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Biomedical subjects

L R Ferguson

Publications and source records attributed to L R Ferguson.

At least 37 records · Page 2Linked to original sources
PubMed2000

Role of DNA minor groove alkylation and DNA cross-linking in the cytotoxicity of polybenzamide mustards.

Interstrand DNA cross-links have been considered essential to the activity of current clinical DNA-alkylating antitumour drugs, which generally alkylate in the major groove. However, the relationship between cross-linking adducts located in the minor groove of DNA with cytotoxicity and antitumour activity has not been extensively investigated. Previous studies have shown that cross-linking ability is not correlated with cytotoxicity in a novel series of polybenzamide-linked nitrogen mustard compounds which alkylate DNA at adenines in the minor groove. In the present study the nature of these cross-linking adducts was explored for a related pair of compounds which are both highly effective cross-linkers but which differ in antitumour potential. Both of these drugs effectively interact with adenines in the minor groove, although their sequence specificity differs. However, the cross-linking event was not inhibited by pre-treatment with Hoechst 33258, although this pre-treatment effectively prevented adenine alkylation. The primary cross-links detected may thus represent guanine N7 alkylations in the major groove. Whether minor groove cross-linking adducts can be formed is uncertain, since the effect of background guanine N7 alkylation may complicate analysis. The cytotoxicity of the polybenzamides may therefore be related to other factors such as their interaction with cellular repair systems.

Adenine↗
PubMed1999

Heterocyclic amine content of cooked meat and risk of prostate cancer.

BACKGROUND: Some epidemiologic studies have described positive associations between prostate cancer risk and meat consumption, but underlying mechanisms have not been identified. Heterocyclic amines are mutagens formed during the cooking of meat. Well-done meat has been associated with increased risks of colorectal and breast cancers in humans. This study examined associations between prostate cancer risk and 1) estimated daily intake of heterocyclic amines from cooked meat and 2) level of cooked-meat doneness. METHODS: A population-based, case-control study involving 317 case patients with prostate cancer and 480 age-matched control subjects was carried out in Auckland, New Zealand. Levels of meat doneness and daily intake of heterocyclic amines were determined from self-reported dietary data and experimentally measured heterocyclic amine levels in locally sourced meat samples cooked under controlled conditions to varying degrees of doneness. RESULTS: The heterocyclic amines found in the highest concentrations in meat samples were 2-amino-1,6-dimethylfuro[3,2-e]imidazo[4,5-b]pyridine (IFP) and 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) from well-done chicken and pork and very well-done beefsteak. Meat doneness was weakly and inconsistently associated with prostate cancer risk for individual types of meat, but increased risk was observed for well-done beefsteak (relative risk = 1.68; 95% confidence interval = 1.02-2.77; two-sided P for trend =.03). A weak positive gradient of increased risk was associated with estimated daily exposure to IFP but not with the other major heterocyclic amines. CONCLUSIONS: Meat doneness and estimated intake of heterocyclic amines from cooked meat were not clearly associated with prostate cancer risk.

Adult↗
PubMed1999

Prospects for cancer prevention.

As in many other countries, the New Zealand Cancer Society produces guidelines for cancer prevention. These recommend avoiding asbestos, smoking, sunlight, alcohol, fatty food and obesity. Women are advised to have a regular cervical smear test. Additional 'probably helpful' suggestions include eating plenty of fresh fruit and vegetables and dietary fibre. However, considerable data from animal studies and more slowly accumulating data from human intervention studies suggest additional and more specific advice may be appropriate. Fruit and vegetable servings should total a minimum of five each day. Some specific fruits and vegetables (e.g., tomato, broccoli, onions) may have particular benefits against individual cancer types. Positive human evidence on potential benefits of increasing dietary fibre comes from studies where wheat bran was added to the diet. This is not a dietary fibre per se, but merely a good fibre source. Indeed, our own studies suggest that it could be various phytochemicals in the bran, rather than dietary fibre, which is beneficial. An increase either in whole wheat or wheat bran, rather than fibre, would be a sounder recommendation. Although there is some evidence that multivitamin supplementation can protect against cancer, this may be only in the special situation where the population is already significantly vitamin-deficient. For example, a combination of beta-carotene, vitamin E and selenium significantly reduced cancer mortality in a Chinese population, whereas lung cancer risks (in already high risk groups) were increased in Finnish and American trials with high dose beta-carotene. Various other chemopreventive drugs are being actively developed and at various stages in clinical trials. The enhanced cancer incidence in the beta-carotene trial illustrates the potential benefit of utilising surrogate endpoints of malignant disease rather than incident cancer as a trial endpoint.

Animals↗
PubMed1999

Dietary fibres may protect or enhance carcinogenesis.

Dietary fibre (DF) is widely considered to protect against cancer, especially colorectal cancer. However, a large prospective epidemiological study has shown no apparent effect of DF intake on the development of colorectal cancer. We suggest that this may be because the term DF represents a wide range of materials, some able to protect, but some able to enhance carcinogenesis. This is consistent with data from animal carcinogenesis experiments. Most of the DF in western diets is in the form of plant cell walls, but these vary in their composition and it is unlikely that all types are protective. The few data available indicate that plant cell walls containing suberin or lignin may be the most protective, although they are present in only small amounts in food plants. DFs are also added to foods. These include components obtained from plant cell walls, such as pectins, as well as soluble DFs from other sources. In general, animal carcinogenesis experiments indicate that soluble DFs do not protect and some may enhance carcinogenesis. Few human intervention studies have been done on DF or sources of DF, with the exception of wheat bran, a good source of DF, which has been shown to protect. Possible mechanisms whereby DF may enhance carcinogenesis are discussed. In addition to DFs, resistant starches and non-digestible oligosaccharides are added to foods; these, like DF, escape digestion in the small intestine. However, so far only a few animal carcinogenesis experiments have been reported using these materials, and no human intervention studies. We believe caution should be exercised in the addition of such materials to food.

Animals↗
PubMed1999

Natural and man-made mutagens and carcinogens in the human diet.

Around 40% of human cancers may relate to dietary factors, including both exogenous and endogenous mutagens. Of exogenous factors, alcohol, certain metals and certain pesticides (both naturally produced or manufactured by the chemical industry), N-nitroso compounds, heterocyclic amines and polycyclic aromatic hydrocarbons are all probable human carcinogens. Despite current negative publicity, genetic engineering appears to be a more precise process and no more likely to lead to cancer risks than conventional breeding processes. Many traditional assessments of cancer hazard from endogenous or exogenous chemicals ignore the presence of modifying factors in the human diet. For example, dietary fat and dietary fibre probably either enhance or protect against cancer, depending upon the exact amounts and chemical nature of the fat fibre. Considerable numbers of other types of antimutagen/anticarcinogens have been identified, with varying modes of action. Additionally, there is an interaction of dietary factors with genetics. Epidemiology will always be important in assessing relative risks, but it is essential to continue developing more sensitive biomonitoring methodologies. It would be desirable to compare precise measures of individual exposure to dietary carcinogens with levels of oxidative damage and evidence of genotoxic effects in a given tissue. Such experimental approaches might be expected to lead a better understanding of the interplay between different dietary factors and also between diet, hereditary and the environment.

Amines↗
PubMed1999

Studies on the mechanism of cancer protection by wheat bran: effects on the absorption, metabolism and excretion of the food carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ).

We examined ways in which dietary supplements of wheat bran may protect against colon cancer. The effects of supplementing the diet of female Wistar rats with 10% wheat bran on the disposition and metabolism of the dietary carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) labelled with (14)C was determined. Our data show that the wheat bran had a major effect on both the distribution and metabolism of IQ. At a low dose of IQ (1 mg/kg), we unexpectedly found that up to 2 h after gavage there were higher concentrations of radioactivity in the plasma of rats fed wheat bran compared with the controls, but there were lower concentrations of radioactivity after 2 h. At a high dose of IQ (50 mg/kg), there were always lower concentrations of radioactivity in the plasma of rats fed wheat bran compared with the control rats. One of the most marked effects of wheat bran was apparently to significantly retard the metabolism of IQ in the plasma when this was fed at either dose. There were also differences between the rats fed wheat bran and the control in the concentrations and types of IQ metabolites in the urine.

Animals↗
PubMed1999

Protection against cancer by wheat bran: role of dietary fibre and phytochemicals.

Human intervention and animal studies have shown that supplementing the diet with wheat bran can protect against the development of a range of cancers, especially those of the colon and breast. Wheat bran is a rich source of dietary fibres (plant cell walls) that have structures and compositions which indicate that they may protect against cancer. Nevertheless, dietary fibre makes up less than half of wheat bran. Other nutrients and phytochemicals are present in wheat bran, some of which may also protect against cancer. These include phytic acid and various phenolic components such as phenolic acids, lignans and flavonoids. A major goal of future research on wheat bran should be to determine the relative roles in cancer prevention of the different components in wheat bran.

Animals↗
PubMed1999

Polybenzamide mustards: structure-activity relationships for DNA sequence-specific alkylation.

A series of cytotoxic polybenzamide mustards targeted to the minor groove of DNA were used to define structure-activity relationships for sequence-specific DNA alkylation. Compounds with an annular structure closely matched to the minor groove of DNA, and with concave-facing, potentially H-bonding NH groups, had a strong preference for alkylating adenines in sequences possessing four or more consecutive adenines. Two compounds whose annular structure matched that of the minor groove better when at least one carboxamide NH group faced outwards showed a high specificity for the consensus sequence (A/T)A(G/C) (A/T)N. Several compounds also alkylated specific guanines, presumably at the N3 position. Modelling studies suggest the most important contribution to sequence-specific alkylation is the H-bonds formed between these compounds and DNA, with factors such as the degree and positioning of cationic charge being less influential.

Adenine↗
PubMed1998

Mutagenic properties of topoisomerase-targeted drugs.

Topoisomerases maintain DNA structure by relieving torsional stress occurring in DNA during transcription, replication and cell division. Topoisomerases are of two main types, causing transient breaks in one (type I) or both (type II) and strands of DNA, and a number of clinical anticancer drugs are thought to act by inhibiting religation of these transient breaks. Topoisomerase II appears to have a close association with the SMC (stable maintenance of chromosomes) family of proteins involved in organisation of the chromatin in a series of loops on the proteinaceous chromosomal scaffold. Inhibition of topoisomerase II function can result in deletions of such loops, probably mediated by reciprocal exchange of topoisomerase subunits. Disruption of topoisomerase I and/or II function during DNA replication results in smaller DNA deletions and other mutations, probably arising from non-homologous recombination. Inhibition of topoisomerase II action during mitosis and meiosis can cause incomplete separation of chromatids and chromosomes, with the consequent production of genomic mutations. Topoisomerase-mediated mutagenicity is important because it can lead not only to drug resistance but also to drug-induced secondary cancers. Mutagenicity of topoisomerase-directed agents has been underestimated in the past, since these drugs are not usually capable of reacting covalently with DNA and usually have low mutagenicity in microbial assays.

Antineoplastic Agents↗
PubMed1998

Suberized plant cell walls suppress formation of heterocyclic amine-induced aberrant crypts in a rat model.

Dietary fibre is believed to protect against a range of Western diseases, including colorectal cancer. Whole plant cell walls make up most of the dietary fibre in Western diets, but their role in disease protection has rarely been studied. At least in vitro, suberized plant cell walls possess novel properties that suggest they could have exceptional potential for cancer protection. Our aim was to test in a rat model the abilities of suberized cell walls from potato skins and commercial cork to decrease gastrointestinal transit time and to protect against the development of aberrant crypts, an early marker of colon cancer. Groups of six rats were fed a modified AIN-76 diet as the control diet and this diet supplemented with 5% dietary fibre from the following sources: commercial cork, commercial-cork cell walls and potato-skin cell walls. A diet supplemented with wheat bran was used as a positive control. The colon carcinogen IQ (2-amino-3-methylimidazo[4,5-f]quinoline) was administered for 3 weeks and after another 12 weeks the number of aberrant crypts determined. Transit times were determined after feeding the diets for 4 weeks. Compared with rats fed the control diet, rats fed diets supplemented with the suberized cell-wall preparations had decreased transit times and had significantly fewer aberrant crypts, with no aberrant crypt foci containing four or more crypts. The diets supplemented with suberized cell walls were more effective than thediet supplemented with wheat bran. We conclude that suberized and lignified cell walls, but particularly suberized, may play an important role in protection against Western diseases, including colorectal cancer. Failure to distinguish suberized and lignified plant cell walls from other sources of non-starch polysaccharides may provide a major limitation in current assessments of the role of dietary fibre in preventing colorectal cancer in humans.

Animals↗
PubMed1998

Effect of selected antimutagens on the genotoxicity of antitumor agents.

Cyclophosphamide (CP), bleomycin (BL), doxorubicin (DOX) and cisplatin (CISP) are potent antitumor drugs used worldwide against many forms of human cancer. As with most such agents, there can be physiological side-effects and the possible induction of mutations and other genotoxic effects in non-tumor cells. It is common for patients to ingest a host of food supplements to diminish the discomforting side-effects of therapy. Because these food supplements are often also rich in antimutagens that could also affect the biological efficacy of the antitumor drugs, we investigated if such antimutagenic agents were indeed antimutagenic to these antitumor drugs. Using the Salmonella/microsome bioassay, we tested CP, BL, DOX, and CP for mutagenicity in the presence and absence of the antimutagens ascorbic acid (AA), chlorophyllin (CHL) and (+)-catechin (CAT). AA was a very effective antimutagen against CISP and less effective against BL and DOX. It was not antimutagenic to CP. CHL was effective as an antimutagen against all four antitumor drugs, and CAT was a strong inhibitor of DOX mutagenicity, but had little effect on BL, CP and CISP. These data now provide a basis for future in vivo antitumor/antimutagen combination studies to determine if these antimutagens function in a manner to reduce genetic effects without having concomitant effects on intended antitumorogenicity of these therapeutic agents.

Antimutagenic Agents↗
PubMed1998

Comparative mutational spectra of the nitrogen mustard chlorambucil and its half-mustard analogue in Chinese hamster AS52 cells.

Nitrogen mustards play an important role in current cancer chemotherapy. The most effective antitumour agents are those carrying two alkylating functions, probably through their ability to form interstrand cross-links in DNA. Such lesions appear to create more of a block in DNA replication and are more difficult to repair than are most monoadducts. Although there were early reports that monofunctional drugs were more mutagenic than the bifunctional drugs, this has not been formally proved using structurally related drugs in a mutagenicity assay capable of detecting a range of different events. We have studied both the mutagenic potency and spectrum of events caused by treatment with the clinical agent, chlorambucil, compared with its half-mustard analogue, in Chinese hamster ovary (CHO)-AS52 cells. Although both drugs caused comparable increases in mutation frequency at doses killing 90% of cells (from around 9x10-6 to around 9x10-5 mutant cells), the nature of events differed significantly between the drugs. By far the majority of mutations caused by the half-mustard were transversion mutations, and almost all of these could be interpreted in relation to the DNA adducts that are known to be formed. In contrast, the majority of chlorambucil-induced mutations were major deletions, and point mutations were only identified from a few clones. Parallel micronucleus assays verified that chlorambucil has a stronger ability to break chromosomes than the half-mustard. These two drugs are thought to form similar monoadducts, but only the full mustard can form interstrand cross-links. The data suggest that DNA cross-links, although only a minor fraction of the total lesions, dominate the mutagenic spectrum and lead to gross changes at the chromosome level that can not be readily associated with individual lesions produced by the drug.

Animals↗
PubMed1998

Inhibitors of topoisomerase II enzymes: a unique group of environmental mutagens and carcinogens.

Many inhibitors of topoisomerase II enzymes are potent mutagens, leading to major chromosomal deletions, illegitimate recombination and aneuploidy. There is increasing evidence that they are also human carcinogens. However, their lack of chemical reactivity means that they may give weak or negative results in commonly used mutagenicity tests, or may give data with characteristics quite distinct from chemicals that alkylate DNA. They do not form DNA adducts and assays such as 32P-postlabelling will not detect their presence in the body. They are generally not point mutagens and may fail to provide distinctive fingerprints in mutation spectra. These characteristics may be limiting a realistic evaluation of their role in human carcinogenesis using current methodologies.

Animals↗
PubMed1998

Adsorption of a hydrophobic mutagen to cereal brans and cereal bran dietary fibres.

The abilities of brans from the cereals barley, oats, maize, rice, and wheat to adsorb in vitro the hydrophobic, environmental mutagen 1,8-dinitropyrene (DNP) were investigated using a mutagenicity assay. These brans were obtained from known cultivars using defined milling conditions and were chemically characterised. The abilities of total and insoluble dietary fibre preparations obtained from these brans to adsorb DNP were also investigated. The predicted weight of each bran required to adsorb 50% of the added DNP was used to compare the adsorptive abilities of the different brans. The brans were ranked in the order (most effective to least effective): rice, wheat, maize, barley, and oats. The adsorptive abilities of the dietary fibre preparations were not significantly different from the bran from which they were prepared. However, if the dietary fibres (cell walls) were the only components adsorbing the DNP, we would have expected the dietary fibre preparations to have adsorbed more DNP than the equivalent unextracted bran. This suggests that other components, probably starch, also adsorb DNP in the unextracted brans. It is not known why brans from different cereal species differ in adsorptive ability but the lignified cell walls in wheat bran may be important in conferring good adsorptive properties to this bran. The possible relationship between adsorptive ability and ability of the bran from a particular species to protect against colorectal cancer is discussed.

Adsorption↗
PubMed1998

Binding of polybenzamides to DNA: studies by DNase I and chlorambucil interference footprinting and comparison with Hoechst 33258.

The DNA sequence-specific binding ability of polybenzamide minor groove binding ligands was investigated. These ligands were compared with the known minor groove binder Hoechst 33258, using both DNase I footprinting and chlorambucil interference footprinting. The monocationic derivative showed some sequence specific binding to A/T-rich sequences, as shown by DNase I footprinting, but results for the biscationic polybenzamide were inconclusive. A general non-specific inhibition of cleavage at high drug concentrations was observed, suggesting these compounds had a low DNA binding affinity compared to Hoechst 33258. Using a complementary technique, chlorambucil interference footprinting, the biscationic derivative displayed a clear preference for sites containing at least three consecutive adenines and in contrast with the monocationic analogue, a lesser affinity for mixed A/T sequences.

Antineoplastic Agents, Alkylating↗
PubMed1998

Amsacrine-induced mutations in AS52 cells.

Amsacrine is an acridine-derived inhibitor of topoisomerase II that intercalates into DNA. We performed a detailed molecular analysis of 6-thioguanine (6-TG)-resistant mutant colonies arising in AS52 cells following Amsacrine treatment. AS52 cells carry a single copy of the bacterial gpt gene, functionally expressed using the SV40 early promoter and stably integrated into the Chinese hamster ovary genome. A 1-hr treatment with 0.1 to 0.5 microM Amsacrine was both cytotoxic and mutagenic, resulting in an average mutant frequency (MF) of 143 x 10(6) at 0.5 microM. Fifty independent 6-TG-resistant colonies were isolated for further study. These clones were initially characterised by PCR to estimate the relative proportion of putative point mutants and deletions or rearrangements; then a subset of mutants was further characterised by Southern blotting, Northern blotting, and DNA sequence analysis. Total deletion of the gpt gene sequences was found in 1 (2%) of the mutants, and 7 (14%) of the mutant clones had altered PCR patterns, suggesting complex deletions or rearrangements. The remaining 42 (84%) mutants had a wild-type PCR profile. Of these, 21 mutants were further analysed by Southern blotting. Interestingly, Southern blotting revealed genomic deletions/rearrangements in 12 of 21 mutants with a wild-type PCR profile. These deletions/rearrangements were further shown to affect gpt gene expression. The remaining nine mutants with a wild-type PCR profile were sequenced. Four of these mutants had mutations in the gpt structural gene. Overall, genomic deletions/rearrangements were observed in 12/21 independent mutants subjected to PCR and Southern blotting. Thus, deletions/rearrangements were the most common mutation observed following Amsacrine treatment of AS52 cells.

Amsacrine↗