Iron toxicity and its possible association with treatment of Cancer: lessons from hemoglobinopathies and rare, transfusion-dependent anemias

Exposure to elevated levels of iron causes tissue damage and organ failure, and increases the risk of cancer. The toxicity of iron is mediated through generation of oxidants. There is also solid evidence indicating that oxidant stress plays a significant role in a variety of human disease states, including malignant transformation. Iron toxicity is the main focus when managing thalassemia. However, the short- and long-term toxicities of iron have not been extensively considered in children and adults treated for malignancy, and only recently have begun to draw oncologists' attention. The treatment of malignancy can markedly increase exposure of patients to elevated toxic iron species without the need for excess iron input from transfusion. This under-recognized exposure likely enhances organ toxicity and may contribute to long-term development of secondary malignancy and organ failure. This review discusses the current understanding of iron metabolism, the mechanisms of production of toxic free iron species in humans, and the relation of the clinical marker, transferrin saturation (TS), to the presence of toxic free iron. We will present epidemiological data showing that high TS is associated with poor outcomes and development of cancer, and that lowering free iron may improve outcomes. Finally, we will discuss the possible relation between some late complications seen in survivors of cancer and those due to iron toxicity.