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MOLECULAR AND CELLULAR MECHANISMS OF NEOPLASTIC CELL TRANSFORMATION

Objective

IN THIS RESEARCH PROGRAMME, MOLECULAR AND CELLULAR MECHANISMS INVOLVED IN THE RADIATION INDUCED CARCINOGENESIS WILL BE STUDIED. IT IS GENERALLY ACCEPTED, THAT CANCER IS THE RESULT OF A TRANSMISSIBLE TRANSFORMATION OF THE CELL WHICH THEREBY BECOMES CAPABLE OF DEVELOPING A TUMOUR UNDER THE INFLUENCE OF PROMOTING FACTORS. TO UNDERSTAND THE REACTION CHAIN LEADING TO CELL TRANSFORMATION, THE STRUCTURAL DAMAGE OF THE DNA SHOULD BE CONSIDERED WHICH IS FOLLOWED BY ITS REPAIR, EITHER ERROR FREE OR ERROR PRONE. THESE EVENTS PROBABLY DETERMINE ALL THE BIOLOGICAL EFFECTS OF RADIATION SUCH AS CELL DEATH, MUTATION AND TRANSFORMATION. AMONG OTHER MECHANISMS, THE TRANSPOSITION (TRANSLOCATION) OF ONCOGENS AND/OR THE MOVEMENT OF CERTAIN VIRAL ENHANCER ELEMENTS (FOR INSTANCE RETROVIRUSES) NEAR TO OR INTO THE PROMOTOR REGIONS OF SILENT CELLULAR ONCOGENES HAVE BEEN DISCOVERED AS ONE MOLECULAR BASIS OF NEOPLASTIC CELL TRANSFORMATION. IN THIS WAY, THERE IS AN ACTIVATION OF ONCOGENES AND NEOPLASTIC CELL TRANSFORMATION MAY OCCUR.
OUR RESEARCH PROGRAMME ABOUT THE MECHANISMS LEADING TO RADIATION INDUCED CELL TRANSFORMATION SHOULD SIMULTANEOUSLY ANALYSE BOTH EVENTS, I.E. THE INDUCIBILITY OF TRANSPORTATION OF GENE ELEMENTS AS WELL AS APPARENT CELL TRANSFORMATION ITSELF. IN THIS WAY, THE GENETICS EVENTS MAY BE COMPARED WITH THE RELEVANT RADIOBIOLOGICAL MORPHOLOGICAL PHENOTYPE. WHEREAS SEVERAL STUDIES HAVE ALREADY BEEN PERFORMED ON RADIATION INDUCED CELL TRANSFORMATION, ONLY A LITTLE INFORMATION IS AVAILABLE ABOUT RADIATION INDUCED TRANSPOSITION OF GENE ELEMENTS. IT IS THE AIM OF THIS - LONG TERM - RESEARCH PROGRAMME, TO STUDY THE RELEVANT RADIOBIOLOGICAL PROBLEMS OF CARCINOGENESIS ON BOTH OF THESE SYSTEMS.
In order to rule out the possibility that the further reduction in neoplastic cell transformation frequency caused by protracting irradiation over several days was due to a decrease in transformation sensitivity as cells divide after plating, experiments were performed with high dose rate irradiation given either 6, 16, 24 or 48 hours after plating, but no significant difference in transformation frequency was found. Therefore, it is concluded that there is a significant sparing effect on cell transformation at very low dose rate.
IN THE FIRST STAGE OF THE PROGRAMME, YEAST (SACCHAROMYCES CEREVISIAE) WILL BE USED TO STUDY THE TRANSPOSITION OF GENETIC ELEMENTS BASED ON ITS WELL KNOWN GENETIC BACKGROUND. ONE MEMBER OF THE COPIA-RETROVIRUS-TY FAMILY WILL SERVE AS A SUITABLE MODEL FOR THE GENETIC BEHAVIOUR OF TRANSPORTABLE ELEMENTS IN MAMMALIAN CELLS. YEAST ARE EUKARYOTES NOT ONLY BY SYSTEMATIC DEFINITION, BUT RESEARCH HAS PROVEN THAT MANY FUNDAMENTAL FUNCTIONS CAN BE CORRELATED BETWEEN THE HIGHER EUKARYOTES SUCH AS VERTEBRATES/MAMMALS AND THE LOWER EUKARYOTE YEAST.
IN DETAIL, IN YEAST, THE TRANSPOSITION OF TY-ELEMENTS FROM AND INTO THE PROMOTOR REGION OF THE ALCOHOLDEHYDRASE II WHICH WAS FOUND IN PRELIMINARY EXPERIMENTS TO BE HIGHLY INDUCIBLE BY IONIZING RADIATION WILL BE ANALYSED. IN A LATER STAGE OF THE RESEARCH PROGRAMME, THE GENETIC STUDIES ABOUT TRANSPOSABLE ELEMENTS ARE PLANNED TO BE EXTENDED ON SYSTEMS WITH MAMMALIAN CELLS. CELL TRANSFORMATION WILL BE STUDIED IN C3H/10T1/2 CELLS.
THE FOLLOWING RELEVANT PROBLEMS OF THE RADIATION INDUCED CARCINOGENESIS WILL BE STUDIED ON BOTH SYSTEMS IN COMPARISON:
A. SHAPE OF THE DOSE EFFECT CURVE.
B. EFFECT OF DOSE RATE AND DOSE FRACTIONATION.
C. EFFECT OF A COMBINED EFFECT OF RADIATION WITH CHEMICALS.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

GSF - FORSCHUNGSZENTRUM FUER UMWELT UND GESUNDHEIT GMBH
Address
Ingolstaedter Landstrasse 1
85764 Neuherberg
Germany