PubMed Health⌕ Search

Biomedical subjects

L R Ferguson

Publications and source records attributed to L R Ferguson.

At least 109 records · Page 6Linked to original sources
PubMed1990

Genetic toxicology of tricyclic carboxamides, a new class of DNA binding antitumour agent.

(N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide (acridine carboxamide; NSC 601316) is an acridine-derived experimental antitumour agent with curative properties against Lewis lung carcinoma in mice. Although it intercalates into DNA and also appears to interact with topoisomerase II, its DNA binding properties appear distinct from other acridine derivatives such as the clinical antitumour drug, amsacrine. The mutagenic properties of acridine carboxamide, together with three related compounds containing either 9-aminoacridine or phenazine chromophores, were studied at the 6-thioguanine and ouabain loci in cultured V79 Chinese hamster fibroblasts. Each compound, when tested at concentrations causing up to 90% kill, had weak but significant activity at the 6-thioguanine but not at the ouabain locus. All drugs were potent inducers of micronuclei, indicating high clastogenic activity. There was a highly significant relationship between mutation frequency (as resistance to 6-thioguanine) and either cytotoxicity (measured as D37 in a clastogenicity assay) or clastogenicity. A broader range of compounds was also tested for microbial mutagenicity. In Salmonella typhimurium strains, none were mutagenic in TA98, TA100 or TA102 but several were mutagenic in TA1537, a frameshift tester strain. Some drugs also caused 'petite' mutagenesis in Saccharomyces cerevisiae. In general, compounds with the phenazine chromophore, which has no positive charge, were the most mutagenic in these systems. However, activity was not related to mammalian mutagenicity or antitumour effect. The results suggest that in mammalian cells, the cytotoxicity, clastogenicity and mutagenic activity of these drugs are mediated by similar mechanisms to those for amsacrine analogues, probably involving the enzyme DNA topoisomerase II.

Acridines↗
PubMed1990

Protection by inhibitors of multidrug resistance against mitochondrial mutagenesis in Saccharomyces cerevisiae.

A number of inhibitors thought to act on the drug efflux mechanism of multidrug-resistant cells have been tested for their ability to inhibit the induction of respiration-deficient (petite) colonies of the yeast Saccharomyces cerevisiae by mitochondrial mutagens. The mutagens tested were 3,6-diamino-9-(4-[(methylsulphonyl)aminophenyl]amino) acridine (an antitumour compound related to both amsacrine and proflavine), ethidium bromide, quinolinium dibromide (NSC 176319, a non-intercalative DNA binding antileukaemia agent) and rhodamine 123. The inhibitors tested included verapamil, perhexiline, chlorpromazine, trifluoperazine, reserpine, chloroquine, quinacrine, tamoxifen, clomiphene, cyclosporin A, valinomycin, amphotericin B and Tween 80. Several of these agents protected against mitochondrial mutagenesis, the most active being verapamil, reserpine, chloroquine, cyclosporin A and Tween 80. The correspondence between activity against multidrug resistance and activity in the yeast system strongly implies some degree of similarity in mechanisms for drug efflux from multidrug-resistant cells and drug uptake into the mitochondria of yeast. Agents protecting against the uptake of drugs into mitochondria of mammalian cells may have use in minimizing the long-term toxicity of anticancer drugs mediated by mitochondrial drug retention.

Aminoacridines↗
PubMed1989

'Petite' mutagenesis and mitotic crossing-over in yeast by DNA-targeted alkylating agents.

Although the biological properties (cytotoxicity, mutagenicity and carcinogenicity) of alkylating agents result from their bonding interactions with DNA, such compounds generally do not show any special binding affinity for DNA. A series of acridine-linked aniline mustards of widely-varying alkylator reactivity have been designed as DNA-directed alkylating agents. We have considered whether such DNA targeting has an effect on mutagenic properties by evaluating this series of drugs in comparison with their untargeted counterparts for toxic, recombinogenic and mutagenic properties in Saccharomyces cerevisiae strain D5. The simple untargeted aniline mustards are effective inducers of mitotic crossing-over in this strain, but resemble other reported alkylators in being rather inefficient inducers of the "petite" or mitochondrial mutation in yeast. However, the majority of the DNA-targeted mustards were very efficient petite mutagens, while showing little evidence of mitotic crossing-over or other nuclear events. The 100% conversion of cells into petites and the lack of a differential between growing and non-growing cells are similar to the effects of the well characterised mitochondrial mutagen ethidium bromide. These data suggest very different modes of action between the DNA-targeted alkylators and their non-targeted counterparts.

Alkylating Agents↗
PubMed1989

Relationships between structure, toxicity and genetic effects in Salmonella typhimurium and Saccharomyces cerevisiae for substituted aniline mustards.

A series of 4-substituted aniline mustards of widely varying reactivities have been evaluated for their mutagenic effects in Salmonella typhimurium strains of varying uvrB gene and plasmid status, and for their ability to cause mitotic crossing-over in Saccharomyces cerevisiae. The 4-methyl aniline mustard N,N-bis(2-chloroethyl)-4-methylaniline and its corresponding half-mustard N-(2-chloroethyl)-4-methylaniline showed widely different effects in the various bacterial strains, with the half-mustard being much less toxic than the full mustard in the uvrB- strain TA100. However, in the uvrB+ strain TA1978+, possessing an intact excision repair system, both compounds were equally toxic and the full mustard was the more mutagenic. Both compounds were equally effective in promoting mitotic crossing-over in yeast. For a series of 4-substituted full mustards, the toxicity in S. typhimurium strain TA100 correlated with substituent electronic parameters in the same way as does mammalian cell toxicity, supporting the view that the primary mode of toxicity is via DNA cross-linking, even for unreactive analogues. However, there were no obvious correlations between substituent physiochemical properties and mutagenic potential in bacteria, suggesting that mutagenic events are subject to a variety of influences other than the reactivity of the mustard group. In contrast, the most chemically reactive compounds were the most toxic and most recombinogenic in yeast.

Alkylating Agents↗
PubMed1989

Mutagenic activity of nitracrine derivatives in Salmonella typhimurium: relationship to drug physicochemical parameters, and to bacterial uvrB and recA genes and plasmid pKM101.

To determine whether it is possible to separate antitumour and mutagenic properties in the nitracrine series, a number of 4-substituted derivatives of the hypoxia-selective drug nitracrine have been evaluated for their mutagenic effects at three loci in several strains of Salmonella typhimurium differing in DNA-repair capacity (uvrB, recA, plasmid pKM101). The drugs divided into two series in terms of their biological effects. Group A compounds (nitracrine and its Cl, F, Me and OMe derivatives) were very toxic to bacteria, and uvrB and recA deletions enhanced toxicity by 10-80-fold. Mutagenic potency was high, being slightly enhanced by uvrB and reduced by recA deletions. In contrast the toxicities and mutagenic potentials of Group B compounds (COOMe, NMe2, and two other bulky amine derivatives) were reduced by at least an order of magnitude, with uvrB and recA deletions showing lesser influence. The COOMe derivative was the only compound showing greater effects at the hisC3076 locus than the hisD3052 or hisG46 loci. The data suggest that all the compounds cause mutations through intercalation and/or monoadduct formation, but only for the COOMe derivative is intercalation the dominant mode of action. Group A compounds appear to have the additional ability to cross-link DNA, a property which amounts for their high potency but which is not compatible with bulky 4-substituents. Apart from these generalizations, there was considerable variation in mutagenic efficiency (as measured by the maximum numbers of revertant colonies) within each series. Of the compounds studied, the 4-OMe derivative appears to best retain the desirable antitumour properties of nitracrine while showing greatly-reduced mutagenic potential, and is an interesting lead for further development.

Aminoacridines↗
PubMed1989

Mutagenicity profiles of newer amsacrine analogues with activity against solid tumours: comparison of microbial and mammalian systems.

Amsacrine, an acridine derivative used clinically in the treatment of acute leukaemia, has formed the basis for the development of further compounds with high activity against experimental solid tumours, one of which is currently in clinical trial. We have compared the ability of these drugs to cause point mutations in bacteria, 'petite' mutations in yeast and mutations in mammalian cells. Several of the compounds are frameshift mutagens in Salmonella typhimurium TA1537 while some cause 'petite' mutagenesis in Saccharomyces cerevisiae. All are highly clastogenic and have significant mutagenic activity at the 6-thioguanine locus in cultured V79 Chinese hamster fibroblasts following 1 h drug exposures. None are mutagenic at the ouabain locus of these cells. The relationship between different indicators of mutagenicity has been studied using an additional set of amsacrine analogues, some of which are mutagenic in S. typhimurium TA98. There is a highly significant relationship between mutation frequency (measured as resistance to 6-thioguanine) and either cytotoxicity (D37 values in a clonogenic assay) or clastogenicity (ability to induce micronuclei). However, there is no correlation with mutagenicity in microbial systems. The results suggest that the cytotoxicity, clastogenicity and mutagenic activity of the amsacrine analogues is mediated by similar mechanisms, probably involving the enzyme DNA topoisomerase II.

Amsacrine↗
PubMed1989

Bacterial mutagenicity studies of DNA-intercalating aniline mustards: an insight into the mode of action of a novel class of anti-tumour drugs.

Bifunctional alkylating agents are reactive compounds which work by crosslinking DNA, but which have no special affinity for it. A series of acridine-linked aniline mustards of widely-varying alkylator reactivity (5-11), designed as DNA-directed alkylating agents, have been evaluated in various strains of Salmonella typhimurium with differing DNA repair capabilities to obtain information about their mechanism of action. The compounds showed greatly increased potency (determined as D37 values) compared with the corresponding untargeted mustards, in the repair-proficient strain TA1978+. All but the most unreactive mustards were considerably more potent (greater than 10-fold) in the corresponding repair-deficient strain TA98, indicating that DNA-crosslinking is the major cytotoxic mechanism. However, the mutagenic profile of the compounds in four Salmonella strains, particularly in the excision repair-deficient strains TA98 and TA100, suggest the compounds also form substantial levels of mutagenic monoadducts. The possibility that intercalative binding by the acridine chromophore provides an additional geometrical restraint on cross-linking by the mustard is an important facet of design which needs further study.

Alkylating Agents↗
PubMed1989

Gender differences in patterns of spatial ability, environmental cognition, and math and English achievement in late adolescence.

Relationships were explored among three measures of spatial ability--the Embedded Figures Test (EFT), the Mental Rotations Test (MRT), and the Differential Aptitude Spatial Relations subtest (DAT)--an environmental cognition task (MAP), American College Testing (ACT) math and English achievement, and gender in a sample of 282 undergraduates. Variance attributable to gender among the spatial tasks ranged from 0.5% in the EFT to 12% in the MRT. Gender accounted for only 1% of the variance in the MAP task. Gender differences were noted in regression analyses; women's math and English achievement scores were both predictive of spatial ability, while for men, only math achievement was predictive of spatial ability. The results were interpreted as substantiating sex role socialization theory of cognitive abilities.

Achievement↗
PubMed1988

Biochemical evidence that high concentrations of the antidepressant amoxapine may cause inhibition of mitochondrial electron transport.

Overdosage with the antidepressant amoxapine causes metabolic acidosis and may lead to brain damage and death. To better understand the metabolic disturbances caused by amoxapine overdose, its effects on three simple systems were studied: growth of Saccharomyces cerevisiae, mitochondrial energy metabolism, and an electron transport system in microsomal membranes. Growth of yeast on all substrates except lactate was inhibited by amoxapine at 50-100 micrograms ml-1. Growth on lactate was observed at 200 micrograms ml-1 of amoxapine. In beef heart mitochondria, amoxapine at 100 micrograms ml-1 inhibited reactions involving large sections of the electron transport chain. Energy-linked reactions in submitochondrial particles were also inhibited. Electron microscopy showed some disruption of the mitochondrial internal structure by amoxapine and a change from orthodox to condensed conformation. Microsomal NADH-cytochrome b5 reductase was inhibited by amoxapine, but at higher amoxapine concentrations than mitochondrial reactions. The results suggest amoxapine disrupts reactions of membrane-associated enzyme complexes, and mitochondrial energy conservation may be one of the first systems affected. We speculate that lactic acid accumulation in patients with amoxapine overdose may be caused by loss of electron acceptor activity in tissues.

Amoxapine↗
PubMed1988

'Petite' mutagenesis in Saccharomyces cerevisiae by a series of 2,7-di-alkyl-substituted derivatives of proflavine with differing DNA-binding properties.

The ability of proflavine (3,6-diaminoacridine) and its 2,7-dimethyl, 2,7-diethyl, 2,7-diisopropyl and 2,7-di-tert.-butyl derivatives to induce the 'petite' mutation in Saccharomyces cerevisiae has been studied in relation to the DNA-binding properties of the compounds. The nature of the binding has been investigated by nuclear magnetic resonance techniques, and the results support and clarify earlier suggestions that the first 3 members of the series intercalate into DNA while the diisopropyl and di-tert.-butyl compounds do not. Toxicity of the drugs was primarily associated with their mode of DNA binding, but lipophilicity had an important secondary effect. It seems likely that the toxic properties of the more lipophilic DNA-intercalating members of the series mask their potential for 'petite' mutagenesis.

Acridines↗
PubMed1988

Mutagenic and clastogenic activity of nitracrine analogues in cultured V79 Chinese hamster cells.

Nitracrine is used clinically as an antitumour agent, and analogues are actively being developed in some laboratories. The mutagenic activity of 9-[(3-dimethylaminopropyl)amino]-acridine and its 1-nitro (nitracrine), 2-, 3- and 4-nitro derivatives was evaluated at the 6-thioguanine and ouabain resistance loci in cultured Chinese hamster fibroblasts (V79-171b cell line). The des-nitro, 2- and 3-nitro caused no statistically significant mutagenic activity at either locus. Each of these 3 compounds weakly increased (approximately 2-fold) the incidence of micronuclei in the same cell line when tested at cytotoxic doses. Both the 1- and 4-nitro compounds increased the incidence of 6-thioguanine resistant cells from around 1 in 10(-6) to approximately 1 in 10(-4). The former compound significantly increased the frequency of ouabain-resistant cells. Both of these compounds were potent inducers of micronuclei in V79-171b cells, indicating high clastogenic activity. It would appear prudent to regard both of these compounds as potential human carcinogens.

Aminoacridines↗
PubMed1988

Comparison of the mutagenicity of amsacrine with that of a new clinical analogue, CI-921.

The mutagenicity of CI-921, the 4-methyl-5-(N-methyl)carboxamide derivative of the clinical antileukaemia agent, amsacrine, has been assessed using both bacterial and mammalian cells. CI-921 is distinguished from amsacrine in its high activity against some experimental tumours and is currently undergoing phase I clinical trial. Like 9-aminoacridine and amsacrine, CI-921 is mutagenic to the Salmonella typhimurium frameshift tester strain TA1537, but shows no sign of inducing base pair changes in strain TA100. In Chinese hamster cell culture, however, it differs from 9-aminoacridine in causing extensive chromosomal aberrations and an increase in mutations at the hypoxanthine-guanine phosphoribosyltransferase locus. It induces the formation of tightly packed and multilayered colonies in treated cultures of C3H/10T1/2 cells, but its action differs from that of benzo[a]pyrene, which induces type III fibroblastic multilayered colonies. Side-by-side comparison of the mutagenic properties of CI-921 and amsacrine showed no substantial differences at similar toxicity, suggesting that the increased lipophilicity and DNA-binding affinity of CI-921, which are thought to contribute to its increased antitumour activity, do not concomitantly increase the efficiency of in vitro mutagenesis or cell transformation.

Amsacrine↗
PubMed1988

Mitotic crossing-over by anticancer drugs in Saccharomyces cerevisiae strain D5.

Treatment with an anticancer drug causing mitotic crossing-over could lead to expression of recessive genes, previously masked in a heterozygote. Used clinically, such drugs might cause an increased risk of cancer in cases of familial tumours, such as Wilm's tumour or retinoblastoma. Potentially, novel forms of drug resistance could also be unmasked by such a recombinogenic event. We have estimated the extent of this potential problem in current clinical drugs by comparing a range of antitumour agents for ability to cause mitotic crossing-over in Saccharomyces cerevisiae strain D5. We have compared these data with ability to cause an increase in total aberrant colonies in the same experiments. Although many of the agents known to cause point mutation also have some ability for mitotic crossing-over, there are also point mutagens which have little recombinogenic potential. Conversely, some effective recombinogens appear to be either very specific or rather ineffective point mutagens. Although the most generally effective agents in the present experiments were alkylating agents, several other types of drug including DNA-cutting agents, topoisomerase inhibitors, other DNA-binding drugs and antimetabolites may stimulate mitotic crossing-over. None of the mitotic inhibitors or the DNA minor groove binding drugs tested caused recombinogenic events. It would seem that the ability to induce mitotic crossing-over is an important endpoint in its own right. Assays for this event might provide an important complement to other assays commonly required for registration of new pharmaceuticals.

Antineoplastic Agents↗
PubMed1988

'Petite' mutagenesis by anticancer drugs in Saccharomyces cerevisiae.

The mitochondria of cancer cells are potential targets for chemotherapy. Drugs which primarily affect mitochondrial DNA can be screened using a 'petite' mutagenesis assay in Saccharomyces cerevisiae. We have used this approach to estimate the antimitochondrial effects of a range of current clinical and experimental antitumour drugs with varying modes of action. Of agents currently in the clinic, the antimetabolites 5-fluorouracil and methotrexate were extremely effective in inducing this respiratory defect, providing cells were growing during treatment. Adriamycin, BCNU, bleomycin, methyl CCNU, cis-platinum, chlorambucil, daunomycin, nitracine, nitrogen mustard and hycanthone were also weakly effective 'petite' mutagens, in either growing or non-growing conditions. None of the currently used agents but some experimental drugs induced high numbers of 'petite' mutants during growing or non-growing conditions. To date, where such agents have been tested clinically, they have proved either ineffective or very toxic. It is possible that antimitochondrial effects on non-proliferating cellular tissues such as the heart might cause unacceptable toxicity and preclude the clinical use of such agents. For those agents effective against proliferating cells, the mitochondria could be an important target for chemotherapy in some cell types. This type of drug appears relatively uncommon in the clinic at present. The 'petite' mutagenesis assay could be more widely used as a screen to optimize this property in development of analogues of current clinical agents, or in developing new types of anticancer drug.

Antineoplastic Agents↗
PubMed1988

Microbial mutagenicity of chlorambucil, its half-mustard and mitomycin C: a modified screening strategy for genetic toxicology of bis-alkylating anti-tumour drugs.

Early assessment of the genetic toxicology of anti-tumour drugs often employs microbial assays, particularly a group of specially developed Salmonella typhimurium strains (uvrB-) which are DNA repair-deficient due to a defective uvrB gene. While such strains are more sensitive than the wild-type to the mutagenic effects of many classes of compound, the DNA cross-linking agent chlorambucil (which is a known human carcinogen) has been shown to be toxic but non-mutagenic in this assay. The mutagenic activities of chlorambucil, its half-mustard analogue and another cross-linking agent (mitomycin C) were thus evaluated in a DNA-proficient strain of the yeast Saccharomyces cerevisiae and also in two isogenic sets of four S. typhimurium strains differing in uvrB gene and plasmid pKM101 presence. In yeast, all three compounds were effective mutagens and recombinogens, while in bacteria the two cross-linking agents were significantly mutagenic in the uvrB+ (DNA repair-proficient) but not in the uvrB- strains. By comparison, the half-mustard was mutagenic in both the uvrB- and uvrB+ strains. This work suggests that it is unwise to rely on results from the commonly used S. typhimurium bacterial strains for evaluating the mutagenicity of DNA cross-linking agents destined as clinical anti-tumour drugs. The use of yeast plus at least one of the sets of four strains employed in this study would provide information more directly relevant to mammalian cells, which are DNA repair-proficient. In addition, a comparison of the patterns of bacterial mutagenicity and toxicity provides evidence for the mode of action (DNA cross-linking or monoadduct formation) of compounds within a series.

Alkylating Agents↗
PubMed1987

Mutagenic, recombinogenic and antimitochondrial effects of nitracrine analogues in Saccharomyces cerevisiae.

The mutagenic and recombinogenic potential of 9-[(3-dimethylaminopropyl)amino]acridine and its 1-, 2-, 3- and 4-nitro derivatives was studied using 3 different strains of Saccharomyces cerevisiae. The parent compound slightly enhanced the frequency of total aberrant colonies in diploid strains D5 and D7, but showed no evidence of recombinogenic effects. Each of the nitroacridines enhanced the frequency of total aberrant colonies in strains D5 and D7, but only the 1- and 4-nitro compounds significantly enhanced mitotic crossing-over (measured as twin spotted colonies in strains D5 and D7) or gene conversion in D7. The 3- and 4-nitro derivatives were effective mitochondrial mutagens, substantially increasing the frequency of 'petite' mutants in strains D5 and 5178B.

Aminoacridines↗
PubMed1987

Mutagenicity of nitracrine analogues in Salmonella typhimurium: mutational specificity and activation by bacterial enzymes and rat-liver S9.

The mutagenic potential of 9-[(3-dimethylaminopropyl)amino]-acridine and its 1-(nitracrine), 2-, 3- and 4-nitro derivatives was studied in several strains of Salmonella typhimurium, using a plate-incorporation assay. In view of the potential importance of DNA binding and nitro group reduction, binding constants and redox potentials were determined. The parent compound was mutagenic only in the frameshift tester strain TA1537, and this effect was not enhanced by the plasmid pKM101. Each of the nitroarenes showed significant activity in S. typhimurium strains TA1537 and TA1538, and this mutagenicity was enhanced by the presence of plasmid pKM101. All caused reversion of the base-pair substitution allele in hisG46 in strain TA100 and this effect was either largely or totally dependent upon the plasmid. The frameshift mutagenic effects of the 3-nitro and 4-nitro compounds appeared to be little dependent upon the classical nitroreductase which is deficient in strain TA98NR, or transacetylase enzyme lacking in strain TA98/1,8-DNP6, whereas the activity of the 1-nitro compound depended partly on that nitroreductase enzyme, and that of the 2-nitro compound on having both activities present. In the latter two cases, the mutagenic effects of the compounds could not be restored by the addition of an S9 mix of mammalian enzymes. Mutagenicity data were compared with physicochemical parameters. The results do not distinguish between the view that the orientation of the nitro group with respect to the aromatic plane dictates mutagenic potential, and the earlier view that the nitro group redox potential is important. However, the extraordinary mutagenic potency of the 1-NO2 derivative is not explainable by its physicochemical properties alone.

Aminoacridines↗