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L R Ferguson

Publications and source records attributed to L R Ferguson.

At least 91 records · Page 5Linked to original sources
PubMed1992

Photo-enhancement of the mutagenicity of 9-anilinoacridine derivatives related to the antitumour agent amsacrine.

The frameshift mutagenicity of the DNA intercalating drug proflavine is known to be enhanced by photoirradiation of bacterial cultures. To determine whether this phenomenon was also present in acridine-derived antitumour drugs, cultures of Salmonella typhimurium were exposed to the antileukaemia agent amsacrine and the experimental agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide dihydrochloride (acridine carboxamide) in the presence or absence of visible light. A small increase in mutagenicity was observed with amsacrine but not with acridine carboxamide. A series of analogues of amsacrine were then tested, and a striking relationship was found between the minimum drug concentration for mutagenicity and DNA binding affinity. In each case, photoirradiation was associated with a small increase in mutagenicity. Each of the compounds showing the photo-enhancement effect was capable of reversible one-electron oxidation. It is suggested that this oxidation occurs in bacteria, and that the DNA binding constant of the resulting acridine radical species will increase because of the extra positive charge. This increased DNA binding would be sufficient to explain the photo-enhancement of mutagenicity of these drugs.

Acridines↗
PubMed1992

Chromosomal changes in Chinese hamster AA8 cells caused by podophyllin, a common treatment for genital warts.

Podophyllin, a plant derivative of variable composition, is used widely within New Zealand as a treatment for genital warts. One local source of podophyllin has been tested for ability to cause mutagenic effects in Salmonella typhimurium as well as for effects on chromosomes of Chinese hamster AA8 cells. Although only weakly mutagenic in one strain of Salmonella, podophyllin caused structural aberrations as well as changes in chromosome number in the Chinese hamster cells. The range of aberrations was similar to those caused by teniposide, a close structural relative of the major component, which was used as a positive control in the Chinese hamster cell experiments. A literature review revealed that podophyllin was shown to cause changes of chromosome number in the mouse cervix in vivo, although aberrations were not studied. Patients treated with podophyllin will usually possess one form of the papilloma virus, and this itself may have some oncogenic potential. We suggest that podophyllin could potentiate these effects and question its continued widespread use.

Animals↗
PubMed1992

In vitro and in vivo mutagenicity studies on sporidesmin, the toxin associated with facial eczema in ruminants.

Sporidesmin, a fungal toxin with widespread distribution within New Zealand, is thought to exert toxic effects through oxidative damage. The purified chemical was tested for its ability to cause point mutations in four strains of Salmonella typhimurium (TA98, TA100, TA102 and TA1537), in the presence and absence of exogenous metabolic activation. Although toxic effects were seen at concentrations exceeding 400 mu gl/plate, there were no significant increases in revertant colonies. In strain TA102, these results were not modified by the presence of glutathione. In AA8 Chinese hamster cells, sporidesmin acted as a potent clastogen, causing chromosomal breaks at concentrations as low as 3 ng/ml, where there was very little reduction in cell viability. Effects were primarily at the chromatid level, but some chromosomal events were also seen. Following low doses, the most common events were chromatid deletions and induction of double minute chromosomes. Interchange events occurred at concentrations of 10 ng/ml and above. The most common of these events was an incomplete chromatid interchange, although some examples of complete chromatid and chromosomal interchange were seen. These in vitro experiments were subsequently extended to an in vivo study of sporidesmin-induced lymphocytic micronuclei (MN) in sheep. In a double blind experiment, 5 sheep were treated with a single high dose of sporidesmin. Blood samples were taken from these, and from 5 untreated sheep, at various intervals before and after treatment. Peripheral blood lymphocytes cultures were harvested and scored for MN in cytokinesis-blocked cells, as a measure of clastogenic activity of sporidesmin in vivo. Following decoding, statistical analysis of the data revealed no significant differences between the MN levels in peripheral blood lymphocytes of sporidesmin-treated and untreated sheep. Although the possibility still exists that clastogenic effects could occur in other species, the data indicate that sporidesmin is not a clastogen in sheep, even though this species is highly susceptible to the toxic effects of sporidesmin.

Animals↗
PubMed1992

Mutagenic activities of azido analogues of amsacrine and other 9-anilinoacridines in Salmonella typhimurium and their enhancement by photoirradiation.

Analogues of amsacrine and other 9-anilinoacridines, bearing azide groups at various positions, were tested for their mutagenic activity in five strains of Salmonella typhimurium, both before and after photoirradiation. Azido substitution at the 2- or 3-position of the acridine or the 1'-position of the aniline led to compounds which were active frameshift mutagens, as detected in strain TA1537. Photoirradiation enhanced both the mutagenicity and the cytotoxicity of the azido compounds. Analogues bearing two azido groups at either the 2,6- or 3,6-positions were less strongly mutagenic in the dark, and light activation led to a toxic but only weakly mutagenic product. The effects of photoirradiation were decreased by aniline ring substitution, and were essentially eliminated by additional methyl substitution in the acridine ring. Comparison of events in TA1537 and TA98 suggested that photoirradiation of the 2- or 3-azido compounds gave a product which was capable of forming covalent bonds with DNA. The azide-containing analogues readily formed single strand DNA breaks on irradiation in the presence of DNA, but the efficiency of this reaction varied considerably.

Amsacrine↗
PubMed1992

Induction of resistance to 6-thioguanine and cytarabine by a range of anticancer drugs in Chinese hamster AA8 cells.

A mutagenicity assay using AA8 Chinese hamster cells has been used to explore the potential of some currently used clinical anticancer drugs to induce cells resistant to 6-thioguanine and cytarabine. Preliminary experiments gave evidence of a "low dose" and "high dose" resistance to cytarabine, and subsequent work considered only the latter of these events. When ethyl methane sulphonate was used as a reference mutagen, induced resistance to cytarabine developed substantially later and at a lower frequency than resistance to 6-thioguanine. Of the clinical drugs tested, carmustine showed the highest ability to induce either 6-thioguanine or cytarabine resistant cells. Bleomycin, daunomycin and amsacrine showed moderate ability, while vincristine was essentially inactive in these assays. Such information could potentially be used in selecting new drug combinations or timing of drug administration in cancer chemotherapy.

Amsacrine↗
PubMed1992

Adsorption of a hydrophobic mutagen to dietary fiber from taro (Colocasia esculenta), an important food plant of the South Pacific.

The incidence of colorectal cancer is lower in Polynesian populations of the South Pacific than in European populations. This difference in incidence of the disease may be, at least partly, related to diet. Dietary fiber is believed to protect against colorectal cancer, and one of the ways it may act is by adsorbing mutagens that are carcinogenic. Very little is known about the chemical composition or the ability to adsorb mutagens of these dietary fibers from South Pacific food plants. In contrast to European food plants, which are mostly dicotyledons, South Pacific food plants are mainly monocotyledons. We isolated cell walls (dietary fiber) from the three edible parts of taro (Colocasia esculenta), which is a monocotyledon and a major South Pacific food plant. The ability of these three unlignified cell-wall preparations to adsorb the hydrophobic environmental mutagen 1,8-dinitropyrene was studied. The greatest adsorption occurred with walls from leaf blade, followed by petiole and corm walls, although the differences were not major. The amount of adsorption was intermediate between the low adsorption previously found with unlignified dicotyledon walls (from the flesh of potato tubers and immature cabbage leaves) and the much higher adsorption found with unlignified walls from monocotyledons of the grass and cereal family (Poaceae) (from leaves of seedling Italian ryegrass). These data are consistent with the monosaccharide compositions of the taro wall preparations, which were more similar to those of unlignified walls of dicotyledons than to unlignified walls of the Poaceae. These findings are consistent with the hypothesis that the composition of the dietary fiber determines its adsorptive properties and that there may be important differences between the major dietary fibers of South Pacific and European food plants.

Adsorption↗
PubMed1991

The genetic toxicology of acridines.

Acridine and its derivatives are planar polycyclic aromatic molecules which bind tightly but reversibly to DNA by intercalation, but do not usually covalently interact with it. Acridines have a broad spectrum of biological activities, and a number of derivatives are widely used as antibacterial, antiprotozoal and anticancer drugs. Simple acridines show activity as frameshift mutagens, especially in bacteriophage and bacterial assays, by virtue of their intercalative DNA-binding ability. Acridines bearing additional fused aromatic rings (benzacridines) show little activity as frameshift mutagens, but interact covalently with DNA following metabolic activation (forming predominantly base-pair substitution mutations). Compounds where the acridine acts as a carrier to target alkylating agents to DNA (e.g. the ICR compounds) cause predominantly frameshift as well as base-pair substitution mutations in both bacterial and mammalian cells. Nitroacridines may act as simple acridines or (following nitro group reduction) as alkylating agents, depending upon the position of the nitro group. Acridine-based topoisomerase II inhibitors, although frameshift mutagens in bacteria and bacteriophage systems, are primarily chromosomal mutagens in mammalian cells. These mutagenic activities are important, since the compounds have considerable potential as clinical antitumour drugs. Although evidence suggests that simple acridines are not animal or human carcinogens, a number of the derived compounds are highly active in this capacity.

Acridines↗
PubMed1991

Adsorption of a hydrophobic mutagen to dietary fibre from the skin and flesh of potato tubers.

One of the theories to explain the protective action of some dietary fibres against colon cancer is that certain mutagens and/or cancer promoters are adsorbed to these dietary fibres making the mutagens and/or cancer promoters less available to gut mucosal cells. The abilities of 2 contrasting cell wall preparations (dietary fibre preparations) from potato tubers to adsorb in vitro the hydrophobic mutagen, 1,8-dinitropyrene (DNP), were studied using an incubation mixture containing DNP in phosphate-buffered saline (PBS). Walls from potato skins strongly adsorbed DNP and, at the highest wall concentration tested, only a small porportion of the DNP remained in solution. In marked contrast to the skin walls, potato flesh walls adsorbed only a small proportion of the DNP. Unexpectedly, the flesh walls also caused a large increase in the proportion of DNP found in solution. When flesh walls were pre-extracted with PBS, the ability of the extracted walls to bind DNP increased. The material extracted from the flesh walls was able to maintain DNP in solution, when added to the incubation medium in the absence of cell walls. Pectic polysaccharides appear to be the soluble component responsible for maintaining the DNP in solution. Competition between soluble and insoluble fibre components may have major implications for the availability and distribution of hydrophobic mutagens in the alimentary tract.

Adsorption↗
PubMed1991

Adsorption of a hydrophobic mutagen to five contrasting dietary fiber preparations.

The ability of five plant cell wall (dietary fiber) preparations with contrasting compositions to adsorb in vitro the hydrophobic, environmental mutagen, 1,8-dinitropyrene (DNP), was investigated. Many of the fruits and vegetables in Western diets are from dicotyledonous (broad leaved) plants and the dietary fiber from these consists mainly of unlignified cell walls. A representative of this wall type, prepared from immature cabbage leaves, showed little ability to adsorb DNP. Two other cell-wall preparations, representing lignified walls of dicotyledons and unlignified walls of vegetative parts of grasses and cereals (monocotyledons belonging to the family Poaceae), adsorbed DNP much more effectively. However, two further preparations, representing suberized walls of cork cells and lignified walls of vegetative parts of grasses and cereals, were the most effective in adsorbing DNP. Extrapolation of these data to the in vivo situation would indicate that increased consumption of the vegetative parts of grasses or cereals and plant material containing cork cells, for example potato skins, could be effective in removing hydrophobic mutagens from potential contact with colonic mucosal cells.

Brassica↗
PubMed1991

Variation in the mutagenic potential of acridines in Salmonella typhimurium, with stage of the culture.

The mutagenic potential of proflavine differed by up to two orders of magnitude in three strains of Salmonella typhimurium carrying the frameshift marker hisC3076, depending upon the stage of the culture. In cultures at a specific stage, proflavine showed decreased mutagenesis in a recA as compared with a wildtupe or uvrB derivative. The related compound 9-aminoacridine also showed marked variation in mutagenic potential with the stage of the bacterial culture, but was equally mutagenic in all three strains, at least in log phase cells. Within the literature, there are conflicting data regarding the mutagenicity of acridines, and the contribution of repair enzymes to this event. We suggest that many of the reported differences can be related to the variations in bacterial growth conditions in different laboratories, and urge authors to supply more details of these.

Aminacrine↗
PubMed1991

Petite mutagenesis in Saccharomyces cerevisiae by a series of bis-cationic trypanocidal drugs.

A group of bis-cationic imidazo[1,2-a]pyridinium salts and related compounds, some of which exhibit in vivo trypanocidal activity, have been investigated for induction of petite mutagenesis in Saccharomyces cerevisiae. All of the compounds which are active trypanocides induce mutagenesis. There appears to be a correlation between trypanocidal activity and mutagenic activity which may have its structural origin in the spatial separation of the cationic centers.

Cations↗
PubMed1990

Structure-activity relationships for the mutagenic activity of tricyclic intercalating agents in Salmonella typhimurium.

A total of 25 different tricyclic DNA-intercalating chromophores bearing a common -CONH(CH2)2N(CH3)2 solubilizing sidechain have been compared with the 'classical' frameshift mutagen 9-aminoacridine for their ability to induce revertants in Salmonella typhimurium strain TA1537 (sensitive to frameshift mutation by acridine mutagens). The compounds showed varying levels of activity in this strain. For the fused linear and fused angular tricyclics, activity varied from zero to similar levels to 9-aminoacridine, but with no discernable relationship between activity and either structure or the measured physico-chemical properties. However, the '2-1' tricyclic compounds had essentially no mutagenic activity. Since several of these compounds have high in vivo antitumor activity, this is useful knowledge.

Frameshift Mutation↗
PubMed1990

The mutagenic effects of diacridines and diquinolines in microbial systems.

Two series of difunctional DNA-intercalating agents (diacridines and diquinolines) were tested for mutagenic properties in Salmonella typhimurium strain TA1537, and for 'petite' mutagenesis activity in Saccharomyces cerevisiae, and also compared in terms of their structural, lipophilic and DNA-binding properties. Diacridines with only a short chain length were monointercalators, while those with an alkyl linker chain longer than C6 were bisintercalators. Although the bisintercalators especially bound very tightly to DNA, none of these compounds was as effective a frameshift mutagen in TA1537 as the parent chromophore 9-aminoacridine. However, the two (monointercalating) diacridines of shortest chain length were still able to cause frameshifts, and this ability returned (albeit weakly) in the bisintercalators of longest chain length. Although 9-aminoacridine showed no ability for 'petite' mutagenesis, the diacridines of longer chain length were very effective in causing this mitochondrial event. In the quinoline series, both the parent chromophore (4-aminoquinoline) and all the diquinolines were weak monointercalators. None of these compounds showed any ability for frameshift mutagenesis, although some were very weak mitochondrial mutagens. It is concluded that linking two acridines produces compounds whose mutagenic properties might have been predicted from our current knowledge of the parent molecules. However, despite a similar ability to intercalate DNA, the diquinolines show no resemblance to acridines in their mutagenic properties.

Acridines↗
PubMed1990

Mutagenic and recombinogenic consequences of DNA-repair inhibition during treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea in Saccharomyces cerevisiae.

The yeast Saccharomyces cerevisiae has been used as a model system to explore whether the clinical combination of the antitumour agent BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea) with DNA-repair inhibitors would affect the drug's mutagenic or recombinogenic potential. Preliminary experiments suggested that mitotic crossing-over and other mutagenic events are controlled in a separate fashion. BCNU was more toxic in yeast derivatives with specific defects in any of the three recognised major DNA repair pathways than in the DNA-repair-proficient parent strain. However, in a diploid homozygous for rad18, BCNU showed enhanced mutagenic and recombinogenic potential. Both of these effects were reduced in a comparable rad3 strain, and mitotic crossing-over but not other types of mutagenic event eliminated in the rad52 derivative. Experiments were performed in the presence of three DNA-repair inhibitors which are currently in clinical use and which might be available for combination chemotherapy. Hydroxyurea and amsacrine themselves caused mitotic crossing-over and other events, and did not reduce mutagenic or recombinogenic potential of the BCNU. Hydroxyurea actually decreased toxicity of the BCNU. Caffeine, however, showed some effect in enhancing toxicity and decreasing both mutagenic and recombinogenic potential of the drug. Development of more specific repair inhibitors related to amsacrine or to caffeine, using these repair-deficient strains as model systems, might lead to an enhanced clinical potential of this bisalkylating drug and related compounds.

Amsacrine↗
PubMed1990

Effects of bile salts on the adsorption of a hydrophobic mutagen to dietary fiber.

The effect of the bile salts, sodium cholate, deoxycholate, glycocholate and taurocholate, on the solubility in aqueous solution of the hydrophobic, environmental mutagen, 1,8-dinitropyrene (DNP), was examined. In the absence of bile salts, the DNP appeared to precipitate out of solution, whereas bile salts at a concentration of greater than or equal to 4 mM maintained the DNP in solution. In the presence of the model dietary fiber, alpha-cellulose, the DNP absorbed to this preferentially. Bile salts reduced this adsorption at low alpha-cellulose levels, but had little effect at high alpha-cellulose levels. The implication of these results is that bile salts have solubilising properties that could affect the distribution of hydrophobic molecules, including mutagens, in the digestive tract.

Adsorption↗
PubMed1990

Direct-acting mutagenic properties of some hair dyes used in New Zealand.

Mutagenicity or carcinogenicity data are not publicly available on many hair dyes or dye components commonly used within New Zealand. Representative mid- to dark-warm brown hair dyes of 12 brands supplying more than 1% of the New Zealand market were tested for direct-acting mutagenicity using the bacterial 'Ames' test. Despite recent scientific advances in the development of non-mutagenic dyes, 23 of the 40 products tested gave positive results in one or both of the tester strains used. There appeared to be differences between distributors in the proportion of their hair dyes which were mutagenic. In the case of 6 out of 10 of the above dyes which had tested positive, in vitro mutagenicity or toxicity was enhanced in the presence of verapamil, suggesting that risks from hair-dye exposure may change in the case of persons using this or similar drugs. It is recognised that there are uncertainties regarding human risks from dyes which are shown to be mutagenic in in vitro tests. However, from the above results, it seems possible to produce non-mutagenic hair dyes in this color range; and in the interests of public reassurance, it may be prudent to require that such dyes be used.

Drug Synergism↗
PubMed1990

A model system for studying the adsorption of a hydrophobic mutagen to dietary fibre.

The adsorption of 1,8-dinitropyrene (DNP) to alpha-cellulose has been studied as a model system for examining the adsorption of a hydrophobic mutagen to dietary fiber. Most of the DNP rapidly disappeared from an aqueous solution and partitioned between the glass wall of the test tube and the alpha-cellulose. Factors affecting DNP distribution included (i) the time of incubation, (ii) the final concentration of the solvent, dimethyl sulphoxide, in which the DNP has been dissolved, and (iii) the relative concentrations of DNP and alpha-cellulose. We suggest that this model system could be applied to other mutagens, and that alpha-cellulose would provide a useful standard fiber to permit inter-laboratory comparisons.

Adsorption↗