Cellular radiotoxicity of iodine-123

Smit, B. S. (2000-03)

Thesis (MSc)--University of Stellenbosch, 2000.

Thesis

ENGLISH ABSTRACT: The Auger electron emitter iodine-123 was examined in the form of 4- [12311iodoantipyrineand as [12311Nal for its effectiveness in killing cells of different sensitivity to photon irradiation. Micronucleus assays showed that 4- [12311iodoantipyrineis two to three times more effective in cell inactivation than C2311Nai.This can be attributed to the fact that antipyrine, for reason of its lipid solubility, can enter cells and can reach the cell nucleus, whereas C231]Nai is excluded from the cytoplasm. The differential targeting of intra- and extracellular compartments was confirmed by radionuclide uptake experiments. In the nucleus, Auger decay conceivably is located on the DNA where it may invoke high-LET irradiation damage. Irradiation damage by [12311Naisl by long range y-irradiation and hence low-LET. Results of the present study demonstrate however that the enhancement of MN-frequency seen with 4-[123I]iodoantipyrine over [12311Nalis similar for all cell lines and that the narrowing of MN-response expected for 4- [12311iodoantipyrinedoes not occur. Experiments with the free radical scavenger, DMSO, indicated nearly identical dose reduction factors for both iodine-123 carriers. These two observations strongly suggest that the cell inactivation by 4- [12311iodoantipyrine is not by high-LET direct ionisation of DNA, but due to an indirect effect. The indirect radiation effect of Auger decay in the nucleus is attributed to shielding of DNA by histones. Such a protection mechanism is not unrealistic if it is realised that histones and DNA associate in a 1: 1 weight ratio and that higher order folding of the nucleosome chain into solenoids, loops, and chromatids generates considerable protein density. In the nucleosome core, the histone acta mer measures 7 nm and closely approximates the 10 nm dimention of the Auger electron range. It is suggested that the interlacing of protein density with DNA density suppresses direct ionisation from Auger decay at the DNA and directs the majority of Auger decay to the histones.

AFRIKAANSE OPSOMMING: Die Auger-elektron-uitstraler, jodium-123, is ondersoek in die vorm van 4- [123l]jodoantipirien en [12311Nal om die effektiwiteit te bepaal waarmee dit selle met verskillende grade van sensitiwiteit vir fotonbestraling doodmaak. Mikrokerntellings toon aan dat 4-[123I]jodoantipirien selle twee tot drie maal meer effektief inaktiveer as [12311Nal.Dit kan toegeskryf word aan die feit dat antipirien, as gevolg van sy vetoplosbaarheidseienskappe, die selle kan binnedring en die kern bereik, teenoor [12311Nalwat uitgesluit word uit die sitoplasma. Die differensiële blootstelling van intra- en ekstrasellulere gebiede is bevestig deur radionukliedopname eksperimente. In die selkern vind Auger verval waarskynlik by die DNA plaas waar dit hoë-LET stralingskade veroorsaak. Stralingskade afkomstig van [1231]Nalis deur langafstand y-strale en dus lae-LET. Die resultate van die huidige studie bewys egter dat die verhoogde mikrokernfrekwensie van 4-[12311jodoantipirienteenoor [1231]Nal dieselfde is vir al die sellyne en dat die vernouïng van mikrokernreaksie soos verwag met 4- [12311jodoantipirien, nie plaasvind nie. Eksperimente met die vryradikaalopruimer, DMSO, dui op feitlik identiese dosis-modifiseringsfaktore vir beide jodium-123 draers. Hierdie twee waarnemings is 'n besliste aanduiding dat die selinaktivering deur 4-[12311jodoantipiriennie deur hoë-LET direkte ionisering van DNA plaasvind nie, maar eerder deur indirekte stralingsaksie. Die indirekte stralingseffek van Augerverval in die kern kan toegeskryf word aan afskerming van DNA deur histone. So 'n beskermingsmeganisme is nie onrealisties nie, as in ag geneem word dat histone en DNA in 'n 1: 1 gewigsverhouding assosieer en dat hoër orde vouïng van die nukleosoomketting tot solenoïede, lusse en chromatiede 'n beduidende protïendigtheid genereer. In die nukleosoomkern is die histoon-oktameer ongeveer 7 nm in deursnit en dus vergelykbaar met die 10 nm reikafstand van die Auger elektrone. Dit word voorgestel dat die ineengeweefdheid van die protien-digtheid met die DNA-digtheid die direkte ionisering van die DNA tydens Auger verval onderdruk en dat die meeste van die Auger verval in die histone plaasvind.

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