Blocking Master Switch Helps Kill Tumors

A recent study revealed that the ability of a tumor to survive radiation therapy depends to a large extent on the activity of the transcription factor hypoxia-inducible factor 1 (HIF-1).

HIF-1 is one of the key regulators of oxygen homeostasis. It regulates the physiological responses to low oxygen levels (hypoxia) and the pathophysiology of heart attack, cancer, stroke and chronic lung disease. HIF-1 is a heterodimeric protein that consists of two subunits, HIF-1a and HIF-1b. Whereas HIF-1b is continually expressed, the expression of HIF-1a is induced by oxygen concentrations below 6%. Several dozen HIF-1-regulated genes have been identified so far, including genes coding for proteins involved in angiogenesis, energy metabolism, erythropoiesis, cell proliferation and viability, vascular remodeling, and vasomotor responses.

Investigators at Duke University Medical Center (Durham, NC, USA; www.duke.edu) treated test animals with drugs that suppressed HIF-1 activity together with radiation therapy. They reported in the May 2004 issue of Cancer Cell that this treatment prevented growth of blood vessels in surviving tumor cells, which resulted in the destruction of the tumor.

"HIF-1 is the switch inside cancer cells that gets turned on by radiation therapy,” said senior author Dr. Mark Dewhirst, professor of radiation oncology at Duke University. "Once it is activated, HIF-1 then triggers the production of well-known growth factors such as VEGF and bFGF, as well as more than forty different protein signals that regulate tumor metabolism, metastasis and angiogenesis. By blocking the master switch, we effectively blocked many of the proteins which promote angiogenesis.”

"We have known that oxygen levels and blood vessel growth inside tumors are two major influences on how a tumor responds to radiation and chemotherapy,” said Dr. Dewhirst. "Now we have shown for the first time that HIF-1 is a major target we could block in combination with radiation therapy or any other therapies that causes oxygen levels to rise after treatment.”



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