Combination Therapy Is More Effective in Stopping Tumor Growth

Cancer researchers have found that treating tumors to inhibit the activity of vascular endothelial growth factor (VEGF) to prevent development of new blood vessels is less effective than combining antiangiogenesis treatment with classical chemotherapy.

Investigators at the University of California, San Diego (La Jolla, CA, USA) worked with a line of mice that had been genetically engineered to lack the gene for VEGF. These animals served as a model emulating the results of antiangiogenesis treatment. The absence of VEGF activity made it easier to study the effects of another growth factor, platelet-derived growth factor (PDGF).

Results published in two papers published in the November 9, 2008, online edition of the journal Nature revealed that VEGF in large quantities, as often found in tumor cells, acted to inhibit the activity of PDGF. This prevented PDGF from activating cells called pericytes that surround and stabilize blood vessels, explaining why tumor blood vessels are often immature and poorly functional.

Inhibition of VEGF promotes PDGF activity, which in turn allows tumor blood vessels to mature. Initially this stimulates growth of the tumor, but increased blood flow then facilitates the transport of chemotherapeutic agents into the tumor.

"We have discovered that when antiangiogenesis drugs are used to lower the level of VEGF within a tumor, it is not so much a reduction in the endothelial cells and losing blood vessels as it is an activation of the tumor blood vessels supporting cells,” explained senior author Dr. David Cheresh, professor of pathology at the University of California, San Diego. "This enables vessels to mature, providing a conduit for better drug delivery to the tumor. While the tumors initially get larger, they are significantly more sensitive to chemotherapeutic drugs. It means that chemotherapy could be timed appropriately. We could first stabilize the blood vessels, and then come in with chemotherapy drugs that are able to treat the cancer.”

"It is not just about the therapy, but also what the host does in response to the cancer that makes a difference whether a tumor lives or dies, and if it is susceptible to a drug or not. We can change the host response to the cancer, which is otherwise resistant, and make the vessels more mature, temporarily increasing blood flow to the cancer. We may be giving the right drugs, but we may not be giving them in the right order. We are just beginning to understand how it works,” said Dr. Cheresh.

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