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L R Ferguson

Publications and source records attributed to L R Ferguson.

At least 55 records · Page 3Linked to original sources
PubMed1997

In vivo effects of chlorophyllin on the antitumour agent cyclophosphamide.

Cyclophosphamide (CP) is a potent antitumour agent used against many forms of cancer and against certain other diseases. Chlorophyllin (CHL), which is obtained by hydrolysis of chlorophyll to remove phytyl alcohol, is an efficient antimutagenic agent and has been used as a dietary supplement or to diminish the intensity of the discomforting side effects of CP therapy. We undertook to determine the antimutagenic effectiveness of CHL against CP in a mouse model and to determine whether the antitumour efficacy of CP was compromised in vivo by CHL treatment. Experiments utilised CHL administered either in drinking water (1%) for 2 days before treatment, or by gavage (200 mg/kg) 2 hr before treatment with CP (220 mg/kg). Urinary mutagenicity following CP treatment, as determined by the Salmonella/microsome assay, was decreased by both regimes of CHL co-treatment. Similarly, the increase in micronuclei in bone marrow polychromatic erythrocytes in response to CP was reduced by concomitant CHL treatment. In contrast, antitumour efficacy, as determined by growth delay of Colon 38 adenocarcinomas, was not diminished by CHL treatment. We conclude that CHL may have beneficial effects when used in combination with CP therapy.

Animals↗
PubMed1997

Micronutrients, dietary questionnaires and cancer.

There is increasing evidence that many chemicals, although present in the diet at only low levels, play an important role in protection against cancer. Micronutrients are defined as nutrients present in the body in amounts less than 0.005% of body weight. Some micronutrients suggested to play a protective role in cancer are beta-carotene, vitamin E and vitamin C. In addition to those chemicals with an established role in nutrition, there is also a less well-defined group of chemicals, often referred to as phytochemicals, which may prove even more important. Examples here are a group of sulphur-containing chemicals present in brassicaceous vegetables, such as broccoli and cabbage, that appear to be very effective anticarcinogens. Epidemiology will be essential in accurately defining the role of phytochemicals and micronutrients in cancer. However, the large prospective studies that would be most desirable increasingly utilize food frequency questionnaires containing a limited number of questions. Such an approach has been well validated for macronutrients. However, there is often less accurate information available on micronutrients and phytochemicals, and the food combinations necessary (and acceptable) for macronutrients may be inappropriate for these other factors. It would be most desirable that fruits and vegetables are individually itemized or grouped according to plant families rather than macronutrient status. This may be the most appropriate way of identifying potentially novel protective factors in the diets of countries such as Morocco or New Zealand.

Anticarcinogenic Agents↗
PubMed1996

The clinical use of mutagenic anticancer drugs.

Cytotoxic chemotherapy is routinely used in the treatment of cancer, and has been an important factor in increasing 5-year survival rates for some types of this disease. A range of drugs are currently available, with differing modes of action. As well as causing some direct toxic effects, most if not all of these drugs are both mutagenic and carcinogenic. Although comparative information on these properties is generally available for anticancer drugs which alkylate DNA, it has been less readily accessible for other drug classes. This special issue contains seven reviews on the mutagenic properties of the major classes of cytotoxic drugs in clinical use, as well as one on a class of drugs that is under development. Some carcinogenicity data are also summarised, where available. Additionally, there are four more general papers, including one on the use of genetic activity profiles for comparing mutagenicity of the drugs, two on germ-cell effects, and one on biomonitoring for exposure to genotoxic anticancer drugs.

Adolescent↗
PubMed1996

Mutagenic and carcinogenic properties of platinum-based anticancer drugs.

Cisplatin (DDP) is currently one of the most effective drugs for the treatment of cancer. It causes primarily intrastrand DNA-DNA cross-links, and is highly mutagenic and carcinogenic in both in vitro and in vivo experimental models. There is, however, considerable variability between the response seen in different cellular systems, probably at least partly because of the different cellular DNA repair capacities. A number of analogues of cisplatin have been developed and one of these, carboplatin (CDDCA), is also in widespread clinical use. Although it is somewhat less toxic, there is no evidence that its mode of action differs from that of cisplatin. A limited amount of mutagenicity data suggests that it has similar mutagenic and carcinogenic consequences as the parent drug. Many further analogues of cisplatin are now in clinical trials, and some of these appear to have different DNA repair responses (and therefore possibly the development of clinical resistance). Although some (e.g., iproplatin and spiroplatin) are less mutagenic than either cisplatin or carboplatin, these appear to be the ones least likely to achieve wide use. There are insufficient data on several of the most promising clinical analogues (e.g., DWA2114R and ACDDP) to judge their relative mutagenic and carcinogenic potential. Detailed studies on the DNA repair and mutagenicity characteristics of these compounds will not only provide clinically relevant data, but may also aid in the selection of further useful antitumour agents in this series.

Animals↗
PubMed1996

Mutagenicity of anticancer drugs that inhibit topoisomerase enzymes.

Topoisomerases are enzymes that catalyse the transient breakage and rejoining of either one (topo I) or two (topo II) DNA strands, to allow one strand to pass through another and prevent unresolvable tangles during processes such as DNA replication. A number of important clinical antitumour agents act through inhibition of topo II enzymes, while some topo I inhibitors appear likely to enter clinical use. Although these chemicals do not covalently interact with DNA, they have strong mutagenic potential, generally causing events at the level of the chromosome rather than that of the gene. Most are recombinogens, may affect gene expression and can also lead to aneuploidy through effects on chromosome segregation. Most topo I and topo II inhibitors primarily cause mutagenic events associated with the replication fork. However, at least in mitotic chromosomes, topo II enzymes are located at the base of chromosome loops, and topo II inhibitors may facilitate subunit exchanges, leading to major deletions and illegitimate recombinational events. There is evidence that programmed cell death provides an alternative pathway to mutagenesis following treatment by either topo I or topo II inhibitors. The final fate of the cell will result from a balance between these two processes.

Animals↗
PubMed1996

The adsorption of heterocyclic aromatic amines by model dietary fibres with contrasting compositions.

It is often recommended that consumption of dietary fibre should in increased to protect against colorectal cancer. However, although more than 95% of dietary fibre is contributed by whole plant cell walls, very little experimental work has been done using whole plant cell walls. These may protect by adsorbing carcinogens, thus lowering their effective concentration in the alimentary tract, and by carrying the carcinogens out of the body in the faeces. However, plant cell walls vary widely in their composition and physical properties, and not all cell walls will necessarily have protective properties. We therefore isolated 4 plant cell-wall preparations with contrasting compositions as models of the types of cell walls that occur in the diet. We investigated the abilities of these preparations to adsorb in vitro 6 heterocyclic aromatic amines (HAAs). HAAs occur in the human diet and several are colon carcinogens, at least in rats. We found that the ability of the HAAs to adsorb to the plant cell walls increased with increasing hydrophobicity of the HAA, measured as the calculated logarithm of the partition coefficient between 1-octanol and water (C logP). A cell-wall preparation containing mainly the walls of parenchyma cells (the most common cell type in food plants) had only poor adsorptive ability. A cell-wall preparation from commercial cork had the best adsorptive ability. This preparation was the most hydrophobic of those examined because the cell walls contained the polymer, suberin, together with associated waxes. The preparation modelled suberized cell walls which occur in the diet, for example in potato skins. The other two cell-wall preparations contained another hydrophobic polymer, lignin, and had intermediate adsorptive abilities which were not significantly different from one another. These preparations modelled lignified cell walls which occur in the diet, for example in wheat bran. Our results indicate that suberized and lignified cell walls may be important in protecting against colorectal cancer.

Adsorption↗
PubMed1996

Studies on the role of specific dietary fibres in protection against colorectal cancer.

Although dietary fibre is generally thought to protect against the development of colorectal cancer, some of the results of animal and epidemiological studies are equivocal. We believe that this may be because the term dietary fibre covers a range of complex materials and some may protect but others may not. Dietary fibre is mainly composed of plant cell walls which vary in composition and properties according cell type and plant species. In addition to polysaccharides, the walls of some plant cell types contain the hydrophobic polymers lignin or suberin. Two groups of mechanisms have been proposed for the way dietary fibres may protect against colorectal cancer: those in which the dietary fibre may act directly and those in which the dietary fibre may have an indirect effect as a consequence of it being degraded by colonic bacterial enzymes and the products fermented. Direct mechanisms include the adsorption of carcinogens onto undegraded dietary fibres which pass out of the intestinal tract in the faeces. we have shown that different types of plant cell walls adsorbed a range of carcinogens, including heterocyclic aromatic amines, to different extents. Cell walls that contained lignin or suberin adsorbed hydrophobic carcinogens particularly well. Furthermore, the presence of lignin, and probably suberin, in the walls makes them resistant to degradation in the colon. Wheat bran, which is a good source of dietary fibre, contains some cell types with lignified walls. We used Fischer-344 rats to test the ability of wheat bran to protect against the formation of aberrant crypts (which are considered to be precursors to colon cancer) caused by the heterocyclic aromatic amine, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). Our results indicate that wheat bran protects and probably does so by a direct mechanism.

Adsorption↗
PubMed1996

Application of fluorescence in situ hybridisation to study the relationship between cytotoxicity, chromosome aberrations, and changes in chromosome number after treatment with the topoisomerase II inhibitor amsacrine.

Amsacrine (4'-(9-acridinylamino)methanesulphon-m-anisidide) is an antileukemic drug which inhibits topoisomerase II (topo II) enzymes. We studied effects of two concentrations of amsacrine on the GM10115A cell line. This is a Chinese hamster line containing a single human chromosome 4, which can be readily visualised using fluorescence in situ hybridisation (FISH). The low amsacrine concentration slowed cell growth but did not cause significant arrest in the G2 phase of the cell cycle, while a higher concentration caused more long-term effects on the growth of the cells and caused G2 arrest. Either concentration led to chromosomal fragments which were lost with increasing time after treatment, and chromosomal translocations which appeared stable for at least 8 days after treatment. At the low concentration, the loss or gain of a single chromosome was a common event. The higher concentration led to polyploid cells, usually containing an uneven number of chromosome 4. We propose two mechanisms for aneuploidy by amsacrine (or related topo II poisons), either of which can be readily detected using FISH. At low drug concentrations, aneuploidy may occur directly through, for example, a failure to resolve catenated chromatids prior to anaphase. However, there has been considerable interest in the role of the cell division control (cdc) kinase and cyclins in regulating the mammalian cell cycle, and these may also be involved in the response of cells to high concentrations of topo II poisons. Cdc2 proteins and cyclins are involved in coordinating diverse activities during the M phase of the cell cycle, including catalysis of chromosome condensation and reorganisation of microtubules to allow chromosome separation during mitosis. Chromosome damage by topo II poisons will lead to G2 arrest, which allows the cells time to repair the damage. During this time, cyclin A and cdc2 levels will fall, preventing the cell from entering mitosis and effectively resetting the clock to G1 and the ploidy to tetraploid. Aneuploid cells will derive from polyploid cells through loss of extra chromosomes.

Amsacrine↗
PubMed1996

Aneuploidy in germ cells: etiologies and risk factors.

A 2 1/2-day workshop on germ cell aneuploidy was convened September 11-13, 1995 at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina to discuss current understandings of the etiology and origin of human aneuploidy, especially in regard to potential environmental causes, and to identify gaps in our research knowledge. The workshop was designed to facilitate interactions among research experts conducting studies on the fundamental biology of chromosomal movement and segregation, on aneuploidy as a human clinical problem, and on toxicological aspects of aneuploidy induction. Overview presentations provided perspectives on aneuploidy as a human clinical problem, the genetics of aneuploidy, and the issues of concern in toxicological testing and regulatory risk assessment. The four chairs introduced the topics for each of their workgroups, setting the stage for subsequent, in-depth discussions on (1) chromosome mover components, (2) altered recombination, (3) parental age effects, and (4) differential chromosome susceptibility. From these discussions, gaps in our research knowledge related to the role of the environment in the etiology of aneuploidy and associated molecular, cellular, and genetic processes involved were identified, and will be used to establish a research agenda for filling those gaps.

Aneuploidy↗
PubMed1996

Meiotic recombination and germ cell aneuploidy.

Data on human trisomic conceptuses suggest that the extra chromosome commonly has a maternal origin, and the amount and position of crossing-over on nondisjoined chromosomes is commonly altered. These observations may provide important clues to the etiology of human germ cell aneuploidy, especially in regard to evaluating whether environmental factors play a role. There is concordance of effects of environmental agents on fungi, plants, and animals, which suggests that the overall process of meiosis is well conserved and that chemical and physical agents can affect meiotic recombination, leading to aneuploidy. It seems likely that meiosis in humans will fit the general pattern of meiosis in terms of sensitivity to radiation and chemicals. Thus studies on other organisms provide some insight into the procedures necessary for obtaining useful human data. For example, frequencies of spontaneous meiotic recombination are not uniform per physical length in Drosophila, and different regions of a chromosome respond differently to treatment. Treatments that relieve constraints on the distribution of meiotic exchange, without changing greatly the overall frequency of exchange, may increase the number of univalents and give the impression that there are chromosome-specific responses. Recombination studies that monitor one or a few relatively short genetic regions may also give a false impression of the effects of a treatment on recombination. In addition, meiotic mutants in Saccharomyces and Drosophila highlight a number of processes that are important for production of an exchange event and the utility of that event in the proper segregation of both homologues and sisters. They also suggest that tests for pairing at pachytene, chiasmata at diplotene, and genetic crossing-over may give different results.

Aneuploidy↗
PubMed1995

The effects of a soluble-fibre polysaccharide on the adsorption of carcinogens to insoluble dietary fibres.

Epidemiology and animal experiments indicate that dietary fibres protect against the development of colorectal cancer. However, insoluble dietary fibres appear to be more effective than soluble dietary fibres and one mechanism by which they may protect is by adsorbing dietary carcinogens. We found previously that the ability of a carcinogen to adsorb in vitro to alpha-cellulose (a model insoluble dietary fibre) was strongly related to the hydrophobicity of the carcinogen, measured as the calculated logarithm of the partition coefficient between 1-octanol and water (C log P). Furthermore, soluble dietary fibres (soluble-fibre polysaccharides), including gum arabic, reduced the adsorption of the hydrophobic carcinogen, DNP, to alpha-cellulose. In the present study we tested the ability of gum arabic to reduce the adsorption in vitro of the carcinogens BaP (C log P = 6.124), DNP (C log P = 4.384), and the heterocyclic amines, Trp-P-1 (C log P = 3.230) and MeIQx (C log P = 1.078). Gum arabic reduced the adsorption to alpha-cellulose of BaP and DNP, but not the adsorption of Trp-P-1 or MeIQx. Gum arabic also reduced the adsorption of BaP to an insoluble, dietary-fibre preparation from commercial cork which contains the hydrophobic component, suberin, but did not affect the adsorption of DNP, Trp-P-1 or MeIQx. It also did not affect the adsorption of DNP to an insoluble, dietary-fibre preparation from wheat straw, which contains the hydrophobic component, lignin. The results are discussed in terms of hydrophobic interactions between carcinogens and insoluble dietary fibres. In vivo, it is likely that soluble dietary fibres reduce the adsorption of only highly hydrophobic carcinogens to some insoluble dietary fibres.

1-Octanol↗
PubMed1995

Microbial mutagenic effects of the DNA minor groove binder pibenzimol (Hoechst 33258) and a series of mustard analogues.

A series of aniline mustards and half-mustards targeted to DNA by linkage (through a polymethylene chain) to the bisbenzimidazole chromophore of pibenzimol (Hoechst 33258) have been evaluated for their mutagenic properties, as estimated in three strains of Salmonella typhimurium, and for their mitotic crossing-over and petite mutagenesis activities in Saccharomyces cerevisiae strain D5. Agarose gel electrophoresis studies showed that only the derivative with the longest linker chain cross-linked DNA, with the remaining compounds being monoalkylators. The parent (non-alkylator) minor groove binding ligand (Hoechst 33258) was inactive in the bacterial strains TA98 or TA100 but weakly mutagenic in TA102, and caused neither mitotic crossing-over nor 'petite' mutagenesis in yeast. Aniline half-mustard itself (monoalkylator) was an effective base-pair substitution mutagen (events in S. typhimurium strain TA100) with some frameshift mutagenesis activity in TA98, but showed only weak effects in the yeast assays, whereas aniline mustard (cross-linker) was inactive in these bacterial systems but caused substantial amounts of mitotic crossing-over in yeast. The composite molecules studied here showed effects more characteristic of the minor groove binding chromophore than of alkylating moieties. All showed weak mutagenic activity in TA102 and none in TA98. The only compound to show significant mitotic crossing-over ability was the long-chain derivative which cross-linked DNA. For most of the compounds, the mutagenicity data provided no supportive evidence for DNA alkylation. Since other evidence suggests this does occur readily, it is likely to have a different target to that seen with untargeted aniline mustards. The significant antitumor activity and low mutagenic potential shown by these compounds make them worthy of further study.

Alkylating Agents↗
PubMed1995

Synthesis, DNA interactions and biological activity of DNA minor groove targeted polybenzamide-linked nitrogen mustards.

A series of polybenzamide DNA minor groove binding ligands bearing either one or two monofunctional mustards have been synthesised, and their cytotoxicities and interactions with DNA have been studied. Analogues with two alkylating functions (e.g. compounds 7 and 14) are the most cytotoxic, with 7 being 1000-fold more potent than the clinical mustard chlorambucil against P388 leukemia in culture, as well as being more potent in vivo. Monofunctional analogues were also significantly more cytotoxic than chlorambucil, despite bearing much less reactive mustard species. These results support the concept that targeting nitrogen mustard alkylating agents to DNA by attachment to DNA-affinic carriers can greatly enhance cytotoxicity due to alkylation, and that even for such DNA-targeted mustards, crosslinking is a more toxic event than monoalkylation. Close analogues of 7 differing only in their radius of curvature, appear to alkylate and crosslink DNA in similar fashion, yet have widely differing cytotoxicities. The most cytotoxic compound (7) possesses a geometry most complementary to that of duplex DNA, suggesting that the most toxic lesions are those which result in least DNA distortion, thus being less easily recognised by DNA repair systems.

Alkylation↗
PubMed1995

Differences in intake of specific food plants by Polynesians may explain their lower incidence of colorectal cancer compared with Europeans in New Zealand.

Epidemiological studies have implicated obesity; high intakes of alcohol, fat, and energy; and low intakes of food plants as risk factors for colorectal cancer. In New Zealand, Polynesians (including Maoris and people from several Pacific Islands) are more likely to be overweight and have higher intakes of fat and energy than Europeans, and they are likely to have similar total intakes of food plants. Yet, in New Zealand, Polynesians have a significantly lower incidence of colorectal cancer than the Europeans. It is possible that the difference in incidence of colorectal cancer is due to differences in consumption of specific food plants by Polynesians and Europeans in New Zealand. Here we have compared the consumption of specific food plants by 429 Maoris, 643 Pacific Islanders, and 4,451 Europeans in paid employment in New Zealand. Of the 51 food plants eaten by New Zealanders, 6 were eaten significantly more frequently and 17 significantly less frequently by the two Polynesian groups than by Europeans. The quantity of any protective chemical components (or other as yet unknown protective factors) in food plants is likely to be related to their botanical classification. Differences in the intake of specific food plants may at least partly explain differences in the incidence of colorectal cancer between Polynesians and Europeans.

Anticarcinogenic Agents↗
PubMed1995

Access to paid in-home assistance among disabled elderly people: do Latinos differ from non-Latino whites?

OBJECTIVES: The purpose of this study was to compare the national prevalences and predictors of paid in-home functional assistance among disabled Latino and non-Latino elderly people who receive such assistance. METHODS: Data were derived from the 1988 wave of the National Center for Health Statistics Longitudinal Study on Aging and the 1988 Commonwealth Fund Commission Survey of Elderly Hispanics. Logistic regression was used to model paid care use and to calculate estimated probabilities of such use. RESULTS: Among Latino and non-Latino Whites 74 years of age and older who received functional assistance, similar proportions used paid assistance. Predictors of paid care coincided with established models for non-Latino Whites only. Disabled Latinos had a lower estimated probability of using paid assistance when they were highly disabled and socially isolated but had a higher estimated probability when their children lived nearby. CONCLUSIONS: The effects of disability and social support differ among non-Latino White and Latino elderly people. Latino elderly people with high anticipated needs obtain less paid assistance than similar non-Latino Whites. In addition to a reduction in financial barriers, improving access to long-term care services requires addressing this diversity in service use patterns.

Activities of Daily Living↗
PubMed1994

Antimutagens as cancer chemopreventive agents in the diet.

It has been suggested that the use of antimutagens and anticarcinogens in everyday life will be the most effective procedure for preventing human cancer and genetic disease. There are several ways in which mutagenesis can be reduced or prevented. Chemicals which act to interfere with DNA repair or with mutagen metabolism can be effective antimutagens: however such compounds may also increase the probability of mutations by different chemicals or at different sites. In contrast, mutagen scavengers may be less prone to increase mutations by other chemicals. Selected examples illustrate that antimutagenic effects are often specific to certain classes of mutagen and/or certain test systems. Thus, if antimutagens are to have any impact on human disease, it is essential that they are specifically directed against the most common mutagens in daily life. On our current understanding, these are quite diverse in nature, so that combinations of antimutagens will probably be necessary. Two groups of mutagen scavengers (porphyrins and some types of dietary fibre) show some selectivity for large planar and hydrophobic types of carcinogen, which appear to be common in a normal Western diet. Increasing consumption of vitamins C and E, either through increased consumption of fruit and vegetables or through dietary supplementation might reduce formation of N-nitroso compounds, another common class of mutagens. Similarly, carotenoids and related compounds, already present at high quantities in some fruits and vegetables, have excellent antioxidant properties and should be able to counteract effects of endogenous metabolism and other events which generate oxidising species and free radicals. Still other types of antimutagen might be necessary to act against smaller non-planar carcinogens, but there is some question as to the importance of this type of carcinogen in a normal Western diet. It may be necessary to adjust the selection of antimutagens for different population groups, or as our understanding of mutagens in the diet develops further. Current assays for cancer chemoprevention in animals are unlikely to detect some important types of antimutagens, such as mutagen scavengers. A structured testing strategy is suggested, progressing from in vitro to in vivo antimutagenicity tests against a selected range of mutagens. Optimal use of antimutagens might be as a dietary supplement, additional to practical advice on increasing consumption of fruit and vegetables.

Animals↗
PubMed1994

Topoisomerase II enzymes and mutagenicity.

Topoisomerase II (topo II) enzymes maintain DNA structure by relieving torsional stress occurring in double-strand DNA during transcription and replication. Topo II causes transient breaks in both strands of DNA, allowing passage of one double helix through another, and probably acts as a structural protein in interphase cells, playing a role in the organisation of mitotic and meiotic chromosomes. A number of clinical anticancer drugs are thought to act on topo II enzymes to stabilise DNA-drug-topo II ternary complexes known as "cleavable complexes." These complexes may lead to illegitimate recombination events, as well as to the formation of other DNA lesions. Topo II-mediated genotoxicity is strongly dependent on the cell cycle status of the target cells. It is now apparent that some dietary components and environmental chemicals may act on topo II. Since the structural features of chemicals that lead to topo II interaction are not clear, it is currently not possible to predict such activity from chemical structure. For many years, the central dogma of chemical carcinogenesis has been that the most carcinogenic chemicals are those that can form a covalent bond with DNA, either directly or after metabolic activation. Topo II-directed drugs are not usually capable of forming covalent bonds with DNA and tend to have low mutagenicity in microbial assays. However, topo II-directed agents are potent cancerogens, inducing characteristic cytogenetic modifications. It is important to define the most sensitive tests to identify topo II-directed mutagens and to develop appropriate strategies for genotoxicity testing of such chemicals.

Animals↗