Abstract

Introduction

Materials & Methods

Results

Discussion & Conclusion

References

Discussion
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Neoplastic cells are often characterised by their ability to proliferate at a rapid rate. Iron (Fe) is an essential growth factor, being part of the active site of the enzyme ribonucleotide reductase, which is rate limiting in DNA synthesis. Since it was first observed that growth of malignant cells is inhibited when cells are cultured without diferric transferrin, Fe depletion has become a potential therapeutic avenue for the treatment of cancer.

Iron chelators have long been investigated as therapeutic agents for diseases of Fe overload, but it is only recently that their potential as anti-neoplastic agents has become apparent. Desferrioxamine (DFO) is used clinically as a chelator of Fe in disorders of Fe overload, but it has also been demonstrated to inhibit cellular proliferation and colony formation in the leukemia cell line HL-60 (Kaplinsky et al., 1987). Subsequent studies have reported a similar effect of DFO on several tumor cell types (eg Becton and Bryles, 1988; Blatt et al.,1988; Nastruzzi et al.,1989; Donfrancesco et al.,1990; Hann et al.,1990; Kemp et al.,1990; Richardson et al.,1994). The antiproliferative effects of DFO on tumor cell growth has also been demonstrated in vivo(Estrov et al 1987).

Other Fe chelators besides DFO are also being examined for their antineoplastic activity. These include parabactin (Teatle et al.,1989), alpha-ketohydroxypyridinones (eg Blatt et al.,1989) and pyridoxal isonicotinoyl hydrazone (PIH) and its analogues (Richardson et al.,1995). Besides their high binding affinity for iron in the ferric and/or ferrous form, other properties such as size and membrane permeability may influence the site and mechanism of Fe chelation. This is a preliminary report on a study designed to investigate the effects of a number of compounds representing different classes of chelators on cell proliferation and Fe uptake by hepatoma cells.

The chelators assessed included desferrioxamine mesylate, (DFO, hydroxamic acids), pyridoxal isonicotinoyl hydrazone (PIH, hydrazones), 1,2-dimethyl-3-hydroxypyridin-4-one (L1, alpha ketohydroxypyridinones), diethylenetriaminepenta-acetic acid (DTPA) and ethylenediaminetetra-acetic acid (EDTA) (polyanionic amines) and the ferrous chelators bathophenanthroline-disulphonic acid (BPS) and alpha alpha-dipyridine (DP). The effects of chelators on Fe uptake in normal rat hepatocytes were also assessed to detect any selectivity of action for cancer cells.

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