Objetivo
The major conclusions from the study are that quantitative data on tumour frequency can be obtained for limited lines of human cells which have already been immortalised. These lines are useful for evaluating radiation risks for smokers, patients with HPV 16 lesions and others with environmental carcinogen exposure and for studying mechanisms or relative effects. The primary human systems can give quantitative information on frequency of relevant early events and inter-individual variation. An approach integrating data from both types of system offers a real alternative to animal models.
QUANTITATIVE ESTIMATION OF CANCER RISK IS A MAJOR PROBLEM IN RADIATION PROTECTION ESPECIALLY AT LOW DOSES. THERE IS VERY LITTLE DATA AVAILABLE ABOUT LOW DOSE EXPOSURE TO HUMAN POPULATIONS. EXTRAPOLATION MUST BE MADE FROM EXISTING HIGH DOSE DATA OR FROM ANIMAL EXPERIMENTS. THE DEVELOPMENT OF NEW SYSTEMS BASED ON ORGANISED CELLS IS ESSENTIAL IF THE RISKS OF CANCER INDUCTION ARE TO BE QUANTIFIED IN A HUMAN POPULATION.
RECENTLY IT HAS BEEN SUGGESTED THAT A RELATIVE RISK MODEL FOR RADIATION INDUCED CANCER IN HUMANS PROVIDES A BETTER FIT TO THE EPIDEMIOLOGICAL DATA THAN AN ABSOLUTE RISK MODEL. THIS HAS IMPORTANT IMPLICATIONS FOR THE DEVELOPMENT OF HUMAN EXPERIMENTAL SYSTEMS, AS IT PROVIDES EVIDENCE THAT RADIATION FORMS PART OF A GENERAL MECHANISM OF CARCINOGENESIS, AND NEED NOT CAUSE ALL THE STEPS ITSELF.
THE PARTNERS IN THIS PROPOSAL ARE WORKING TOWARDS A CUMULATIVE FREQUENCY MODEL. THE BASIS OF THIS MODEL IS THAT THE CARCINOGENIC PROCESS CAN BE DIVIDED INTO A SERIES OF STEPS INVOLVING DISCRETE CELLULAR CHANGES. USING THIS MODEL INITIAL EVENTS CAN BE STUDIED ON HUMAN PRIMARY CULTURES, PROMOTION CAN BE STUDIED ON ALREADY INITIATED CULTURES, AND PROGRESSION CAN BE STUDIED IN ORGANOTYPIC CULTURE OR IN MOUSE XENOGRAFTS. THIS ALLOWS PROBABILITIES TO BE OBTAINED FOR THE VARIOUS STAGES OF THE CARCINOGENIC PROCESS, AND A CUMULATIVE PROBABILITY TO BE OBTAINED FOR THE COMPLETE PROCESS.
THE APPROACH TO BE USED WILL BE TO IDENTIFY OR DEVELOP IN VITRO SYSTEMS WHICH DEMONSTRATE VARYING DEGREES OF ADVANCEMENT ALONG THE CARCINOGENESIS PATHWAY AND TO QUANTIFY THE EFFECTIVENESS OF RADIATION IN CAUSING CERTAIN WELL-ESTABLISHED EVENTS IN CARCINOGENIC DEVELOPMENT. THESE WILL INCLUDE P53 OR RB MUTATION AND ALLELIC DELETION, ACQUISITION OF INVASIVE POTENTIAL OR EXPRESSION OF THE MNI GENE, WHICH IS RELATED TO METASTATIC POTENTIAL.
THIS APPROACH WILL PERMIT QUANTITATIVE DATA ON THE CARCINOGENICITY OF RADIATION TO BE OBTAINED WITHOUT THE MANDATORY RELIANCE ON DEMONSTRATION OF OVERT CANCER PRODUCTION IN A DIFFERENT SPECIES. THIS LAST APPROACH HAS PROVED TO BE MOST UNREWARDING OVER THE PAST 30 ODD YEARS.
Ámbito científico
Programa(s)
Tema(s)
Data not availableConvocatoria de propuestas
Data not availableRégimen de financiación
CSC - Cost-sharing contractsCoordinador
8 DUBLIN
Irlanda