scholarly journals Transient activation of topoisomerase I in leukotriene D4 signal transduction in human cells

1990 ◽  
Vol 265 (1) ◽  
pp. 101-107 ◽  
Author(s):  
M R Mattern ◽  
S Mong ◽  
S M Mong ◽  
J O'L Bartus ◽  
H M Sarau ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Topoisomerase I ◽  
Culture Medium ◽  
U937 Cells ◽  
Leukotriene D4 ◽  
Strand Breakage ◽  
Acid Metabolites ◽  
Acid Release ◽  
Dna Strand ◽  
Dna Strand Breakage

U937 human monoblast cells incubated with leukotriene D4 (LTD4) rapidly released arachidonic acid metabolites into the culture medium. Release was suppressed by the high-affinity LTD4 receptor antagonist SK&F 104353. Arachidonic acid release induced by LTD4 has been linked to a rapid induction of gene expression, and the propagation of the receptor binding signal is probably associated with enzymes that regulate gene expression. We have studied the participation of DNA topoisomerase I in LTD4 signal transduction. LTD4-specific release of arachidonic acid metabolites was inhibited (60-80%) by the topoisomerase I inhibitor camptothecin. LTD4 increased protein-linked DNA strand breakage induced by camptothecin in U937 cells; this enhancement was prevented by coincubation of the cells with LTD4 plus the receptor antagonist SK&F 104353. In addition, LTD4 produced a rapid transient increase in extractable topoisomerase I activity, which was maximum within the first 10 min after addition of LTD4 to the culture medium. Incubation of cultures for greater than 10 min with LTD4 before the addition of camptothecin resulted in no enhancement of camptothecin-induced DNA strand breakage, consistent with a reversal of topoisomerase I activation. Staurosporine, an inhibitor of protein kinase C, blocked LTD4-induced arachidonic acid release and attenuated the effect of LTD4 on camptothecin-induced DNA strand breakage. These results are consistent with the view that the regulation of topoisomerase I activity is involved in the propagation of LTD4-mediated signals in U937 cells.

scholarly journals Stimulation of intracellular topoisomerase I activity by vasopressin and thrombin. Differential regulation by pertussis toxin

1989 ◽  
Vol 262 (2) ◽  
pp. 485-489 ◽  
Author(s):  
P Nambi ◽  
M Mattern ◽  
J O Bartus ◽  
N Aiyar ◽  
S T Crooke
Keyword(s):  
Pertussis Toxin ◽  
Topoisomerase I ◽  
Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Strand Breaks ◽  
Surface Receptors ◽  
Aortic Smooth Muscle ◽  
Strand Breakage ◽  
Dna Strand ◽  
Dna Strand Breakage

Incubation of cultured rat aortic smooth muscle cells (A-10, ATCC CRL 1476) with [8-arginine]vasopressin (AVP) or thrombin increased the amount of DNA strand breakage induced by camptothecin, an inhibitor of topoisomerase I (DNA topoisomerase; EC 5.99.1.2) and transiently stimulated the extractable activity of this enzyme. Both topoisomerase-related responses were prevented by treatment of the cells with AVP or thrombin plus the appropriate receptor antagonist. The increase in strand breakage mediated by AVP and thrombin depended on the concentration of hormone. Neither AVP nor thrombin had any effect on strand breaks obtained with the epipodophyllotoxin VM-26, an inhibitor of topoisomerase II [DNA topoisomerase (ATP-hydrolysing); EC 5.99.1.3]. Pretreatment of the cells with pertussis toxin partially inhibited thrombin-mediated increases in camptothecin-induced strand breakage whereas AVP-mediated increases were unaffected. These results are consistent with the notion that AVP and thrombin induce a transient increase in intracellular topoisomerase I activity via interactions with their respective cell surface receptors and that the effects of the activation of these receptors are mediated by different G-proteins.

scholarly journals Potentiation of Topoisomerase I and II Inhibitors Cell Killing by Tumor Necrosis Factor: Relationship to DNA Strand Breakage Formation

1992 ◽  
Vol 83 (11) ◽  
pp. 1132-1136 ◽  
Author(s):  
Giorgia Orengo ◽  
Elvira Noviello ◽  
Guido Cimoli ◽  
Gabriella Pagnan ◽  
Silvio Parodi ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Topoisomerase I ◽  
Tumor Necrosis ◽  
Cell Killing ◽  
Strand Breakage ◽  
Dna Strand ◽  
Necrosis Factor ◽  
Dna Strand Breakage

Topoisomerase Inhibitors and Targeted Delivery in Cancer Therapy

2019 ◽  
Vol 19 (9) ◽  
pp. 713-729 ◽  
Author(s):  
Fei You ◽  
Changshou Gao
Keyword(s):  
Side Effects ◽  
Anticancer Agents ◽  
Targeted Delivery ◽  
Topoisomerase I ◽  
Clinical Use ◽  
Topoisomerase Inhibitors ◽  
Strand Breakage ◽  
Dna Strand ◽  
New Generation ◽  
Dna Strand Breakage

DNA topoisomerases are enzymes that catalyze the alteration of DNA topology with transiently induced DNA strand breakage, essential for DNA replication. Topoisomerases are validated cancer chemotherapy targets. Anticancer agents targeting Topoisomerase I and II have been in clinical use and proven to be highly effective, though with significant side effects. There are tremendous efforts to develop new generation of topoisomerase inhibitors. Targeted delivery of topoisomerase inhibitors is another way to reduce the side effects. Conjugates of topoisomerases inhibitors with antibody, polymer, or small molecule are developed to target these inhibitors to tumor sites.

scholarly journals Synthesis and DNA Strand Breakage Activity of Some 1,4-Diazepines

2003 ◽  
Vol 51 (1) ◽  
pp. 27-31 ◽  
Author(s):  
Nobuko Mibu ◽  
Miho Yukawa ◽  
Nobuhiro Kashige ◽  
Yukiko Iwase ◽  
Yoshinobu Goto ◽  
...  
Keyword(s):  
Strand Breakage ◽  
Dna Strand ◽  
Dna Strand Breakage

Factors which affect DNA strand breakage in human leukocytes exposed to a tumor promoter, phorbol myristate acetate

1982 ◽  
Vol 60 (11) ◽  
pp. 1359-1366 ◽  
Author(s):  
H. C. Birnboim
Keyword(s):  
Hydrogen Peroxide ◽  
Dna Damage ◽  
Phorbol Myristate Acetate ◽  
Respiratory Burst ◽  
Superoxide Anion ◽  
Tumor Promoter ◽  
Myristate Acetate ◽  
Strand Breakage ◽  
Dna Strand ◽  
Dna Strand Breakage

We have recently reported that phorbol myristate acetate (PMA) induces extensive DNA strand break damage in human peripheral blood leukocytes. The mechanism of action involves superoxide anion and hydrogen peroxide which are generated by phagocytes during the "respiratory burst." In this report, we describe the effect of various inhibitors and scavengers on PMA-induced DNA damage. Azide and cyanide greatly increased the level of damage; sulfhydryl compounds (glutathione, cysteine, and cysteamine) and ascorbate markedly decreased the level of damage. Hydroxyl radical scavengers such as dimethyl sulfoxide (DMSO) and glycerol also decreased the level of damage but apparently did so by inhibiting the respiratory burst. Diethyldithiocarbamate (DDC) increased the level of DNA damage at low concentrations (<1 mM), but decreased DNA damage at ≥1 mM. The results are consistent with a mechanism involving superoxide anion and hydrogen peroxide, but the precise reaction (free radical or enzymatic) responsible for DNA strand breakage has not been determined. The PMA-stimulated phagocyte is an interesting model system for looking at "active oxygen" mediated DNA damage and factors which influence it.

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