The long-term aims of this research are to improve knowledge of the mechanisms of action of carcinogenic polycyclic hydrocarbons and to provide better means both for monitoring human exposure to these compounds and for evaluating the risks of that exposure. The proposed research will concentrate on five main aspects of polycyclic hydrocarbon carcinogenesis: (i) examination of the specificity of the interaction of diol-epoxides and triol-epoxides, candidate ultimate carcinogens, with proto-oncogene DNA sequences implicated in the process of malignant transformation; (ii) comparison of the metabolism and DNA adduct forming ability of active and inactive dibenztetracenes, in order to identify differences that might account for their respective activities; (iii) examination of the DNA adducts formed by complex mixtures of polycyclic aromatic hydrocarbons in order to identifY their potential genotoxic activity and to identify which components of the mixtures may be responsible for their biological activity; (iv) development of a simple procedure which, when applied to the analysis of adducts formed by complex mixtures in animal and human tissues, will facilitate a more rapid determination of the overall level of DNA adduct formation; and (v) study of the persistence of hydrocarbon-DNA adducts in rodent skin from different species in order to investigate the basis for differences in tissue and species susceptibility to carcinogenesis by polycyclic hydrocarbons. The methods to be used include in vitro metabolism by rat liver microsomal fractions, treatment of skin in vivo and of keratinocytes in vitro and mutagenicity in V79 cells. Metabolites will be synthesized by chemical-oxidation and characterized by uv and mass spectrometry. DNA adducts will be detected and quantitated using 32p-postlabelling analysis, a procedure already well established in this laboratory. High pressure liquid chromatography will assist in the metabolic studies and will be incorporated into the 32p-postlabelling assay. Proto-oncogene activation will be investigated in the NIH 3T3 cell transfection system and the sites of DNA modification by hydrocarbons and the nature of the mutations will be determined using gene amplification, oligonucleotide hybridization and DNA sequencing techniques. Since some complex mixtures of polycyclic hydrocarbons are known to cause tumours in man, improved knowledge of their biological significance and mode of action will be central to attempts to reduce the incidence of some forms of human cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA021959-14
Application #
3165676
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1977-09-01
Project End
1992-08-31
Budget Start
1990-09-06
Budget End
1991-08-31
Support Year
14
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of London
Department
Type
DUNS #
City
London
State
Country
United Kingdom
Zip Code
Phillips, D H; Alldrick, A J (1994) Tumorigenicity of a combination of psoriasis therapies. Br J Cancer 69:1043-5
Carmichael, P L; Platt, K L; She, M N et al. (1993) Evidence for the involvement of a bis-diol-epoxide in the metabolic activation of dibenz[a,h]anthracene to DNA-binding species in mouse skin. Cancer Res 53:944-8
Hughes, N C; Phillips, D H (1993) 32P-postlabelling analysis of the covalent binding of benzo[ghi]perylene to DNA in vivo and in vitro. Carcinogenesis 14:127-33
Hughes, N C; Pfau, W; Hewer, A et al. (1993) Covalent binding of polycyclic aromatic hydrocarbon components of coal tar to DNA in mouse skin. Carcinogenesis 14:135-44
Glatt, H; Wameling, C; Elsberg, S et al. (1993) Genotoxicity characteristics of reverse diol-epoxides of chrysene. Carcinogenesis 14:11-9
Pfau, W; Hughes, N C; Grover, P L et al. (1992) HPLC separation of 32P-postlabelled benzo[b]fluoranthene-DNA adducts. Cancer Lett 65:159-67
Lecoq, S; Pfau, W; Grover, P L et al. (1992) HPLC separation of 32P-postlabelled DNA adducts formed from dibenz[a,h]anthracene in skin. Chem Biol Interact 85:173-85
Marsch, G A; Jankowiak, R; Small, G J et al. (1992) Evidence of involvement of multiple sites of metabolism in the in vivo covalent binding of dibenzo[a,h]pyrene to DNA. Chem Res Toxicol 5:765-72
Carmichael, P L; Ni She, M; Hewer, A et al. (1992) DNA adduct formation in mice following treatment with used engine oil and identification of some of the major adducts by 32P-postlabelling. Cancer Lett 64:137-44
Carmichael, P L; She, M N; Phillips, D H (1992) Detection and characterization by 32P-postlabelling of DNA adducts induced by a Fenton-type oxygen radical-generating system. Carcinogenesis 13:1127-35

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