[PDF][PDF] Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity

BJ Moeller, MR Dreher, ZN Rabbani, T Schroeder… - Cancer cell, 2005 - cell.com
BJ Moeller, MR Dreher, ZN Rabbani, T Schroeder, Y Cao, CY Li, MW Dewhirst
Cancer cell, 2005cell.com
We have previously shown that radiation increases HIF-1 activity in tumors, causing
significant radioprotection of the tumor vasculature. The impact that HIF-1 activation has on
overall tumor radiosensitivity, however, is unknown. We reveal here that HIF-1 plays an
important role in determining tumor radioresponsiveness through regulating four distinct
processes. By promoting ATP metabolism, proliferation, and p53 activation, HIF-1 has a
radiosensitizing effect on tumors. Through stimulating endothelial cell survival, HIF-1 …
Summary
We have previously shown that radiation increases HIF-1 activity in tumors, causing significant radioprotection of the tumor vasculature. The impact that HIF-1 activation has on overall tumor radiosensitivity, however, is unknown. We reveal here that HIF-1 plays an important role in determining tumor radioresponsiveness through regulating four distinct processes. By promoting ATP metabolism, proliferation, and p53 activation, HIF-1 has a radiosensitizing effect on tumors. Through stimulating endothelial cell survival, HIF-1 promotes tumor radioresistance. As a result, the net effect of HIF-1 blockade on tumor radioresponsiveness is highly dependent on treatment sequencing, with "radiation first" strategies being significantly more effective than the alternative. These data provide a strong rationale for pursuing sequence-specific combinations of HIF-1 blockade and conventional therapeutics.
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