Improving Radiation’s Effectiveness with Anti-Angiogenic Drugs

By Rachael Myers Lowe

(December 20, 2004) - Timing is critical. That"s the conclusion of researchers investigating cancer therapies that combine radiation with drugs that limit a tumor"s ability to grow new blood vessels.

Despite promising tests in laboratory animals, anti-angiogenesis drugs have shown mixed results in slowing tumor growth in humans. It"s been necessary to combine such agents with either chemotherapy or radiation to get good anti-tumor results. Dr. Rakesh K. Jain, from the Steele Laboratory for Tumor Biology at Massachusetts General Hospital in Boston, and colleagues, sought to better understand why this is. They have published their findings in the December 20 issue of Cancer Cell.

Tumors need new blood vessels to grow. But while the process of blood vessel growth in normal tissue is orderly, in tumors, it is chaotic and uneven, and the resulting web of new blood vessels has areas of weakness. The delivery of oxygen and nutrients to the tumor is uneven. In the same way, delivery of chemotherapy drugs or cell-damaging radiation induced free-radicals to the tumor is uneven too.

Anti-angiogenic drugs tend to weed out a tumor"s poorly performing blood vessels and, for a short time anyway, direct resources to shoring up growth of stronger blood vessels. After the drug is administered there"s a period of time when a tumor enjoys an improved quality of mature blood vessels better able to deliver oxygen, nutrients, and, paradoxically, anti-tumor therapies to the tumor. This period of time is called the "normalization window."

The window, according to Jain, is not open long. About 8 days after the anti-angiogenic treatment is started, the tumor establishes workarounds to counteract the drug’s effects and new blood vessel growth picks up again.

This window of normalization is the window of opportunity for attacking a tumor most effectively with radiation, Jain believes even though his work dealt exclusively with radiation ant-cancer therapy, the principal should hold true for chemotherapy too.

Studying the process in mice, Jain and colleagues found that when radiotherapy was administered four days after the beginning of anti-angiogenic treatment, tumor growth was slowed considerably.

“What we discovered in this paper is that this duration is not infinite, it’s finite,” Jain told cancerpage.com “It starts on day two after treatment with anti-angiogenic therapy begins and it goes back after about day eight so you have about five to six days.”

Jain says his group’s work suggests patients could benefit from a regimen that included pre-treatment with anti-angiogenic therapy two days before radiotherapy. But he cautions, clinical trials must be conducted to test the theory before he’d recommend this treatment for patients. 

Jain says he expects to begin a trial in humans the second half of 2005.

SOURCES:  

• Cancer Cell, Volume 6, Number 6, December 2004, pages 553-563.
• Cancerpage telephone interview with Dr. Rakesh K. Jain, 12-20-04.