PubMed Health⌕ Search

Biomedical subjects

S Stasiewicz

Publications and source records attributed to S Stasiewicz.

15 recordsLinked to original sources
PubMed2001

The Tg.AC (v-Ha-ras) transgenic mouse: nature of the model.

The Tg.AC (v-Ha-ras) transgenic mouse model provides a reporter phenotype of skin papillomas in response to either genotoxic or nongenotoxic carcinogens. In common with the conventional bioassay, the Tg.AC model responds to known human carcinogens and does not respond to noncarcinogens. It also does not respond to most chemicals that are positive in conventional bioassays principally at sites of high spontaneous tumor incidence. The mechanism of response of the Tg.AC model is related to the structure and genomic position of the transgene and the induction of transgene expression through specific mediated interactions between the chemicals and target cells in the skin.

Academies and Institutes↗
PubMed2000

Responses of transgenic mouse lines p53(+/-) and Tg.AC to agents tested in conventional carcinogenicity bioassays.

The haplo-insufficient p53 knockout (p53+/-) and zetaglobin v-Ha-ras (Tg.AC) transgenic mouse models were compared to the conventional two rodent species carcinogen bioassay by prospectively testing nine chemicals. Seven of the chemicals classified as carcinogens in the conventional bioassay induced tumors in the liver or kidneys of B6C3F1 mice, and one (pentachlorophenol) also induced tumors in other tissues. Only three chemicals, furfuryl alcohol, pyridine, and pentachlorophenol, induced tumors in rats. The tumorigenic effect of pyridine was seen in F344 rats but not in Wistar strain rats. None of the chemicals induced tumors in the p53+/- transgenic mice, which is consistent with the absence of genotoxicity of these chemicals. Only two of the seven nongenotoxic carcinogens were positive in the Tg.AC model (lauric acid diethanolamine and pentachlorophenol). These results show that these transgenic models do not respond to many chemicals that show strain- or species-specific responses in conventional bioassays.

Administration, Oral↗
PubMed2000

Statistical analysis of skin tumor data from Tg.AC mouse bioassays.

New strategies for identifying chemical carcinogens and assessing risk have been proposed based on the Tg.AC (zetaglobin promoted v-Ha-ras) transgenic mouse. Preliminary studies suggest that the Tg. AC mouse bioassay may be an effective means of quickly evaluating the carcinogenic potential of a test agent. The skin of the Tg.AC mouse is genetically initiated, and the induction of epidermal papillomas in response to dermal or oral exposure to a chemical agent acts as a reporter phenotype of the activity of the test chemical. In Tg.AC mouse bioassays, the test agent is typically applied topically for up to 26 weeks, and the number of papillomas in the treated area is counted weekly. Statistical analyses are complicated by within-animal and serial dependency in the papilloma counts, survival differences between animals, and missing data. In this paper, we describe a statistical model for the analysis of skin tumor data from a Tg.AC mouse bioassay. The model separates effects on papilloma latency and multiplicity and accommodates important features of the data, including variability in expression of the transgene and dependency in the tumor counts. Methods are described for carcinogenicity testing and risk assessment. We illustrate our approach using data from a study of the effect of 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) exposure on tumorigenesis.

Administration, Topical↗
PubMed1990

Prediction of the outcome of rodent carcinogenicity bioassays currently being conducted on 44 chemicals by the National Toxicology Program.

This paper was written to enable evaluation of the concept that knowledge about chemical structure combined with limited short-term genotoxicity and toxicity test results can be used to predict potential carcinogens. Previous attempts have been potentially biased by prior knowledge about the tumorigenicity of chemicals in animals or humans, but the 44 chemicals that are currently being bioassayed for carcinogenicity by the National Toxicology Program provide an opportunity prospectively to evaluate factors that may be predictive of chemical carcinogenicity. Predictions of rodent carcinogenicity for these 44 agents are presented as an example of what we believe is the best available approach at this time. This publication will also enable others to make their own predictions (using whatever methods they believe to have high predictive value) before the results of the animal assays are known.

Animals↗
PubMed1989

Classification according to chemical structure, mutagenicity to Salmonella and level of carcinogenicity of a further 42 chemicals tested for carcinogenicity by the U.S. National Toxicology Program.

This paper is an extension and update of an earlier review published in this journal (Ashby and Tennant, 1988). A summary of the rodent carcinogenicity bioassay data on a further 42 chemicals tested by the U.S. National Toxicology Program (NTP) is presented. An evaluation of each chemical for structural alerts to DNA-reactivity is also provided, together with a summary of its mutagenicity to Salmonella. The 42 chemicals were numbered and evaluated as an extension of the earlier analysis of 222 NTP chemicals. The activity patterns and conclusions derived from the earlier study remain unchanged for the larger group of 264 chemicals. Based on the extended database of 264 NTP chemicals, the sensitivity of the Salmonella assay for rodent carcinogens is 58% and the specificity for the non-carcinogens is 73%. A total of 32 chemicals were defined as equivocal for carcinogenicity and, of these, 11 (34%) are mutagenic to Salmonella. An evaluation is made of instances where predictions of carcinogenicity, based on structural alerts, disagree with the Salmonella mutagenicity result (12% of the database). The majority of the disagreements are for structural alerts on non-mutagens, and that places these alerts as a sensitive primary screen with a specificity lower than that of the Salmonella assay. That analysis indicates some need for assays complementary to the Salmonella test when screening for potential genotoxic carcinogens. It also reveals that the correlation between structural alerts and mutagenicity to Salmonella is probably greater than 90%. Chemicals predicted to show Michael-type alkylating activity (i.e., CH2 = CHX; where X = an electron-withdrawing group, e.g. acrylamide) have been confirmed as a structural alert, and the halomethanes (624 are possible) have been classified as structurally-alerting. To this end an extended carcinogen-alert model structure is presented. Among the 138 NTP carcinogens now reviewed, 45 (33%) are non-mutagenic to Salmonella and possess a chemical structure that does not alert to DNA-reactivity. These carcinogens therefore either illustrate the need for complementary genetic screening tests to the Salmonella assay, or they represent the group of non-genotoxic carcinogens referred to most specifically by Weisburger and Williams (1981); the latter concept is favoured.

Animals↗
PubMed1987

Prediction of chemical carcinogenicity in rodents from in vitro genetic toxicity assays.

Four widely used in vitro assays for genetic toxicity were evaluated for their ability to predict the carcinogenicity of selected chemicals in rodents. These assays were mutagenesis in Salmonella and mouse lymphoma cells and chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells. Seventy-three chemicals recently tested in 2-year carcinogenicity studies conducted by the National Cancer Institute and the National Toxicology Program were used in this evaluation. Test results from the four in vitro assays did not show significant differences in individual concordance with the rodent carcinogenicity results; the concordance of each assay was approximately 60 percent. Within the limits of this study there was no evidence of complementarity among the four assays, and no battery of tests constructed from these assays improved substantially on the overall performance of the Salmonella assay. The in vitro assays which represented a range of three cell types and four end points did show substantial agreement among themselves, indicating that chemicals positive in one in vitro assay tended to be positive in the other in vitro assays.

Animals↗
PubMed1987

Comparative evaluation of genetic toxicity patterns of carcinogens and noncarcinogens: strategies for predictive use of short-term assays.

The results of a recent comprehensive evaluation of the relationship between four measures of in vitro genetic toxicity and the capacity of the chemicals to induce neoplasia in rodents carry some important implications. The results showed that while the Salmonella mutagenesis assay detected only about half of the carcinogens as mutagens, the other three in vitro assays (mutagenesis in MOLY cells or induction of aberrations or SCEs in CHO cells) did not complement Salmonella since they failed to effectively discriminate between the carcinogens and noncarcinogens found negative in the Salmonella assay. The specificity of the Salmonella assay for this group of 73 chemicals was relatively high (only 4 of 29 noncarcinogens were positive). Therefore, we have begun to evaluate in vivo genetic toxicity assays for their ability to complement Salmonella in the identification of carcinogens.

Animals↗
PubMed1986

Comparison of multiple parameters of rodent carcinogenicity and in vitro genetic toxicity.

The relationship between chemically induced patterns of tumorigenesis in rodents and of in vitro genetic toxicity was evaluated for 73 substances. tumorigenicity patterns were defined according to sex and species effects, the induction of common or uncommon tumors, and benign or malignant tumors. These results and the genetic toxicity results derived from the testing of chemicals under code were compared. Chemicals that induced tumors in both sexes of both rodent species (trans-sex/species carcinogens) were divided into those that showed multiple responses in genetic toxicity assays and those that showed little or no response. Some of the nongenotoxic trans-sex/species carcinogens exhibit properties that do not necessarily fit classification as only tumor promoters and may involve some other mode(s) of action. Those chemicals showing tumorigenicity in only one of the four groups exposed (uni-sex/species carcinogens) generally showed little or no response in genetic toxicity assays. Uni-sex/species carcinogens may be difficult to identify by in vitro assays because of their high tissue specificity. Chemicals that are tumorigenic in both sexes of both species are logically more likely to be tumorigenic in a third species than are those that are tumorigenic in only one sex of the exposed species. Therefore, while positive genetic toxicity test results are not predictive of all carcinogens, a consistent positive response among the multiple endpoints in these assays is more likely to identify chemicals with the potential for trans-sex/species carcinogenesis. Such trans-sex/species carcinogens may have the most direct implication for human health effects.

Animals↗
PubMed1985

Comparative evaluation of three mammalian cell transformation assay systems.

One cellular transformation assay system (Syrian hamster embryo (SHE) primary cells) and two viral mediated transformation systems (primary Syrian hamster embryo cells infected with Simian adenovirus type 7 (SHE/SA7), and a rat fibroblast cell line (2FR450) infected with Rauscher leukemia virus (Rat/RLV] were evaluated using a group of nine "model" and five coded chemicals. The purpose of the project was to establish the intra- and interlaboratory reproducibility of the assays and to provide a basis for objective comparisons between the systems. This is a preliminary evaluation of the assay systems using the results for these chemicals tested in eight collaborating laboratories under the auspices of the National Toxicology Program (NTP). The endpoint measured in each system is very different and a positive response in each had to be separately defined. The assay systems all produced a response to carcinogens and in most instances the responses could be qualitatively reproduced in the different laboratories. However, the assays differed significantly in their ability to demonstrate dose-related effects. In addition, multiple tests or modified assay procedures were required with every system in order to insure that chemicals had been adequately tested. In each system, technical or procedural limitations exist that preclude the application of these assays to routine chemical testing at this time. Among these limitations were ambiguity in scoring morphological transformation, significant but poorly defined influence of reagents such as serum or metabolic activation systems on test performance, and difficulty in repeating responses to a given chemical. Additional efforts to overcome these limitations will be necessary in order to make these test systems of use in routine testing of unknown chemicals for genetic toxicity.

Animals↗
PubMed1984

Chemicals showing no evidence of carcinogenicity in long-term, two-species rodent studies: the need for short-term test data.

Studies to determine the performance of short-term tests (STT) in predicting chemical carcinogenicity are frequently characterized by a poor representation of noncarcinogens among the test chemicals. As a result, the performance of several STT is well characterized with carcinogenic chemicals, but the ability of the tests to discriminate between carcinogens and noncarcinogens is largely unknown because of the shortage of test results for noncarcinogens. A list of 70 chemicals that have been tested by the National Cancer Institute or the National Toxicology Program in long-term rodent carcinogenicity studies and that have yielded no evidence of cancer induction in male and female rats and mice is presented. The list helps document the shortage of STT results of noncarcinogens and provides a potential source of chemicals for consideration in future studies designed to assess the ability of STT to predict chemical carcinogenicity.

Animals↗
PubMed1983

Meiotic DNA metabolism in wild-type and excision-deficient yeast following UV exposure.

The effects of UV irradiation on DNA metabolism during meiosis have been examined in wild-type (RAD+) and mitotically defined excision-defective (rad1-1) strains of Saccharomyces cerevisiae that exhibit high levels of sporulation. The rad1-1 gene product is not required for normal meiosis: DNA synthesis, RNA synthesis, size of parental and newly synthesized DNA and sporulation are comparable in RAD+ and rad1-1 strains. Cells were UV irradiated at the beginning of meiosis, and the fate of UV-induced pyrimidine dimers as well as changes in DNA and DNA synthesis were followed during meiosis. Excision repair of pyrimidine dimers can occur during meiosis and the RAD1 gene product is required; alternate excision pathways do not exist. Although the rate of elongation is decreased, the presence of pyrimidine dimers during meiosis in the rad1-1 strain does not block meiotic DNA synthesis suggesting a bypass mechanism. The final size of DNA is about five times the distance between pyrimidine dimers after exposure to 4 J/m2. Since pyrimidine dimers induced in parental strands of rad1-1 prior to premeiotic DNA synthesis do not become associated with newly synthesized DNA, the mechanism for replicational bypass does not appear to involve a recombinational process. The absence of such association indicates that normal meiotic recombination is also suppressed by UV-induced damage in DNA; this result at the molecular level is supported by observations at the genetic level.

DNA Repair↗
PubMed1983

Genetic effects of UV irradiation on excision-proficient and -deficient yeast during meiosis.

The lethal and recombinational responses to ultraviolet light irradiation (UV) by excision-proficient (RAD+) and deficient strains (rad1) of Saccharomyces cerevisiae has been examined in cells undergoing meiosis. Cells that exhibit high levels of meiotic synchrony were irradiated either at the beginning or at various times during meiosis and allowed to proceed through meiosis. Based on survival responses, the only excision repair mechanism for UV damage available during meiosis is that controlled by the RAD1 pathway. The presence of pyrimidine dimers at the beginning of meiosis does not prevent cells from undergoing meiosis; however, the spore products exhibit much lower survival than cells from earlier stages of meiosis. The reduced survival is probably due to effects of UV on recombination. Meiotic levels of gene conversion are reduced only two to three times in these experiments; however, intergenic recombination is nearly abolished after a dose of 4 J/m2 to the rad1 strain. Exposure to 25 J/m2 had little effect on the wild-type strain. Since normal meiotic reciprocal recombination is generally considered to involve gene conversion-type intermediates, it appears that unrepaired UV damage dissociates the two processes. These results complement those obtained with the mei-9 mutants of Drosophila which also demonstrate a dissociation between gene conversion and reciprocal recombination. These results are consistent with molecular observations on the UV-irradiated rad1 strain in that there is no excision of pyrimidine dimers or exchange of dimers during meiosis.

DNA Repair↗
PubMedDate not supplied

Phenolphthalein induces thymic lymphomas accompanied by loss of the p53 wild type allele in heterozygous p53-deficient (+/-) mice.

Epidemiology studies have indicated that many human cancers are influenced by environmental factors. Genetically altered mouse model systems offer us the opportunity to study the interaction of chemicals with genetic predisposition to cancer. Using the heterozygous p53-deficient (+/-) mouse, an animal model carrying one wild type p53 gene and one p53 null allele, we studied the effects of phenolphthalein on tumor induction and p53 gene alterations. Earlier studies showed that phenolphthalein caused carcinogenic effects in Fisher 344 rats and B6C3F1 mice after a 2-yr dosing period (Dunnick and Hailey, Cancer Res. 56: 4922-4926, 1996). The p53 (+/-) mice received phenolphthalein in the feed at concentrations of 200, 375, 750, 3,000, or 12,000 ppm (approximately 43, 84, 174, 689, or 2,375 mg/kg body weight/day or 129, 252, 522, 2,867, or 7,128 mg/m2 body surface area/day) for up to 6 mo. A target organ cancer site that accumulated p53 protein in the B6C3F1 mouse (i.e., thymic lymphoma) was also a target site for cancer in the p53 (+/-) mouse. In the p53 (+/-) mouse, treatment-related atypical hyperplasia and malignant lymphoma of thymic origin were seen in the control and dosed groups at a combined incidence of 0, 5, 5, 25, 100, and 95%, respectively. Twenty-one of the thymic lymphomas were examined for p53 gene changes, and all showed loss of the p53 wild type allele. Chemical-induced ovarian tumors in the B6C3F1 mouse showed no evidence for p53 protein accumulation and did not occur in the p53 (+/-) mouse. The p53-deficient (+/-) mouse model responded to phenolphthalein treatment with a carcinogenic response in the thymus after only 4 mo of dosing. This carcinogenic response took 2 yr to develop in the conventional B6C3F1 mouse bioassay. The p53-deficient (+/-) mouse is an important model for identifying a carcinogenic response after short-term (< 6 mo) exposures. Our studies show that exposure to phenolphthalein combined with a genetic predisposition to cancer can potentiate the carcinogenic process and cause p53 gene alterations, a gene alteration found in many human cancers.

Animals↗