Cell cycle stage-dependent variations in drug-induced topoisomerase II mediated DNA cleavage and cytotoxicity

Biochemistry ◽  
1987 ◽  
Vol 26 (14) ◽  
pp. 4338-4344 ◽  
Author(s):  
Elihu Estey ◽  
Ramesh C. Adlakha ◽  
Walter N. Hittelman ◽  
Leonard A. Zwelling
Keyword(s):  
Cell Cycle ◽  
Dna Cleavage ◽  
Topoisomerase Ii ◽  
Drug Induced ◽  
Cell Cycle Stage

scholarly journals Topoisomerase-specific drug sensitivity in relation to cell cycle progression.

1987 ◽  
Vol 7 (9) ◽  
pp. 3119-3123 ◽  
Author(s):  
K C Chow ◽  
W E Ross
Keyword(s):  
Cell Cycle ◽  
Dna Cleavage ◽  
Cell Cycle Progression ◽  
Topoisomerase Ii ◽  
Drug Sensitivity ◽  
S Phase ◽  
Synthesis Inhibitor ◽  
Drug Induced ◽  
Cycle Progression ◽  
Serum Stimulation

The nuclear enzyme DNA topoisomerase II catalyzes the breakage and resealing of duplex DNA and plays an important role in several genetic processes. It also mediates the DNA cleavage activity and cytotoxicity of clinically important anticancer agents such as etoposide. We have examined the activity of topoisomerase II during the first cell cycle of quiescent BALB/c 3T3 cells following serum stimulation. Etoposide-mediated DNA break frequency in vivo was used as a parameter of topoisomerase II activity, and enzyme content was assayed by immunoblotting. Density-arrested A31 cells exhibited a much lower sensitivity to the effects of etoposide than did actively proliferating cells. Upon serum stimulation of the quiescent cells, however, there was a marked increase in drug sensitivity which began during S phase and reached its peak just before mitosis. Maximal drug sensitivity during this period was 2.5 times greater than that of log-phase cells. This increase in drug sensitivity was associated with an increase in intracellular topoisomerase II content as determined by immunoblotting. The induction of topoisomerase II-mediated drug sensitivity was aborted within 1 h of exposure of cells to the protein synthesis inhibitor cycloheximide, but the DNA synthesis inhibitor aphidicolin had no effect. In contrast to the sensitivity of cells to drug-induced DNA cleavage, maximal cytotoxicity occurred during S phase. A 3-h exposure to cycloheximide before etoposide treatment resulted in nearly complete loss of cytotoxicity. Our findings indicate that topoisomerase II activity fluctuates with cell cycle progression, with peak activity occurring during the G2 phase. This increase in topoisomerase II is protein synthesis dependent and may reflect a high rate of enzyme turnover. The dissociation between maximal drug-induced DNA cleavage and cytotoxicity indicates that the topoisomerase-mediated DNA breaks may be necessary but are not sufficient for cytotoxicity and that the other factors which are particularly expressed during S phase may be important as well.

Topoisomerase-specific drug sensitivity in relation to cell cycle progression

1987 ◽  
Vol 7 (9) ◽  
pp. 3119-3123
Author(s):  
K C Chow ◽  
W E Ross
Keyword(s):  
Cell Cycle ◽  
Dna Cleavage ◽  
Cell Cycle Progression ◽  
Topoisomerase Ii ◽  
Drug Sensitivity ◽  
S Phase ◽  
Synthesis Inhibitor ◽  
Drug Induced ◽  
Cycle Progression ◽  
Serum Stimulation

The nuclear enzyme DNA topoisomerase II catalyzes the breakage and resealing of duplex DNA and plays an important role in several genetic processes. It also mediates the DNA cleavage activity and cytotoxicity of clinically important anticancer agents such as etoposide. We have examined the activity of topoisomerase II during the first cell cycle of quiescent BALB/c 3T3 cells following serum stimulation. Etoposide-mediated DNA break frequency in vivo was used as a parameter of topoisomerase II activity, and enzyme content was assayed by immunoblotting. Density-arrested A31 cells exhibited a much lower sensitivity to the effects of etoposide than did actively proliferating cells. Upon serum stimulation of the quiescent cells, however, there was a marked increase in drug sensitivity which began during S phase and reached its peak just before mitosis. Maximal drug sensitivity during this period was 2.5 times greater than that of log-phase cells. This increase in drug sensitivity was associated with an increase in intracellular topoisomerase II content as determined by immunoblotting. The induction of topoisomerase II-mediated drug sensitivity was aborted within 1 h of exposure of cells to the protein synthesis inhibitor cycloheximide, but the DNA synthesis inhibitor aphidicolin had no effect. In contrast to the sensitivity of cells to drug-induced DNA cleavage, maximal cytotoxicity occurred during S phase. A 3-h exposure to cycloheximide before etoposide treatment resulted in nearly complete loss of cytotoxicity. Our findings indicate that topoisomerase II activity fluctuates with cell cycle progression, with peak activity occurring during the G2 phase. This increase in topoisomerase II is protein synthesis dependent and may reflect a high rate of enzyme turnover. The dissociation between maximal drug-induced DNA cleavage and cytotoxicity indicates that the topoisomerase-mediated DNA breaks may be necessary but are not sufficient for cytotoxicity and that the other factors which are particularly expressed during S phase may be important as well.

The effect of staurosporine on drug-induced, topoisomerase II-mediated DNA cleavage in human leukemia cells

1991 ◽  
Vol 29 (1) ◽  
pp. 48-52 ◽  
Author(s):  
Leonard A. Zwelling ◽  
Elizabeth Altschuler ◽  
Janice Mayes ◽  
Michael Hinds ◽  
Diana Chan
Keyword(s):  
Dna Cleavage ◽  
Topoisomerase Ii ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Drug Induced ◽  
Human Leukemia Cells

Effect of bryostatin 1 on drug-induced, topoisomerase II-mediated DNA cleavage and topoisomerase 11 gene expression in human leukemia cells

1991 ◽  
Vol 41 (5) ◽  
pp. 829-832 ◽  
Author(s):  
Leonard A. Zwelling ◽  
Diana Chan ◽  
Elizabeth Altschuler ◽  
Janice Mayes ◽  
Michael Hinds ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Cleavage ◽  
Topoisomerase Ii ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Bryostatin 1 ◽  
Drug Induced ◽  
Human Leukemia Cells

In Vitro Antitumor Evaluation of Some Hybrid Molecules Containing Coumarin and Quinolinone Moieties

2020 ◽  
Vol 19 (16) ◽  
pp. 2010-2018
Author(s):  
Youstina W. Rizzk ◽  
Ibrahim M. El-Deen ◽  
Faten Z. Mohammed ◽  
Moustafa S. Abdelhamid ◽  
Amgad I.M. Khedr
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Cancer Cell ◽  
Anticancer Agents ◽  
Topoisomerase Ii ◽  
Cancer Cell Lines ◽  
Bax Protein ◽  
Hybrid Molecules ◽  
Mcf 7

Background: Hybrid molecules furnished by merging two or more pharmacophores is an emerging concept in the field of medicinal chemistry and drug discovery. Currently, coumarin hybrids have attracted the keen attention of researchers to discover their therapeutic capability against cancer. Objective: The present study aimed to evaluate the in vitro antitumor activity of a new series of hybrid molecules containing coumarin and quinolinone moieties 4 and 5 against four cancer cell lines. Materials and Methods: A new series of hybrid molecules containing coumarin and quinolinone moieties, 4a-c and 5a-c, were synthesized and screened for their cytotoxicity against prostate PC-3, breast MCF-7, colon HCT- 116 and liver HepG2 cancer cell lines as well as normal breast Hs-371 T. Results: All the synthesized compounds were assessed for their in vitro antiproliferative activity against four cancer cell lines and several compounds were found to be active. Further in vitro cell cycle study of compounds 4a and 5a revealed MCF-7 cells arrest at G2 /M phase of the cell cycle profile and induction apoptosis at pre-G1 phase. The apoptosis-inducing activity was evidenced by up-regulation of Bax protein together with the downregulation of the expression of Bcl-2 protein. The mechanism of cytotoxic activity of compounds 4a and 5a correlated to its topoisomerase II inhibitory activity. Conclusion: Hybrid molecules containing coumarin and quinolinone moieties represents a scaffold for further optimization to obtain promising anticancer agents.

scholarly journals EPCT-16. A PHASE IB STUDY OF PTC596 IN CHILDREN WITH NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA AND HIGH GRADE GLIOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii306-iii307
Author(s):  
Natasha Pillay Smiley ◽  
Patricia Baxter ◽  
Shiva Kumar ◽  
Eugene Hwang ◽  
John Breneman ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dose Level ◽  
Diffuse Intrinsic Pontine Glioma ◽  
High Grade ◽  
Newly Diagnosed ◽  
Post Translational Modification ◽  
Pontine Glioma ◽  
M Cell ◽  
Drug Induced ◽  
Level 1

Abstract BACKGROUND BMI-1 is highly expressed in DIPG. Downregulation leads to inhibition of cell proliferation, cell cycle signaling, self-renewal, telomerase expression, activity, and suppression of DIPG cell migration. Targeted inhibition of BMI-1 sensitizes DIPG cells to radiation and drug-induced DNA damage. PTC596 (formulated by PTC Therapeutics, Inc.) is a novel, orally available drug that inhibits microtubule polymerization, resulting in G2/M cell cycle arrest and post-translational modification of BMI-1 protein and reduced BMI-1 protein levels. OBJECTIVES: To estimate the maximum tolerated dose and describe dose limiting toxicities, pharmacokinetics and pharmacodynamics of PTC596 in children 3–21 years of age with newly diagnosed diffuse intrinsic pontine glioma and high-grade gliomas. METHODS PTC596 is administered twice per week orally during radiotherapy and as maintenance for up to two years. The starting dose of PTC596 was 200 mg/m2, with a subsequent dose level of 260mg/m2/dose. Pharmacokinetics are performed in Cycles 1 and 2. RESULTS This study is currently ongoing. Nine patients (7 with DIPG, 2 with HGG), 8 evaluable, have been enrolled. At dose level 1, 200 mg/m2, three evaluable patients were enrolled and experienced no DLTs. At dose level 2, among 5 evaluable patients, 2 experienced dose-limiting grade 4 neutropenia. PTC596 has been otherwise well tolerated. Five patients remain in Cycles 2–11. CONCLUSION This phase I trial is ongoing. PTC596 is tolerable at dose level 1. We are amending the protocol to introduce tablets that can be dissolved in liquid to allow enrollment of younger patients and those unable to swallow whole tablets.

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