Antiangiogenic Therapy

Definition

Antiangiogenesis therapy is one of two types of drugs in a new class of medicines that restores health by controlling blood vessel growth. The other medication is called pro-angiogenic therapy.

Purpose

Antiangiogenic therapy inhibits the growth of new blood vessels. Because new blood vessel growth plays a critical role in many disease conditions, including disorders that cause blindness, arthritis, and cancer, angiogenesis inhibition is a "common denominator" approach to treating these diseases. Antiangiogenic drugs exert their beneficial effects in a number of ways: by disabling the agents that activate and promote cell growth, or by directly blocking the growing blood vessel cells. Angiogenesis inhibitory properties have been discovered in more than 300 substances, ranging from molecules produced naturally in animals and plants, such as green tea extract, to new chemicals synthesized in the laboratory. A number of medicines already approved by the U.S. Food and Drug Administration (FDA) have also been found to possess antiangiogenic properties, including celecoxib (Celebrex), bortezomib (Velcade), and interferon. Many inhibitors are currently being tested in clinical trials for a variety of diseases in human patients, and some in veterinary settings.

These diseases include:

• Eye disease—Excessive new blood vessels growing in the eye can cause vision loss and lead to blindness. Antiangiogenic treatments may prevent progressive loss of vision or even improve eyesight in patients.
• Arthritis—Blood vessels that invade the joint release enzymes that destroy cartilage and other tissues in arthritis. Antiangiogenic drugs may relieve the arthritic pain and prevent bone joint destruction caused by these pathological and destructive blood vessels.
• Cancer—Tumors recruit their own private blood supply to obtain oxygen and nourishment for cancer cells. By cutting off tumor vasculature (the arrangement of blood vessels in the body or in a particular organ or tissue), antiangiogenesis therapies may literally starve tumors, and prevent their growth and spread. Antiangiogenesis may also prove to be useful when combined with conventional chemotherapy or radiation therapy, as part of a "multiple warhead" approach to attack cancer via different strategies simultaneously.

Currently, more than 80 antiangiogenic drugs are being tested worldwide in human clinical trials sponsored by biotechnology and pharmaceutical companies, top medical centers, and the U.S. National Cancer Institute. The Angiogenesis Foundation is leading the application of antiangiogenic therapy in veterinary medicine, for treatment of certain conditions in dogs, cats, and exotic animal species.

Pro-angiogenic therapy works the opposite way as antiangiogenic therapy by using angiogenic growth factors or gene therapy to stimulate blood vessel growth in tissues that require an improved blood supply. A number of angiogenic growth factors and gene therapies are currently undergoing clinical trials in human patients suffering from the following conditions: ischemic heart disease, stroke, peripheral vascular disease, and chronic wounds.

Precautions

Since antiangiogenic therapy is still experimental, only people enrolled in a clinical trial of a particular drug therapy can use it. The only FDA-approved drug, bevacizumab (Avastin), is prescribed to treat colon-rectal cancer. Avastin can result in intestinal perforation and can cause wounds that have been stitched to break open, sometimes causing death. Intestinal perforation, sometimes associated with abscesses inside the abdomen, occurred throughout treatment with Avastin. Symptoms included abdominal pain associated with constipation and vomiting. Avastin therapy should be permanently discontinued in patients with intestinal perforation or wound breaks requiring medical intervention. Serious, and in some cases fatal, hemoptysis (coughing up of blood or mucus containing blood) has occurred in patients with non-small cell lung cancer treated with chemotherapy and Avastin.

Description

In the late 1990s, many medical researchers believed that the Holy Grail of cancer treatment had been found. Antiangiogenesis therapy was safe, elegant, and at first apparently effective. But the clinical results soon fell short of expectations. The tumors, it seemed, had found a way to circumvent even this most ingenious of treatment approaches. Despite the setbacks, however, angiogenesis remains a very tempting target, and researchers are exploring new agents and approaches to maximize the effects of antiangiogenic therapies.

Newer studies have demonstrated that in addition to differences in the regulation of new blood vessel formation in cancer compared with normal tissues, the actual blood vessels that are "created" in cancers are different from those created in normal tissues. These differences have allowed a number of antiangiogenic drugs to be developed that specifically damage tumor-associated blood vessels and not normal vessels. The goal of these drugs is to attack cancers by damaging their blood supply. Many antiangiogenic agents also appear to hasten the death of tumor-associated blood vessels.

With the success of targeted agents such as the biotechnology company Genentech's Avastin, the only antiangiogenic drug approved by the FDA to treat cancer, new efforts are underway to widen and optimize the field of antiangiogenic agents. As oncology (the study of cancer) drug development accelerates, new indications are beginning to emerge for diseases such as ocular neovascularization and even obesity.

Antiangiogenic therapy represents a novel, potentially effective, and non-toxic treatment for cancer. It is likely that these drugs will provide the next major breakthrough in the management of people and pets with cancer. Antiangiogenic therapy will likely become part of the conventional treatment of cancer and will be used in combination with surgery, radiation therapy and chemotherapy. These agents are currently in clinical trials and may become available to both people and pets in the near future.

KEY TERMS

Angiogenesis— The formation of new blood vessels, for example, as a result of a tumor.

Chemotherapy— The use of chemical agents to treat diseases, infections, or other disorders, especially cancer.

Endothelial— A layer of cells that lines the inside of certain body cavities, for example, blood vessels.

Epidermal— Referring to the thin outermost layer of the skin, itself made up of several layers, that covers and protects the underlying dermis (skin).

Fibroblast— A large flat cell that secretes the proteins that form collagen and elastic fibers and the substance between the cells of connective tissue.

Ischemic— An inadequate supply of blood to a part of the body, caused by partial or total blockage of an artery.

Ocular neovascularization— Abnormal or excessive formation of blood vessels in the eye.

Peripheral vascular disease— A disease affecting blood vessels, especially in the arms, legs, hands, and feet.

Vascular— Relating to blood vessels.

Antiangiogenic therapy offers a number of advantages over traditional therapies for cancer:

• Tumor cells often mutate and become resistant to chemotherapy. Because antiangiogenic drugs only target normal endothelial cells (a layer of cells that lines the inside of certain body cavities, such as blood vessels), these cells are less likely to develop acquired drug resistance.
• All tumors rely upon host vessels. Antiangiogenic agents are therefore effective against a broad range of cancers.
• Conventional chemotherapy and radiotherapy indiscriminately attacks all dividing cells in the body, leading to side effects such as diarrhea, mouth ulcers, hair loss, and weakened immunity. Antiangiogenic drugs selectively target dividing blood vessels and cause fewer side effects.
• Antiangiogenic drugs are relatively nontoxic and work at levels well below the maximum tolerated dose, so may be given in lower doses over longer periods of time.
• Antiangiogenic treatment may take weeks or even months to exhibit its full beneficial effect, but this allows for continuous, chronic control of disease.
• Antiangiogenic drugs may also serve as a powerful supplement to traditional chemotherapy or radiation therapy.

Preparation

Since antiangiogenic drugs are either injected or administered orally, little or no preparation is needed. For injections, the site should be first swabbed with alcohol.

Aftercare

Little or no aftercare is needed following the administering of antiangiogenic therapy, except for a small bandage on the injection site.

Although many of these agents are currently being tested in clinical trials, no reliable way to monitor the effects of many, if not most, of these therapeutic agents on the inhibition of the complicated process of angiogenesis exists. However, in late 2004, scientists uncovered critical information that may lead to an urgently needed method for effectively monitoring antiangiogenic cancer therapies. The research is likely to facilitate development of new antiangiogenic drugs or treatment strategies and allow for accurate determination of the optimal drug doses to use for such therapies. The researchers found that measuring peripheral blood cells can be used as a reliable way to monitor antiangiogenic drug activity, which can be used to help establish the optimal biologic dose of such drugs.

Risks

In general, early research has found the side effects of antiangiogenesis agents to be mostly minimal. Because these drugs use proteins that are produced in the human body, there is less likelihood that they will produce the bad side effects common in radiation treatments and chemotherapy. Still, one cancer study found that 6 of the 99 patients taking an antiangiogenesis drug experienced severe bleeding in the tumors being treated. Four of those patients died from this complication.

Since antiangiogenesis drugs could affect a developing fetus, they will probably not be used for pregnant women or women who might become pregnant. They may also need to be stopped before surgery, since blood vessels that are cut at such times need to repair themselves. Also, people who have damaged blood vessels (such as those with heart disease or stroke) may not be able to take these drugs. Other side effects in people are being determined. Doctors, scientists and specialists at the FDA will be monitoring these other side effects to better understand the toxicity and risks of these drugs.

Normal results

Since all antiangiogenic therapies are still experimental and in clinical trials, it is difficult to determine what normal results should be. The goal of antiangiogenic drugs is to stop the development and spread of certain diseases, especially some cancers. At least four major proteins and their receptors and signaling pathways commonly govern angiogenesis in solid tumors: platelet-derived growth factor, epidermal growth factor, vascular endothelial growth factor (VEGF), and fibroblast growth factor (basic and acidic). Therapies that either target these molecules or block their signaling pathways should be effective in preventing solid tumor growth and spread of the cancer by preventing the formation of new blood vessels.

Resources

BOOKS

Cooke, Robert. Dr. Folkman's War: Angiogenesis and the Struggle to Defeat Cancer Collingdale, PA: Diane Publishing Co., 2003.

Teicher, Beverly A. Antiangiogenic Agents in Cancer Therapy Totowa, NJ: Humana Press, 1999.

PERIODICALS

Frankish, Helen. "Researchers Target Tumour Blood Vessels With Antiangiogenic Gene Therapy." The Lancet (June 29, 2002): 2256.

Guttman, Cheryl. "Anti-Angiogenic Therapy Explored for Retinoblastoma." Ophthalmology Times (September 1, 2004): 11.

March, Keith. "New Approach for Easing Angina." Medical Update (December 2003): 6.

Sullivan. Michele G. "Experimental Antiangiogenic (Therapy) May Battle Drug-Resistant Tumors." Family Practice News (February 15, 2003): 42.

ORGANIZATION

The Angiogenesis Foundation. P.O. Box 382111, Cambridge, MA 02139. (617) 576-5708. [email protected]. or (for veterinary information) [email protected]. http://www.angio.org.