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L R Ferguson

Publications and source records attributed to L R Ferguson.

At least 127 records · Page 7Linked to original sources
PubMed1987

Frameshift mutagenesis by nitracrine analogues in wild-type, uvrB, polA and recA strains of Salmonella typhimurium, with and without plasmid pKM101.

The mutagenic potential of 9-[(3-dimethylaminopropyl)amino]-acridine and its 1-, 2-, 3- and 4-nitro derivatives was studied in several strains of Salmonella typhimurium carrying the frameshift marker hisC3076. The strains all carried deep rough (rfa) mutations, and were either wild-type with respect to DNA repair capacity or carried recA, uvrB, polA1 or polA3 (amber) mutations. Derivatives with and without plasmid pKM101 were also studied. The des-nitro compound resembled 9 aminoacridine and other simple intercalating compounds. Both toxicity and mutagenesis were apparently unaffected by the uvrB and recA mutations or by the presence of plasmid pKM101. However, mutagenicity was reduced by the polA1 mutation, and virtually eliminated by the polA3 mutation. The drug was substantially more toxic in the latter, slightly more toxic in the former, of these polA- strains. Plasmid pKM101 enhanced mutagenesis and protected from toxicity in both polA1- and polA3- strains, although it did not restore either of these parameters to the level in the wild-type strain. The 2-nitro compound was generally similar to the des-nitro compound, except that it was considerably more toxic and apparently non-mutagenic in the recA-bearing strain. By contrast, mutagenicity of the 3- and 4-nitro compounds was enhanced by the uvrB mutation and by the presence of the plasmid. These compounds were highly toxic but non-mutagenic in the recA- strain, and showed some increased toxicity in polA1- and polA3- strains. The 1-nitro compound has been previously found to cross-link DNA. Unlike well-characterised cross-linkers such as mitomycin C it was highly mutagenic in the uvrB- strain, and this mutagenesis was enhanced by plasmid pKM101, but eliminated by the recA mutation. At high doses, where the drug was completely toxic towards uvrB- or recA-carrying strains, it became mutagenic in the DNA-repair-proficient strains. This 'high-dose' mutagenesis was enhanced by plasmid pKM101, but reduced by the polA1 mutation and almost eliminated by the polA3 mutation. Although there are several possible interpretations of these data, they are compatible with the suggestion that the lesion induced by high doses (but not by low doses) of nitracrine is a cross-link, but that this is not the major mutagenic lesion.

Aminoacridines↗
PubMed1987

Anaerobic incubation and mutagenicity of nitracrine analogues in Salmonella typhimurium.

Nitracrine [1-nitro-9-(dimethylaminopropylamino)-acridine] is a clinical antitumour agent with hypoxia-selective cytotoxicity and radiosensitizing activity. Developments in tumour therapy using either nitracrine itself or some of its analogues under development are likely to be targeted at anaerobic regions of tumours. We have investigated the effects of anaerobiosis on mutagenic activity of nitracrine and a small series of analogues in three derivatives of Salmonella typhimurium frameshift strain hisC3076. Nitracrine-induced mutagenicity was apparently enhanced by a period of anaerobic incubation followed by an aerobic period, with maximal mutagenic effectiveness (as revertants/nmol) being seen at 24 h anaerobiosis. However, the maximal number of nitracrine-induced revertants was not increased by anaerobic incubation, and the relationship between mutagenicity and toxicity remained similar. Comparisons of the effects of anaerobiosis on mutagenicity of bacterial strains with different DNA repair capacities suggested that anaerobiosis was not simply depressing 'SOS' repair. Comparisons of nitracrine with four of its analogues showed that this effect was not a universal characteristic of either acridine derivatives or of nitracrine analogues. Rather, the dose displacements obtained paralleled hypoxic cell selective cytotoxicity in mammalian cells. If this result extends to other compounds, experiments of this nature using the bacterial strains could provide a novel and useful screening system to identify hypoxia-selective cytotoxic anticancer drugs of potential clinical value.

Aminoacridines↗
PubMed1986

Morphological transformation and chromosome damage by amsacrine in C3H/10T1/2 clone 8 cells.

Morphological transformation, cell survival, chromosomal aberrations and micronuclei were measured in C3H/101/2CL8 cells after 24 h exposure to amsacrine. A weak but dose-related increase in the percentage of dishes containing transformed foci occurred. As previously reported for alkylating agents, this effect was increased by treating 5 days instead of 1 day after plating. There was no evidence for gene mutation at the Na/K ATPase locus, although amsacrine induced micronuclei in a large percentage of cells and chromosomal aberrations, including interchange events and double minute chromosomes, in dividing cells. In would appear that transformation and chromosomal events may be related in amsacrine-treated C3H/10T1/2CL8 cells. The results strongly suggest that amsacrine has carcinogenic potential, possibly related to its chromosome-breaking properties.

Aminoacridines↗
PubMed1985

Inverse correlation between bacterial frameshift mutagenicity and yeast mitochondrial effects of antitumour anilinoacridines.

The mutagenicity of a series of derivatives of 9-anilinoacridine, including the clinical antitumour agent amsacrine, has been assessed using a bacterial frameshift tester strain (Salmonella typhimurium TA1537) and a yeast petite colony assay (Saccharomyces cerevisiae 5178B). The results have been compared with microbial mammalian cell cytotoxicity, DNA binding affinity and acridine base strength (pKa). Compounds containing strong electron donor substituents on the acridine ring, and which have a high acridine pKa, show minimal frameshift mutagenicity but are strong inducers of petite yeast mutants. Conversely, some compounds which have a high DNA binding constant but a significant proportion of uncharged form at neutral pH, show high frameshift mutagenicity but minimal induction of petite mutants. It is hypothesised that this inverse relationship arises from the presence of trans-membrane drug transport mechanisms which act to exclude some compounds, particularly strongly basic compounds from the cytoplasm and to concentrate them in mitochondria.

Aminoacridines↗
PubMed1985

Three consistent patterns of response to substituted acridines in a variety of bacterial tester strains used for mutagenicity testing.

91 substituted acridines were tested for mutagenicity in 1 strain of Escherichia coli (TA78) and 4 strains of Salmonella typhimurium (TA90, TA1537, TA98 and TA100). In general, compounds fall into 3 groups: (i) inactive in all strains, (ii) active in TA78, TA90 and TA1537, or (iii) active in TA98 and often one or more of the other frameshift strains. Compounds of class iii have previously been shown to differ from the others in causing excisible damage to DNA and in showing an enhanced mutagenic response when the plasmid pKM101 is present.

Acridines↗
PubMed1985

DNA-damaging activity in ethanol-soluble fractions of feces from New Zealand groups at varying risks of colorectal cancer.

Using repair-proficient and repair-deficient strains of E. coli, we investigated the application of a liquid incubation assay to measure the DNA-damaging activity of ethanol-soluble fecal extracts. This method appears to be suitable for the study of a wide range of sample types. It was used to measure the DNA-modifying activity of ethanol-soluble fecal extracts from a group of European colorectal cancer patients. Data were compared with those from Europeans of similar age and sex distribution who did not have bowel cancer. We also studied groups of Maoris, Samoans, and European Seventh-Day Adventists who followed an ovo-lacto vegetarian diet. There are significant levels of DNA-modifying materials in the feces of many Europeans on a mixed diet, regardless of whether or not they have cancer. The number of positive samples was less in the Polynesian groups, and there were no samples that could be unequivocally scored as positive in the Seventh-Day Adventist groups. We conclude that diet can significantly reduce the level of ethanol-soluble mutagens, at least in New Zealand Europeans. The data may provide an explanation for the reduced incidence of bowel cancer in Seventh-Day Adventist groups.

Adult↗
PubMed1984

Quantitation of free and conjugated bile acids in human feces using a high-pressure liquid chromatography counterion method.

A method has been developed for extraction and purification of the major bile acids in human feces, and for their quantitative estimation using high-pressure liquid chromatography. Freeze-dried fecal material was extracted with alkaline ethanol and, after removal of neutral steroids, was subjected to thin-layer chromatography, followed by reversed-phase C18 silica cartridge (Sep-Pak) purification. The mixture was further separated into free, and glyco and tauro conjugates by ion-exchange chromatography. Subsequent resolution of individual bile acids was accomplished by HPLC using a counterion pairing method.

Bile Acids and Salts↗
PubMed1984

Apparent changes in structure-activity relationships for antimitochondrial effects of 9-anilinoacridines according to Saccharomyces cerevisiae strain and methodology.

Sensitivity of detection of antimitochondrial effects in S. cerevisiae as measured by the induction of 'petite' mutants, has been investigated in a closely related series of 9-anilinoacridines, using a new microtitre test which has been compared to a range of other techniques. Drugs were chosen to span antimitochondrial activity between the inactive compounds 9-amino- or 3-amino-acridine and the moderately active proflavine, also between proflavine and the strong antimitochondrial agent, ethidium bromide. As previously reported using other techniques, no compound without an amino substituent caused antimitochondrial effects, whereas all 9 anilinoacridines with a 1'-substituted anilino group and 3,6-diamino-substituted acridine ring acted like ethidium in causing strong 'petite' mutagenesis. Compounds with a single acridine 3-amino group, together with proflavine, might or might not be scored as an antimitochondrial agent depending on the time and conditions of drug exposure and, more importantly, on the selection of yeast strain used in the screening. Measurement of 'petite' mutagenesis in strain 5178B, using the microtitre assay, provided the most sensitive and efficient means of detection of antimitochondrial effects for all physical DNA-binding agents. Detailed interpretation of structure-activity relationships and prediction of carcinogenic activity based upon induction of 'petite' mutagenesis would vary considerably if this procedure is not followed.

Aminacrine↗
PubMed1984

Frameshift mutagenesis by acridines in wild-type, uvrB and polA strains of Salmonella typhimurium with and without plasmid pKM101.

A large range of acridines, including several anilinoacridines which are active as antitumour agents, have been studied for their ability to revert derivatives of Salmonella typhimurium strains carrying the frameshift marker hisC3076. The strains used all carried deep-rough (rfa) mutations, and were either wild-type with respect to DNA-repair capacity or carried uvrB, polA1 or polA3 (amber) mutations. Derivatives with and without the mutation-enhancing N group plasmid pKM101 were also used. 9-Aminoacridine and other acridines appeared similar to the anilinoacridines for the most part, in that frameshift mutagenesis and toxicity appeared to be unaffected by the uvrB mutation or by the presence of plasmid pKM101. Exceptions were ICR191, 3-NO2-acridine and 1- or 3-NO2-anilinoacridine derivatives in which mutagenesis was increased in uvrB strains and also when pKM101 was present. These compounds were slightly more toxic in the uvrB background, but less toxic when pKM101 was present in either the uvrB or wild-type backgrounds. Mutagenesis by most compounds was reduced by the polA1 mutation and virtually eliminated (except in the case of ICR191) by the polA3 mutation. Plasmid pKM101 occasionally enhanced mutagenesis in the polA1 strain, whereas in the polA3 it appeared to have no effect whatsoever. Again, there were no obvious differences in toxicity between Pol+ and Pol- strains.

Acridines↗
PubMed1984

Mitotic aneuploidy as a possible mechanism for tumour promoting activity in bile acids.

A range of conjugated and free bile acids were assayed for their ability to induce a variety of genetic endpoints in growing cells of yeast. None of the bile acids showed any activity in assays for the induction of mitotic crossing-over and mutation whereas the free bile acids lithocholic, chenodeoxycholic, deoxycholic and cholic acid were potent inducers of mitotic chromosome aneuploidy. In contrast, both conjugated bile acids, taurodeoxycholic and glycodeoxycholic lacked the ability to induce mitotic aneuploidy. When the potency of the free bile acids were compared, lithocholic and chenodeoxycholic acids showed higher levels of induction of mitotic aneuploidy per lethal event compared with cholic and deoxycholic acids. In view of the previously observed correlation between the ability of a chemical to induce chromosome aneuploidy and tumour promotional activity, the results indicate that the levels of free bile acids in the colon may be significant factors in the etiology of colonic cancer.

Aneuploidy↗
PubMed1984

Relationship between the induction of chromosome damage and cytotoxicity for amsacrine and congeners.

The antitumor drug amsacrine causes chromosomal aberrations both in cultured cells (L1210 murine leukemia and HeLa cells) and in vivo (L1210 leukemia). The proportions of different types of aberrations, mainly chromatid gaps, chromatid exchanges, and acentric chromosome fragments, are similar in both the in vivo and in vitro experiments. A small proportion of cells, particularly after drug exposure for 24 hours, show extensively damaged or pulverized chromosomes. In in vitro experiments using HeLa cells and amsacrine together with two analogs of amsacrine with differing cytotoxic activity, an inverse relationship between the frequency of chromosomal aberrations and cell survival has been demonstrated. The results are consistent with the proposal that for this class of drugs, the induction of chromosomal aberrations, both in vivo and in vitro, leads to cell death.

Aminoacridines↗
PubMed1984

Comparison of the mutagenic and clastogenic activity of amsacrine and other DNA-intercalating drugs in cultured V79 Chinese hamster cells.

The acridine derivative amsacrine (m-AMSA) is used clinically for the treatment of acute leukemias. The mutagenic activity of this drug has been evaluated at the 6-thioguanine (6-TG) and ouabain resistance loci in cultured Chinese hamster fibroblasts (V79-171b cell line). m-AMSA was found to have weak but significant mutagenic activity at the 6-TG but not at the ouabain resistance locus, after either 1- or 45-hr exposures at concentrations causing up to 90% cell kill. Two other intercalating agents with antitumor activity, Adriamycin and actinomycin D, provided essentially identical results. All three drugs were potent inducers of micronuclei in V79-171b cells, indicating high clastogenic activity. For these intercalating agents, the yield of 6-TG-resistant mutants was approximately 100-fold lower than that for ethyl methanesulfonate after exposures causing equivalent toxicity or equivalent chromosome breakage. The acridine half-mustard ICR-191 resembled ethyl methanesulfonate rather than the other intercalating agents in providing a high yield of 6-TG-resistant mutants relative to its clastogenic activity. The tumor-inactive intercalator 9-aminoacridine demonstrated only low clastogenic activity with a lack of significant mutagenic activity at toxic concentrations. These results suggest that, for m-AMSA, Adriamycin, and actinomycin D, both cell killing and mutagenesis could be direct consequences of chromosome breakage, while 9-aminoacridine may kill cells by a different mechanism. In view of its mutagenic and clastogenic activity at clinically achievable exposures and the similarity of its genotoxic properties to Adriamycin, m-AMSA should be considered a potential carcinogen.

Aminoacridines↗
PubMed1983

Induction of petite mutants in yeast by non-intercalative DNA-binding antitumour agents.

A series of 17 bis-charged non-intercalative DNA-binding antitumour agents and 7 related inactive compounds have been tested for the induction of respiratory deficient (petite) mutants in Saccharomyces cerevisiae D5. Many compounds were strong inducers of petite mutants at concentrations which were not toxic to the growth of the yeast cells. Mutagenicity is only weakly correlated with in vitro inhibition of L1210 cell growth; however, mutagenicity, yeast toxicity and in vitro and in vivo antitumour activity are all correlated with selective binding to polydeoxy(adenylic-thymidylic) acid rather than polydeoxy(guanylic-cytidylic) acid, as measured by an ethidium competition assay. It is concluded that A-T-rich DNA may be a target for all the biological effects measured in this study. Furthermore, the possibility that the target for antitumour action may be tumour cell mitochondrial DNA is supported by these results.

Animals↗
PubMed1983

Carotid plaques and retinal emboli: a clinical, angiographic and morphological study.

The angiographic criteria for the significance of a carotid lesion and the contribution of embolic versus haemodynamic factors in stroke pathogenesis are currently unresolved. This study evaluated correlations between the clinical features, presence of retinal emboli, angiographic appearance of the carotid bifurcation and morphology of the surgically excised plaque in 32 consecutive patients with symptomatic carotid lesions. Retinal emboli were found in 22% of patients, including some without a history of amaurosis fugax. The carotid plaques were complicated by ulceration, intraplaque haemorrhage and/or intraluminal debris in 91% of cases. The degree of carotid stenosis seen at operation correlated well with the angiographic estimate. Plaque complications could not be accurately predicted angiographically, however. The high frequency of plaque complications, and the presence of retinal emboli, suggested that embolisation was the likely pathogenetic mechanism of stroke in most of these patients.

Arteriosclerosis↗
PubMed1982

DNA binding and growth inhibitory properties of a series of 2,7-di-alkyl-substituted derivatives of proflavine.

Proflavine (3,6-diaminoacridine) and its 2,7-dimethyl, 2,7-diethyl, 2,7-diisopropyl and 2,7 di-t-butyl derivatives have been compared with respect to their DNA binding and biological properties. The binding of the first three members of the series to covalently closed circular duplex DNA showed the unwinding properties expected of intercalators. The 2,7-diisopropyl showed intermediate properties and the 2,7-di-t-butyl derivative failed to unwind this DNA. Antibacterial toxicity, measured in cultures of Salmonella typhimurium, increased with increasing lipophilic character of the compounds. Mutagenicity in the TA1537 frameshift tester strain was restricted to the first two members of the series, although the mutagenicity of the more lipophilic members may have been masked by toxicity. In contrast, toxicity towards cultures of L1210 cells showed a possible transition between intercalating and non-intercalating derivatives. It is proposed that DNA intercalation provides the major component of the toxicity towards cultured leukaemia cells, whereas lipophilicity provides the major component towards bacteria.

Acridines↗