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J L Redpath

Publications and source records attributed to J L Redpath.

108 records · Page 6Linked to original sources
PubMed1975

Irradiation-induced adduct formation of RNA with carcinogenic arylamine derivatives.

Radiolysis of N2O-saturated solutions of transfer RNA (tRNA) and the arylacethydroxamic acids, N-hydroxy-N-2-acetylaminofluorene and N-hydroxy-N-4-acetylaminobiphenyl; their corresponding acetamides, 2-acetylaminofluorene and 4-acetylaminofluorene; or the O-glucuronide of N-hydroxy-N-2-acetylaminofluorene resulted in adduct formation of the nucleic acid with these carcinogenic arylamine derivatives. The yield of adducts on irradiation of the arylacethdroxamic acids with tRNA was greater than that for their corresponding acetamides or the O-glucuronide. The fluorenylacethydroxamic acid and acetamide were also more reactive than the biphenyl analogs. Adduct formation resulting from radiolysis of tRNA and the arylacethydroxamic acids or the O-glucuronide proceeded with retention of both the aromatic nucleus and the N-acetyl group. The yields of adducts were much greater for irradiated mixtures than for irradiation of either component alone followed by mixing. Evaluation of the data shows that initial modification of the tRNA or the carcinogen can lead to adduct formation. In the case of primary radical attack of the nucleic acid, it has been shown that short-lived reactive RNA intermediates are responsible for a major fraction of the observed yield of adducts in the irradiated mixtures. Comparative studies showed that irradiation under conditions that favor reaction of oxidizing radicals enhanced formation of the adducts. Oxygen was shown to protect RNA from irradiation-induced binding of the arylacethydroxamine acids due to competition of O2 with the carcinogen for the reactive RNA intermediates.

Aminobiphenyl Compounds↗
PubMedDate not supplied

Radiation-induced neoplastic transformation in vitro: evidence for a protective effect at low doses of low LET radiation.

The study of radiation-induced transformation in vitro has long been an experimental approach to examine mechanisms underlying radiation carcinogenesis. Even though the major concern of exposure to radiation is the risk of cancer induction at low radiation doses, most laboratory mechanistic studies have focused on high dose effects. This, coupled with the fact that epidemiologic data are rarely powerful enough to accurately discriminate this risk at doses <5 cGy, has led in recent years to an increased effort to study low dose effects using the endpoint of neoplastic transformation in vitro. Since transformation frequencies at low doses are typically low (< 10(-4)), such studies are, by necessity, large and labor intensive. However, they have yielded quantitative dose-response data, as well as insights into underlying cellular and molecular mechanisms. An interesting, and potentially important, finding is that low doses of low LET radiation can suppress neoplastic transformation in vitro to levels below that seen spontaneously. Mechanistic studies have revealed that multiple mechanisms are likely to be involved, and these include both the death of a subpopulation of cells prone to spontaneous neoplastic transformation and the induction of DNA repair. The relative contribution of these mechanisms appears to be dose-dependent. The relevance of in vitro studies to carcinogenesis in vivo is discussed.

Animals↗
PubMedDate not supplied

In vitro chemopreventive efficacy screening using human keratinocytes and the in vivo data correlation.

Agents with potential cancer preventive activity were screened for efficacy in the Human Epidermal Cell (HEC) Assay. The HEC Assay measures inhibition of propane sultone-induced changes in the growth and/or differentiation in early passage keratinocyte cultures. The assay biomarkers were calcium tolerance, growth inhibition, and involucrin induction. The HEC Assay also provides information on the cytotoxicity of the agents following acute and chronic exposure. Agents were evaluated at non-toxic doses in the HEC Assay. The HEC Assay has been used to screen twenty-eight agents for chemopreventive efficacy. A positive response in one or more endpoints of the HEC Assay correlates 100% (16/16) with a positive response in one or more of the animal cancer prevention models (J. Cell. Biochem., 26S:29-53, 1996). The overall sensitivity for predicting efficacy in animals is 84%. The available data suggest that a positive assay response appears to be highly predictive of efficacy in vivo.

Animals↗
PubMedDate not supplied

Correlation of chemopreventive efficacy data from the human epidermal cell assay with in vivo data.

Continuous exposure to low doses of potentially mutagenic and carcinogenic chemicals over the human lifetime makes the identification of agents, which could reduce the ensuing risk of cancer, beneficial. The Human Epidermal Cell (HEC) Assay includes multiple exposures to low, non-toxic doses of propane sultone, which increases cellular growth and inhibits differentiation, and co-exposure to potential chemopreventive agents to determine their ability to inhibit the increased growth or increase differentiation. Original data are presented on the efficacy of twenty potential cancer chemopreventive agents were screened for efficacy in the HEC Assay. Efficacy was determined by the ability of agents, at nontoxic concentrations, to reverse either of the propane sultone-induced biomarkers, enhanced growth and reduced involucrin expression. Based on the number of positive concentrations and the lack of toxicity, 1,2-dithiol-3-thione, oltipraz, and a synthetic retinoid, Ro 16-9100, were the most active. Eleven of seventeen positive agents were active for both endpoints. S-Allylcysteine was only active for the growth inhibition endpoint, and DFMO, Iycopene, perillyl alcohol, ursodiol, and black tea polyphenols were only active for the involucrin endpoint. The three agents that have been shown to be negative in animal models, diphenhydramine, d-mannitol, and nordihydroguaiaretic acid, were correctly identified as negative by the assay. When the data from previous studies (Elmore et al, Anticancer Res, 19: 909-918, 1999) are included, a positive response in one or more endpoints of the HEC Assay correlates 100% (26/26) with a positive response in one or more of the animal cancer prevention models (8). The available data suggest that the HEC Assay response is highly predictive of efficacy in animals in vivo with an overall accuracy of 90%. Future studies will include data with additional negative agents. The correlation of the HEC Assay data with data from in vivo studies in animal models, which utilize multiple carcinogens and multiple target organs, would suggest that this in vitro assay has the ability to identify agents with the potential to prevent carcinogen-induced cancer. While our ultimate goal is to identify agents with potential efficacy for preventing human cancer, sufficient human data are not yet available to make this correlation.

Anticarcinogenic Agents↗
PubMedDate not supplied

Chemoprevention by difluoromethylornithine: correlation of an in vitro human cell assay with human clinical data for biomarker modulation.

The efficacy of difluoromethylornithine (DFMO) as a chemopreventive agent has been tested in vitro using a human epidermal cell (HEC) assay with growth inhibition and involucrin induction as endpoints. Suppression of polyamine content is currently being utilized as a biomarker in clinical trials for the chemopreventive efficacy of DFMO against colon cancer formation. We have now examined the effects of DFMO on suppression of polyamine content in the HEC assay. The findings indicate 1) the % change in spermidine to spermine ratio and the depletion of putrescine show excellent correlation with chemopreventive efficacy in vitro; 2) the effective concentrations in vitro overlap the plasma concentrations in the clinical trial. These observations serve as further validation of the usefulness of the HEC assay as a screen for chemopreventive efficacy.

Antineoplastic Agents↗