New mechanism explains how the body prevents formation of blood vessels

If the body can prevent formation of blood vessels, can one's own anti-angiogenesis predisposition help it along?

Giving low doses of several drugs every day by mouth. There would be no needles and the side effects are expected to be mild. Unlike standard chemotherapy, which is given in high doses to kill as many cancer cells as possible, the lower-dose regimen is meant to attack the blood vessels that feed the tumor. Tumors create their own supply lines by secreting substances that stimulate the formation of new blood vessels and researchers suspect that frequent low doses of certain drugs may disrupt the growth of those new vessels, starving the tumor.

The treatment includes small daily doses of standard chemotherapy drugs and two other drugs that have been found to inhibit the formation of new blood vessels, called angiogenesis. One is Celebrex and the other is Thalidomide. It is offered only to people who have no other options, who have advanced tumors that standard treatment cannot cure or those for whom standard chemotherapy has quit working.

Women with advanced breast or ovarian cancer are being given smaller, more frequent doses of chemotherapy to reduce side effects. It is hoped that low-dose treatment may help other cancer patients, not just those who are considered terminal. It may work just as well or even better, maybe through this ability to cause an anti-angiogenesis effect.

This approach to treatment is based on something that can frequently occur in people, when a tumor becomes resistant to chemotherapy and high doses stop working. It is believed that angiogenesis plays a role. Angiogenesis is essential to the survival of many tumors. Many chemotherapy drugs, in addition to killing tumor cells, also fight angiogenesis. But, if these medicines stop angiogenesis, chemotherapy should work better than it does. Blood vessel cells are less likely than tumor cells to become resistant to chemotherapy, so if cancer cells become drug resistant, these medicines should still be able to shrink tumors by destroying their blood supply.

The reason chemotherapy was not stopping angiogenesis was that chemotherapy is usually given in big doses, with breaks of several weeks between doses to let the body recover. During the breaks, the tumor's blood vessels could grow back. By giving chemotherapy more often, at lower doses, it might prevent the regrowth of blood vessels and kill the tumor or at least slow its growth.

It is especially important to study low-dose therapies now because they are being used increasingly in clinics. Doses, timing and combinations all need to be worked out. Doctors need to find out whether the treatments can make patients live longer and whether tumors will eventually outsmart the drugs and find ways to survive even without angiogenesis.

Source: Jefferson Medical College

Radiation oncologists at Thomas Jefferson University Hospital are rethinking how to give chemotherapy, taking advantage of its unique properties. They are giving chemotherapy more frequently than usual and in tinier doses, targeting the process by which a new blood supply is created feeding tumor growth, called angiogenesis.

Traditionally, most cancer therapies are used in highest possible doses, says Adam Dicker, M.D., Ph.D., assistant professor of radiation oncology at Jefferson Medical College of Thomas Jefferson University in Philadelphia and at Jefferson's Kimmel Cancer Center. But anti-angiogenesis drugs have caused people to rethink chemotherapy. "Instead of targeting the tumor, perhaps you can target the tumor-associated blood supply," he says.

Dr. Dicker and his Jefferson co-workers studied the chemotherapy drug docitaxel (Taxotere) in the laboratory in lower-than-usual doses, about one-tenth the clinical dose. They wanted to see the effects of radiation and the drug, which makes cancer cells more vulnerable to radiation, on endothelial cells, which are involved in angiogenesis. They found the lower doses of drug affect different parameters of angiogenesis and can increase the effects with radiation. "This is a unique approach in combination therapy, targeting the vasculature," Dr. Dicker said.

Dr. Dicker will presented the group's findings at an annual meeting of the American Association for Cancer Research meeting in New Orleans.

"What's unique about this is that we've used a common chemotherapy agent in an antiangiogenic manner and potentiated that," Dr. Dicker says. "This area is particularly interesting because these drugs, which are FDA approved, can have antiangiogenic effects.

"It's a totally new way of thinking, it's completely changed the paradigm," says Dr. Dicker. "With all the interest in anti-angiogenesis, you can rethink how you give chemotherapy and radiation."

According to Dr. Dicker, recent research have shown dramatic effects with conventional chemotherapy, but used in a different way. Instead of using large doses infrequently, every three weeks or so, for example, giving the time the body needs to recover from chemotherapy, preclinical studies have been using lower doses more frequently, maybe twice a week.

They next plan to take this approach, using low-dose docetaxel and radiation therapy, in a study in lung cancer together with colleague Maria Werner-Wasik, M.D., assistant professor of radiation oncology at Jefferson Medical College.

Angiogenesis Inhibitors in Cancer Research

Angiogenesis inhibitors - drugs which prevent new blood vessel development - may be the cancer treatment of the future. Here's a discussion of the clinical trials in place to study these exciting new drugs.

One promising avenue of cancer research is the study of a group of compounds called angiogenesis inhibitors. These are drugs that block angiogenesis, the development of new blood vessels. Solid tumors cannot grow beyond the size of a pinhead (1 to 2 cubic millimeters) without inducing the formation of new blood vessels to supply the nutritional needs of the tumor. By blocking the development of new blood vessels, researchers are hoping to cut off the tumor's supply of oxygen and nutrients, and therefore its continued growth and spread to other parts of the body.

About 20 angiogenesis inhibitors are currently being tested in human trials. Most are in early phase I or II clinical (human) studies. Three are in phase III testing and the results for one are expected by the end of 1999. (See list of Angiogenesis Inhibitors in Clinical Trials.) Phase I/II trials include a limited number of people to determine the safety, dosage, effectiveness, and side effects of a drug. In phase III trials, hundreds of people around the country are assigned at random to receive either the new treatment or the standard treatment.

Background

In normal tissue, new blood vessels are formed during tissue growth and repair, and the development of the fetus during pregnancy. In cancerous tissue, tumors cannot grow or spread (metastasize) without the development of new blood vessels. Blood vessels supply tissues with oxygen and nutrients necessary for survival and growth.

Endothelial cells, the cells that form the walls of blood vessels, are the source of new blood vessels and have a remarkable ability to divide and migrate. The creation of new blood vessels occurs by a series of sequential steps. An endothelial cell forming the wall of an existing small blood vessel (capillary) becomes activated, secretes enzymes that degrade the extracellular matrix (the surrounding tissue), invades the matrix, and begins dividing. Eventually, strings of new endothelial cells organize into hollow tubes, creating new networks of blood vessels that make tissue growth and repair possible.

Most of the time endothelial cells lie dormant. But when needed, short bursts of blood vessel growth occur in localized parts of tissues. New capillary growth is tightly controlled by a finely tuned balance between factors that activate endothelial cell growth and those that inhibit it.

About 15 proteins are known to activate endothelial cell growth and movement, including angiogenin, epidermal growth factor, estrogen, fibroblast growth factors (acidic and basic), interleukin 8, prostaglandin E1 and E2, tumor necrosis factor-, vascular endothelial growth factor (VEGF), and granulocyte colony-stimulating factor. Some of the known inhibitors of angiogenesis include angiostatin, endostatin, interferons, interleukin 1 ( and ß), interleukin 12, retinoic acid, and tissue inhibitor of metalloproteinase-1 and -2. (TIMP-1 and -2).

At a critical point in the growth of a tumor, the tumor sends out signals to the nearby endothelial cells to activate new blood vessel growth. Two endothelial growth factors, VEGF and basic fibroblast growth factor (bFGF), are expressed by many tumors and seem to be important in sustaining tumor growth.

Angiogenesis is also related to metastasis. It is generally true that tumors with higher densities of blood vessels are more likely to metastasize and are correlated with poorer clinical outcomes. Also, the shedding of cells from the primary tumor begins only after the tumor has a full network of blood vessels. In addition, both angiogenesis and metastasis require matrix metalloproteinases, enzymes that break down the surrounding tissue (the extracellular matrix), during blood vessel and tumor invasion.

Strategies

Of the anti-angiogenesis drugs now in clinical trials, some were designed to target specific molecules involved in new blood vessel formation. For others, the exact mechanism of the drug is not known, but it has been shown to be anti-angiogenic by specific laboratory tests (in the test tube or in animals).

In general, four strategies are being used by investigators to design anti-angiogenesis agents:
Block the factors that stimulate the formation of blood vessels
Use natural inhibitors of angiogenesis
Block molecules that allow newly forming blood vessels to invade surrounding tissue
Incapacitate newly dividing endothelial cells

Standard Chemotherapy Versus Angiogenesis Inhibitors

Several differences between standard chemotherapy and anti-angiogenesis therapy result from the fact that angiogenesis inhibitors target dividing endothelial cells rather than tumor cells. Anti-angiogenic drugs are not likely to cause bone marrow suppression, gastrointestinal symptoms, or hair loss -- symptoms characteristic of standard chemotherapy treatments. Also, since anti-angiogenic drugs may not necessarily kill tumors, but rather hold them in check indefinitely, the endpoint of early clinical trials may be different than for standard therapies. Rather than looking only for tumor response, it may be appropriate to evaluate increases in survival and/or time to disease progression.

Drug resistance is a major problem with chemotherapy agents. This is because most cancer cells are genetically unstable, are more prone to mutations and are therefore likely to produce drug resistant cells. Since angiogenic drugs target normal endothelial cells which are not genetically unstable, drug resistance may not develop. So far, resistance has not been a major problem in long-term animal studies or in clinical trials.

Finally, anti-angiogenic therapy may prove useful in combination with therapy directly aimed at tumor cells. Because each therapy is aimed at a different cellular target, the hope is that the combination will prove more effective.