449 results on '"DiGiovanni J"'
Search Results
2. Inhibition of Chemical Carcinogenesis
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DiGiovanni, J., Cooper, Colin S., editor, and Grover, Philip L., editor
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- 1990
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3. Mitochondrial respiratory uncoupling promotes keratinocyte differentiation and blocks skin carcinogenesis
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Lago, C U, Nowinski, S M, Rundhaug, J E, Pfeiffer, M E, Kiguchi, K, Hirasaka, K, Yang, X, Abramson, E M, Bratton, S B, Rho, O, Colavitti, R, Kenaston, M A, Nikawa, T, Trempus, C, DiGiovanni, J, Fischer, S M, and Mills, E M
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- 2012
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4. Constitutive activation and targeted disruption of signal transducer and activator of transcription 3 (Stat3) in mouse epidermis reveal its critical role in UVB-induced skin carcinogenesis
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Kim, D J, Angel, J M, Sano, S, and DiGiovanni, J
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- 2009
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5. Forced expression of a constitutively active form of Stat3 in mouse epidermis enhances malignant progression of skin tumors induced by two-stage carcinogenesis
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Chan, K S, Sano, S, Kataoka, K, Abel, E, Carbajal, S, Beltran, L, Clifford, J, Peavey, M, Shen, J, and DiGiovanni, J
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- 2008
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6. Sulforaphane induces phase II detoxication enzymes in mouse skin and prevents mutagenesis induced by a mustard gas analog
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Abel, E. L., Boulware, S., Fields, T., McIvor, E., Powell, K. L., DiGiovanni, J., Vasquez, K. M., and MacLeod, M. C.
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- 2013
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7. Genetic Determinants of Cancer Susceptibility
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Angel, J.M., primary, Abel, E.L., additional, and DiGiovanni, J., additional
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- 2010
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8. Genetics of Skin Tumor Promotion
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Angel, J.M., primary and DiGiovanni, J., additional
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- 1999
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9. 7.15 - Genetic Determinants of Cancer Susceptibility
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Angel, J.M. and DiGiovanni, J.
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- 2018
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10. 559 Development of a unique biologic for treating cysteine-dependent malignancies
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Stone, E., primary, Cramer, S., additional, Saha, A., additional, Tiziani, S., additional, Digiovanni, J., additional, and Georgiou, G., additional
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- 2014
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11. Constitutive expression of insulin-like growth factor-1 in epidermal basal cells of transgenic mice leads to spontaneous tumor promotion
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DiGiovanni J, Dk, Bol, Wilker E, Beltrán L, Carbajal S, Moats S, Angel Ramirez, Jorcano J, and Kiguchi K
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Male ,Skin Neoplasms ,Recombinant Fusion Proteins ,Mice, Transgenic ,Protein Serine-Threonine Kinases ,Receptor, IGF Type 1 ,Mice ,Phosphatidylinositol 3-Kinases ,Epidermal Cells ,Gene Expression Regulation ,Proto-Oncogene Proteins ,Animals ,Humans ,Keratins ,Tetradecanoylphorbol Acetate ,Cattle ,Female ,Transgenes ,Epidermis ,Insulin-Like Growth Factor I ,Mitogen-Activated Protein Kinases ,Promoter Regions, Genetic ,Proto-Oncogene Proteins c-akt ,Skin - Abstract
Transgenic mice overexpressing insulin-like growth factor-1 (IGF-1) in the basal layer of skin epidermis were generated using the bovine keratin 5 promoter (BK5). Neonatal transgenic mice were slightly smaller at birth and exhibited early ear unfolding, wrinkled and thickened skin, and slightly enlarged ears compared with nontransgenic littermates. Morphological evaluation of the skin revealed that persistent overexpression of IGF-1 in the basal layer of the epidermis resulted in epidermal hyperplasia, hyperkeratosis, and an increased labeling index that persisted in adult mice. Phenotypic changes observed in skin were associated with transgene expression in the basal layer of the epidermis and activation of the IGF-1 receptor. Squamous papillomas (some of which converted to carcinomas) developed in a significant proportion (approximately 50%) of older BK5.IGF-1 mice. Treatment of BK5.IGF-1 transgenic mice with multiple topical applications of the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate, in the absence of tumor initiation led to the development of additional skin papillomas. Furthermore, treatment of BK5.IGF-1 transgenic mice with an initiating dose of 7,12-dimethylbenz[a]anthracene only led to the formation of additional papillomas in the absence of promotion. In two-stage carcinogenesis experiments, BK5.IGF-1 transgenic mice developed 7-fold more papillomas than nontransgenic littermates. Phosphatidylinositol-3-kinase and protein kinase B (Akt) activities were elevated (3-4-fold), and mitogen-activated protein kinase activity was elevated approximately 1.7-fold in the epidermis of transgenic mice compared with nontransgenic mice. In addition, UV light-induced epidermal apoptosis was significantly suppressed in BK5.IGF-1 transgenic mice. These data suggest that persistent activation of IGF-1 receptor signaling pathways in basal epithelial cells leads to spontaneous tumor promotion and that up-regulation of both mitogenic and cell survival signaling pathways may play an important role in the action of IGF-1 in this model system.
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- 2000
12. Genome-wide expression profiling of five mouse models identifies similarities and differences with human psoriasis
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Swindell, W.R. (William R.), Johnston, A. (Andrew), Carbajal, S. (Steve), Han, G. (Gangwen), Wohn, C.T. (Christopher), Lu, J. (Jun), Xing, X. (Xianying), Nair, R.P. (Rajan P.), Voorhees, J.J. (John), Elder, J.T. (James), Wang, X.J. (Xian Jiang), Sano, S. (Shigetoshi), Prens, E.P. (Errol), DiGiovanni, J. (John), Pittelkow, M.R. (Mark R.), Ward, N.L. (Nicole), Gudjonsson, J.E. (Johann Eli), Swindell, W.R. (William R.), Johnston, A. (Andrew), Carbajal, S. (Steve), Han, G. (Gangwen), Wohn, C.T. (Christopher), Lu, J. (Jun), Xing, X. (Xianying), Nair, R.P. (Rajan P.), Voorhees, J.J. (John), Elder, J.T. (James), Wang, X.J. (Xian Jiang), Sano, S. (Shigetoshi), Prens, E.P. (Errol), DiGiovanni, J. (John), Pittelkow, M.R. (Mark R.), Ward, N.L. (Nicole), and Gudjonsson, J.E. (Johann Eli)
- Abstract
Development of a suitable mouse model would facilitate the investigation of pathomechanisms underlying human psoriasis and would also assist in development of therapeutic treatments. However, while many psoriasis mouse models have been proposed, no single model recapitulates all features of the human disease, and standardized validation criteria for psoriasis mouse models have not been widely applied. In this study, whole-genome transcriptional profiling is used to compare gene expression patterns manifested by human psoriatic skin lesions with those that occur in five psoriasis mouse models (K5-Tie2, imiquimod, K14-AREG, K5-Stat3C and K5-TGFbeta1). While the cutaneous gene expression profiles associated with each mouse phenotype exhibited statistically significant similarity to the expression profile of psoriasis in humans, each model displayed distinctive sets of similarities and differences in comparison to human psoriasis. For all five models, correspondence to the human disease was strong with respect to genes involved in epidermal development and keratinization. Immune and inflammation-associated gene expression, in contrast, was more variable between models as compared to the human disease. These findings support the value of all five models as research tools, each with identifiable areas of convergence to and divergence from the human disease. Additionally, the approach used in this paper provides an objective and quantitative method for evaluation of proposed mouse models of psoriasis, which can be strategically applied in future studies to score strengths of mouse phenotypes relative to specific aspects of human psoriasis.
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- 2011
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13. Genome-Wide Expression Profiling of Five Mouse Models Identifies Similarities and Differences with Human Psoriasis
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Swindell, WR, Johnston, A, Carbajal, S, Han, GW, Wohn, Christian, Lu, J, Xing, XY, Nair, RP, Voorhees, JJ, Elder, JT, Wang, XJ, Sano, S, Prens, Errol, DiGiovanni, J, Pittelkow, MR, Ward, NL, Gudjonsson, JE, Swindell, WR, Johnston, A, Carbajal, S, Han, GW, Wohn, Christian, Lu, J, Xing, XY, Nair, RP, Voorhees, JJ, Elder, JT, Wang, XJ, Sano, S, Prens, Errol, DiGiovanni, J, Pittelkow, MR, Ward, NL, and Gudjonsson, JE
- Abstract
Development of a suitable mouse model would facilitate the investigation of pathomechanisms underlying human psoriasis and would also assist in development of therapeutic treatments. However, while many psoriasis mouse models have been proposed, no single model recapitulates all features of the human disease, and standardized validation criteria for psoriasis mouse models have not been widely applied. In this study, whole-genome transcriptional profiling is used to compare gene expression patterns manifested by human psoriatic skin lesions with those that occur in five psoriasis mouse models (K5-Tie2, imiquimod, K14-AREG, K5-Stat3C and K5-TGFbeta1). While the cutaneous gene expression profiles associated with each mouse phenotype exhibited statistically significant similarity to the expression profile of psoriasis in humans, each model displayed distinctive sets of similarities and differences in comparison to human psoriasis. For all five models, correspondence to the human disease was strong with respect to genes involved in epidermal development and keratinization. Immune and inflammation-associated gene expression, in contrast, was more variable between models as compared to the human disease. These findings support the value of all five models as research tools, each with identifiable areas of convergence to and divergence from the human disease. Additionally, the approach used in this paper provides an objective and quantitative method for evaluation of proposed mouse models of psoriasis, which can be strategically applied in future studies to score strengths of mouse phenotypes relative to specific aspects of human psoriasis.
- Published
- 2011
14. Stage-specific disruption of Stat3 demonstrates a direct requirement during both the initiation and promotion stages of mouse skin tumorigenesis
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Kataoka, K., primary, Kim, D. J., additional, Carbajal, S., additional, Clifford, J. L., additional, and DiGiovanni, J., additional
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- 2008
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15. Loggerhead turtle Caretta caretta density and abundance in Chesapeake Bay and the temperate ocean waters of the southern portion of the Mid-Atlantic Bight
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Barco, SG, Burt, ML, DiGiovanni Jr, RA, Swingle, WM, and Williard, AS
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Zoology ,QL1-991 ,Botany ,QK1-989 - Abstract
We conducted aerial surveys of sea turtles in 2011 and 2012, incorporating corrections for perception and availability bias in Chesapeake Bay and near-shore continental shelf waters of the Mid-Atlantic Bight off the US states of Virginia and Maryland. Results of these surveys and ancillary research to determine surface times for loggerhead turtles provide us with a new baseline population estimate for turtles in the region. Prior surveys were conducted in Chesapeake Bay in the mid-1980s and early 2000s, and in ocean waters in the late 1970s and early 1980s. Although comparison of density estimates not corrected for availability between prior surveys and this effort suggests that the population of sea turtles, especially loggerhead turtles, is higher than previous estimates, differences between surveys may be the result of survey methodologies and cannot be assumed to be true changes in density. Surface time for availability corrections was calculated using dive summaries from satellite telemetry on 27 loggerhead turtles tracked between 2011 and 2015. We calculated stratified seasonal availability corrections for bay and ocean waters based on assumed differences in turtle behavior and water clarity between the 2 habitats. For each habitat, we provided seasonal corrections for 3 detection depth bins (shallow, moderate, and deep) to account for differences in sub-surface detection ranges. Differences and trends toward differences among availability corrections underscore the need to better understand the many variables that affect surface time for sea turtles in temperate waters, and the effect that availability has on abundance and density estimates.
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- 2018
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16. Forced expression of a constitutively active form of Stat3 in mouse epidermis enhances malignant progression of skin tumors induced by two-stage carcinogenesis
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Chan, K S, primary, Sano, S, additional, Kataoka, K, additional, Abel, E, additional, Carbajal, S, additional, Beltran, L, additional, Clifford, J, additional, Peavey, M, additional, Shen, J, additional, and DiGiovanni, J, additional
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- 2007
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17. Development and initial characterization of several new inbred strains of SENCAR mice for studies of multistage skin carcinogenesis
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Coghlan, L. G., primary, Gimenez-Conti, I., additional, Kleiner, H. E., additional, Fischer, S. M., additional, Rundhaug, J. E., additional, Conti, C. J., additional, Slaga, T. J., additional, and DiGiovanni, J., additional
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- 2000
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18. Mechanism-Based Cancer Prevention Approaches: Targets, Examples, and the Use of Transgenic Mice
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Hursting, S. D., primary, Slaga, T. J., additional, Fischer, S. M., additional, DiGiovanni, J., additional, and Phang, J. M., additional
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- 1999
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19. CANCER BIOLOGY: Regression and progression characteristics of papillomas induced by chrysarobin in SENCAR mice
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Battalora, M.St J., primary, Conti, C.J., additional, Aldaz, C.M., additional, Slaga, T.J., additional, Johnston, D.A., additional, and DiGiovanni, J., additional
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- 1996
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20. 405 km of repeaterless transmission at 5 Gb/s utilizing a post-amplifier and a remotely preamplified receiver with forward error correction
- Author
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Alphonsus, J.E.J., primary, Hansen, P.B., additional, Eskildsen, L., additional, Truxal, D.A., additional, Grubb, S.G., additional, DiGiovanni, J., additional, Strasser, T.A., additional, and Beck, E.C., additional
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- 1995
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21. Further studies on the influence of initiation dose on papilloma growth and progression during two-stage carcinogenesis in SENCAR mice
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DiGiovanni, J., primary, Walker, S.E., additional, Aldaz, C.M., additional, Slaga, T.J., additional, and Conti, C.J., additional
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- 1993
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22. C57BL/6 mice are resistant to tumor promotion by full thickness skin wounding
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DiGiovanni, J., primary, S.Bhatt, T., additional, and E.Walker, S., additional
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- 1993
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23. Lack of effect of a 60 Hz magnetic field on biomarkers of tumor promotion in the skin of SENCAR mice.
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DiGiovanni, J, Johnston, DA, Rupp, T, Sasser, LB, Anderson, LE, Morris, JE, Miller, DL, Kavet, R, and Walborg, EF
- Abstract
It has been proposed that extremely low frequency magnetic fields may enhance tumorigenesis through a co-promotional mechanism. This hypothesis has been further tested using the two-stage model of mouse skin carcinogenesis, i.e. 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced promotion of skin carcinogenesis in mice initiated by a single subcarcinogenic dose of 7,12-dimethylbenz[a]anthracene. Experimentation utilized three different doses of TPA within its dose-response range (0.85, 1.70 or 3.40 nmol) and examined the following early biomarkers of tumor promotion after 1, 2 and 5 weeks of promotion: increases in epidermal thickness and the labeling index of epidermal cells, induction of epidermal ornithine decarboxylase activity and down-regulation of epidermal protein kinase C activity. Mice exposed to a 60 Hz magnetic field having a flux density of 2 mT for 6 h/day for 5 days/week were compared with mice exposed to an ambient magnetic field. Within the sensitivity limits of the biomarker methodology and the exposure parameters employed, no consistent, statistically significant effects indicative of promotion or co-promotion by the magnetic field were demonstrated. [ABSTRACT FROM PUBLISHER]
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- 1999
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24. Lack of a co-promoting effect of a 60 Hz magnetic field on skin tumorigenesis in SENCAR mice.
- Author
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Sasser, LB, Anderson, LE, Morris, JE, Miller, DL, Walborg, EF, Kavet, R, Johnston, DA, and DiGiovanni, J
- Abstract
It has been proposed that extremely low frequency (ELF) magnetic fields may enhance tumorigenesis through a co-promotional mechanism. This hypothesis has been further tested using the two-stage model of mouse skin carcinogenesis, i.e. 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced promotion of skin tumors in mice initiated by a single subcarcinogenic dose of 7,12-dimethylbenz[a]anthracene. Experimentation described herein utilized the SENCAR mouse and examined the effect of a magnetic field on skin tumor promotion induced by three different doses of TPA within its dose-response range, i.e. 0.85, 1.70 or 3.40 nmol, administered twice per week. SENCAR mice (56/treatment group) were exposed to a 60 Hz magnetic field having a flux density of 2 mT for 6 h/day for 5 days/week and compared with mice exposed to the ambient magnetic field. Tumor incidence and multiplicity were monitored weekly for 23 weeks of TPA promotion. Statistical evaluation of the effects of the magnetic field on tumor incidence and multiplicity did not reveal any statistically significant effects; thus, within the sensitivity limits imposed by the animal model and the exposure parameters employed, no promotional or co-promotional effect of a 2 mT magnetic field on skin tumor development in SENCAR mice could be demonstrated. [ABSTRACT FROM PUBLISHER]
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- 1998
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25. Papillomas at high risk for malignant progression arising both early and late during two-stage carcinogenesis in SENCAR mice.
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DuBowski, A, Johnston, DA, Rupp, T, Beltran, L, Conti, CJ, and DiGiovanni, J
- Abstract
The current study was designed to further establish that most papillomas produced in SENCAR mice during two-stage skin carcinogenesis are, in fact, premalignant lesions and to specifically determine the malignant conversion potential of papillomas that arise at different times during the carcinogenesis process. A method was established to physically map and monitor the lifespan of all papillomas produced in SENCAR mice during the course of an initiation-promotion experiment using DMBA as the initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as the promoter. The results from these experiments showed that in groups of mice initiated with either 0.5 or 2.0 μg DMBA, long-term (60 weeks) treatment with TPA yielded a significantly higher number of SCCs compared to short-term treatment (7 weeks). Papillomas that emerged after 11 weeks and thereafter in all treatment groups had the ability to progress to SCCs. The median conversion time for all papillomas in all groups was 26 weeks. When corrected for median conversion time, papillomas that emerged in week 11 and thereafter in all treatment groups had similar or greater conversion ratios compared to those that emerged within the first 10 weeks. Interestingly, the median conversion time was significantly shorter (18 versus 27 weeks, respectively; P <0.0002) for papillomas that emerged in week 11 and thereafter compared to those that emerged at or prior to 10 weeks for all groups. The data in this study demonstrate that papillomas arising throughout a two-stage carcinogenesis protocol in SENCAR mice progress to SCCs. Many papillomas that arise later in two-stage carcinogenesis protocols do not have sufficient time to allow for conversion and should be excluded from the analyses. Furthermore, another novel finding of the current study was the observation that papillomas arising later in the two-stage protocol (>11 weeks) progressed to SCCs at a faster rate than those that arose earliest in the protocol. [ABSTRACT FROM PUBLISHER]
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- 1998
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26. Analysis of two inbred strains of mice derived from the SENCAR stock with different susceptibility to skin tumor progression.
- Author
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Stern, MC, Gimenez-Conti, IB, Budunova, I, Coghlan, L, Fischer, SM, DiGiovanni, J, Slaga, TJ, and Conti, CJ
- Abstract
The SENCAR stock of mice has proved to be a useful model in dissecting out the multistage nature as well as the critical mechanisms involved in skin tumorigenesis. This outbred stock was selectively bred to be susceptible to initiation with 7,12-dimethylbenz[a]anthracene (DMBA) and promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). In order to obtain mice more suitable for genetic analyses of tumor susceptibility and tissue transplantation studies, several inbred lines of mice were derived from the SENCAR stock. One of these lines, the SSIN mice, has a higher susceptibility to tumor promotion compared to the SENCAR stock but is very resistant to tumor progression. On the other hand, the SENCAR B/Pt mice, derived also from the outbred stock, not only have a tumor promotion susceptibility almost identical to the SSIN mice, but they also have a high susceptibility to tumor progression. In order to understand the nature of the phenotypic differences between these two inbred lines we have characterized them using several parameters and markers that are associated with the progression of papillomas to squamous cell carcinoma (SCC). In this sense we analysed the tumor multiplicity and SCC incidence, and the expression of markers of progression and cell cycle related proteins in papillomas derived from both strains. Our results showed that while both strains have a similar papilloma multiplicity and incidence the SENCAR B/Pt mice have 67% incidence of SCC, compared to 0% in the SSIN. SENCAR B/Pt papillomas at 30 weeks of promotion have a higher and aberrant expression of K13, and loss of connexin 26. TGF-β1 was found to be over-expressed in the suprabasal and superficial cells in the SENCAR B/Pt papillomas, while it was only expressed in the superficial cell layer in those derived from SSIN. The SENCAR B/Pt papillomas also showed an enlarged proliferative compartment with overexpression of cyclin D1 and PCNA as seen by immunohistochemistry and Western blot. [ABSTRACT FROM PUBLISHER]
- Published
- 1998
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27. Effect of naturally occurring coumarins on the formation of epidermal DNA adducts and skin tumors induced by benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene in SENCAR mice.
- Author
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Cai, Y, Kleiner, H, Johnston, D, Dubowski, A, Bostic, S, Ivie, W, and DiGiovanni, J
- Abstract
Several naturally occurring coumarins previously found to be potent inhibitors of mouse hepatic ethoxyresorufin-O-deethylase (EROD) and/or pentoxyresorufin-O-dealkylase (PROD) were examined for their effects on formation of benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracene (DMBA) DNA adducts in mouse epidermis, as well as, their effects on skin tumor initiation by these polycyclic aromatic hydrocarbons (PAH). Bergamottin, a potent inhibitor of hepatic EROD, given topically 5 min prior to an initiating dose of B[a]P, significantly decreased total covalent binding of B[a]P to DNA in a dose-dependent manner 24 h after treatment. A dose of 400 nmol bergamottin reduced covalent binding of B[a]P by 72%. Coriandrin, at a dose of 400 nmol also significantly reduced total covalent binding of B[a]P by 59%. In addition, formation of the major (+)anti-B[a]P-diol epoxide-N2-dGuo adduct was selectively reduced by both of these coumarins. In contrast, bergamottin and coriandrin did not significantly decrease covalent binding of DMBA to epidermal DNA at doses of either 400 nmol or 800 nmol. Imperatorin and isopimpinellin, which are more potent inhibitors of hepatic PROD activity, significantly reduced overall binding of DMBA to epidermal DNA by 67% and 52%, respectively, when applied at doses of 400 nmol. These two coumarins also inhibited B[a]P-DNA adduct formation at similar doses but to a lesser extent. Imperatorin at a dose of 400 nmol dramatically decreased formation of covalent DNA adducts derived from both the anti and syn diol epoxides of DMBA. Bergamottin was a potent inhibitor of tumor initiation by B[a]P while coriandrin was less effective in this regard. Imperatorin was an effective inhibitor of skin tumor initiation by DMBA and also inhibited complete carcinogenesis by this PAH. At dose levels higher than those effective against DMBA, imperatorin also inhibited tumor initiation by B[a]P. The results demonstrate that several naturally occurring coumarins possess the ability to block DNA adduct formation and tumor initiation by PAHs such as B[a]P and DMBA. The mechanism for reduced DNA adduct formation and tumor initiation appears to involve inhibition of the P450s involved in the metabolic activation of these hydrocarbons. Finally, the differential effects of certain coumarins on B[a]P vs DMBA DNA adduct formation and tumor initiation may be useful for dissecting the role of specific cytochromes P450 in their metabolic activation. [ABSTRACT FROM PUBLISHER]
- Published
- 1997
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28. Analysis of 7-methylbenz[a]anthracene-DNA adducts formed in SENCAR mouse epidermis by 32P-postlabeling.
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Baer-Dubowska, W, Vulimiri, S V, Harvey, R G, Cortez, C, and DiGiovanni, J
- Abstract
The present study has analysed the DNA adducts formed in SENCAR mouse epidermis following topical application of 7-methylbenz[a]anthracene (7-MBA). Mice were treated with 400 nmol of 7-MBA, which represents an initiating dose of this hydrocarbon for SENCAR mice. DNA adducts were analysed 24 h after topical application of the hydrocarbon by 32P-postlabeling coupled with either HPLC analysis or an improved TLC procedure giving better resolution of DNA adducts through the use of a D6 solvent [isopropanol:4N NH4OH (1:1)] following D5. Twenty-four hours after topical application of 400 nmol 7-MBA, the level of total covalent binding was 0.37 +/- 0.07 pmol/mg DNA as determined by 32P-postlabeling. This level of binding correlated well with the relative tumor initiating activity of this hydrocarbon compared to 7,12-dimethylbenz[a]anthracene (6.4 +/- 0.01 pmol/mg DNA) and dibenz[a,j]anthracene (0.03 +/- 0.01 pmol/mg DNA). Analysis of the 32P-labeled 3',5'-diphosphodeoxyribonucleosides by HPLC and TLC revealed the presence of deoxyguanosine (dGuo) and deoxyadenosine (dAdo) adducts formed from both the anti- and syn-bay-region diol-epoxides of 7-MBA (anti- and syn-7-MBADEs). The major DNA adduct derived from 7-MBA in mouse epidermis was tentatively identified as (+) anti-7-MBADE-trans-N2-dGuo. In addition, a minor dGuo adduct derived from the bay-region syn-diol-epoxide of 7-MBA was detected as well as a minor dAdo adduct from this diol-epoxide. Another minor dAdo adduct was also detectably present which arose from either the anti- or syn-diol epoxide. Furthermore, several unidentified DNA adducts were present in both HPLC and TLC chromatograms of DNA samples from 7-MBA-treated mice. These results are discussed in terms of the role of specific 7-MBA-DNA adducts in tumor initiation by this hydrocarbon. [ABSTRACT FROM PUBLISHER]
- Published
- 1997
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29. Inhibitory effects of naturally occurring coumarins on the metabolic activation of benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene in cultured mouse keratinocytes.
- Author
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Cai, Y, Baer-Dubowska, W, Ashwood-Smith, M, and DiGiovanni, J
- Abstract
Several naturally occurring coumarins to which humans are routinely exposed have been previously found to be potent inhibitors and inactivators of cytochrome P450 (P450) 1A1-mediated monooxygenase in both murine hepatic microsomes and in a reconstituted system using purified human P450 1A1 [Cai et al. (1993) Chem. Res. Toxicol., 6, 872-879 and Cai et al. (1996) Chem. Res. Toxicol., 9, 729-736]. In the present study, several of these coumarins were investigated for their inhibitory effects on the metabolism and metabolic activation of benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracene (DMBA) in cultured mouse keratinocytes. Initial analysis of B[a]P metabolism in cultured keratinocytes showed that imperatorin, isoimperatorin, coriandrin, and bergamottin, at concentrations of 2 nM equal with B[a]P, reduced the formation of water-soluble metabolites of B[a]P by 33% to 57%. Bergamottin and coriandrin were the most potent inhibitors of the compounds examined. HPLC analysis of organic solvent-soluble metabolites of B[a]P indicated that all the coumarins tested significantly reduced the formation of individual B[a]P metabolites (including phenols, diols and tetraols). However, the greatest effect was on the formation of B[a]P tetraols. Additional experiments determined the ability of selected coumarins to block covalent binding of B[a]P and DMBA to DNA in keratinocytes. Bergamottin preferentially inhibited the binding of B[a]P to DNA by 56%, while coriandrin preferentially inhibited the binding of DMBA to DNA by 48%. Notably, analysis of individual DNA adducts formed from B[a]P and DMBA indicated that both bergamottin and coriandrin specifically inhibited the formation of anti diol-epoxide DNA adducts derived from both hydrocarbons. The preferential inhibitory effect of bergamottin and coriandrin on the formation of anti diol-epoxide adducts derived from DMBA was further confirmed by separation of anti- and syn-diol-epoxide-DNA adducts using immobilized boronate chromatography. The current study demonstrates that certain naturally occurring coumarins inhibited metabolic activation of B[a]P and DMBA in cultured mouse keratinocytes and specifically inhibited the formation of DNA adducts derived from the anti diol-epoxide diastereomers from either hydrocarbon. The current data also suggest that certain naturally occurring coumarins may possess anticarcinogenic activity toward polycyclic aromatic hydrocarbons. [ABSTRACT FROM PUBLISHER]
- Published
- 1997
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30. DBA/2 mice are as sensitive as SENCAR mice to skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate.
- Author
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DiGiovanni, J., Prichett, W. P., Decina, P. C., and Diamond, L.
- Abstract
Mice of the inbred strain DBA/2 responded to a two-stage, initiation-promotion tumorigenesis protocol when high initiating doses (400 nmol/mouse) of 7,12-dimethylbenz[a]- anthracene were utilized. They also responded when N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was used as the initiating agent. The tumor response in both cases was characterized by a rapid rate of tumor development with the maximal tumor responses reached on or before the 15th week of promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). When DBA/2 mice were compared with SENCAR mice for promotion sensitivity following initiation with MNNG, the two mouse stocks responded with a nearly identical tumor response. C57BL/6 mice were essentially resistant to TPA promotion regardless of the initiator or the dose of initiator used. A preliminary study was conducted to determine how susceptibility to tumor promotion by TPA was inherited in F mice derived from DBA/2 (sensitive) and C57BL/6 (resistant) parents. The B6D2F mice were as sensitive as the DBA/2 parent, suggesting that susceptibility in these two inbred mouse strains is inherited as an autosoma1 dominant trait. The results show that these two inbred mouse strains may provide a model system for studying genetic factors controlling susceptibility to phorbol ester skin tumor promotion. [ABSTRACT FROM PUBLISHER]
- Published
- 1984
31. Tumor promoting activity of 1,8-dihydroxy-3-methyl-9-anthrone (chrysarobin) in female SENCAR mice.
- Author
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DiGiovanni, J. and Boutwell, R.K.
- Abstract
Purified 1,8-dihydroxy-3-methyl-9-anthrone or chrysarobin was found to be an effective skin tumor-promoter in SENCAR mice, although, at the dose used, it was ˜43-fold less active than 12-O-tradecanoylphorbol-13-acetate (TPA). When non-promoting doses of chrysarobin were applied 30 min prior to each application of TPA, a marked potentiation in the promoting response to TPA was observed. Chrysarobin will provide a valuable tool for studying the mechanism of action of anthracene-derived mouse skin tumor promoters. [ABSTRACT FROM PUBLISHER]
- Published
- 1983
32. Comparison of the tumor-initiating activity of 7,12-dimethylbenz[a]anthracene and benzo[a]pyrene in female SENCAR and CD-1 mice1.
- Author
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DiGiovanni, J., Slaga, T.J., and Boutwell, R.K.
- Abstract
The derivation of mice resistant and susceptible to skin tumorigenesis using the initiation-promotion regimen is described. Dose-response relationships for tumor-initiating activities of 7,12-dimethylbenz[a]-anthracene (DMBA) and benzo[a]pyrene (BP) in the susceptible line (SENCAR) are presented. A single topical dose of either 0.1, 1.0, 10 or 100 nmol DMBA, followed one week later by twice weekly applications of 8.5 nmol 12–0-tetradecanoylphorbol-13-acetate (TPA) for 19 weeks, produced 0, 3.3, 4.9 and 23.1 papillomas per mouse, respectively. Single topical initiating doses of either 50, 100 or 200 nmol BP produced 1.7, 3.8 or 7.8 papillomas per mouse, respectively, after 28 weeks of promotion with 8.5 nmol TPA. SENCAR mice were compared with CD-1 mice for the initiating activity of DMBA and BP. Initiating doses of 0.1, 1.0, 10 and 100 nmol DMBA produced 0.6, 3.8, 7.0 and 24 papillomas per mouse, respectively, in SENCAR mice and in CD-1 mice produced 0, 0.2, 3.0 and 5.6 papillomas per mouse, respectively, after 25 weeks of promotion with TPA. With BP as the initiator, 10, 50, 100 and 200 nmol doses produced 0.9, 1.6, 3.8 and 8.3 papillomas per mouse, respectively, in SENCAR mice and in CD-1 mice produced 0.1, 0.7,1.8 and 3.8 papillomas per mouse, respectively, after 25 weeks of promotion with TPA. SENCAR mice were compared with CD-1 mice for possible differences in the oxidative metabolism of DMBA using epidermal homogenates as the enzyme source. Basal levels of monooxygenase activity toward DMBA were similar in both mouse stocks. Epidermal monooxygenase activities following pre-treatment with inducers including DMBA, 3-methylcholanthrene, dibenz[a,c]anthracene, Aroclor 1254 and 2,3,7,8-tetrachlorodibenzo-p-dioxin, also were quite similar in both mouse stocks. High-pressure liquid chromatographic profiles of ethyl acetate/ acetone (2:1) extractable metabolites revealed a close similarity in the patterns as well as the rates of formation of specific metabolites. Metabolites of DMBA tentatively identified based on cochromato-graphy with purified reference standards included phenols, 12-hydroxymethyl-7-methylbenz[a]anthracene, 7-hydroxymethyl-12-methylbenz[a]antnracene, 7,12-dihydroxymethylbenz[a]anthracene, (±)-trans-8,9-dihydro-8,9-dihydroxy-7,12-dimethylbenz[a]anthracene and (±)-trans-5,6-dihydro-5,6-dihydroxy-7,12-dimethylbenz[a]anthracene. The results suggested that differences in oxidative metabolism of DMBA were not responsible for the differences in sensitivity to tumor-initiation between SENCAR and CD-1 mice. [ABSTRACT FROM PUBLISHER]
- Published
- 1980
33. Biotransformation of 7,12-dimethylbenz [a] anthracene by mouse epidermal cells in culture.
- Author
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DiGiovanni, J., Viaje, A., Fischer, S., Slaga, T.J., and Boutwell, R.K.
- Abstract
The formation of cell- and medium-associated metabolites of 7,12-dimethylbenz[a]anthracene (DMBA) by primary mouse epidermal cells was examined using high-pressure liquid chromatography. Cells were cultured in the presence of C DMBA for various time periods prior to harvesting. Ethyl acetate/acetone (2:1) extractable metabolites found associated with cells cochromatographed with 7-hydroxymethyl-12-methylbenz[a]anthracene (7-OHM-12-MBA), 12-hydroxymethyl-7-methylbenz[a]anthracene (12-OHM-7-MBA), (±)-trans-3,4-dihydro-3,4-dihydroxy-7, 12-dimethylbenz[a]anthracene ((±)-trans-DMBA-3, 4-diol) and phenols. The major metabolite(s) found within cells cochromatographed with DMBA-phenol(s). Ethyl acetate/acetone extractable metabolites found in the medium cochromatographed with 7-OHM-12-MBA, 12-OHM-7-MBA, (±)-trans-DMBA-3,4-diol, (±)-trans-8,9-dihydro-8,9-dihydroxy-7, 12-dimethylbenz[a]anthracene ((± -trans-DMBA-8,9-diol) and phenols. The major ethyl acetate/acetone soluble metabolite found in the medium cochromatographed with (±)-trans-DMBA- 8,9-diol. This metabolite is rapidly excreted unchanged from the cells into the medium. In addition, primary epidermal cells rapidly converted C DMBA to water soluble metabolites that could not be extracted from the medium with ethyl acetate/acetone. Approximately 50% of these water soluble metabolites were extractable with organic solvent upon treatment of the medium with β-glucuronidase. Phenolic metabolite(s) represented 75–85% of the total β-glucuronidase releasable material. The results indicated that primary mouse epidermal cells in culture rapdly converted DMBA to a variety of hydroxylated products some of which were conjugated with glucuronic acid. In addition, the formation of (±)-trans-DMBA-3,4-diol and its retention within the cells provides additional support for an important role for this metabolite in carcinogenesis by DMBA. [ABSTRACT FROM PUBLISHER]
- Published
- 1980
34. Role of Cytochrome P4501 Family Members in the Metabolic Activation of Polycyclic Aromatic Hydrocarbons in Mouse Epidermis
- Author
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Kleiner, H. E., Vulimiri, S. V., Hatten, W. B., Reed, M. J., Nebert, D. W., Jefcoate, C. R., and DiGiovanni, J.
- Abstract
Polycyclic aromatic hydrocarbons (PAHs) are known to be activated by the cytochrome P450 (P450) 1 family. However, the precise role of individual P4501 family members in PAH bioactivation remains to be fully elucidated. We therefore investigated the formation of PAH−DNA adducts in the epidermis of Cyp1a2(−/−), Cyp1b1(−/−), and Ahr(−/−) knockout mice. A panel of different PAHs was used, ranging in carcinogenic potency. Mice were treated topically on the dorsal skin with the following tritium-labeled PAHs: dibenzo[a,l]pyrene (DB[a,l]P), 7,12-dimethylbenz[a]anthracene (DMBA), benzo[a]pyrene (B[a]P), dibenzo[a,h]anthracene (DB[a,h]A), benzo[g]chrysene (B[g]C), and benzo[c]phenanthrene (B[c]P). At 24 h after treatment, mice (two male and two female mice per group) were sacrificed, and epidermal DNA was isolated and hydrolyzed with DNase I; subsequently, DNA adducts were quantitated by liquid scintillation counting. In the DB[a,l]P-treated mice, levels of DNA adducts were significantly lower in Cyp1a2(−/−) and Cyp1b1(−/−) mice by 57 and 46%, respectively, as compared to wild-type (WT) mice (C57BL/6 background). The levels of DB[a,l]P DNA adducts formed in Ahr(−/−) mice were 26% lower, but this was not statistically significant. The levels of DMBA−DNA adducts in Cyp1a2(−/−) mice were not different than the WT mice but were significantly lower in Cyp1b1(−/−) and Ahr(−/−) mice by 64 and 52%, respectively. DMBA−DNA adduct samples were further analyzed by HPLC following further digestion to deoxyribonucleosides. HPLC analysis of individual DMBA−DNA adducts revealed differences in the ratio of syn-DMBA-diol epoxide- to anti-DMBA-diol epoxide-derived adducts in the Ahr(−/−) and Cyp1b1(−/−) mice. The ratio of syn-/anti-derived adducts in WT mice was 0.49. This ratio was 0.23 in the Cyp1b1(−/−) mice and 0.87 in the Ahr(−/−) mice. In contrast to the results with DB[a,l]P and DMBA, the levels of B[a]P−, DB[a,h]A−, B[g]C−, and B[c]P−DNA adducts were significantly lower in Ahr(−/−) mice by 73, 75, 50, and 81%, respectively, as compared to WT mice but were not significantly lower in the Cyp1a2(−/−) or Cyp1b1(−/−) mice. Collectively, these and other results support a role for both P4501A1 and P4501B1 in the bioactivation of DMBA; P4501A2, P4501B1, and possibly P4501A1 in the bioactivation of DB[a,l]P; and P4501A1 in the bioactivation of B[a]P, DB[a,h]A, B[g]C, and B[c]P in mouse epidermis. Furthermore, in the metabolic activation of DMBA in mouse epidermis, P4501B1 shows a preference for the formation of syn-DMBA-diol epoxide adducts, whereas P4501A1 shows a preference for the formation of anti-DMBA-diol epoxide adducts.
- Published
- 2004
35. Naturally Occurring Coumarins Inhibit Human Cytochromes P450 and Block Benzo[a]pyrene and 7,12-Dimethylbenz[a]anthracene DNA Adduct Formation in MCF-7 Cells
- Author
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Kleiner, H. E., Reed, M. J., and DiGiovanni, J.
- Abstract
Naturally occurring coumarins (NOCs) inhibit polycyclic aromatic hydrocarbon-induced skin tumor initiation in mice by blocking cytochrome P450 (P450)-mediated bioactivation of benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracene (DMBA). Bergamottin selectively inhibits tumor initiation by B[a]P, whereas imperatorin and isopimpinellin inhibit tumor initiation with both carcinogens. The goals of the current study were to examine the ability of NOCs to inhibit human P450s in vitro and to establish whether NOCs, which are anticarcinogenic in mice, can block carcinogen bioactivation in cultured human cells. For the initial experiments, incubations containing 5 μM P450, P450 substrate, an NADPH generating system, and NOCs were used to determine the concentrations of each inhibitor that blocked 50% of P450 activity (IC
50 ). These results confirmed that NOCs are capable of inhibiting multiple human P450s and that they exhibit selectivity for certain isoforms of human P450s. In subsequent experiments, we examined the effects of bergamottin, imperatorin, and isopimpinellin on DMBA and B[a]P DNA adduct formation in the human breast MCF-7 adenocarcinoma cell line. Coincubation of cells with the three different NOCs significantly inhibited DMBA DNA adduct formation by 29−82% at doses ranging from 2 to 10 μM and significantly inhibited B[a]P DNA adduct formation by 37−80% at doses ranging from 20 to 80 μM. HPLC analysis of the DNA hydrolysates demonstrated that inhibition of DNA adducts corresponded to inhibition of the major B[a]P and DMBA diol-epoxide-derived adducts. Although bergamottin was not effective at blocking DMBA bioactivation in the mouse skin model, it was similar in effectiveness to imperatorin and isopimpinellin in MCF-7 cells. These results demonstrate that NOCs, which are present in citrus fruits and other components of the human diet, are capable of inhibiting carcinogen metabolizing enzymes and blocking bioactivation of both B[a]P and DMBA in MCF-7 cells.- Published
- 2003
36. Role of Cytochrome P450 1a1 and 1b1 in the Metabolic Activation of 7,12-Dimethylbenz[a]anthracene and the Effects of Naturally Occurring Furanocoumarins on Skin Tumor Initiation
- Author
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Kleiner, H. E., Vulimiri, S. V., Reed, M. J., Uberecken, A., and DiGiovanni, J.
- Abstract
The current study was designed to determine the mechanistic basis for differences in the effects of naturally occurring furanocoumarins on skin tumor initiation by 7,12-dimethylbenz[a]anthracene (DMBA). Female SENCAR mice were pretreated topically with bergamottin, imperatorin, or isopimpinellin (100−3200 nmol), 7,8-benzoflavone (7,8-BF, 5−40 nmol, a known inhibitor of DMBA skin carcinogenesis in mice), or acetone (vehicle control) 5 min prior to topical treatment with DMBA (10 nmol). Imperatorin, isopimpinellin, and 7,8-BF, but not bergamottin, significantly blocked total DMBA-DNA adduct formation. HPLC analysis of DNA adducts revealed that bergamottin preferentially inhibited formation of anti-DMBA diol-epoxide (DMBADE) derived DNA adducts, imperatorin, and isopimpinellin inhibited both anti- and syn- derived adducts, whereas 7,8-BF showed some selectivity for reduction of syn-DMBADE-DNA adducts. Mouse embryo fibroblast C3H/10T1/2 (10T1/2) cells, and mouse hepatoma-derived 1c1c7 (Hepa-1) cells, which preferentially express P450 1b1 and P450 1a1, respectively, were co-incubated with 2 μM bergamottin, imperatorin, isopimpinellin, and 7,8-BF, and with DMBA (2 μM). Hepa-1 cells (P450 1a1) formed mainly anti-DMBADE-DNA adducts. In contrast, 10T1/2 cells (P450 1b1) formed mainly syn-DMBADE-DNA adducts. Bergamottin inhibited DMBA metabolism to DMBA-3,4-diol and blocked DNA adduct formation in Hepa-1 cells, but had little effect in 10T1/2 cells. In contrast, 7,8-BF completely blocked DMBA metabolism and DNA adduct formation in 10T1/2 cells, but had little effect in Hepa-1 cells. Imperatorin and isopimpinellin inhibited DMBA bioactivation in both cell lines. These results indicate that bergamottin is a more selective inhibitor of P450 1a1 and overall a less effective inhibitor of the metabolic activation of DMBA in mouse epidermis. In contrast, imperatorin, isopimpinellin, and especially 7,8-BF, which block metabolic activation of DMBA in mouse epidermis, appear more selective for P450 1b1. On the basis of our studies using 10T1/2 cells and Hepa-1 cells, it appears that P450 1a1 is primarily responsible for converting DMBA-3,4-diol to anti-DMBADE, whereas P450 1b1 is primarily responsible for converting DMBA-3,4-diol to syn-DMBADE. These data demonstrate the role of P450 1a1 and 1b1 in the metabolic activation of DMBA in mouse epidermis and provide a mechanistic explanation for the differential effects of naturally occurring furanocoumarins (and 7,8-BF) on polycyclic aromatic hydrocarbon skin carcinogenesis.
- Published
- 2002
- Full Text
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37. Lack of effect of 94 GHz radio frequency radiation exposure in an animal model of skin carcinogenesis.
- Author
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Mason, P A, Walters, T J, DiGiovanni, J, Beason, C W, Jauchem, J R, Dick, E J, Mahajan, K, Dusch, S J, Shields, B A, Merritt, J H, Murphy, M R, and Ryan, K L
- Abstract
Although there is no evidence that electromagnetic energy in the radio frequency radiation (RFR) band is mutagenic, there have been suggestions that RFR energy might serve as either a promoter or co-promoter in some animal models of carcinogenesis. Recent developments in electromagnetic technology have resulted in the manufacture of RFR sources capable of generating frequencies in the millimeter wavelength (MMW) range (30-300 GHz). Because absorption of MMW energy occurs in the skin, it is to be expected that long-term detrimental health effects, if any, would most likely be manifest in the skin. In this study we investigated whether a single (1.0 W/cm(2) for 10 s) or repeated (2 exposures/week for 12 weeks, 333 mW/cm(2) for 10 s) exposure to 94 GHz RFR serves as a promoter or co-promoter in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced SENCAR mouse model of skin carcinogenesis. Neither paradigm of MMW exposure significantly affected papilloma development, as evidenced by a lack of effect on tumor incidence and multiplicity. There was also no evidence that MMW exposure served as a co-promoter in DMBA-induced animals repeatedly treated with 12-O-tetradecanoylphorbol 13-acetate. Therefore, we conclude that exposure to 94 GHz RFR under these conditions does not promote or co-promote papilloma development in this animal model of skin carcinogenesis.
- Published
- 2001
- Full Text
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38. Oral administration of naturally occurring coumarins leads to altered phase I and II enzyme activities and reduced DNA adduct formation by polycyclic aromatic hydrocarbons in various tissues of SENCAR mice.
- Author
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Kleiner, H E, Vulimiri, S V, Miller, L, Johnson, W H, Whitman, C P, and DiGiovanni, J
- Abstract
Several naturally occurring coumarins, to which humans are routinely exposed in the diet, were previously found to inhibit P450-mediated metabolism of benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracene (DMBA) in vitro, block DNA adduct formation in mouse epidermis and inhibit skin tumor initiation by B[a]P and/or DMBA when applied topically to mice. The present study was designed to investigate the effects of two of these compounds, of the linear furanocoumarin type, when given orally (70 mg/kg per os, four successive daily doses), on P450 and glutathione S-transferase (GST) activities and DNA adduct formation by B[a]P and DMBA in various mouse tissues. Imperatorin and isopimpinellin significantly blocked ethoxyresorufin O-deethylase (EROD) and pentoxyresorufin O:-dealkylase (PROD) activities in epidermis at 1 and 24 h after oral dosing. Imperatorin and isopimpinellin modestly inhibited EROD activities in lung and forestomach at 1 h and significantly inhibited PROD activities in lung and forestomach at 1 h after the final oral dose. Twenty-four hours after the final oral dose of imperatorin or isopimpinellin EROD and PROD activities remained inhibited in epidermis and lung. However, forestomach P450 activity had returned to control levels. Interestingly, imperatorin and isopimpinellin treatment inhibited liver EROD activity at 1 h, had no effect on PROD activity at this time point, but elevated both these enzyme activities at 24 h. Elevated EROD and PROD activities coincided with elevated hepatic P450 content. Imperatorin and isopimpinellin treatment also increased liver cytosolic GST activity at both 1 and 24 h after the final oral dose by 1.6-fold compared with corn oil controls. Oral administration of imperatorin and isopimpinellin also had a protective effect against DNA adduct formation by B[a]P and DMBA. Imperatorin pretreatment decreased formation of DNA adducts by DMBA in forestomach. Pretreatment with isopimpinellin led to reduced DNA adduct levels in liver (B[a]P), lung (B[a]P) and mammary epithelial cells (DMBA). These results suggest that imperatorin and isopimpinellin may have potential chemopreventive effects when administered in the diet.
- Published
- 2001
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39. Characterization of the major DNA adducts in the liver of rats chronically exposed to tamoxifen for 18 months
- Author
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Firozi, P. Firoz, Vulimiri, S. V., Rajaniemi, H., Hemminki, K., Dragan, Y., Pitot, H. C., DiGiovanni, J., Zhu, Y. H., and Li, D.
- Published
- 2000
- Full Text
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40. Analysis of Highly Polar DNA Adducts Formed in SENCAR Mouse Epidermis Following Topical Application of Dibenz[a,j]anthracene
- Author
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Vulimiri, S. V., Baer-Dubowska, W., Harvey, R. G., Zhang, J.-T., and DiGiovanni, J.
- Abstract
The formation of DNA adducts in mouse epidermis has been examined following topical application of dibenz[a,j]anthracene (DB[a,j]A) and its metabolites, i.e., DB[a,j]A-3,4-diol, DB[a,j]A-3,4-10,11-bis-diol, DB[a,j]A-3,4-8,9-bis-diol, 10-OH-DB[a,j]A-3,4-diol, or 11-OH-DB[a,j]A-3,4-diol, using a 32P-postlabeling assay. At initiating doses (400−1600 nmol), DB[a,j]A produced at least 23 DNA adduct spots, including four less polar (derived from the bay-region syn- and anti-diol-epoxides) and 19 highly polar DNA adducts. DB[a,j]A-3,4-diol produced 13 DNA adduct spots, four less polar and nine highly polar DNA adducts, and DB[a,j]A-3,4-10,11-bis-diol produced nine highly polar DNA adducts. Eight and seven of the highly polar DNA adducts generated by DB[a,j]A-3,4-diol and DB[a,j]A-3,4-10,11-bis-diol, respectively, migrated in the chromatography system like the highly polar DNA adducts produced by the parent compound. Sufficient amounts of radioactivity were associated with highly polar adduct spots 11, 13, and 22 to confirm their chromatogaphic identity in DNA samples from DB[a,j]A-, DB[a,j]A-3,4-diol-, and DB[a,j]A-3,4-10,11-bis-diol-treated mice. 10-OH-DB[a,j]A-3,4-diol and 11-OH-DB[a,j]A-3,4-diol did not produce any highly polar DNA adducts that could be detected under our experimental conditions. At an initiating dose of 400 nmol, DB[a,j]A, DB[a,j]A-3,4-diol, and DB[a,j]A-3,4-10,11-bis-diol produced 22.4 ± 13.0, 15.6 ± 10.1, and 5.5 ± 0.3 (mean ± SD) adducts/109 nucleotides, of which 77, 65, and 100%, respectively, represented highly polar DNA adducts. At the same dose of 400 nmol per mouse, DB[a,j]A and its 3,4-diol were able to initiate papillomas in SENCAR mouse skin (3.08 ± 1.89 and 3.48 ± 2.72 papillomas per mouse, respectively, after 16 weeks of promotion with 12-O-tetradecanoyl phorbol 13-acetate), while the 3,4-10,11-bis-diol of DB[a,j]A was inactive as a tumor initiator. A quantitative correlation (r = 0.935; p = 0.0196) between levels of less polar DNA adducts and tumor-initiating activity of DB[a,j]A, DB[a,j]A-3,4-diol, and anti-DB[a,j]ADE was observed. This study demonstrates that the highly polar DNA adducts formed from DB[a,j]A in mouse epidermis arise primarily from the DB[a,j]A-3,4-10,11-bis-diol. However, the contribution of this metabolite to the tumor-initiating activity of DB[a,j]A appears to be small.
- Published
- 1999
41. Lack of effect of a 60 Hz magnetic field on biomarkers of tumor promotion in the skin of SENCAR mice
- Author
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Kavet, R., DiGiovanni, J., Walborg, E., Sasser, L., Anderson, L., Morris, J., Miller, D., Johnston, D., and Rupp, T.
- Abstract
It has been proposed that extremely low frequency magnetic fields may enhance tumorigenesis through a co-promotional mechanism. This hypothesis has been further tested using the two-stage model of mouse skin carcinogenesis, i.e. 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced promotion of skin carcinogenesis in mice initiated by a single subcarcinogenic dose of 7,12-dimethylbenz[a]anthracene. Experimentation utilized three different doses of TPA within its dose-response range (0.85, 1.70 or 3.40 nmol) and examined the following early biomarkers of tumor promotion after 1, 2 and 5 weeks of promotion: increases in epidermal thickness and the labeling index of epidermal cells, induction of epidermal ornithine decarboxylase activity and down-regulation of epidermal protein kinase C activity. Mice exposed to a 60 Hz magnetic field having a flux density of 2 mT for 6 h/day for 5 days/week were compared with mice exposed to an ambient magnetic field. Within the sensitivity limits of the biomarker methodology and the exposure parameters employed, no consistent, statistically significant effects indicative of promotion or co-promotion by the magnetic field were demonstrated.
- Published
- 1999
42. Lack of a co-promoting effect of a 60 Hz magnetic field on skin tumorigenesis in SENCAR mice
- Author
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DiGiovanni, J., Walborg, E., Kavet, R., Johnston, D., Sasser, L., Anderson, L., Morris, J., and Miller, D.
- Abstract
It has been proposed that extremely low frequency (ELF) magnetic fields may enhance tumorigenesis through a co-promotional mechanism. This hypothesis has been further tested using the two-stage model of mouse skin carcinogenesis, i.e. 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced promotion of skin tumors in mice initiated by a single subcarcinogenic dose of 7,12-dimethylbenz[a]anthracene. Experimentation described herein utilized the SENCAR mouse and examined the effect of a magnetic field on skin tumor promotion induced by three different doses of TPA within its dose-response range, i.e. 0.85, 1.70 or 3.40 nmol, administered twice per week. SENCAR mice (56/treatment group) were exposed to a 60 Hz magnetic field having a flux density of 2 mT for 6 h/day for 5 days/week and compared with mice exposed to the ambient magnetic field. Tumor incidence and multiplicity were monitored weekly for 23 weeks of TPA promotion. Statistical evaluation of the effects of the magnetic field on tumor incidence and multiplicity did not reveal any statistically significant effects; thus, within the sensitivity limits imposed by the animal model and the exposure parameters employed, no promotional or co-promotional effect of a 2 mT magnetic field on skin tumor development in SENCAR mice could be demonstrated.
- Published
- 1998
43. Papillomas at high risk for malignant progression arising both early and late during two-stage carcinogenesis in SENCAR mice
- Author
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DiGiovanni, J., DuBowski, A., Johnston, D., Rupp, T., Beltran, L., and Conti, C.
- Abstract
The current study was designed to further establish that most papillomas produced in SENCAR mice during two-stage skin carcinogenesis are, in fact, premalignant lesions and to specifically determine the malignant conversion potential of papillomas that arise at different times during the carcinogenesis process. A method was established to physically map and monitor the lifespan of all papillomas produced in SENCAR mice during the course of an initiation-promotion experiment using DMBA as the initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as the promoter. The results from these experiments showed that in groups of mice initiated with either 0.5 or 2.0 μg DMBA, long-term (60 weeks) treatment with TPA yielded a significantly higher number of SCCs compared to short-term treatment (7 weeks). Papillomas that emerged after 11 weeks and thereafter in all treatment groups had the ability to progress to SCCs. The median conversion time for all papillomas in all groups was 26 weeks. When corrected for median conversion time, papillomas that emerged in week 11 and thereafter in all treatment groups had similar or greater conversion ratios compared to those that emerged within the first 10 weeks. Interestingly, the median conversion time was significantly shorter (18 versus 27 weeks, respectively; P <0.0002) for papillomas that emerged in week 11 and thereafter compared to those that emerged at or prior to 10 weeks for all groups. The data in this study demonstrate that papillomas arising throughout a two-stage carcinogenesis protocol in SENCAR mice progress to SCCs. Many papillomas that arise later in two-stage carcinogenesis protocols do not have sufficient time to allow for conversion and should be excluded from the analyses. Furthermore, another novel finding of the current study was the observation that papillomas arising later in the two-stage protocol (>11 weeks) progressed to SCCs at a faster rate than those that arose earliest in the protocol.
- Published
- 1998
44. Formation of benzo(α)pyrene metabolites and DNA adducts catalyzed by a rat liver mitochondrial monooxygenase system
- Author
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Niranjan, B.G., Avadhani, N.G., and DiGiovanni, J.
- Abstract
Sonic disrupted mitoplasts from 3-methylcholanthrene (MCA) treated rats can catalize the formation of benzo(a)pyrene (BaP) adducts with calf thymus DNA in the presence of an NADPH generating system. The mitoplasts used in this study contained<1% microsomal marker enzymes: rotenone insensitive NADPH cytochrome c reductase and glucose-6-phosphatase. The rates of BaP metabolism and DNA adduct formation per nanomole cytochrome P-450 were different for MCA induced mitochondrial and microsomal enzymes. The major B(a)P DNA adducts formed in incubations with lysed mitoplasts were derived from reaction of 9-OH-B(a)P-4,5 oxide with deoxyguanosine. The results suggest a potential role of mitochondrial monooxygenase activity in the covalent binding of B(a)P to mitochondrial DNA.
- Published
- 1985
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45. The Effect of Fluoro Substituents on Reactivity of 7-Methylbenz[a]anthracene Diol Epoxides
- Author
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Baer-Dubowska, W., Nair, R. V., Dubowski, A., Harvey, R. G., Cortez, C., and DiGiovanni, J.
- Abstract
The present study has examined potential mechanisms for the influence of F-substituents on the biologic activity of methylbenz[a]anthracenes. DNA adducts derived from reaction of the racemic bay-region anti-diol epoxides of 7-methylbenz[a]anthracene, and its 9- and 10-fluoro derivatives, with calf thymus DNA in vitro were partially characterized. All three hydrocarbon diol epoxides produced similar DNA adduct profiles upon reaction with calf thymus DNA in vitro that were composed of two deoxyguanosine and two deoxyadenosine adducts (tentatively identified as trans addition products). The extent of covalent binding to calf thymus DNA, as estimated by 32P-postlabeling, was similar for all three diol epoxides. The reactivity of the unsubstituted and 10-F-substituted diol epoxide was further assessed by measuring overall pseudo-first-order rate constants for hydrolysis in water or 0.1 M Tris-HCl buffer, pH 7.0, and in the presence or absence of native or denatured DNA. The rate constant for hydrolysis of 7-methylbenz[a]anthracene diol epoxide in the absence of DNA was similar to that of 10-F-7-methylbenz[a]anthracene diol epoxide (t
1/ 2 = 138 min vs 115 min in water, respectively, and 93 vs 83 min in 0.1 M Tris-HCl buffer, respectively). In addition, the presence of DNA accelerated hydrolysis rates to similar extents for both diol epoxides. The skin tumor-initiating activities of the 9- and 10-F-substituted 3,4-diols of 7-methyl-, 12-methyl-, and 7,12-dimethylbenz[a]anthracene were determined in SENCAR mice. The presence of F-substituents in the 9- or 10-position did not enhance or in some cases reduced the tumor-initiating activity of the 3,4-diols of these hydrocarbons. Collectively, these results, as well as previous results from our laboratory, suggest that the influence of a F-substituent at position 10 of the benz[a]anthracene nucleus is not due to increased or altered reactivity of the bay-region diol epoxide but rather likely on the initial formation of the 3,4-diol.- Published
- 1996
46. Mechanism-Based Inactivation of Hepatic Ethoxyresorufin O-Dealkylation Activity by Naturally Occurring Coumarins
- Author
-
Cai, Y., Baer-Dubowska, W., Ashwood-Smith, M. J., Ceska, O., Tachibana, S., and DiGiovanni, J.
- Abstract
Several naturally occurring coumarins contained in the human diet have been found to be effective inhibitors and inactivators of murine hepatic ethoxyresorufin O-dealkylase (EROD) and pentoxyresorufin O-dealkylase in vitro [Cai, Y., Bennett, D., Nair, R. V., Ceska, O., Ashwood-Smith, M., and DiGiovanni, J. (1993) Chem. Res. Toxicol.
6 , 872−879]. In the present study, these same coumarins decreased the content of cytochrome P450 (P450) in either 3-methylcholanthrene (MC)- or phenobarbital-induced murine hepatic microsomes but did not have a major effect on heme content. Detailed in vitro studies with [14C]coriandrin, which selectively inhibits and inactivates P450 1A1-mediated EROD activity, demonstrated that it covalently bound, in a preferential manner, to hepatic microsomal protein from MC-pretreated mice. A linear relationship was observed between covalent binding and loss of EROD activity. The inclusion of electrophile trapping agents in the incubations significantly inhibited the covalent binding of [14C]coriandrin to microsomal protein. In addition, the covalent binding of [14C]coriandrin was decreased 46% by 7,8-benzoflavone (7,8-BF), 58% by a monoclonal antibody with specificity toward MC-induced form(s) of P450, and 60% by ethoxyresorufin, implicating the bioactivation of coriandrin by P450 1A1. Analysis by sodium dodecyl sulfate−polyacrylamide gel electrophoresis of [14C]coriandrin-bound microsomal protein from MC-pretreated mice showed that [14C]coriandrin bound covalently to a protein with an approximate molecular mass of 49 kDa. Again, addition of 7,8-BF or polyclonal antibody against P450 1A1 reduced the covalent binding of [14C]coriandrin to this specific protein band. Interestingly, coriandrin was also found to be a potent inhibitor and inactivator of purified human P450 1A1. These results demonstrate that certain coumarins to which humans are exposed in the diet are bioactivated by P450 1A1 to reactive intermediates that subsequently form covalent adducts with the apoprotein, effectively destroying enzyme activity. Thus, certain naturally occurring coumarins may have a significant effect on human health.- Published
- 1996
47. The effects of calcium antagonists on anthrone skin tumor promotion and promoter-related effects in SENCAR mice
- Author
-
Battalora, M. S. J., Johnston, D. A., and DiGiovanni, J.
- Published
- 1995
- Full Text
- View/download PDF
48. Regression and progression characteristics of papillomas induced by chrysarobin in SENCAR mice.
- Author
-
Battalora, M S, Conti, C J, Aldaz, C M, Slaga, T J, Johnston, D A, and DiGiovanni, J
- Abstract
The present study was designed to test the effects of a free radical generating tumor promoter, chrysarobin (1,8-dihydroxy-3-methyl-9-anthrone), on the growth and progression of papillomas generated in the skin of SENCAR mice. In the first set of experiments, papillomas were generated by initiation with 6.4 microg of 7,12-dimethylbenz[a]anthracene (DMBA) followed by promotion with once-weekly applications of 52.8 microg chrysarobin for 10 weeks. The fate of individual papillomas was then monitored for a 20 week interval following cessation of promoter treatment. Five weeks after the cessation of chrysarobin treatment, the papilloma response reached a maximum of 13.2 papillomas/mouse. By the end of the 20 week interval 19% and 18% of the papillomas had regressed or coalesced respectively. A three-stage treatment protocol was also utilized to test the ability of chrysarobin to enhance the progression of pre-existing papillomas to squamous cell carcinomas (SCCs). In stage I, mice were initiated with 0.5 microg of DMBA. In stage II, mice were promoted with twice-weekly applications of 1 or 2 microg of 12-0-tetradecanoylphorbol-13-acetate (TPA) for 15 weeks. Then, in stage III, mice were treated with acetone, TPA (1 or 2 microg), chrysarobin (52.8 microg) or benzoyl peroxide (BzPo; 20 mg) for the next 45 weeks. The mean number of papillomas per mouse at plateau was very similar for all groups. The carcinoma incidence was also similar for all groups regardless of the treatment protocol used, as was the mean number of carcinomas per mouse. The ratio of papillomas that converted to SCCs in mice treated with chrysarobin during stage III was not significantly different from the acetone controls or any of the other treatment groups (P > 0.05, Kruskal-Wallis analysis). In addition, BzPo did not enhance the progression of papillomas to SCCs under the current experimental conditions. Collectively, the results indicate that papillomas promoted by chrysarobin have growth properties similar to those promoted by TPA under similar experimental conditions. Furthermore, despite its ability to generate free radical intermediates, chrysarobin does not enhance the malignant progression of pre-existing papillomas induced by TPA treatment.
- Published
- 1996
- Full Text
- View/download PDF
49. Intragastric mefloquine is absorbed rapidly in patients with cerebral malaria
- Author
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Chanthavanich, P., Looareesuwan, S., Nicholas White, Warrell, D. A., Warrell, M. J., Digiovanni, J. H., and Bredow, J.
- Subjects
parasitic diseases - Abstract
Mefloquine has proved effective in chloroquine- and quinine-resistant falciparum malaria, but it cannot be given parenterally. We have measured the absorption of mefloquine hydrochloride suspension (mean 15.6, range 9.7-28.6 mg/kg) given by nasogastric tube to 19 cerebral malaria patients already receiving intravenous quinine. Absorption was rapid with both dose schedules used; mean absorption half-times were 1.5 and 1.8 hr, and plasma mefloquine concentrations exceeded 200 ng/g within 3 hr of completing administration in all but one exceptionally ill patient who died 40 hr later. Steady state plasma concentrations over 7 days ranged from 300 to 1,050 (mean 561) ng/g. Bioavailability of mefloquine suspension in cerebral malaria therefore appears to be adequate for treatment in all but the most severely ill patients. Although intragastric mefloquine cannot now be recommended as an alternative to intravenous quinine for the treatment of severe chloroquine-resistant falciparum malaria, this situation could change if quinine resistance increases further.
- Published
- 1985
50. Distribution of covalent DNA adducts in mouse epidermal subpopulations after topical application of benzo(a)pyrene and 7,12-dimethylbenz(a)anthracene
- Author
-
Wanda Baer-Dubowska, Rj, Morris, Rd, Gill, and DiGiovanni J
- Subjects
Acetone ,Mice ,Time Factors ,Epidermal Cells ,9,10-Dimethyl-1,2-benzanthracene ,Administration, Topical ,Benzo(a)pyrene ,Animals ,Cell Separation ,DNA ,Epidermis ,Chromatography, High Pressure Liquid ,DNA Damage - Abstract
The distribution of benzo(a)pyrene [B(a)P] and 7,12-dimethylbenz(a)anthracene (DMBA):DNA adducts was examined in five different subpopulations of SENCAR mouse epidermal cells separated based on buoyant density in continuous gradients of 61.5% Percoll. Three fractions consisted of primarily basal cells (Fractions 3 to 5), while two less dense fractions (Fractions 1 and 2) consisted of primarily differentiating keratinocytes. The levels of B(a)P and DMBA:DNA adducts were examined at 1 h, 6 h, 24 h, 72 h (except DMBA), and 28 days after a single topical application of an initiating dose. Among the basal cell subpopulations, the level of covalent B(a)P:DNA adducts in Fraction 5 cells was significantly higher (P less than 0.05) than Fractions 3 and 4 at every time point examined. On the other hand, B(a)P:DNA adduct levels in Fraction 5 were only significantly higher than Fraction 2 at 6 h and 72 h and not significantly different from Fraction 1 at any time point. With DMBA, no significant differences were initially observed in the levels of covalent DNA adducts among the various Percoll fractions at 1 h and 6 h after treatment. However, at 24 h and at 28 days. Fraction 5 cells had significantly higher (P less than 0.05) levels of covalent DMBA:DNA adducts than Fractions 1 to 4. To explore whether the observed differences in DNA adduct levels were due to differences in metabolic activation, we examined the levels of covalent adducts among epidermal subpopulations after topical application of (+/-)-anti-benzo(a)pyrene-7,8-diol-9,10-epoxide (anti-BPDE). Interestingly, 3 h after treatment with anti-BPDE, significantly higher (P less than 0.05) levels of binding were found in Fraction 5 compared with Fractions 1 to 4. High-pressure liquid chromatographic analyses of B(a)P and DMBA:DNA adducts 6 h and 24 h after treatment did not show any significant differences in adduct profiles among the various subpopulations. These results demonstrate the presence and persistence of hydrocarbon:DNA adducts in all epidermal subpopulations isolated on continuous Percoll gradients for at least 28 days after treatment. Furthermore, of the three basal cell subpopulations, the most dense cells (Fraction 5) developed the highest DNA adduct levels within 24 h and retained these higher levels over 28 days. Finally, differences in DNA adduct levels among epidermal subpopulations do not appear to result from different metabolic capabilities of the cells. The potential significance of these results is discussed in terms of the process of skin tumor initiation.
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