Obiettivo Exocyclic base adducts in human DNA such as the etheno (epsilon) adducts epsilon dA and epsilon dC are formed by environmental and endogenous genotoxins that are generated from oxidative stress, dietary factors and metal storage diseases. A third epsilon-adduct, epsilon dG, has been detected in rodent tissues upon exposure to epsilon-adduct forming chemicals. To assess the role of these promutagenic DNA lesions in human malignant diseases, four representatives of epsilon-adduct generating chemicals (trans-4-hydroxy-2-nonenal,2-chloro-acetaldehyde, chloro-ethylene oxide and vinyl carbamate, a reactive metabolise of urethane) will be investigated by the following approaches: (i) Quantification of epsilon dA and epsilon dC in cell/tissue DNA of humans, mice, Drosophila and E. cold by ultrasensitive methods, recently developed by study partners; development of a new sensitive method for analysis of epsilon dG in human DNA. (ii) Studies on diet-related formation of epsilon-adducts in rodents, and the proportionality between epsilon-adducts in DNA of white blood cells vs. those in breast and colon; comparison of DNA epsilon-adduct levels and repair activities in lung tissues and lymphocytes from lung cancer patients. (iii) Identification and purification of repair enzymes that remove of epsilon dG and epsilon dC in human cells and in E. coli; construction of E. cold repair-deficient strains for defining mutation specificity of epsilon bases; correlation of the persistence/repair of epsilon-bases with biological endpoints (free radical induced cytotoxicity; cancer) measured in knock-out mice deficient in repair (ADPRT) and tumor supressor (p53) genes. (iv) Development of methods for analyzing formation/repair of DNA epsilon-adducts at specific target gene (p53) and at nucleotide resolution level. (v) Dosimetry-based comparisons, particularly at low doses, of SCE's, chromosome aberrations, micronuclei and hprt-mutations in human hepatoma cells, and of several genetic endpoints in Drosophila; characterization of mutation spectra in hprt (hep-g2) and in vermilion/rosy genes (Drosophila). (vi) Carcinogenic risk assessment in humans, qualitative and quantitative structure-activity relationships (QSAR's, SAR's). Campo scientifico natural sciencesbiological sciencesgeneticsDNAmedical and health sciencesclinical medicineoncologylung cancernatural sciencesbiological sciencesgeneticsmutationnatural sciencesbiological sciencesgeneticsnucleotidesnatural sciencesbiological sciencesgeneticschromosomes Programma(i) FP4-ENV 2C - Specific programme of research and technological development in the field of environment and climate, 1994-1998 Argomento(i) 02020101 - Risks to human health Invito a presentare proposte Data not available Meccanismo di finanziamento CSC - Cost-sharing contracts Coordinatore GERMAN CANCER RESEARCH CENTER Contributo UE Nessun dato Indirizzo Im Neuenheimer Feld 280 69120 HEIDELBERG Germania Mostra sulla mappa Costo totale Nessun dato Partecipanti (3) Classifica in ordine alfabetico Classifica per Contributo UE Espandi tutto Riduci tutto CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE Francia Contributo UE Nessun dato Indirizzo 39,Rue Camille Desmoulins 39 94805 VILLEJUIF Mostra sulla mappa Costo totale Nessun dato INTERNATIONAL AGENCY FOR RESEARCH ON CANCER Francia Contributo UE Nessun dato Indirizzo 150,Cours Albert-Thomas 150 69372 LYON Mostra sulla mappa Costo totale Nessun dato Rijksuniversiteit Leiden Paesi Bassi Contributo UE Nessun dato Indirizzo 72,Wassenaarseweg 2300 RA Leiden Mostra sulla mappa Costo totale Nessun dato
