RADIOTOXICITY OF IODINE-125-LABELED OLIGODEOXYRIBONUCLEOTIDES IN MAMMALIAN-CELLS

We investigated the distribution, stability and radiotoxicity of I-125 - oligodeoxyribonucleotides (I-125-ODN) in human fibrosarcoma HT-1080 cells to study the radiotoxic effects of the Auger electron emitter I- 125 delivered to the cells by ODN. Methods: We delivered I-125-ODN int o the cells via complexing with a liposomal delivery system. To assess the intracellular distribution and stability of I-125-ODN delivered b y the liposomal delivery system, we used autoradiography, fluorescent and confocal microscopy and electrophoresis. To study the radiotoxicit y of the unbound I-125-ODN, we used a clonogenic assay. The radiotoxic ity of I-125-ODN delivered by the liposomal delivery system was compar ed with that of freely diffusible I-125-antipyrine, membrane-excluded I-125-bovine serum albumin and DNA incorporated I-125-deoxyuridine (I- 125-UdR). Results: Oligodeoxyribonucleotides accumulated in the cell n ucleus within a few hours of incubation, On the basis of the number of decays at 37% survival, I-125-ODN are 2 times more radiotoxic than I- 125-antipyrine, which is freely diffusible into cells, and 8 times mor e radiotoxic than I-125-bovine serum albumin, which remains outside ce lls. However, the radiotoxicity of unbound I-125-ODN is almost 3 order s of magnitude lower than that of DNA-incorporated I-125-UdR. The I-12 5-ODN are not significantly degraded by intracellular nucleases during the time of uptake incubation. Conclusion: The dramatic difference in radiotoxicity between I-125-ODN and 125I-UdR confirms that, despite t he nuclear localization, I-125-ODN are not bound to or incorporated wi thin the genomic DNA. Our data demonstrate that the radiotoxicity of A uger electron emitters is determined by the radiation dose delivered t o nuclear DNA, not necessarily to the nucleus. Therefore, relatively h igh intracellular concentrations of unbound I-125-ODN can be achieved without causing significant cell death.