Objective
THIS STUDY WILL USE PRIMARY HUMAN CULTURES TO STUDY THE INTERACTION BETWEEN RADIATION AND KNOWN OR SUSPECTED ENVIRONMENTAL CARCINOGENS, PROMOTORS OR MUTAGENS. THE RESPONSE WILL BE ASSESSED USING SURVIVAL AND TRANSFORMATION ENDPOINTS WITH EMPHASIS PLACED ON DESIGNING SYSTEMS TO EXAMINE TISSUES WHERE RADIATION IS A KNOWN CARCINOGEN, EG. SKIN, LUNG, BREAST AND THYROID. THIS SECTION OF THE WORK WILL RUN IN PARALLEL TO AN ASSOCIATED PROJECT CURRENTLY FUNDED BY EURATOM WHICH INVOLVES STUDYING THE EFFECT OF RADIATION ON TRANSFORMATION OF HUMAN CELLS.
The results presented indicate that low doses of carcinogens combined with low (< 5 GY) doses of radiation can stimulate the outgrowth of cells from oesophageal and urothelial tissue explants and cause the proliferation of endothelial cells. Each carcinogen shows a different pattern of dose response and growth peaks at a different combination of treatments.
In this case, nitrosamine and radiation were used in combination. It is difficult to say whether the nitrosamine was acting by protecting the cells against radiation damage or by enhancing the growth rate of survivors but the immunocytochemical evidence would suggest that proliferation of at least certain groups of cells is actively stimulated by the presence of nitrosamine during irradiation.
THE PROJECT WILL BE DIVIDED INTO THREE MAJOR SECTIONS:
SECTION 1 WILL BE CONCERNED WITH IDENTIFYING KNOWN OR SUSPECTED ENVIRONMENTAL CARCINOGENS, MUTAGENS OR COMMON POLLUTANTS WHICH FROM THEIR CHEMICAL STRUCTURE, CELLULAR FUNCTION OF FROM EPIDEMIOLOGICAL RISK ASSESSMENT SURVEYS WOULD BE LIKELY TO INTERACT WITH RADIATION. THESE SUBSTANCES INCLUDE POLYCYLIC HYDROCARBONS, BENZO(A)PYRENE AND SULPHYR DIOXIDE, DICHLOROVOS FROM INDUSTRIAL EFFLUENT, ASBESTOS - KNOWN TO POTENTIATE THE TRANSFORMING EFFECT OF RADIATION IN THE MOUSE C3H 1OT1/2 SYSTEM - AND NITROSAMINES, HEAVY METALS AND BETA PROPIOLACTONE WHICH ARE KNOWN OR SUSPECTED ENVIRONMENTAL CARCINOGENS. IT IS INTENDED TO EXAMINE THE EFFECT OF THESE CARCINOGENS AND MUTAGENS ON HUMAN TISSUES IN CULTURE FOR SYNERGISTIC EFFECTS WITH RADIATION. INITIALLY SKIN KERATINOCYTES AND INTESTINAL MUCOSA WILL BE INVESTIGATED AND LATER, AS RESULTS FROM THE ASSOCIATED PROJECT BECOME AVAILABLE, BREAST AND LUNG WILL BE STUDIED. ENDPOINTS OF RADIATION RESPONSE WILL BE SURVIVAL, INDUCTION OF IMMORTALITY, INDUCTION OF TRANSFORMED CHARACTERISTICS (SUCH AS LOSS OF ANCHORAGE DEPENDENCE, LOSS OF CONTACT INHIBITION) AND BIOCHEMICAL CHANGES. THE BIOCHEMICAL CHANGES WHICH WILL BE INVESTIGATED, BECAUSE OF THEIR ESTABLISHED LINKS WITH MALIGNANT TRANSFORMATION INCLUDE KERATIN FILAMENTS, LDH ISOENZYMES AND PHOSPHOFRUCTOKINASE ISOENZYMES, WHICH ARE KNOWN TO CHANGE IN CELLS UNDERGOING MALIGNANT CHANGE. THE RELEVANCE OF OTHER KNOWN TUMOUR AND DIFFERENTIATION MARKERS THAT HAVE BEEN DETECTED FOR ANIMAL AND EX-VIVO SYSTEMS, WILL ALSO BE ASSESSED.
SECTION 2 WHERE A CHEMICAL IS FOUND TO POTENTIATE OR REDUCE THE EFFECT OF RADIATION ON A HUMAN TARGET ORGAN IN CULTURE, A DETAILED INVESTIGATION WILL BE MADE TO ELUCIDATE MECHANISMS. THE APPROACH WHICH WILL DEPEND ON THE NATURE OF THE EFFECT, WILL INVOLVE STUDIES OF ANALOGUES OF THE CHEMICAL OF INHIBITORS OF ITS BIOLOGICAL ACTIVITIES.
SECTION 3 USING EPIDEMIOLOGICAL DATA FROM IRELAND AND EUROPE IN COMBINATION WITH RESULTS EMERGING FROM THIS STUDY, A RISK ASSESSMENT ANALYSIS AND MODEL FOR TISSUE-SPECIFIC CARCINOGENESIS WILL BE PRODUCED WITH THE AIM OF IDENTIFYING GEOGRAPHICAL AREAS WHERE A COMBINATION OF RADIATION AND CHEMICAL FACTORS MIGHT BE RESPONSIBLE FOR HIGH CANCER/MUTATION LEVELS.
Fields of science
Topic(s)
Data not availableCall for proposal
Data not availableFunding Scheme
CSC - Cost-sharing contractsCoordinator
DUBLIN 2
Ireland