Turning an 'Achilles' Heel' into an asset--activation of HIF-1alpha during angiostatic therapy will increase tumor sensitivity to iron-catalyzed oxidative damage.

During angiostatic therapy, tumor hypoxia will activate the transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha), and will select for mutations which up-regulate the activity of this factor. This adaptation will increase tumor angiogenic capacity, while aiding the survival of poorly nourished cancer cells. A further effect of HIF-1alpha is to increase expression of transferrin receptors. The natural antimalarial drug artemisinin is selectively toxic to iron-loaded cells (such as malarial parasites), and it has recently been suggested that, inasmuch as many cancers overexpress transferrin receptors, such cancers might be treatable with a regimen comprised of iron supplementation and high-dose artemisinin. Thus, it can be anticipated that many tumors which evolve relative resistance to angiostatic therapy will be selectively susceptible to attack by the iron-loading/artemisinin strategy.