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L R Ferguson

Publications and source records attributed to L R Ferguson.

142 records · Page 8Linked to original sources
PubMed1981

The relationship between frameshift mutagenicity and DNA-binding affinity in a series of acridine-substituted derivatives of the experimental antitumour drug 4'-(9-acridinylamino)methanesulphonanilide (AMSA).

The mutagenicity of DNA-binding affinity of members of a series of acridine-substituted derivatives of 4'-(9-acridinylamino)methanesulphonanilide (AMSA) have been compared. The series includes compounds ranging from highly active to inactive in the L1210 murine leukaemia. Binding to DNA was measured by an ethidium displacement technique, with a correction being made for acridine-induced quenching of ethidium. Mutagenicity was assessed by measuring the reversion frequencies of the frameshift tester strain Salmonella typhimurium TA1537 in liquid culture. The results indicate that maximum mutagenicity is found in a "window" of DNA-binding affinities between 10(6) and 5 X 10(6) M-1 (determined at 0.01 ionic strength). Compounds with binding affinities below 10(6) M-1 generally lacked both antitumour and mutagenic activity, whereas those with affinities above 5 X 10(6) M-1 were active against L1210 leukaemia but virtually inactive in inducing frameshift mutations.

Aminacrine↗
PubMed1981

Induction of petite formation in Saccharomyces cerevisiae by experimental antitumour agents. Structure--activity relationships for 9-anilinoacridines.

A series of 9-anilinoacridine derivatives has been compared in terms of DNA binding, ability to inhibit the growth of L1210 murine leukaemia cells in vitro, and ability to induce the formation of respiration-deficient (petite) mutations in Saccharomyces cerevisiae. The acridine ring in the derivatives was either unsubstituted, or substituted with amino groups at the 3 and/or 6 positions. The 9-anilino group was para-substituted with a variety of substituents. 3-Aminoacridine, 3,6-diaminoacridine (proflavine) and ethidium were included for comparison. The results show that: (i) at least one acridinyl amino group is necessary for conferring petite inducing activity in the yeast system; (ii) for 3-amino-9-anilinoacridine congeners, small anilino substituents provide compounds which resemble proflavine in their ability to produce petite mutants, whereas large substituents abolish activity; (iii) the 3,6-diamino-substituted anilinoacridines resemble ethidium rather than proflavine in being highly efficient inducers of petites; (iv) the requirements for optimal activity in L1210 leukaemia cell cultures are different to those for petite formation in yeast. It is concluded that the size of the anilino substituent, as well as its contribution to DNA binding, is critical in conferring biological activity in each system.

Aminoacridines↗
PubMed1980

The role of dimer excision in liquid-holding recovery of UV-irradiated haploid yeast.

We have directly tested the theory that liquid-holding recovery is due to an increase in the efficiency of excision-repair during holding in non-growth conditions, by assaying the dimers present in UV-irradiated cells held in saline, in growth medium or first in saline then in growth medium. We observed no differences in the amount of excision in any conditions. By assaying the kinetics of excision and comparing that with the timing of DNA synthesis, we have tested the theory that holding in growth medium allows more repair by extending the time available for it. We found that the observations were more consistent with the onset of DNA synthesis being dependent on the amount of repair rather than the converse. We have analysed the role of repair in liquid-holding recovery in a series of split-dose experiments. As Parry and Parry found, yeast cells which have been irradiated and held in non-growth conditions were much more resistant to further UV-irradiation. The increase in resistance was proportional both to the degree of fractionation of the dose and to the size of the first dose. No effect was observed if this was below 30 J . m-2. We found that the cells were able to excise more of the dimers induced if the UV dose was fractionated. We have shown that part of this increase in efficiency of excision is due to the relief of "dimer interference". "Dimer interference" is the name given to the inhibition of excision of a dimer by the presence of a neighbouring dimer. Most of the increase in efficiency, however, was due to the induction of more efficient excision repair per se, that is the excision of a greater fraction of the dimers present than could be excised in uninduced cells. Among the incidental observations we have made which are new and likely to be of interest are (1) that stationary phase cells showed a lag in the onset of excision, but log phase cells did not; (2) that excision was nevertheless constitutive in that it occurred in the presence of concentrations of cycloheximide inhibitory to protein synthesis and (3) that caffeine affected but did not inhibit dimer excision.

Culture Media↗
PubMed1980

Potential antitumor agents. 33. Quantitative structure--activity relationships for mutagenic activity and antitumor activity of substituted 4'-(9-acridinylamino)methanesulfonanilide derivatives.

A series of substituted 4'-(9-acridinylamino)methanesulfonanilide (AMSA) derivatives have been tested for mutagenicity using Salmonella typhimurium strain TA 1537 and for antitumor activity against the L1210 leukemia in mice. Two measures of mutagenic activity were determined and quantitative structure--activity relationships (QSAR) developed for them. M50, the percentage of drug-induced mutant colonies observed at the concentration providing 50% inhibition of bacterial growth, is a measure of mutagenic efficiency. The lowest molar drug concentration (1/C) needed to induce a fixed proportion of revertants (chosen as 50 per 10(8) bacteria) is a measure of mutagenic effectiveness. The two measures of antitumor activity modeled were ILSmax (the percent increase in life span observed for each derivative at its LD10 dose), a measure of tumor cell selectivity, and 1/D40 (the dose of drug to provide an ILS of 40%), a measure of dose potency. These measures of bioactivity were intercompared and modeled in terms of a number of drug physicochemical properties. The results show that drug lipophilic/hydrophilic balance is the dominant factor in determining both mutagenic and antitumor activity, although other factors are involved. The two different types of activity can be readily separated in the AMSA drug series by appropriate choice of substituent and adjustment of overall drug lipophilic/hydrophilic balance.

Aminoacridines↗
PubMed1975

Spinal ischemia following abdominal aortic surgery.

Serious spinal cord ischemia may follow infrarenal abdominal aortic surgery. Five cases are summarized and added to the 23 previously published cases in order to identify this syndrome, emphasize its importance, and draw attention to the possibility of spontaneous recovery which may occur. The multifactorial complex which comprises each patient's clinical picture clouds a precise and specific cause for paraplegia in these cases. However, neither hypotension, steal phenomena nor emboli are necessary for completion of the syndrome. The relevant spinal cord arterial anatomy indicates that the common anomalies which occur favor development of spinal cord ischemia in the arteriosclerotic population which requires aortic surgery. No means of prevention is possible at this time.

Aged↗
PubMedDate not supplied

Condensed tannins induce micronuclei in cultured V79 Chinese hamster cells.

The tannins, delphinidin and procyanidin were isolated from flowers of white clover (Trifolium repens) and the leaves of Arnot Bristly Locust (Robina fertilis) respectively, and tested for mutagenic properties in a range of systems. There was no evidence for either compound causing significant levels of frameshift or base-pair mutagenesis in bacterial mutagenicity assays, although both were weakly positive in a bacterial DNA-repair test. Both compounds very slightly increased the frequency of petite mutagenesis in Saccharomyces cerevisiae strain D5. In V79 Chinese hamster cells, both were efficient inducers of micronuclei. In each of these test systems, increasing the potential of the compound for metabolic activation by addition of 'S9' mix had little effect on toxicity or mutagenicity of either tannin. It would seem that potential chromosome-breaking activity of condensed tannins could represent a carcinogenic hazard for animals grazing on pastures of white clover in flower. It may also have wider implications for human carcinogenesis by some, if not all, condensed tannins.

Animal Feed↗
PubMedDate not supplied

Chromosome damage by dothistromin in human peripheral blood lymphocyte cultures: a comparison with aflatoxin B1.

The clastogenic potential of the pine tree fungal toxin dothistromin was studied by metaphase chromosome analysis of stimulated human peripheral blood lymphocytes exposed in vitro. The frequency of gaps, breaks, deletions and exchanges was scored in a series of cultures from 3 different donors. 50 cells were analysed for each dose level on coded slides. Testing was performed with and without added metabolic activation (as S9 mix) and aflatoxin B1 was used as a positive control in all experiments. Dothistromin caused a dose-dependent increase in the frequency of gaps and deletions which was not dependent on added metabolic activation. Even at high doses of dothistromin only a very small number of complex exchange-type aberrations were seen. This is in contrast to aflatoxin B1 where such aberrations were seen at low dose levels and especially in cultures to which S9 mix was added. High doses of dothistromin caused culture toxicity manifesting as haemolysis of the donor red blood cells and reduction of mitotic index. Culture toxicity occurred without a marked increase in aberration frequency. This toxicity may be masking any major potential for clastogenicity by dothistromin.

Aflatoxin B1↗
PubMedDate not supplied

Verapamil as a co-mutagen in the Salmonella/mammalian microsome mutagenicity test.

Verapamil is a calcium-channel blocking agent, commonly used for chronic treatment of heart conditions. We have previously demonstrated that verapamil acts as a co-mutagen in a bacterial mutagenicity test for some experimental anilinoacridine antitumour drugs. Within the anilinoacridines series there are several compounds which are apparently non-mutagenic (or very weak mutagens) in the absence of verapamil, but strong mutagens in its presence. We have now tested a wider range of materials for verapamil enhancement of mutagenicity, to include some of those to which persons on verapamil therapy might be exposed through life-style or occupation. Some verapamil enhancement of mutagenicity was seen with most mutagenic compounds including anticancer drugs, antiparasitic agents, one biological stain and one hair dye. A number of tricyclic antidepressants and biological stains were tested and found to be non-mutagenic. If these results extrapolate to mammalian cells, long-term verapamil therapy could potentially increase the effects of certain environmental mutagens.

Drug Synergism↗
PubMedDate not supplied

Antimutagens in food plants eaten by Polynesians: micronutrients, phytochemicals and protection against bacterial mutagenicity of the heterocyclic amine 2-amino-3-methylimidazo[4,5-f]quinoline.

We have previously suggested that differences in cancer incidence between Polynesians (including Maoris and people from several Pacific islands) and Europeans in New Zealand may at least partially relate to differences in the species of food plants (fruits, vegetables and cereals) preferentially eaten by these groups. Twenty-five food plants that are typically eaten in different amounts by these two population groups were selected for detailed study. Antimutagenic properties of three extracts from each of the selected plants were investigated using a preincubation mutagenicity assay with Salmonella typhimurium strain TA1538 against the mutagenicity of the heterocyclic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). The data revealed strong antimutagenic properties in several of the food plants commonly eaten by Polynesians, especially rice, watercress, pawpaw, taro leaves, green banana and mango. Using the New Zealand food database, a number of nutrients and micronutrients with antimutagenic and anticarcinogenic potential were identified from the selected food plants. Some of these were tested for antimutagenic potential in parallel experiments to those done with the food plant extracts. Although some of these micronutrients are antimutagens against IQ, their concentrations in the food plants failed to explain the protection against mutagenicity found in the experiments with extracts of the food plants. Thus, other types of chemical, not identified in the database, must be leading to antimutagenesis. Possible active molecules include chlorophylls, carotenoids, flavonoids and coumarins, many of which are also known to be anticarcinogens. If human cancer data are to be interpreted in terms of cancer protection, these components need urgently to be quantified in food plants in the New Zealand diet, especially in those food plants eaten in large amounts by Polynesians.

Animals↗