Hoyes, Katherine Pippin; (1992) Cellular interactions with iron chelators. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The experiments contained within this thesis have characterized the ability of desferrioxamine (DFO) and 3-hydroxypyridin-4-one (3-HP-4-one) iron chelators to enter cells and mobilise iron from intracellular iron pools. Radiolabelled 1,2,-diethyl-3-hydroxypyridin-4-one (CP94) and DFO have been used to study their cellular uptake and subcellular distribution. CP94 had rapid passage into and out of K562 erythroleukaemia cells in both the iron-free and iron-complexed form by simple diffusion. In contrast, DFO was found to enter cells by a facilitated mechanism, possibly along an electrochemical gradient, and accumulated within cells at concentrations in excess of that in the extracellular medium. Iron chelated as FO passed out of the cell relatively slowly and it is proposed that the charged nature of FO may delay its egress from the cell. Whilst the major intracellular site of chelation by both compounds was the low molecular weight cytosolic iron pool, CP94 was more efficient at mobilising iron from intracellular organelles than DFO. The effects of such iron depletion on cell function have been examined using in vivo and in vitro models of cellular proliferation. In vitro DFO and CP94 inhibited cell growth in a dose dependent manner. At chelator concentrations above 30μM this was concomitant with inhibition of DNA synthesis and ribonucleotide reductase activity. However, lower chelator concentrations exerted an inhibitory effect on cell growth that was independent of DNA synthesis suggesting that iron chelators may affect other intracellular iron dependent pathways necessary for proliferation. Unlike DFO, CP94 and other 3-HP-4-ones were found to act as potent cell cycle synchronisation agents. Inhibition of bone marrow progenitor growth in vitro was also dose dependent for DFO and the 3-HP-4-ones. Furthermore in vivo chronic administration of the chelators led to the suppression of haemopoiesis. The 3-HP-4-ones possess a greater ability to mobilise iron from cells and intracellular organelles than DFO and these findings have important implications for the use of such compounds in both iron overloaded and non-overloaded conditions.

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