DENVER-Research on angiogenesis is revealing the role this phenomenon plays in the response of cancers to radiation and, in the process, providing some important lessons for clinicians, according to a keynote address given by Judah Folkman, MD, professor of cell biology, Children's Hospital and Harvard Medical School, at the 47th Annual Meeting of the American Society for Therapeutic Radiology and Oncology.
"In 1971, I published this hypothesis that tumors are angiogenesis dependent, and I thought that the field would explode after this paper. But nothing happened," Dr. Folkman said. "In fact, nothing happened for 10 years . . . until the early 1980s, when we isolated basic fibroblast growth factor (bFGF) from tumors; then critics converted to competitors and the field has taken off. There are now 70 papers a week with angiogenesis in the title."
Experts now regard angiogenesis as a critical phenomenon in cancer (as well as other diseases), view angiogenesis inhibitors as the fourth modality in cancer therapy, and credit them with most of the recent gains in survival of colon, lung, and breast cancer, Dr. Folkman said. "Therefore, it is timely to ask about the role that the process of angiogenesis plays in the radiation response and to ask what lessons have been learned from angiogenesis research."
Turning to tumor biology, Dr. Folk-man addressed a series of questions about angiogenesis and radiation response, the first among them, can antiangiogenic therapy increase blood flow and oxygen in a tumor-changes in the tumor microenvironment that may increase the effectiveness of radiation.
"Conventional wisdom was that antiangiogenic therapy would always reduce oxygen in a tumor," he noted. But a 1995 study showed that administration of an angiogenesis inhibitor (the investigational agent TNP-470, an analog of fumagillin) to mice after tumor implantation led to a 17% increase in intratumoral oxygen, as well as a 2.2-fold increase in tumor growth delay after radiation therapy-findings that were counterintuitive.
This, in turn, leads to a second question, he said: How does antiangiogenic therapy increase tumor blood flow and oxygen? A series of studies showed that one mechanism was a reduction in vascular leakage, an action that has been shown for caplostatin, endostatin, thalidomide (Thalomid), and etoposide.