ICRF-187 rescue in etoposide treatment in vivo. A model targeting high-dose topoisomerase II poisons to CNS tumors

1996 ◽  
Vol 38 (3) ◽  
pp. 203-209 ◽  
Author(s):  
B. Holm ◽  
Peter Buhl Jensen ◽  
Maxwell Sehested
Keyword(s):  
Topoisomerase Ii ◽  
Cns Tumors ◽  
High Dose ◽  
Topoisomerase Ii Poisons ◽  
Etoposide Treatment

scholarly journals Interaction between DNA damage response, translation and apoptosome determines cancer susceptibility to TOP2 poisons

2019 ◽  
Author(s):  
Chidiebere U Awah ◽  
Li Chen ◽  
Mukesh Bansal ◽  
Aayushi Mahajan ◽  
Jan Winter ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Lines ◽  
Topoisomerase Ii ◽  
Cancer Susceptibility ◽  
Protein Subunit ◽  
Ribosomal Subunits ◽  
Topoisomerase Ii Poisons ◽  
Etoposide Treatment ◽  
A Genome ◽  
Genome Scale

AbstractTopoisomerase II poisons are one of the most common class of chemotherapeutics used in cancer. We show that glioblastoma (GBM), the most malignant of all primary brain tumors in adults is responsive to TOP2 poisons. To identify genes that confer susceptibility to this drug in gliomas, we performed a genome-scale CRISPR knockout screen with etoposide. Genes involved in protein synthesis and DNA damage were implicated in etoposide susceptibility. To define potential biomarkers for TOP2 poisons, CRISPR hits were overlapped with genes whose expression correlates with susceptibility to this drug across glioma cell lines, revealing ribosomal protein subunit RPS11, 16, 18 as putative biomarkers for response to TOP2 poisons. Loss of RPS11 impaired the induction of pro-apoptotic gene APAF1 following etoposide treatment, and led to resistance to this drug and doxorubicin. The expression of these ribosomal subunits was also associated with susceptibility to TOP2 poisons across cell lines from multiple cancers.Graphical Abstract

scholarly journals In vivo inhibition of trypanosome mitochondrial topoisomerase II: effects on kinetoplast DNA maxicircles.

1994 ◽  
Vol 14 (9) ◽  
pp. 5891-5897 ◽  
Author(s):  
T A Shapiro ◽  
A F Showalter
Keyword(s):  
Topoisomerase Ii ◽  
Potent Inhibitor ◽  
Complex Structure ◽  
Sedimentation Coefficient ◽  
Cleavage Product ◽  
Unit Size ◽  
Kinetoplast Dna ◽  
Etoposide Treatment ◽  
Minicircle Dna

Kinetoplast DNA, the mitochondrial DNA of trypanosomes, is a topologically complex structure composed of interlocked minicircles and maxicircles. We previously reported that etoposide, a potent inhibitor of topoisomerase II, promotes the cleavage of about 20% of network minicircle DNA (T. A. Shapiro, V. A. Klein, and P. T. Englund, J. Biol. Chem. 264:4173-4178, 1989). We now find that virtually all maxicircles are released from kinetoplast DNA networks after trypanosomes are treated with etoposide. As expected for a topoisomerase II cleavage product, the linearized maxicircles have protein bound to both 5' ends. After etoposide treatment, the residual minicircle catenanes have a sedimentation coefficient which is only 70% that of controls, and by electron microscopy the networks are less compact. Double-size networks, the characteristic dumbbell-shape forms that normally arise in the final stages of network replication, are replaced by aberrant unit-size forms.

In vivo inhibition of trypanosome mitochondrial topoisomerase II: effects on kinetoplast DNA maxicircles

1994 ◽  
Vol 14 (9) ◽  
pp. 5891-5897
Author(s):  
T A Shapiro ◽  
A F Showalter
Keyword(s):  
Topoisomerase Ii ◽  
Potent Inhibitor ◽  
Complex Structure ◽  
Sedimentation Coefficient ◽  
Cleavage Product ◽  
Unit Size ◽  
Kinetoplast Dna ◽  
Etoposide Treatment ◽  
Minicircle Dna

Kinetoplast DNA, the mitochondrial DNA of trypanosomes, is a topologically complex structure composed of interlocked minicircles and maxicircles. We previously reported that etoposide, a potent inhibitor of topoisomerase II, promotes the cleavage of about 20% of network minicircle DNA (T. A. Shapiro, V. A. Klein, and P. T. Englund, J. Biol. Chem. 264:4173-4178, 1989). We now find that virtually all maxicircles are released from kinetoplast DNA networks after trypanosomes are treated with etoposide. As expected for a topoisomerase II cleavage product, the linearized maxicircles have protein bound to both 5' ends. After etoposide treatment, the residual minicircle catenanes have a sedimentation coefficient which is only 70% that of controls, and by electron microscopy the networks are less compact. Double-size networks, the characteristic dumbbell-shape forms that normally arise in the final stages of network replication, are replaced by aberrant unit-size forms.

Melatonin Loading Chitosan-Tripolyphosphate Nanoparticles: Application in Attenuating Etoposide-Induced Genotoxicity in HepG2 Cells

Pharmacology ◽  
2018 ◽  
Vol 102 (1-2) ◽  
pp. 74-80 ◽  
Author(s):  
Mohammad Shokrzadeh ◽  
Nasrin Ghassemi-Barghi
Keyword(s):  
Hepg2 Cells ◽  
Topoisomerase Ii ◽  
Reactive Oxygen Species Generation ◽  
Chemotherapeutic Agents ◽  
Free Radical Scavenger ◽  
Control Group ◽  
Radical Scavenger ◽  
Etoposide Treatment

Etoposide is one of the most effective chemotherapeutic agents used in the treatment of various types of cancers. However, as a Topoisomerase II inhibitor, during clinical use, several side effects may occur. In addition, in several in vivo and in vitro studies, etoposide has been shown to have a range of genotoxic effects including single and double strand breaks. Melatonin is an anti-aging and antioxidant hormone synthesized from the pineal gland. The genoprotective, antioxidant, and free radical scavenger properties of melatonin have been well explained in various studies. The aim of this study was to explore whether melatonin nanoparticles protects against etoposide-induced genotoxicity in the HepG2 cell line. HepG2 cells (25 × 104 cells/well) were cultured in 24-well plates: a control group and 3 melatonin and its nanoparticles + etoposide groups (pre- and cotreatment conditions). Our results show that etoposide induced a noticeable genotoxic effect in HepG2 cells. Melatonin reduced the effects of etoposide significantly in both types of experiment conditions, through the reduction of the level of DNA damage measured via comet assay. Furthermore, melatonin decreased the intracellular reactive oxygen species generation. It also increased the intracellular glutathione levels in HepG2 cells. Nano melatonin is more effective than regular melatonin. The most protective effect was observed with melatonin when it was administrated 24 h before etoposide treatment.

The in vivo distribution and dynamics of DNA topoisomerase II in Drosophila embryonic nuclei and chromosomes

1993 ◽  
Vol 51 ◽  
pp. 74-75
Author(s):  
Jason R. Swedlow ◽  
Neil Osheroff ◽  
Tim Karr ◽  
John W. Sedat ◽  
David A. Agard
Keyword(s):  
Topoisomerase Ii ◽  
Biochemical Characterization ◽  
Developmental Cycle ◽  
Dna Topoisomerase Ii ◽  
Chromosomal Distribution ◽  
Dna Topoisomerase ◽  
Ideal System ◽  
Dnase Treatment

DNA topoisomerase II is an ATP-dependent double-stranded DNA strand-passing enzyme that is necessary for full condensation of chromosomes and for complete segregation of sister chromatids at mitosis in vivo and in vitro. Biochemical characterization of chromosomes or nuclei after extraction with high-salt or detergents and DNAse treatment showed that topoisomerase II was a major component of this remnant, termed the chromosome scaffold. The scaffold has been hypothesized to be the structural backbone of the chromosome, so the localization of topoisomerase II to die scaffold suggested that the enzyme might play a structural role in the chromosome. However, topoisomerase II has not been studied in nuclei or chromosomes in vivo. We have monitored the chromosomal distribution of topoisomerase II in vivo during mitosis in the Drosophila embryo. This embryo forms a multi-nucleated syncytial blastoderm early in its developmental cycle. During this time, the embryonic nuclei synchronously progress through 13 mitotic cycles, so this is an ideal system to follow nuclear and chromosomal dynamics.

Significance of Platelet β-Adrenoceptors for Platelet Responses In Vivo and In Vitro

1992 ◽  
Vol 68 (06) ◽  
pp. 687-693 ◽  
Author(s):  
P T Larsson ◽  
N H Wallén ◽  
A Martinsson ◽  
N Egberg ◽  
P Hjemdahl
Keyword(s):  
Ex Vivo ◽  
High Dose ◽  
Platelet Aggregability ◽  
Adrenoceptor Agonist ◽  
Dose Infusion ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Factor Antigen

SummaryThe significance of platelet β-adrenoceptors for platelet responses to adrenergic stimuli in vivo and in vitro was studied in healthy volunteers. Low dose infusion of the β-adrenoceptor agonist isoprenaline decreased platelet aggregability in vivo as measured by ex vivo filtragometry. Infusion of adrenaline, a mixed α- and β-adrenoceptor agonist, increased platelet aggregability in vivo markedly, as measured by ex vivo filtragometry and plasma β-thromboglobulin levels. Adrenaline levels were 3–4 nM in venous plasma during infusion. Both adrenaline and high dose isoprenaline elevated plasma von Willebrand factor antigen levels β-Blockade by propranolol did not alter our measures of platelet aggregability at rest or during adrenaline infusions, but inhibited adrenaline-induced increases in vWf:ag. In a model using filtragometry to assess platelet aggregability in whole blood in vitro, propranolol enhanced the proaggregatory actions of 5 nM, but not of 10 nM adrenaline. The present data suggest that β-adrenoceptor stimulation can inhibit platelet function in vivo but that effects of adrenaline at high physiological concentrations are dominated by an α-adrenoceptor mediated proaggregatory action.

Methylprednisolone on circulating eicosanoids and vasomotor tone after endotoxin

1986 ◽  
Vol 61 (1) ◽  
pp. 185-191 ◽  
Author(s):  
C. A. Hales ◽  
R. D. Brandstetter ◽  
C. F. Neely ◽  
M. B. Peterson ◽  
D. Kong ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Vascular Resistance ◽  
Systemic Blood Pressure ◽  
Physiological Effect ◽  
High Dose ◽  
Systemic Blood ◽  
Eicosanoid Production ◽  
Circulating Levels

Acute pulmonary and systemic vasomotor changes induced by endotoxin in dogs have been related, at least in part, to the production of eicosanoids such as the vasoconstrictor thromboxane and the vasodilator prostacyclin. Steroids in high doses, in vitro, inhibit activation of phospholipase A2 and prevent fatty acid release from cell membranes to enter the arachidonic acid cascade. We, therefore, administered methylprednisolone (40 mg/kg) to dogs to see if eicosanoid production and the ensuing vasomotor changes could be prevented after administration of 150 micrograms/kg of endotoxin. The stable metabolites of thromboxane B2 (TxB2) and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) were measured by radioimmunoassay. Methylprednisolone by itself did not alter circulating eicosanoids but when given 2.5 h before endotoxin not only failed to inhibit endotoxin-induced eicosanoid production but actually resulted in higher circulating levels of 6-keto-PGF1 alpha (P less than 0.05) compared with animals receiving endotoxin alone. Indomethacin prevented the steroid-enhanced concentrations of 6-keto-PGF1 alpha after endotoxin and prevented the greater fall (P less than 0.05) in systemic blood pressure and systemic vascular resistance with steroid plus endotoxin than occurred with endotoxin alone. Administration of methylprednisolone immediately before endotoxin resulted in enhanced levels (P less than 0.05) of both TxB2 and 6-keto-PGF1 alpha but with a fall in systemic blood pressure and vascular resistance similar to the animals pretreated by 2.5 h. In contrast to the early steroid group in which all of the hypotensive effect was due to eicosanoids, in the latter group steroids had an additional nonspecific effect. Thus, in vivo, high-dose steroids did not prevent endotoxin-induced increases in eicosanoids but actually increased circulating levels of TxB2 and 6-keto-PGF1 alpha with a physiological effect favoring vasodilation.

scholarly journals Spatio-temporal biodistribution of 89Zr-oxine labeled huLym-1-A-BB3z-CAR T-cells by PET imaging in a preclinical tumor model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Naomi S. Sta Maria ◽  
Leslie A. Khawli ◽  
Vyshnavi Pachipulusu ◽  
Sharon W. Lin ◽  
Long Zheng ◽  
...  
Keyword(s):  
T Cells ◽  
Real Time ◽  
Pet Imaging ◽  
Dose Group ◽  
Low Dose ◽  
High Dose ◽  
Car T Cells ◽  
Nsg Mice ◽  
Car T

AbstractQuantitative in vivo monitoring of cell biodistribution offers assessment of treatment efficacy in real-time and can provide guidance for further optimization of chimeric antigen receptor (CAR) modified cell therapy. We evaluated the utility of a non-invasive, serial 89Zr-oxine PET imaging to assess optimal dosing for huLym-1-A-BB3z-CAR T-cell directed to Lym-1-positive Raji lymphoma xenograft in NOD Scid-IL2Rgammanull (NSG) mice. In vitro experiments showed no detrimental effects in cell health and function following 89Zr-oxine labeling. In vivo experiments employed simultaneous PET/MRI of Raji-bearing NSG mice on day 0 (3 h), 1, 2, and 5 after intravenous administration of low (1.87 ± 0.04 × 106 cells), middle (7.14 ± 0.45 × 106 cells), or high (16.83 ± 0.41 × 106 cells) cell dose. Biodistribution (%ID/g) in regions of interests defined over T1-weighted MRI, such as blood, bone, brain, liver, lungs, spleen, and tumor, were analyzed from PET images. Escalating doses of CAR T-cells resulted in dose-dependent %ID/g biodistributions in all regions. Middle and High dose groups showed significantly higher tumor %ID/g compared to Low dose group on day 2. Tumor-to-blood ratios showed the enhanced extravascular tumor uptake by day 2 in the Low dose group, while the Middle dose showed significant tumor accumulation starting on day 1 up to day 5. From these data obtained over time, it is apparent that intravenously administered CAR T-cells become trapped in the lung for 3–5 h and then migrate to the liver and spleen for up to 2–3 days. This surprising biodistribution data may be responsible for the inactivation of these cells before targeting solid tumors. Ex vivo biodistributions confirmed in vivo PET-derived biodistributions. According to these studies, we conclude that in vivo serial PET imaging with 89Zr-oxine labeled CAR T-cells provides real-time monitoring of biodistributions crucial for interpreting efficacy and guiding treatment in patient care.

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