3,6-dideoxy-3-amino glycosyl donors, equipped with an alkynylbenzoate anomeric leaving group, and the doxorubicin aglycon acceptor. The majority of these glycosylations proceeded in a highly stereoselective manner to provide the desired axial α-linkage. We show that both stereochemistry of the 3-amine carbon and N-substitution state are critical for anthracycline cytotoxicity and generally improve cellular uptake. ,-Dimethylepirubicin is identified as the most potent anthracycline that does not induce DNA damage while remaining cytotoxic.
Topics: Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Agents; DNA Topoisomerases, Type II; Doxorubicin
PubMed: 33783212
DOI: 10.1021/acs.joc.1c00220