In an earlier study, Dr. Mark W. Dewhirst and colleagues from Duke University Medical Center reported that radiation treatment increases hypoxia-inducible factor-1 (HIF-1) levels in tumors and that elevated HIF-1 can promote the resistance of tumors to radiation because it has a protective effect on tumor blood vessels. Although this work suggested that inhibition of HIF-1 would make tumors more sensitive to radiation treatment, HIF-1 can also influence tumor metabolism and growth in complex ways that were not completely understood and required further examination.
Now Dr. Dewhirst and his team report that, in addition to sensitizing blood vessels to radiation, blockade of HIF-1 also impacts multiple aspects of tumor biology in a manner that depends strongly on the local environment of the tumor cells. For proximal tumor cells that are close to blood vessels and are therefore well oxygenated, HIF-1 is unlikely to be activated, and its inhibition will probably not have any effect. However, for distal tumor cells that are both oxygen starved and lacking access to nutrients because they are farther away from the tumor vasculature, HIF-1 inhibition may actually lead to significant resistance to radiation treatment.
"If one hopes to optimize the combination of HIF-1-inhibiting and cytotoxic therapies, then, the strategy used should aim to maximize the effects of HIF-1 blockade on the vasculature while minimizing effects on the distal tumor cells. This could be achieved either through spatial or temporal selectivity of HIF-1 blockade," offers Dr. Dewhirst. This work may have important implications for the way in which HIF-1 inhibitors are used in the clinic with regards to identification of the types of tumors that are most likely to respond well to treatment and the optimal timing of combination chemotherapy and radiation therapy.
The researchers include Benjamin J. Moeller, Matthew R. Dreher, Zahid N. Rabbani, Thies Schroeder, Yiting Cao, Chuan Y. Li, and Mark W. Dewhirst of the Duke University Medical Center in Durham, North Carolina. This work was supported by funds from the Duke SPORE in breast cancer, NIH/NCI CA40355, Aeolus Pharmaceuticals, the Howard Hughes Medical Institute, and the Duke Medical Scientist Training Program.
Moeller et al.: "Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity" Publishing in Cancer Cell, Vol. 8, August 2005, pages 99-110. DOI 10.1016/j.ccr.2005.06.016 www.cancercell.org