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Biomedical subjects

C S Baxter

Publications and source records attributed to C S Baxter.

12 recordsLinked to original sources
PubMed1992

Stimulation of TGF-beta 1 mRNA concentration in mouse skin treated with benzo[a]pyrene.

Topical application of benzo[a]pyrene (B[a]P) at dose rates of 32 or 64 micrograms/week to the dorsal skin of female Swiss (ICR) mice resulted in a marked and rapid increase in concentration of RNA for transforming growth factor beta 1 (TGF-beta 1) in epidermis. Two RNA species 1.9 and 2.5 kb, detected by a mouse TGF-beta 1 cDNA probe, were coordinately expressed. The concentration of these species appeared to be maximal 6-12 h after application, and returned to control levels after 48 h. A second, less intense maximum was observed 72-96 h after treatment. Similar effects were observed in CD-1 and HRS (both hr/hr and hr/+) mice, which are also sensitive to B[a[] tumorigenesis. In comparison with 32 and 64 micrograms/week a dose rate of 16 micrograms/week was essentially without activity in increasing TGF-beta 1 RNA concentration. All three dose rates induced an increase in epidermal RNA for ornithine decarboxylase, however, and with kinetics similar to those observed with the potent tumor-promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate. The results obtained support other findings made in this laboratory, that at high dose rates above 16 micrograms tumorigenesis by B[a]P involves a strong tumor-promoting component. The latter further appears to be mediated by increased TGF-beta 1 expression.

Animals↗
PubMed1992

Carba-prostacyclin inhibits 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced transformation in sensitive murine epidermal JB6 cells.

The ability of carba-prostacyclin (cPGI2), a stable analog of prostacyclin (PGI2), to inhibit 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced transformation of JB6 cells was investigated. JB6 cells sensitive (P+) and resistant (P-) to TPA-induced transformation to anchorage-independent growth were plated in soft agar in the presence or absence of cPGI2 for 14-21 days. Transformation frequencies were determined by recording colony numbers. cPGI2 was found to inhibit TPA-induced transformation of P+ cells in a dose-dependent fashion with 1 microM cPGI2 producing approximately 50% inhibition of colonies in soft agar. Our findings are consistent with the hypothesis that TPA-induced transformation in JB6 cell variants is mediated by PGI2 via regulation of adenylate cyclase activity and cAMP accumulation, with resultant inhibition of expression of the transformed phenotype, reflected in anchorage-independent growth.

Animals↗
PubMed1992

JB6 murine epidermal cell lines sensitive and resistant to 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced transformation exhibit differential arachidonic acid metabolism in response to TPA and the calcium ionophore A23187.

In a study of arachidonic acid metabolism in murine epidermal JB6 cells, promoter-sensitive (P+) and promoter-resistant (P-) variants, labeled with [3H]arachidonic acid, were treated successively with 12-O-tetradecanoylphorbol-13-acetate (TPA) and the calcium ionophore A23187. Released radiolabel was separated by HPLC and identified by coelution of standards. Prostacyclin release was then quantified by radioimmunoassay for 6-keto prostaglandin (PG)F1 alpha. A23187 alone resulted in a small but significant enhanced release of radiolabel from both cell variants (0.7 +/- 0.2% for P- and 0.6 +/- 0.3% for P+ cells; mean +/- SD). Treatment with TPA and subsequent treatment with A23187 resulted in a synergistically enhanced release of radiolabel from both cell variants (4.1 +/- 0.8% for P- and 3.4 +/- 0.9% for P+ cells) relative to that with either agent alone. Although the predominant product for each treatment regimen was prostaglandin E2 (PGE2), the TPA-resistant cells (P-) released significantly more 6-keto PGF1 alpha, a stable breakdown product of PGI2, than did the TPA-sensitive (P+) cells. These results indicate differential arachidonic acid metabolism between JB6 cell variants resistant and sensitive to TPA-induced transformation.

6-Ketoprostaglandin F1 alpha↗
PubMed1991

Effect of tumor-promoting agents on density and morphometric parameters of mouse epidermal Langerhans and Thy-1+ cells.

Topical application of tumor-promoting agents to the dorsal skin of female SENCAR mice on a twice-weekly basis resulted in a reduction in density per unit area of bone marrow-derived Thy-1+ dendritic cells. Activity was observed for well-established tumor-promoting doses of promoting agents of several different chemical types, including 12-O-tetradecanoylphorbol-13-acetate (TPA, diterpene diester), anthralin (dihydroxyanthrone), and n-dodecane (n-alkane). A reduction in density of the same cells was also observed on the basis of the asialoGM1 lipid as a surface marker after TPA treatment. No parallel effect was observed for epidermal Langerhans (Ia+) cells, the second major epidermal immunofunctional cell type, except in the case of anthralin, a finding which is consistent with the reported toxicity of this agent. The stage 2 promoting agent mezerein was unique in inducing a consistent increase in Langerhans cell densities, but did not affect the density of Thy-1+ cells when applied for a prolonged period unless applied following four doses of TPA. In contrast to the SENCAR strain, the promotion-resistant Balb/c and C56BL/6 strains showed no response with respect to TPA-induced reduction of Thy-1+ cell density. In addition to effects on density, the above tumor-promoting agents induced morphological changes in both Thy-1+ and Langerhans cells. When these changes were placed on a quantitative basis by the calculation of shape and area fraction parameters, marked and significant effects were observed for the above agents, but not for the partial promoting agent mezerein nor the non-promoting phorbol diester 4-O-methyl-TPA. The effects of TPA were largely blocked by the potent anti-promoting agent fluocinolone acetonide, moreover. These findings further support an important role for quantitative and qualitative alterations in dendritic epidermal cells in tumor promotion.

Alkanes↗
PubMed1991

Benzo[a]pyrene-induced skin damage and tumor promotion in the mouse.

Epidermal cell kinetics and DNA adduct levels, and skin morphological changes were measured following weekly topical applications for 29 weeks of high (16, 32 and 64 micrograms) benzo[a]pyrene (B[a]P) doses to female ICR/Harlan mice, in order to investigate the relationship of these parameters to the timing, incidence and morphology of the elicited tumors. During the tumor latency period, [3H]thymidine labeling index, mitotic index, epidermal cell stacking, incidence of pyknotic and dark basal keratinocytes and labeled mitoses were periodically measured, as were nuclear area and DNA content. DNA adducts in skin epidermis were measured by an ELISA method over a period of 9 weeks of single weekly applications of 64, 32, 16 or 8 micrograms B[a]P. There was an initial linear increase in DNA adducts with dose in the epidermis but the increase was much less steep above 32 micrograms/week. This did not correlate with the sharp rise in tumor response above the 32 micrograms/week dose rate. Cell kinetic changes in response to the 64 micrograms/week dose reached a plateau in the first few weeks of the tumor latent period. There was little epidermal hyperplasia but an associated dose-dependent increase in [3H]thymidine labeling index, mitotic index and incidence of pyknotic and dark cells. This evidence indicated that B[a]P produced extensive cytotoxicity and cell death with regenerative proliferation under these conditions. Giant keratinocytes occurred in all dose groups. Analysis of a labeled mitosis curve indicated that B[a]P produced a G2/M block. There was a marked inflammatory response in the dermis at all B[a]P doses. Mice were observed weekly for tumor formation. Virtually all of the tumors were papillomas on initial appearance and required an average of 8 weeks to convert to carcinomas. The substantial cell killing and regenerative proliferation, and the correspondence between the dose-response patterns for epidermal damage and tumors, together with the initial appearance of tumors in the benign form, a characteristic of the action of promoting agents, provided evidence that the tissue damage associated with the high dose levels of B[a]P used in this study reflected tumor-promoting activity in this mouse epidermal tumorigenesis model. The implication of the results for mathematical models of tumor formation are discussed.

Animals↗
PubMed1978

Displacement and aberrant methylation in vitro of H-1 histone in rat liver nuclei after half-saturation of chromatin with polycations.

Radiomethyl incorporation in vitro into Nepsilon-methyllysine of histones from rat liver nuclei incubated in the presence of S-adenosyl[methyl-3H]methionine is stimulated if the polycations polylysines, protamines, or histones are added to the incubation mixture. Maximal stimulation occurs at a cation/nucleotide ratio of 0.5. Past this point stimulation drops, except in the case of very lysine-rich histone H-1, for which the maximal level of incorporation remains constant upon further addition of this histone. Bio-Gel P-10 chromatography, differential precipitation, and gel electrophoresis of radiomethylated histones indicate that although the usual incorporation of radiomethyl into histone H-3 is not affected, active methylation of H-1 occurs in the presence of polycations. Column chromatographic amino acid analysis reveals that the methylation of H-1 will specifically generate Nepsilon-monomethyllysine. Except for this condition, H-1 is never methylated in vivo or in incubated cell nuclei. Because H-1 is the weakest bound histone in chromatin, the above phenomena may be explained by assuming that, within the chromatin, polycations displace the lysine-rich histone towards the nucleosome, which results in its abberant methylation, assuming that the native nucleosome is the seat of the histone lysine methyltransferase.

Animals↗
PubMed1978

Effect of alkane tumor-promoting agents on chemically induced mutagenesis in cultured V79 Chinese hamster cells.

Linear alkanes of specific chain length between 6 and 16 carbon atoms, an aryl derivative of dodecane, and a phorbol diester were tested in a cell culture system for relative ability to enhance mutagenesis induced by a chemical carcinogen, methylazoxymethanol acetate (MAM). Mutation frequencies at the ouabain-resistance locus were measured. Results indicated an excellent correlation between the relative activities of the above compounds in enhancing mutagenesis in the in vitro culture system and their tumor-promoting activities in mouse skin. None of the compounds tested showed mutagenic activity per se, further lending support to the theory that promoters act via derepression of latent carcinogen-induced damage to the genome.

Alkanes↗
PubMed1976

Myocardial infarction in car assembly workers.

The incidence of myocardial infarction and the return to work for survivors were studied among the employees of an English car assembly plant by analysing 12 811 medical records of persons employed during the seven years between January 1966 and December 1972. The standardized morbidity ratio of myocardial infarction found in this study calculated on the basis of incidence rates reported by Kinlen )1973) for the Oxford community in which the factory was situated was 90. The standardized morbidity ratio from production line workers only was 66 and that for the monthly paid staff 272. Of the production line workers who survived the attack 22 (90%) returned to their previous jobs without undue difficulty and with two exceptions within four months of the onset of their illness; there was no relation between length of absence and age at the time of attack. These findings suggest that workers in mass production jobs such as car assembly are not special risk from myocardial infarction, and most of those who survive a heart attack are able to return to their former work. Taken with Kinlen's (1973) study and that of Armstrong et al. (1972) in Edinburgh, they also bear out mortality data by indicating that in Oxfordshire the incidence of coronary heart disease is lower than the British average.

Absenteeism↗