Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Caffeine was found to inhibit both type I and type II topoisomerases in vivo as judged by its effects on replicating simian virus 40 (SV40) chromosomes. The study was facilitated by the use of a rapid filter assay for the detection and characterization of topoisomerase inhibitors. The assay, which requires neither purified enzymes nor substrates, was able to identify both antagonists and poisons of type I and type II topoisomerases.
Teratog Carcinog Mutagen 1990
PMID:Rapid evaluation of topoisomerase inhibitors: caffeine inhibition of topoisomerases in vivo. 197 68

In recent years, evidence has accumulated that suggests that mammalian topoisomerase may play a role in the formation of spontaneous or chemically induced sister chromatid exchange (SCE). In microbial systems, nalidixic acid is known to disrupt the function of a topoisomerase-like enzyme, DNA gyrase. To explore the possible relationship to topoisomerase function and SCE formation in mammalian cells, an analog of nalidixic acid with potent topoisomerase II inhibitory activity was selected for examination in a variety of genetic toxicology assays. This analog, CP-67,015, proved to be a positive direct-acting mutagen in the L5178Y/TK+/-, CHO/HGPRT, and V79/HGPRT systems. However, no gene mutational activity was observed using the Ames test in direct plate, mouse and rat metabolic activation, and mouse urine tests. In vitro cytogenetic studies showed strong clastogenic activity in human lymphocytes and in CHO cells. Compound-induced chromosome damage was also observed in vivo in mouse bone marrow cells. Surprisingly, SCE studies in vitro in human lymphocytes or CHO cells showed only slight increases, even at levels producing severe chromosome breakage. Mouse bone marrow showed no significant elevation of SCE following parenteral treatment with CP-67,015. These results, taken together, demonstrate that CP-67,015 is a direct-acting mutagen in mammalian cells with both gene and chromosomal level effects. The relative ineffectiveness in producing SCEs suggests that CP-67,015 may interfere with a DNA replicative/repair process, perhaps by alteration of one or more DNA polymerase activities. This suggestion is based in part on the known effect of the analog nalidixic acid on DNA gyrase in microbial cells and on topoisomerase in mammalian cells. The profile of genetic activity of CP-67,015, coupled with its inhibitory effect on topoisomerase function, gives rise to a model for SCE formation that is based on anomalies of topoisomerase activity during DNA synthesis.
Environ Mol Mutagen 1989
PMID:Genetic profile of a nalidixic acid analog: a model for the mechanism of sister chromatid exchange induction. 253 98

A human Burkitt's lymphoma cell line (Raji-HN2) made resistant to nitrogen mustard, a bifunctional alkylating agent, was used to study the mechanism of resistance to nitrogen mustard. A comparative study of Raji-HN2 and the parental sensitive Raji cell lines revealed the following: (1) The DNA of Raji-HN2 cells was crosslinked by nitrogen mustard to a lower extent than Raji DNA; (2) once interstrand crosslinks were formed, they were repaired at the same rate in both cell lines; (3) DNA crosslink formation in Raji-HN2, but not in Raji cells, was enhanced by novobiocin, a topoisomerase II inhibitor; (4) Raji-HN2 cells had elevated topoisomerase II activity and were hypersensitive to topoisomerase inhibitors (amsacrine, novobiocin, teniposide); (5) similar amounts of topoisomerase I were found in both cell lines; and (6) the chromatin of Raji-HN2 but not of Raji cells, was hypersensitive to DNase I digestion. The relationship between DNA repair, topoisomerase II activity, chromatin structure and drug resistance is discussed.
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PMID:Elevated topoisomerase II activity and altered chromatin in nitrogen mustard-resistant human cells. 281 39

A human Burkitt lymphoma cell line, Raji-HN2, made 10-fold more resistant to nitrogen mustard (HN2) than the parental Raji cell line, exhibited the following characteristics when compared to the parental Raji cells: (i) decreased HN2-induced DNA interstrand crosslinking; (ii) increased (3-fold) DNA topoisomerase II [DNA topoisomerase (ATP-hydrolyzing), EC 5.99.1.3] activity; (iii) increased (4- to 11-fold) sensitivity to topoisomerase II inhibitors; (iv) increased (2-fold) glutathione content; and (v) increased (2-fold) cell doubling time. The resistant phenotype was unstable and was maintained by weekly treatment of the cells with HN2. Growing the resistant cells in the absence of HN2 resulted in a time-dependent decrease in both resistance to HN2 and topoisomerase II activity and an increase in DNA interstrand crosslinking induced by HN2. We hypothesize that HN2 resistance is due to enhanced monoadduct repair with resultant decreased DNA crosslinking and that this process is mediated by topoisomerase II.
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PMID:Elevated DNA topoisomerase II activity in nitrogen mustard-resistant human cells. 282 70

Recently, the antitumor agent 4'-(9-acridinylamino)-methanesulfon-m-anisidide (m-AMSA) was shown to revert a frameshift mutant of T4 (rFC11), and its mutagenicity was shown to be mediated by T4 DNA topoisomerase II [Ripley et al.: J Mol Biol 200: 665-680, 1988]. Here we report dose-response data on the mutagenicity and toxicity of m-AMSA in T4 rFC11. We find that m-AMSA is among the most potent frameshift mutagens observed in T4, inducing a 10-fold increase in mutant frequency in the absence of toxicity and a 500-fold increase in mutant frequency at 31% survival. In addition to m-AMSA, the topoisomerase-active agents ellipticine, oxolinic acid, and nalidixic acid also reverted rFC11; however, they required concentrations 10-100 times greater than those required by m-AMSA in order to be mutagenic, and they did not produce mutant frequencies as high as those produced by m-AMSA. Unlike m-AMSA, all three agents were mutagenic only at toxic doses. The other agents evaluated--actinomycin D, adriamycin, 9-aminoellipticine, 9-methoxyellipticine, teniposide (VM-26), and novobiocin--were toxic but not mutagenic to T4 rFC11. Thus, m-AMSA appears to be distinctly different from the other topoisomerase-active agents in exhibiting such potent mutagenic activity in T4 rFC11. Because E. coli DNA gyrase may substitute for T4 topoisomerase II, we examined the ability of two inhibitors of E. coli DNA gyrase, novobiocin and nalidixic acid, to inhibit m-AMSA's mutagenicity. Both agents substantially reduced the mutagenicity of m-AMSA in T4 rFC11, further suggesting that topoisomerase mediates the mutagenicity of m-AMSA.
Teratog Carcinog Mutagen 1988
PMID:Mutagenicity of topoisomerase-active agents in bacteriophage T4. 290 38

Poly(ADP-ribose) is synthesized in response to DNA strand breaks and covalently modifies numerous intracellular proteins. We have proposed that this modification regulates, i.e., inhibits, the activity of these enzymes, e.g., topoisomerases and proteases, which could otherwise cause additional DNA damage or alterations in chromatin structure. Inhibition of poly(ADP-ribose) polymerase by 3-amino-benzamide (3AB) in cells exposed to DNA-damaging agents would, according to this proposal, eliminate the regulatory role of ADP-ribosylation. When Chinese hamster ovary cells are cultured with methyl methanesulfonate (MMS) and 3AB, a synergistic increase in sister chromatid exchange frequency is observed. We investigated the regulatory role of poly(ADP-ribose) polymerase to see if topoisomerases or proteases are involved in this synergistic increase. Cells were exposed to MMS or the intercalating agent 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA), 3AB, and either the topoisomerase inhibitor novobiocin or the protease inhibitor antipain. Neither novobiocin nor antipain affected the synergistic response of MMS and 3AB or the additive response of m-AMSA and 3AB. These results suggest that topoisomerases or proteases do not account for the effect of 3AB on sister chromatid exchange frequency after DNA damage.
Environ Mutagen 1986
PMID:Potentiation of sister chromatid exchange by 3-aminobenzamide is not modulated by topoisomerases or proteases. 301 82

The frequency of sister chromatid exchanges (SCEs), both spontaneous and induced by UV-light, X-rays, mitomycin C and ethylmetansulphonate (EMS), has been investigated in cultured human peripheral blood lymphocytes. Besides, frequency of spontaneous and induced SCEs was studied under the action of the inhibitors of topoisomerase II, polymerase poly(ADP-ribose), and DNA repair, i. e. novobiocin, 3-metoxybenzamide, and caffeine, respectively. It is shown that the base-line SCEs in lymphocytes of the patient with xeroderma pigmentosum II (XP2LE) is dramatically higher compared to that in normal and pigmented xerodermoid cells (XP3LE). The above inhibitors of DNA synthesis and repair enhance the rate of spontaneous SCEs in normal, XP2LE and XP3LE cells. UV-, X-ray and chemical mutagens induced an increased frequency of SCEs in these cells. Simultaneous treatment with mutagenes and inhibitors of DNA synthesis and DNA repair enhanced the rate of SCEs in lymphocytes of healthy donors and in the XP3LE patient. The frequency of the XP2LE cells. Novobiocin, 3-MBA and caffeine significantly decreased the frequency of SCEs in mitomycin C- and EMS-treated XP2LE lymphocyte, which nevertheless was much higher than that in normal cells treated with the same agents.
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PMID:[Spontaneous and induced sister chromatid exchanges in the blood lymphocytes of healthy persons and of xeroderma pigmentosum patients exposed to the inhibitors of DNA repair and replication caffeine, 3-methoxybenzamide and novobiocin]. 308 51

Etoposide (VP-16) is used as an antineoplastic drug in humans. It inhibits topoisomerase II(topoII) activity by forming a ternary complex (DNA-etoposide-topoII). This complex prevents the DNA-strand rejoining activity of topo II, which results in DNA-strand breaks and the formation of structural chromosome aberrations. Topo II activity is also required for removing regions of DNA catenation prior to chromosome segregation. The possibility exists that patients undergoing etoposide chemotherapy may incur genetic damage and, consequently, may be at a greater risk for developing secondary tumors and having genetically abnormal offspring. We studied the ability of etoposide for inducing both structural chromosome aberrations and aneuploidy in mouse oocytes. Different dosages of etoposide were given to female mice at various times before and after human chronic gonadotrophin injection, and ovulated oocytes were collected 17 h later. The proportions of chromatid acentric fragments and of hyperploid metaphase II oocytes were significantly higher (P < 0.01) in the etoposide groups than in concurrent controls. These results indicate that both structural and numerical aberrations can be induced without direct interaction with DNA or with the various organelles associated with chromosome segregation. Additionally, unlike other compounds (vinblastine, colchicine, benomyl, and griseofulvin) that induce both meiotic delay (ovulated metaphase I oocytes and polyploidy) and aneuploidy, etoposide did not cause meiotic delay in oocyte maturation.
Teratog Carcinog Mutagen 1994
PMID:Preferential pericentric lesions and aneuploidy induced in mouse oocytes by the topoisomerase II inhibitor etoposide. 791 Apr 18

The genotoxic and cytotoxic effects of etoposide (VP-16), a topoisomerase II inhibitor, on male rat spermatogenic cells were studied by analysing induction of micronuclei during meiosis. Micronuclei (MN) were scored in early spermatids after different time intervals corresponding to exposure of different stages of meiotic prophase. Etoposide had a strong effect on diplotene-diakinesis I cells harvested 1 day after exposure, and a significant effect also on late pachytene cells harvested 3 days after exposure. The effect at 18 days corresponding to exposure of preleptotene stage of meiosis (S-phase) was weaker but also statistically significant. Adriamycin was used as a positive control in this study. The results indicate a different mechanism of action of etoposide compared with adriamycin and other chemicals studied previously with the spermatid micronucleus test. DNA flow cytometry was carried out to assess cytotoxic damage at the same time intervals (1, 3, and 18 days after treatment) at stages I and VII of the seminiferous epithelial cycle allowing a study of cytotoxicity to different spermatogenic cell stages. Damage of differentiating spermatogonia was observed by a decrease in the cell numbers of the 2C peak 1 and 3 days after treatment and by a reduction of the number of 4C cells (primary spermatocytes) 18 d after etoposide treatment. Adriamycin also killed differentiating spermatogonia. Since the cell population which showed a high induction of MN by etoposide was not reduced in number, the genotoxic effect is remarkable. We conclude that etoposide is a potent inducer of genotoxicity and patients treated with this agent during cancer chemotherapy are at a risk of genetic damage.
Environ Mol Mutagen 1994
PMID:Etoposide (VP-16) is a potent inducer of micronuclei in male rat meiosis: spermatid micronucleus test and DNA flow cytometry after etoposide treatment. 795 23

The suspect human carcinogen, etoposide, is known to be genotoxic, producing both gene and chromosomal mutations, probably by virtue of its ability to inhibit topoisomerase II activity. The present paper describes assays conducted using the Salmonella assay, the mouse lymphoma tk+/- assay (gene and chromosomal mutation analysis and molecular analysis of tk-/- mutants) and the mouse bone marrow micronucleus assay. Nonreproducible, weak, dose-related increases in mutation frequency in strain TA98 (but not TA1538 or TA1537) of Salmonella typhimurium were observed. Etoposide was highly mutagenic at the heterozygous thymidine kinase (tk+/-) locus of L5178Y mouse lymphoma cells at concentrations below 0.1 micrograms/ml. Mostly small colony mutants were induced, consistent with the potent clastogenicity also observed. Molecular analysis of mutants indicated that 83% and 92% of large and small colony mutants, respectively, had lost the entire target gene sequence. Chromosomally aberrant L5178Y cells were approximately 2 to 600-fold more prevalent than small tk-/- mutant colonies. This suggests that the viable target for etoposide-mediated clastogenesis in the selective assay is approximately one-fifth of chromosome 11b, itself being approximately one-fortieth of the mouse genome. An unusually potent response was observed for etoposide in the mouse bone marrow micronucleus assay (63.1 +/- 18 MPE/1,000 PE 24 hours after an oral dose of 1 mg/kg). The minimum detectable dose level in the assay was between 0.01 and 0.1 mg/kg. At dose levels between 1 and 15 mg/kg, an inverse dose response was observed. This reduction in assay response was not due to the small concommitant decrease in the incidence of polychromatic erythrocytes, a conclusion based on studies with N-methyl-N-nitrosourea. Animals sampled 48 hours after dosing with etoposide (10 mg/kg) had no polychromatic erythrocytes in the bone marrow. These observations for the micronucleus assay await explanation. The chemical structure of etoposide is displayed and discussed within the context of such strong mutagenic activity being associated with a nonelectrophilic agent.
Environ Mol Mutagen 1994
PMID:Potent clastogenicity of the human carcinogen etoposide to the mouse bone marrow and mouse lymphoma L5178Y cells: comparison to Salmonella responses. 773 7


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