Search PubMed⌕ Search

Biomedical subjects

J Ashby

Publications and source records attributed to J Ashby.

At least 163 records · Page 9Linked to original sources
PubMed1994

Potent clastogenicity of the human carcinogen etoposide to the mouse bone marrow and mouse lymphoma L5178Y cells: comparison to Salmonella responses.

The suspect human carcinogen, etoposide, is known to be genotoxic, producing both gene and chromosomal mutations, probably by virtue of its ability to inhibit topoisomerase II activity. The present paper describes assays conducted using the Salmonella assay, the mouse lymphoma tk+/- assay (gene and chromosomal mutation analysis and molecular analysis of tk-/- mutants) and the mouse bone marrow micronucleus assay. Nonreproducible, weak, dose-related increases in mutation frequency in strain TA98 (but not TA1538 or TA1537) of Salmonella typhimurium were observed. Etoposide was highly mutagenic at the heterozygous thymidine kinase (tk+/-) locus of L5178Y mouse lymphoma cells at concentrations below 0.1 micrograms/ml. Mostly small colony mutants were induced, consistent with the potent clastogenicity also observed. Molecular analysis of mutants indicated that 83% and 92% of large and small colony mutants, respectively, had lost the entire target gene sequence. Chromosomally aberrant L5178Y cells were approximately 2 to 600-fold more prevalent than small tk-/- mutant colonies. This suggests that the viable target for etoposide-mediated clastogenesis in the selective assay is approximately one-fifth of chromosome 11b, itself being approximately one-fortieth of the mouse genome. An unusually potent response was observed for etoposide in the mouse bone marrow micronucleus assay (63.1 +/- 18 MPE/1,000 PE 24 hours after an oral dose of 1 mg/kg). The minimum detectable dose level in the assay was between 0.01 and 0.1 mg/kg. At dose levels between 1 and 15 mg/kg, an inverse dose response was observed. This reduction in assay response was not due to the small concommitant decrease in the incidence of polychromatic erythrocytes, a conclusion based on studies with N-methyl-N-nitrosourea. Animals sampled 48 hours after dosing with etoposide (10 mg/kg) had no polychromatic erythrocytes in the bone marrow. These observations for the micronucleus assay await explanation. The chemical structure of etoposide is displayed and discussed within the context of such strong mutagenic activity being associated with a nonelectrophilic agent.

Animals↗
PubMed1994

The time trade-off technique: how do the valuations of breast cancer patients compare to those of other groups?

The time trade-off method was incorporated into a study of valuation of health states following treatment for breast cancer. A major aim of the work was to determine whether different groups give different valuations. The time trade-off technique was simple and quick to administer, acceptable to subjects, and produced different values in different groups. Age and sex of valuers had some influence: the most striking differences were found between women who had experienced breast cancer and those who had not. The time trade-off method has considerable potential in health state valuation. The choice of valuers needs to be further explored.

Adult↗
PubMed1994

Effect of essential fatty acids on circulating T cell subsets in patients with colorectal cancer.

The effect of essential fatty acids (EFA), given orally as dietary supplements, on the responsiveness in vitro of peripheral blood lymphocytes (PBL), to the mitogen concanavalin A have been studied in 10 patients with localized and 14 patients with advanced colorectal cancer. The degree of lymphocyte activation was assessed by measuring the amount of tritiated [3H]thymidine incorporated into newly synthesised lymphocyte DNA. The results were expressed as stimulation indices. T cell responses to concanavalin A stimulation showed a significant reduction of stimulation indices following EFA supplementation, in both the localized (P = 0.026) and advanced (P = 0.016) tumour groups, when compared with pretreatment activity in vitro. Mixing experiments, using EFA-supplemented and non-EFA-supplemented lymphocytes with concanavalin A, suggest no enhancement of T suppressor cell activity. Cell surface marker analysis (fluorescence-activated cell sorting for CD phenotyping) revealed a reduction of absolute numbers of CD4+ and CD8+ lymphocytes following EFA supplementation. The stimulation indices returned to pre-supplementation values 3 months following cessation of EFA intake. There was no significant change of these indices in the control (no EFA supplementation) advanced tumour group tested. This study suggests that EFA supplementation in patients with colorectal cancer selectively reduces circulating PBL, and T cell subset (including suppressor cells) numbers and/or activity. Such effects may have an important outcome in patients with malignant disease.

Administration, Oral↗
PubMed1994

Mutagenicity of o-anisidine to the bladder of lacI- transgenic B6C3F1 mice: absence of 14C or 32P bladder DNA adduction.

Earlier studies have established that the rodent bladder carcinogen o-anisidine (OA) gives negative results in all of the standard rodent genetic toxicity assays. In the present study, a single oral administration of the maximum tolerated dose level (750 mg/kg) of OA to B6C3F1 mice yielded negative results in 32P-post-labelling assays of bladder and liver DNA (24 h after dosing). Likewise, 14C-ring-labelled OA administered orally to B6C3F1 mice gave no evidence of DNA binding 6, 12 or 24 h later. Administration of OA (750 mg/kg) to transgenic lacI- mice (Big Blue) led to a small increase in mutation frequency (MF) in the bladder, but not in the liver. Increased MFs were observed in the bladder following 1, 3 or 10 daily doses with sampling times of 1 or 2 weeks after the final dose. However, statistical significance (P < 0.01) was only reached 2 weeks after either 3 or 10 daily administrations of OA. The positive control chemical (dimethylnitrosamine) gave a positive result (P < 0.01) in the liver, but not the bladder, 7 days after a single administration of 10 mg/kg. The possibility that OA is mutagenic and carcinogenic to the rodent bladder via formation of radical species is suggested.

Aniline Compounds↗
PubMed1994

Genetic toxicity and potential carcinogenicity of taxol.

The activity of the antineoplastic agent taxol depends upon its ability to inhibit tubulin disassembly in dividing cells. We show here that taxol gives a strong positive response in the mouse bone marrow micronucleus assay. This is the first report of its genetic toxicity. The majority of antineoplastic agents are carcinogenic to humans, and the majority of human carcinogens are active in the mouse bone marrow micronucleus assay. The present data therefore indicate a carcinogenic potential of taxol for humans, which should be considered in the risk-benefit analysis of its increasing clinical use.

Animals↗
PubMed1994

Prediction of rodent carcinogenicity for 44 chemicals: results.

Methods by which rodent carcinogenicity can be predicted have been prospectively validated for 40 chemicals evaluated for carcinogenicity by the US National Toxicology Program. It is concluded that a chemical of unknown carcinogenicity can be predicted to be in one of three possible categories--probably carcinogenic, probably non-carcinogenic or of uncertain activity. The last category is unlikely to contain genotoxic trans-species and/or multiple-site carcinogens. The component parameters of such predictions are one or more of several aspects of chemical structure, genotoxicity and rodent toxicity. Each of these parameters requires refinement but all are developed to the point that they can be integrated to make assessment of possible carcinogenicity. Carcinogenicity tends to be overpredicted by this integrated technique, each part of which has already been simulated by computer modelling. Improvements in predictive methodology will flow from three assumptions: (i) that emphasis must be placed equally on the properties of the test chemical and the responses it elicits in tissues for which carcinogenicity is to be predicted, (ii) that the integration of different predictive technique is preferable to the exclusive use of a single technique, and (iii) that the general predictivity of any technique or combination of techniques appears to be limited to < or = 80%, imposed by inadequate knowledge, and uncertainties in the experimental evaluation and classification of carcinogenic responses for diverse chemicals. This last statement does not preclude the attainment of higher accuracy within a congeneric series of chemicals. Foreknowledge of the likely outcome of a rodent carcinogenicity bioassay is now possible and will contribute to the focusing of animal testing resources.

Animals↗
PubMed1994

Use of transgenic mouse lacI/Z mutation assays in genetic toxicology.

The Big Blue (lacI) and the Muta Mouse (lacZ/GalE) assays offer a practical means to generate mutation data from a wide range of tissues of treated animals. Our experience with these assays has so far been encouraging, but several fundamental questions require addressing. Chief among these is whether these assays are to be regarded as replacements for standard rodent genotoxicity assays, or if they are to be regarded as assays for the prediction of potential carcinogenic organotropy using a multiple-dose protocol. The interplay between the independent chemical properties of mitogenesis and DNA adduction require also to be studied. The value and sensitivity of these assays can only be assessed when these questions have been internationally addressed and concluded.

Animals↗
PubMed1994

Reconciliation of five negative and four positive reports of the activity of dimethylnitrosamine in the mouse bone marrow micronucleus assay.

Five positive and four negative reports of the activity of dimethylnitrosamine (DMN) in the mouse bone marrow micronucleus assay exist in the literature: toxicity and micronucleus experiments have been conducted to resolve this finely balanced conflict of data. The maximum dose at which mice can survive a single treatment with DMN is 10-12.5 mg/kg. A dose of 15 mg/kg is lethal within 4 days while higher doses are lethal within 1-2 days. None the less, micronucleus assays can be conducted with DMN up to dose levels of 100 mg/kg if animals are sampled within 24 h of dosing, i.e. before they die. We have demonstrated clear positive assay responses for DMN at lethal dose levels (30 and 60 mg/kg). At non-lethal (maximum tolerated) dose-levels (10 and 12.5 mg/kg) marginal positive or negative responses were observed. Both the oral and intraperitoneal injection routes of exposure have been studied. These observations enable the nine previous and divergent literature reports to be explained. The present data for DMN focus attention on the need to consider carefully the selection of dose-levels for use in short-term in vivo genotoxicity assays. In particular, it is suggested that many of the conflicts of assay data that exist in the literature may be caused by the failure of investigators to study, adequately, the toxicity of chemicals. It is proposed that positive genotoxicity test data generated only at lethal dose-levels are of no toxicological value.

Animals↗
PubMed1994

A preliminary evaluation of the performance of the Muta Mouse (lacZ) and Big Blue (lacI) transgenic mouse mutation assays.

All of the published mutagenicity data generated using the Muta Mouse (lacZ) and the Big Blue (lacI) transgenic mouse mutation assays have been re-presented in a standard format. To date, 26 chemicals have been evaluated in one or other of the assays, and eight tissues have been sampled. The present analysis should expedite the further validation of these assays. In particular, it is suggested that data on the present 26 chemicals should be consolidated rather than the generation of partial data sets on additional chemicals.

Animals↗
PubMed1994

Mechanistically-based human hazard assessment of peroxisome proliferator-induced hepatocarcinogenesis.

In this review we have evaluated the relationship between peroxisome proliferation and hepatocarcinogenesis. To do so, we identified all chemicals known to produce peroxisome proliferation and selected those for which there are data (on peroxisome proliferation and hepatocarcinogenesis) which meet certain criteria chosen to facilitate comparison of these phenomena. The summarised data and definition of the methodology used has been collected in appendices. These comparisons enabled us to evaluate the relationship between these phenomena using reliable data. As there is a good correlation between them, we further explored the mechanisms of action that have been proposed (direct genotoxic activity, production of hydrogen peroxide, cell proliferation and receptor activation). The relationship between these events in other species, including humans, was also reviewed and finally an overview of the assessment of human hazard is presented in section IX. Some of the first chemicals which were shown to produce peroxisome proliferation were also hepatocarcinogens whose carcinogenicity could not be readily explained by genotoxic activity. This raised the suggestion that the unusual phenomenon of peroxisome proliferation was intricately linked to the carcinogenic activity of these agents. Three questions have exercised the attention of regulatory, industrial and academic toxicology since then; are chemicals which elicit peroxisome proliferation in the liver actually a coherent class of chemical carcinogens?; does the early biological phenomenon of peroxisome proliferation have real predictive value for and mechanistic association with rodent carcinogenesis?; and what hazard/risk do these agents pose to humans that may be exposed to them? Whether peroxisome proliferators are indeed a discrete class of rodent carcinogens would appear to be the single, most important question. If so, then the assumptions and procedures relevant to human hazard and risk assessment should be applied to the class and should be essentially generic; if not, each chemical should be considered independently. Our critical analysis of the published data for over 70 agents which have been shown to possess intrinsic ability to induce peroxisome proliferation in the livers of rodents has led to the conclusion that there exists a strong correlation between peroxisome proliferation as n early effect in the liver and hepatocarcinogenicity in chronic exposure studies. An almost perfect correlation was observed between the induction of peroxisomes in the rodent liver and the eventual appearance of tumours following chronic exposure The few exceptions to this were largely explainable (section II).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Evaluation of the genetic toxicity of the peroxisome proliferator and carcinogen methyl clofenapate, including assays using Muta Mouse and Big Blue transgenic mice.

The rodent liver carcinogen and hepatic peroxisome proliferator methylclofenapate (MCP) has been evaluated for genetic toxicity in a range of in vitro and rodent genotoxicity assays. It gave a negative response in each of the following assays: mutagenicity to S. typhimurium and E. coli (+/- S9 mix, plate and pre-incubation assays), clastogenicity to cultured human lymphocytes and CHO cells (+/- S9 mix), a mouse bone marrow micronucleus assay (24h and 48h sampling), a rat liver assay for UDS in vivo (12h sampling), assays for lac I (Big Blue) and lac Z (Muta Mouse) mutations in the liver of transgenic mice, and an assay of the ability of MCP to modify the mutagenicity to the liver of dimethylnitrosamine in both transgenic mutation assays. The micronucleus and UDS assays were conducted using a single administration of MCP at its maximum tolerated dose, while the transgenic assays were conducted using nine daily administrations of MCP at its cancer bioassay dose level. These nine daily administrations were shown to double the weight of the liver of non-transgenic, Big Blue and Muta Mice, as well as leading to a dramatic proliferation of peroxisomes (electron microscopy) in the livers of each strain. These changed parameters had returned to control levels when the mutation analyses were conducted (10 days after the final dose of MCP). Despite the liver enlargement observed following MCP administration, no evidence of mitotic activity was observed in treated livers, although an increased number of cells were undergoing replicative DNA synthesis during the final 3 days of the 9 days of administration (BUdR assessment of S-phase). Liver biochemistry parameters (ALT, AST, AP, CK, GGT and albumin) were unaffected by the chronic (9 day) administration of MCP indicating an absence of hepatic toxicity. These combined observations favour a non-genotoxic mechanism of action for the hepatic carcinogenicity of MCP. The clastogenicity in vitro of the perixisome proliferator Wyeth 14,643 has been confirmed in CHO cells, but it is noted that this chemical is more soluble than is MCP. In particular, at the highest dose level at which MCP could be tested, Wy 14,643 was also non-clastogenic.

Animals↗
PubMed1994

Comparative activity of human carcinogens and NTP rodent carcinogens in the mouse bone marrow micronucleus assay: an integrative approach to genetic toxicity data assessment.

The mouse bone marrow micronucleus (MN) assay holds a key position in all schemes for detecting potential human carcinogens and mutagens. It was therefore of concern when Shelby et al. reported that only 5 of 25 rodent carcinogens defined by the U.S. NTP were positive in the assay. Further, each of these positive responses was weak and indistinguishable from the 4 positive responses observed among the 24 NTP noncarcinogens tested. To focus these findings, the activity in the MN assay of 26 human carcinogens, 6 reference rodent genotoxins, and the 9 NTP chemicals positive in the MN assay have been displayed in a common format. This involved plotting the minimum positive dose level (expressed as mumole/kilogram) and the maximum fold-increase in micronucleated polychromatic erythrocytes frequency observed at any dose level. By displaying the high sensitivity of the micronucleus assay to the reference human and rodent genotoxins, this analysis emphasizes the weakness in the MN assay responses given by the NTP carcinogens reported by Shelby et al. This, in turn, poses questions about the intrinsic hazard of this selection of NTP rodent carcinogens. Using fotemustine and vitamin C as models of a toxic and a nontoxic chemical known to be active in the MN assay, this analysis describes a method by which their relative potential human hazard can be distinguished (a synthetic, as opposed to an analytical approach to data assessment). The possibility that some weak responses observed in the MN assay at elevated dose levels may be stress induced is considered.

Animals↗
PubMed1994

L-arginine stimulates host defenses in patients with breast cancer.

BACKGROUND: The amino acid L-arginine is known to have immunostimulatory effects in animals and healthy human volunteers. We have studied the effect of dietary supplementation with L-arginine (30 gm/day for 3 days) on host defenses in patients with breast cancer. METHODS: Mitogenic responses of peripheral blood lymphocytes to concanavalin A, phytohemagglutinin, and pokeweed mitogen and phenotype analysis of lymphocyte subsets and activation markers were assessed before and after 3 days of L-arginine supplementation. The effect of L-arginine supplementation on natural killer and lymphokine-activated killer cell cytotoxicity and serum levels of the cytokines interleukin-1 beta and 2, interferon-gamma, and tumor necrosis factor-alpha were also measured. RESULTS: L-arginine significantly increased lymphocyte mitogenic reactivity to concanavalin A, phytohemagglutinin, and pokeweed mitogen (mean percentage increases: 64% [p < 0.001], 65% [p < 0.001], and 48% [p < 0.05], respectively). Natural killer and lymphokine-activated killer cell cytotoxicity was also significantly enhanced after L-arginine intake (mean percentage increase, 81% and 107% [p < 0.001]). However, no corresponding increase in circulating CD16+ and CD56+ cells was obtained: Arginine supplementation did not increase the level of serum cytokines. CONCLUSIONS: Dietary supplementation with L-arginine in patients with breast cancer significantly enhances host defenses and therefore may have a role in adjuvant treatment.

Aged↗