Iron Chelator Research: Past, Present, and Future

Abstract

The occurrence of in vivo iron toxicity in the human body can be categorized into iron overload and non-iron overload conditions. Iron overload conditions are common in beta-thalassemia and hereditary hemochromatosis patients, and anthracycline mediated cardiotoxicity is an example of a non-iron overload condition in cancer patients, in which the toxicity is iron-dependent. While hundreds of iron chelators have been evaluated in animal studies, only a few have been studied in humans. Examples of iron chelator drugs are desferrioxamine (DFO), deferiprone (L1), and dexrazoxane (ICRF 187). The compound ICL670 has completed phase II clinical trials and a phase III trial is planned in 2003. Triapine is currently in phase II clinical trial as an anticancer agent. CP502, GT56-252, NaHBED, and MPB0201 are examples of new chelators in preclinical/clinical development. In the past decade, many new viable utilities for iron chelators have been reported. This includes the use of iron chelators as antiviral, photoprotective, antiproliferative, and antifibrotic agents. This review will focus on the status of drug development for the treatment of iron overload in patients with beta-thalassemia and the potential use of iron chelators in the prevention and treatment of other diseases.

Iron Deprivation Suppresses Hepatocellular Carcinoma Growth in Experimental Studies

“…The amount of protein was quantified by densitometry, normalized to the amount of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and shown below. evaluated in clinical trials for cancer therapy (33,34), mainly because of the low efficiency of iron chelation in vivo as well as the toxicity. More effective chelators have now been developed.…”

A Ferrous-triapine complex mediates formation of reactive oxygen species that inactivate human ribonucleotide reductase

“…The effects of ROS on DNA, proteins, and other biomolecules are well documented (28). In vivo, ROS are toxic to proteins other than ribonucleotide reductase causing side effects, such as methemoglobinemia and hypoxia, which result in acute symptoms in patients with limited pulmonary or cardiovascular reserve (18).…”

A multifunctional cytoprotective agent that reduces neurodegeneration after ischemia

“…It is also superior to the manganese superoxide dismutase mimetic M40401, which is reported to reduce MCAoinduced infarct volume by 73% when animals are pretreated but fails to reduce lesion volume significantly when administered subsequent to MCAo (27). The superior efficacy of PAN-811 in blocking both acute and delayed neurodegeneration, its low neural toxicity, dual functions of calcium chelation and free radical scavenging, potent neuroprotection in vivo, known human safety profile (10,11,21), and favorable therapeutic window suggest a significant potential for PAN-811 as a neuroprotective agent for use in stroke and certain chronic neurodegenerative disorders.…”

“…PAN-811 itself is currently under investigation in several phase II clinical trials for cancer therapy (11). HCTs are efficient chelators of metal ions and are known as potent ribonucleotide reductase inhibitors that function via quenching a tyrosyl free radical required for enzymatic function (12).…”