As a step to reducing potentially carcinogenic exposures for the gastrointestinal (GI) tract, novel semi-permeable magnetic microcapsules are shown capable of revealing the presence in vivo of carcinogen metabolites, nitrosating agents and potentially genotoxic cross-linking agents; trapping is shown to be highly dependent upon diet in an epidemiologically-relevant manner. These versatile microcapsules could ultimately be used in molecular and nutritional epidemiology; the present proposal is focussed on establishing and validating them both for the aforementioned agents and as-yet unknown endogenous DNA- damaging agents. In the next three years, this project continuation has three aims: (a) To validate the microcapsule system in vivo using model carcinogens, nitrosating and cross-linking agents, both regarding adduct formation and its relationship to several biological end- points within and exterior to the intestine. (b) To further develop microcapsules containing target moieties (nucleic and amino acids) that can subsequently be cleaved out with their adducts for ultra-sensitive analysis (32 P-post-labelling, mass spectrometry, etc.); this takes advantage both of microcapsules as a stable vehicle for gut transit and recent analytical advances for DNA/hemoglobin adducts. (c) To apply the microcapsule to a set of GI risk-related substances (fecapentaenes, N-nitrosated bile acids, cross-linking agents) and utilise our discovery of dietary influence on trapping of carcinogens. Monitoring of the GI cavity is of high priority due to known high risk, high exposure and seemingly facile, non-invasive investigation, but no other method is available and so this microcapsule system could have many future applications within the GI tract (and e.g. environmental applications). The methodologies proposed above seem not to include any crucial unexplored steps, and mainly consist of validation and extension of preliminary work performed under previous support.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA039417-03A1
Application #
3178354
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1988-07-01
Project End
1991-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
International Agency for Research on Cancer
Department
Type
DUNS #
279551881
City
Lyon
State
Country
France
Zip Code
69372
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Alexakis, T; Boadi, D K; Quong, D et al. (1995) Microencapsulation of DNA within alginate microspheres and crosslinked chitosan membranes for in vivo application. Appl Biochem Biotechnol 50:93-106
O'Neill, I; Bingham, S; Ellul, A et al. (1993) Magnetic microcapsule exploration in the gastrointestinal cavity of the origins of colorectal cancer-associated DNA-damaging agents in the human diet. Environ Health Perspect 99:161-7
O'Neill, I; Ridgway, O; Ellul, A et al. (1993) Gastrointestinal monitoring of DNA-damaging agents with magnetic microcapsules. Mutat Res 290:127-38
Rumney, C J; Rowland, I R; Coutts, T M et al. (1993) Effects of risk-associated human dietary macrocomponents on processes related to carcinogenesis in human-flora-associated (HFA) rats. Carcinogenesis 14:79-84
O'Neill, I (1993) Reactive microcapsules for detection of carcinogen sources in the gut. J Microencapsul 10:283-308
Bingham, S A; Ellul, A; Cummings, J H et al. (1992) Novel detection by magnetic microcapsules in the human gastrointestinal tract of cross-linking agents and diet-dependent reactive oxygen species. Carcinogenesis 13:683-90
O'Neill, I; Ohgaki, H; Ellul, A et al. (1992) Entrapment by magnetic microcapsules of the protein pyrolysates IQ, PhIP and Glu-P-1, and alteration of IQ metabolite exposure within the rat gastrointestinal tract by risk-modulating components of the human diet. Carcinogenesis 13:2353-9
O'Neill, I K; Goldberg, M T; el Ghissassi, F et al. (1991) Dietary fibre, fat and beef modulation of colonic nuclear aberrations and microcapsule-trapped gastrointestinal metabolites of benzo[a]pyrene-treated C57/B6 mice consuming human diets. Carcinogenesis 12:175-80
Ellul, A; Povey, A; O'Neill, I K (1990) Presence of endogenous cross-linking/bifunctional agents in gastrointestinal cavity as detected by transit of magnetic PEI microcapsules. Carcinogenesis 11:1577-82

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