Cytogenetic Studies with Cyclamate and Related Compounds

Stoltz, D.R.; Khera, K. S.; Bendall, R.; Gunner, S. W.

doi:10.1126/science.167.3924.1501

Cited by 52 publications

(17 citation statements)

References 3 publications

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“…About 15 hr before harvest, the antioxidants and carcinogens were added separately in 0.2 ml of 2% bovine-serum albumin. Stoltz (19) observed no significant increase of chromosomal aberrations between 5 and 25 hr of carcinogenic exposure. Just before use all antioxidants 42.0%; and dl-a-tocopherol, 63.2%.…”

mentioning

confidence: 99%

Carcinogen-Induced Chromosomal Breakage Decreased by Antioxidants

Shamberger

Baughman

Kalchert

et al. 1973

Proc. Natl. Acad. Sci. U.S.A.

117

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Blood leukocyte cultures were incubated with antioxidants and the carcinogens sodium cyclamate and 7,12-dimethylbenz(a) The antioxidants, selenium (1-3), dl-a-tocopherol (1, 2), and ascorbic acid (4), applied to mouse skin, significantly reduced tumor formation induced by 7,12-dimethylbenz(a)anthracene and croton oil. Dietary selenium has decreased the number of mouse-skin tumors induced by dimethylbenzanthracene-croton oil (1), rat-liver tumors induced by N-2-fluorenylacetamide (5), and liver tumors induced by diethylaminoazobenzene (6). Rats fed tocopherol-rich wheat-germ oil had fewer mixed tumors (7) after intraperitoneal injection of 3-methylcholanthrene than rats fed a control diet. Haber and Wissler (8) have reported that a tocopherol-supplemented diet had an inhibitory effect on subcutaneous sarcoma from injection of methylcholanthrene in mice. The incidence of gastric cancer in mice decreased after the mice were given the potent food antioxidants, butylated hydroxyanisole and butylated hydroxytoluene (9). After application of dimethylbenzanthracene to mouse skin on day 1, an increase of peroxidation (4) was observed until day 20. When antioxidants were applied to mice treated with dimethylbenzanthracene on days 2-21, the number of tumors developed with croton oil in the mice treated with antioxidant was considerably decreased (2).The current belief about the mechanism of carcinogenesis is that a carcinogen, virus, or other factors alter a macromolecule such as DNA, and change the inherent information that can be transmitted to daughter cells or change the encoded information needed for metabolic function and control during the life of the cell. Marked damage of DNA has been induced with H202 or the organic peroxide, ascaridole (10); H202 destroys the pyrimidine moieties of nucleotides, and has other effects 1461 on the DNA molecule (11-13). The chemical linkage of the polycyclic hydrocarbons, benzo(a)pyrene, 3-methylcholanthrene, and dimethylbenzanthracene, to calf-thymus DNA has been induced by incubation with dilute solutions of H202 (14). Because antioxidants prevent carcinogenesis in animals (1-9) and possibly prevent certain types of human cancer (15-17) Procedure. Several tubes containing about 4.5 ml of heparinized blood were drawn from a 38-year-old male volunteer each morning before breakfast throughout the experiment. A modified macrotechnique of chromosome production was then used (18). Phytohemagglutinin M, 0.2 ml, was injected through the stopper. The tubes were inverted several times, and then placed into an ice-water bath for 1 hr. The blood samples, with the rubber stoppers intact to minimize bacterial contamination, were centrifuged in a Phillips Drucker model L-708 table centrifuge at 400 rpm for 5 min. The stoppers were removed, and 2.0 ml of plasma was transferred aseptically to a tube of chromosomal medium 1A.The tubes containing the chromosomal medium were incubated at 37 for 3 days. About 15 hr before harvest, the antioxidants and carcinogens were added separately in 0.2 ...

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mentioning

confidence: 99%

Carcinogen-Induced Chromosomal Breakage Decreased by Antioxidants

Shamberger

Baughman

Kalchert

et al. 1973

Proc. Natl. Acad. Sci. U.S.A.

117

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“…However, there are references about genotoxic effects of gliotoxin and verruculogen, secondary metabolites of Aspergillus fumigatus (Golden et al, 1998;Nieminen, 2002;Sabater-Vilar, 2003). In addition, there are data regarding genotoxic effects of dicyclohexilamine, a compound similar to fumagillin, obtained either in in vitro mammalian tests (Stoltz et al, 1970;Kuli}, 2006) or in bacterial mutagenicity tests (Purchase et al, 1978;Mortelmans et al, 1986;Heil, 1996). The abovementioned require further investigations in both in vitro as well as in in vivo mammalian tests systems, even more so as fumagillin, contrary to dicyclohexilamine, has primarily two epoxide structures capable of alkylating proteins involved in the packaging of DNA (Birch and Hussain, 1969) thereby establishing conditions for damaging DNA.…”

Section: Resultsmentioning

confidence: 95%

“…As regarding dicyclohexilamine, which is similar to fumagillin, in a cytogenetic study conducted by Stoltz et al (1970), lymphocytes from human blood samples incubated with dicyclohexilamine sulfate expressed a concentration-depended increase in aberration rate from approximately 6% in the controls to nearly 16% in the experimental groups.…”

Section: Introductionmentioning

confidence: 93%

Evaluation of genotoxic effects of fumagillin by sister chromatide exchange and chromosomal aberration tests in human cell cultures

Stanimirović¹,

Pejin²,

Kulišić³

et al. 2007

Acta vet. (Beogr.)

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Fumagillin is a naturally secreted antibiotic of the fungus Aspergillus fumigatus. In veterinary medicine fumagillin is used against nosemosis in bees and microsporidiosis in fish. Since fumagillin is stable in honey in a honey bee hive there is a possible genotoxic risk to beekeepers and consumers of honey contaminated with this substance. The genotoxic effect of fumagillin was evaluated in sisterchromatid exchange (SCE) and chromosome aberration tests in cultured human peripheral blood lymphocytes at three concentrations (1.02, 3.07 and 9.20 _g/mL), with 1:1 water-sugar syrup as the negative control and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) as the positive control. The mitotic and proliferative indices were calculated to detect the cytostatic effect of fumagillin. The results revealed that all tested concentrations of fumagillin (1.02, 3.07 and 9.20 _g/mL) significantly (p<0.001) increased the SCE frequency per cell and decreased the proliferative activity of human cultured lymphocytes which was manifested in the decrease in mitotic and proliferative indices. Significant increase (p<0.001) in aneuploidy and polyploidy was induced by medium and maximum concentrations of fumagillin. Besides, maximum concentrations of fumagillin significantly (p<0.001) increased the frequency of monitored structural aberrations of gap, break and insertion type. The results of this study demonstrate the genotoxic potential of fumagillin in vitro

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“…Moreover, investigations of the DNA-damaging effect of dicyclohexylamine in the UMU test and in the DNA synthesis inhibition test in HeLa S3 cells, gave no indication that dicyclohexylamine had a damaging effect on DNA (Heil et al, 1996), which is rather surprising considering that fumagillin has primarily two epoxide structures capable of alkylating proteins involved in the packaging of DNA (Birch and Hussain, 1969) thereby establishing conditions for DNA damage. However, in cytogenetic studies carried out by Stoltz et al (1970) dicyclohexylamine sulfate showed a concentration-depended increase in the aberration rate from approx. 6% in the controls to approx.…”

Section: Discussionmentioning

confidence: 92%

“…The available data referring to genotoxic effects of fumagillin (dicyclohexylamine) obtained by in vitro investigations are equivocal, i.e. either positive (Stoltz et al, 1970;Stanimirovic et al, 1999;Stevanovic et al, 2000) or negative (Purchase et al, 1978;Mortelmans et al, 1986;Heil et al, 1996) and there are no references regarding genotoxic effects of fumagillin in vivo (Toxicological Evaluation, 2000).…”

Section: Discussionmentioning

confidence: 99%

Monitoring of mitotic index and frequency of micronuclei in evaluation of genotoxic potential of fumagillin (dicyclohexylamine) in vivo

Stevanović¹,

Stanimirović²,

Pejin³

et al. 2006

Acta vet. (Beogr.)

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Fumagillin (dicyclohexylamine) is a natural antibiotic, secreted by Aspergillus fumigatus. It is used in veterinary medicine against microsporidiosis in bees and fish, as well as in human medicine for the treatment of intestinal amebiasis, microsporidial keratoconjunctivitis and intestinal microsporidiosis due to Enterocytozoon bieneusi in patients with AIDS and other types of immunodeficiency. In this study, the genotoxicity of fumagillin was evaluated in mouse bone marrow cells using the mitotic index (MI) and micronucleus (MN) assay. Fumagillin was administered to BALB/c mice by gavage in doses of 25, 50, 75 mg/kg b.w., repeated for 7 days at 24h intervals, with water-sugar syrup as the negative control and cyclophosphamide as the positive control (40 mg/kg b.w) All experimental doses of fumagillin induced a significant decrease (p<0.001) in MI (3.47 ± 0.04%, 3.17 ± 0.01% and 2.27 ± 0.02%, respectively) in comparison with the negative control (6.00 ± 0.01%) and with the positive control (14.78 ± 0.09). Fumagillin significantly (p<0.001) increased the frequency of MN (4.98 ± 0.35, 8.45 ± 0.57 and 12.02 ± 0.37, respectively) over the negative control (1.04 ± 0.28). These results suggest that fumagillin (dicyclohexilamine) has an antiproliferative and genotoxic potential in mammal in vivo test

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Cytogenetic Studies with Cyclamate and Related Compounds

Abstract: Cyclamate, cyclohexylamine, N-hydroxycyclohexylamine, and dicyclohexylamine can induce chromosomal damage in human leukocyte cultures.

Cited by 52 publications

References 3 publications

Carcinogen-Induced Chromosomal Breakage Decreased by Antioxidants

Carcinogen-Induced Chromosomal Breakage Decreased by Antioxidants

Evaluation of genotoxic effects of fumagillin by sister chromatide exchange and chromosomal aberration tests in human cell cultures

Monitoring of mitotic index and frequency of micronuclei in evaluation of genotoxic potential of fumagillin (dicyclohexylamine) in vivo

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