Inhibitors of topoisomerases do not block the passage of human lymphocyte chromosomes through mitosis

1992 ◽  
Vol 103 (1) ◽  
pp. 105-115
Author(s):  
A.T. Sumner
Keyword(s):  
Chromosome Segregation ◽  
Human Lymphocyte ◽  
Topoisomerase I ◽  
Topoisomerase Ii ◽  
Human Lymphocytes ◽  
Chromosome Breakage ◽  
Chromosome Condensation ◽  
Complete Fusion ◽  
Topoisomerase Inhibitors ◽  
Topoisomerase Ii Inhibitors

Cultured human lymphocytes have been treated with a number of topoisomerase inhibitors, to see whether topoisomerase II is involved in the process of chromosome segregation at anaphase. Results were assessed by examination of cytogenetical preparations of spread chromosomes. Four effects were observed, although no inhibitor produced all four effects. These effects were: inhibition of entry into mitosis; chromosome breakage and rearrangement; inhibition of chromosome condensation; and inhibition of chromosome segregation. Evidence for the last was ambiguous. Although there was evidence that separation of chromatids was affected when cells were treated with colchicine as well as topoisomerase II inhibitors (most notably with nalidixic acid, which resulted in complete fusion of the chromatids), no evidence was obtained to show that, in the absence of colchicine, cells treated with inhibitors could not proceed through anaphase normally. The topoisomerase I inhibitor, camptothecin, differed from the topoisomerase II inhibitors in not showing any effect on chromosome condensation or any significant effect on segregation.

scholarly journals Transcriptional Consequences of Topoisomerase Inhibition

2001 ◽  
Vol 21 (24) ◽  
pp. 8437-8451 ◽  
Author(s):  
Irene Collins ◽  
Achim Weber ◽  
David Levens
Keyword(s):  
Topoisomerase I ◽  
Topoisomerase Ii ◽  
Biological Response ◽  
Topoisomerase Inhibitors ◽  
Torsional Strain ◽  
Dna Damaging Agents ◽  
Topoisomerase Inhibition ◽  
Physical Barriers ◽  
Transcription Complexes

ABSTRACT In principle, the generation, transmission, and dissipation of supercoiling forces are determined by the arrangement of the physical barriers defining topological boundaries and the disposition of enzymes creating (polymerases and helicases, etc.) or releasing (topoisomerases) torsional strain in DNA. These features are likely to be characteristic for individual genes. By using topoisomerase inhibitors to alter the balance between supercoiling forces in vivo, we monitored changes in the basal transcriptional activity and DNA conformation for several genes. Every gene examined displayed an individualized profile in response to inhibition of topoisomerase I or II. The expression changes elicited by camptothecin (topoisomerase I inhibitor) or adriamycin (topoisomerase II inhibitor) were not equivalent. Camptothecin generally caused transcription complexes to stall in the midst of transcription units, while provoking little response at promoters. Adriamycin, in contrast, caused dramatic changes at or near promoters and prevented transcription. The response to topoisomerase inhibition was also context dependent, differing between chromosomal or episomal c-myc promoters. In addition to being well-characterized DNA-damaging agents, topoisomerase inhibitors may evoke a biological response determined in part from transcriptional effects. The results have ramifications for the use of these drugs as antineoplastic agents.

scholarly journals Nature and distribution of chromosomal intertwinings in Saccharomyces cerevisiae.

1994 ◽  
Vol 14 (2) ◽  
pp. 1465-1476 ◽  
Author(s):  
R M Spell ◽  
C Holm
Keyword(s):  
Chromosome Segregation ◽  
Topoisomerase Ii ◽  
Acrocentric Chromosome ◽  
Chromosome Breakage ◽  
Chromosomal Dna ◽  
Dna Topoisomerase ◽  
Telocentric Chromosome ◽  
Small Arms ◽  
Yeast Chromosome ◽  
And Behavior

To elucidate yeast chromosome structure and behavior, we examined the breakage of entangled chromosomes in DNA topoisomerase II mutants by hybridization to chromosomal DNA resolved by pulsed-field gel electrophoresis. Our study reveals that large and small chromosomes differ in the nature and distribution of their intertwinings. Probes to large chromosomes (450 kb or larger) detect chromosome breakage, but probes to small chromosomes (380 kb or smaller) reveal no breakage products. Examination of chromosomes with one small arm and one large arm suggests that the two arms behave independently. The acrocentric chromosome XIV breaks only on the long arm, and its preferred region of breakage is approximately 200 kb from the centromere. When the centromere of chromosome XIV is relocated, the preferred region of breakage shifts accordingly. These results suggest that large chromosomes break because they have long arms and small chromosomes do not break because they have small arms. Indeed, a small metacentric chromosome can be made to break if it is rearranged to form a telocentric chromosome with one long arm or a ring with an "infinitely" long arm. These results suggest a model of chromosomal intertwining in which the length of the chromosome arm prevents intertwinings from passively resolving off the end of the arm during chromosome segregation.

Synthesis and biological evaluation of new 2,5-dimethylthiophene/furan based N-acetyl pyrazolines as selective topoisomerase II inhibitors

RSC Advances ◽  
2016 ◽  
Vol 6 (18) ◽  
pp. 14880-14892 ◽  
Author(s):  
Darpan Darpan ◽  
Gaurav Joshi ◽  
Suyog M. Amrutkar ◽  
Ashish T. Baviskar ◽  
Harveen Kler ◽  
...  
Keyword(s):  
Topoisomerase Ii ◽  
Biological Evaluation ◽  
Topoisomerase Inhibitors ◽  
Topoisomerase Ii Inhibitors ◽  
Synthesis And Biological Evaluation

Based on reported pharmacophores as topoisomerase inhibitors, 2,5-dimethylthiophene/furan basedN-acetyl pyrazolines were designed and envisaged as topoisomerase inhibitors.

scholarly journals DNA topoisomerase II must act at mitosis to prevent nondisjunction and chromosome breakage.

1989 ◽  
Vol 9 (1) ◽  
pp. 159-168 ◽  
Author(s):  
C Holm ◽  
T Stearns ◽  
D Botstein
Keyword(s):  
Chromosome Segregation ◽  
Mitotic Spindle ◽  
Generation Time ◽  
Topoisomerase Ii ◽  
Chromosome Breakage ◽  
Restrictive Temperature ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Sister Chromatids ◽  
A Minor

The hypothesis that DNA topoisomerase II facilitates the separation of replicated sister chromatids was tested by examining the consequences of chromosome segregation in the absence of topoisomerase II activity. We observed a substantial elevation in the rate of nondisjunction in top2/top2 cells incubated at the restrictive temperature for one generation time. In contrast, only a minor increase in the amount of chromosome breakage was observed by either physical or genetic assays. These results suggest that aneuploidy is a major cause of the nonviability observed when top2 cells undergo mitosis at the restrictive temperature. In related experiments, we determined that topoisomerase II must act specifically during mitosis. This latter observation is consistent with the hypothesis that the mitotic spindle is necessary to allow topoisomerase II to complete the untangling of sister chromatids.

scholarly journals Analysis of Delphinidin and Luteolin Genotoxicity in Human Lymphocyte Culture

2015 ◽  
Vol 5 (2) ◽  
pp. 41-45 ◽  
Author(s):  
Jasmin Ezić ◽  
Amina Kugić ◽  
Maida Hadžić ◽  
Anja Haverić ◽  
Kasim Bajrović ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Human Lymphocyte ◽  
Chromosome Aberrations ◽  
Topoisomerase Ii ◽  
Human Lymphocytes ◽  
Lymphocyte Culture ◽  
Genotoxic Effects ◽  
Genotoxic Potential

Introduction: Bioflavonoids delphinidin (2-(3,4,5-Trihydroxyphenyl)chromenylium-3,5,7-triol) and luteolin (2-(3,4-Dihydroxyphenyl)-5,7-dihydroxy-4-chromenone) have been recognized as promising antioxidants and anticancer substances. Due to their extensive use, the goal of the research was to determine whether they have any genotoxic potential in vitro.Methods: Analysis of genotoxic potential was performed applying chromosome aberrations test in human lymphocyte culture, as this kind of research was not conducted abundantly for these two bioflavonoids. Delphinidin and luteolin were dissolved in DMSO and added to cultures in final concentrations of 25, 50 and 100 μM.Results: In human lymphocytes cultures Delphinidin induced PCDs in all treatments, potentially affecting the cell cycle and topoisomerase II activity. In concentration of 50 μM luteolin showed strong genotoxic effects and caused significant reduction of cell proliferation.Conclusion: Luteolin exhibited certain genotoxic and cytostatic potential. Delphinidin was not considered genotoxic, however its impact on mitosis, especially topoisomerase II activity, was revealed.

DNA topoisomerase II must act at mitosis to prevent nondisjunction and chromosome breakage

1989 ◽  
Vol 9 (1) ◽  
pp. 159-168
Author(s):  
C Holm ◽  
T Stearns ◽  
D Botstein
Keyword(s):  
Chromosome Segregation ◽  
Mitotic Spindle ◽  
Generation Time ◽  
Topoisomerase Ii ◽  
Chromosome Breakage ◽  
Restrictive Temperature ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Sister Chromatids ◽  
A Minor

The hypothesis that DNA topoisomerase II facilitates the separation of replicated sister chromatids was tested by examining the consequences of chromosome segregation in the absence of topoisomerase II activity. We observed a substantial elevation in the rate of nondisjunction in top2/top2 cells incubated at the restrictive temperature for one generation time. In contrast, only a minor increase in the amount of chromosome breakage was observed by either physical or genetic assays. These results suggest that aneuploidy is a major cause of the nonviability observed when top2 cells undergo mitosis at the restrictive temperature. In related experiments, we determined that topoisomerase II must act specifically during mitosis. This latter observation is consistent with the hypothesis that the mitotic spindle is necessary to allow topoisomerase II to complete the untangling of sister chromatids.

Recent Advances in Use of Topoisomerase Inhibitors in Combination Cancer Therapy

2019 ◽  
Vol 19 (9) ◽  
pp. 730-740 ◽  
Author(s):  
Wenjie Wang ◽  
Yuk-Ching Tse-Dinh
Keyword(s):  
Side Effects ◽  
Cancer Therapy ◽  
Topoisomerase I ◽  
Cellular Response ◽  
Topoisomerase Ii ◽  
Topoisomerase Inhibitors ◽  
Topoisomerase Ii Alpha ◽  
Combination Strategies ◽  
Development Of Resistance ◽  
Combination Cancer Therapy

Inhibitors targeting human topoisomerase I and topoisomerase II alpha have provided a useful chemotherapy option for the treatment of many patients suffering from a variety of cancers. While the treatment can be effective in many patient cases, use of these human topoisomerase inhibitors is limited by side-effects that can be severe. A strategy of employing the topoisomerase inhibitors in combination with other treatments can potentially sensitize the cancer to increase the therapeutic efficacy and reduce resistance or adverse side effects. The combination strategies reviewed here include inhibitors of DNA repair, epigenetic modifications, signaling modulators and immunotherapy. The ongoing investigations on cellular response to topoisomerase inhibitors and newly initiated clinical trials may lead to adoption of novel cancer therapy regimens that can effectively stop the proliferation of cancer cells while limiting the development of resistance.

Novel Angular Benzophenazines:  Dual Topoisomerase I and Topoisomerase II Inhibitors as Potential Anticancer Agents

2002 ◽  
Vol 45 (3) ◽  
pp. 721-739 ◽  
Author(s):  
Nigel Vicker ◽  
Luke Burgess ◽  
Irina S. Chuckowree ◽  
Rory Dodd ◽  
Adrian J. Folkes ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Topoisomerase I ◽  
Topoisomerase Ii ◽  
Topoisomerase Ii Inhibitors

Nature and distribution of chromosomal intertwinings in Saccharomyces cerevisiae

1994 ◽  
Vol 14 (2) ◽  
pp. 1465-1476
Author(s):  
R M Spell ◽  
C Holm
Keyword(s):  
Chromosome Segregation ◽  
Topoisomerase Ii ◽  
Acrocentric Chromosome ◽  
Chromosome Breakage ◽  
Chromosomal Dna ◽  
Dna Topoisomerase ◽  
Telocentric Chromosome ◽  
Small Arms ◽  
Yeast Chromosome ◽  
And Behavior

To elucidate yeast chromosome structure and behavior, we examined the breakage of entangled chromosomes in DNA topoisomerase II mutants by hybridization to chromosomal DNA resolved by pulsed-field gel electrophoresis. Our study reveals that large and small chromosomes differ in the nature and distribution of their intertwinings. Probes to large chromosomes (450 kb or larger) detect chromosome breakage, but probes to small chromosomes (380 kb or smaller) reveal no breakage products. Examination of chromosomes with one small arm and one large arm suggests that the two arms behave independently. The acrocentric chromosome XIV breaks only on the long arm, and its preferred region of breakage is approximately 200 kb from the centromere. When the centromere of chromosome XIV is relocated, the preferred region of breakage shifts accordingly. These results suggest that large chromosomes break because they have long arms and small chromosomes do not break because they have small arms. Indeed, a small metacentric chromosome can be made to break if it is rearranged to form a telocentric chromosome with one long arm or a ring with an "infinitely" long arm. These results suggest a model of chromosomal intertwining in which the length of the chromosome arm prevents intertwinings from passively resolving off the end of the arm during chromosome segregation.

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