Cancer cells have a high requirement for
iron (Fe) as it plays a crucial role in a variety of metabolic processes including energy production and
DNA synthesis. Studies in vitro and in vivo have demonstrated that the Fe
chelator in current clinical use,
desferrioxamine (DFO), can effectively inhibit the growth of some
neoplasms, including
leukemia and
neuroblastoma. Unfortunately, DFO suffers from a number of serious disadvantages, including its high cost, the need for prolonged
subcutaneous infusion (12-24 h/day, 5-6 nights/week), and its poor intestinal absorption precluding
oral administration. Hence, the development of more effective Fe
chelators is necessary. The Fe
chelator,
pyridoxal isonicotinoyl hydrazone (PIH), was initially identified as a
ligand that showed high activity at mobilizing Fe from cells. More recently, a range of PIH analogues have been examined for their anti-proliferative effect, with several classes of these compounds showing high activity at inhibiting
tumor growth in vitro. In fact, some of these
hydrazones, particularly those derived from 2-hydroxy-1-naphthylaldehyde, showed comparable activity to the cytotoxic drugs cis-platin and
bleomycin. In this review the role of Fe in cellular proliferation will be examined followed by a description of the most recent studies using the PIH analogues as effective anti-proliferative agents. Further studies in vivo with these Fe
chelators are essential to determine their potential as chemotherapeutic agents.