Magic bullets. That's how we've come to know a group of chemical compounds that have an uncanny ability to home in on particular targets within the body. Their "magic" is provided by chemically attached radioactive isotopes, labels made of small quantities of radioactive material that enable physicians to obtain detailed images of internal organs, deliver doses of radiation to specific destinations, and trace the movement of medications--all without picking up a scalpel.

In recent years, a barrage of magic bullets has been fired from laboratories around the country, but because of their long and involved development process, relatively few have been tested in human patients--fewer still have found commercial applications. Despite these odds, the researchers of ORNL's Nuclear Medicine Group have gained reputations as sharpshooters, thanks to four new magic bullets now in clinical testing--a radiolabeled antibody that targets colon cancer cells, a test agent for pancreas problems, and imaging agents for monitoring blood flow in the heart and detecting early signs of heart disease. A fifth agent that promises to help track the changes in brain chemistry resulting from Alzheimer's and related diseases is undergoing preclinical studies.

Aiming for a Killer

Colorectal cancer is expected to claim 57,000 lives this year in the United States, making it among the most deadly forms of the disease. This grim distinction places it high on the "hit lists" of scientists who work to make magic bullets ever more effective. One of the obstacles facing these researchers is the need for radiolabeled compounds that not only do the diagnostic or therapeutic job they were designed for, but also are easy and convenient to use.

A new radioisotope generator system developed at ORNL promises to make the versatile radioisotope, rhenium-188, readily available for the treatment of colon cancer and arthritis for weeks at a time. "Rhenium-188 is expected to have several applications," says Russ Knapp, head of ORNL's Nuclear Medicine Group. "It can be attached to therapeutic agents and used as a tracer to monitor their movements through the body, or it can deliver a dose of radiation to shrink or kill an inoperable tumor. It may also be attached to small ceramic particles and injected into patients' abdominal cavities to treat uterine cancer. Members of the group who have made important contributions to the development of this generator system include Al Callahan, Ed Lisic, Saed Mirzadeh, and Arnold Beets.

View a video clip on rhenium-188 (QuickTime, 1.5 minutes, 2.1 MB)

In addition, the rhenium isotope can be used to treat rheumatoid arthritis in knees and other, fluid-filled joints. In this treatment the isotope is bonded to compounds that are injected into the fluid of the joint; the energy released as the rhenium decays helps relieve the painful swelling and inflammation of joint membranes. Similar applications have been suggested for reducing the pain associated with bone cancer.

The grapefruit-size rhenium-188 generator system has two advantages over systems that produce other therapeutic radionuclides. First, rhenium-188's parent isotope, tungsten-188, which is produced at ORNL's High Flux Isotope Reactor, has a half-life of 69.5 days. So, it takes about 10 weeks for half of the tungsten-188 to change or "decay" into rhenium-188. The tungsten's gradual decay provides a constant supply of rhenium for several weeks--making it much more convenient to use than most other radioisotopes. In addition, as it decays, the rhenium isotope produces photons, short bursts of energy in the form of light, which allow its distribution to be monitored with the photon-sensitive cameras that are already widely used for imaging in health-care facilities.

Working with David Goldenberg and his colleagues at the Center for Molecular Medicine and Immunology at the University of New Jersey, researchers have developed a quick and easy procedure for chemically linking rhenium-188 to an antibody that homes in on colon cancer cells. This combination, known as an immunoconjugate, delivers a precisely targeted dose of radiation to colorectal tumors. Although the half-life of radioactive rhenium is only 16.9 hours, the radiation it releases can penetrate nearly a centimeter into tumor tissue, suggesting this technique could be useful for treating larger tumors.

Initial studies in a group of 12 patients with tumors that had not responded to other treatments demonstrated the immunoconjugate's knack for concentrating in colorectal cancer cells. Full-scale clinical trials for the compound are scheduled to begin in the near future.

Targeting Pancreatic Disease

The pancreas is a gland located behind the stomach that secretes both insulin, a hormone that enables the body to absorb sugar, and enzymes that help digest food, including fat. The role of the pancreas in digestion begins after food is eaten and partially digested in the stomach. When food enters the upper intestinal tract, it stimulates the pancreas to secrete its digestive enzymes. Most fat can't be absorbed by the small intestine. It must first be broken apart by digestive enzymes, then absorbed by intestinal cells, and finally reassembled and transported to the liver and other tissues for storage or use.

The failure of the pancreas to produce enough of these enzymes often signals serious problems, such as pancreatic cancer or inflammation of the pancreas.

Traditional tests for measuring the performance of the fat-digesting enzymes produced by the pancreas are impractical and unpleasant because they usually require a chemical analysis of fecal samples to determine how much fat has passed through the digestive system without being absorbed.

Over the years, researchers studying alternatives to traditional techniques began to experiment with oral doses of oils or fats tagged with radioactive iodine-131. Once a fat or oil molecule was digested, the radioactive tag--still attached to a portion of the original fat or oil molecule--was released into the blood or urine.

Analysis of the radioactive contents of the blood was eventually discontinued because of purity and stability problems with the radioactive fat test agent and the agent's tendency to lose its radioactive tag in the body. There was also disagreement over the correlation between levels of radioactivity in the blood and the amount of fat in fecal samples. Early urine tests were also abandoned because digestion of the fats and oils used in these tests did not produce enough radioactive by-products in the urine for analysis.

Recently, ORNL's Nuclear Medicine Group has overcome the problems that plagued earlier research efforts and developed a test that produces enough radioactive by-products in the urine to provide a direct measure of the metabolism of fat by pancreatic enzymes. This technique, which has been proven successful in both animal tests and initial human studies, was designed by Knapp while he was conducting research as a Senior American Scientist of the Alexander von Humboldt Foundation at the University of Bonn in Germany.

"We asked ourselves whether the problem was with the concept of what should be measured or with the chemical structure of the radiolabeled fat that was used," says Knapp. "We decided that, if we could synthesize a fat whose radiolabeled by-products would probably be excreted in the urine, we could develop an effective test." While in Bonn, Knapp synthesized a new triglyceride fat containing the iodine-131-labeled fatty acid residue. This radiolabeled test agent is stable, can be stored for several weeks, and most importantly, its radiolabeled component is released in the urine. The amount of radioactivity in urine samples is then analyzed and compared to the amount administered to determine the rate at which the fatty acid residue is being metabolized by the pancreas.

Initial studies in laboratory rats were conducted at ORNL with an iodine-125-labeled compound by Nuclear Medicine Group members Kathleen Ambrose, Al Callahan, Carla Lambert, and Dan McPherson. The iodine-125 tag has a longer half-life than iodine-131 (60 days versus 8), making it more convenient to use in animal experiments. The results of these studies were very promising--18.9% of the radioactivity from the orally administered test agent was released in the urine during the first 24 hours.

Knapp then developed a test procedure and synthesized the iodine-131-labeled agent for initial tests in humans conducted by Joachim Kropp, M.D., at the Clinic for Nuclear Medicine in Bonn. Of the 23 individuals participating, 20 had normal pancreatic function and 3 had previously documented pancreatic insufficiency. The results of these studies showed that participants with normal function released an average of 61.8% of the iodine-131 in their urine after 48 hours. The patients with impaired function released only 18.9%--significantly less than the control group.

These preliminary results demonstrate that this technique provides a simple test for pancreatic insufficiency. "This approach is not as direct as a typical nuclear medicine imaging procedure, such as imaging a tumor," says Ambrose, "but it gives indirect proof of pancreatic disease or intestinal absorption problems. Low excretion levels identify individuals who need to undergo further testing."

Over the next year, Knapp and his collaborators Joachim Kropp and Hans Biersack, both of the University of Bonn, plan to gather more extensive data from a larger group of control patients and also from several different groups of patients with various other types of gastrointestinal disease.

Tracing Blood Flow in the Heart

Heart function tests are administered to thousands of Americans each year. These tests are of critical importance in diagnosing and treating both congenital defects and diseases of the heart. In a typical heart function test, a photon-emitting isotope is injected into the patient's bloodstream and a photon-sensitive camera then captures an image of blood flow through the heart's chambers and within the heart muscle itself.

One of ORNL's contributions to cardiac imaging has been the development of a generator system for producing iridium-191m. This ephemeral test agent is the product of the decay of osmium-191, which has a 15-day half-life and is produced at ORNL's High Flux Isotope Reactor. Because iridium-191m has a half-life of less than 5 seconds and emits photons, it provides a safe, fast method of obtaining high-quality cardiac images. In fact, the isotope's short half-life enables tests to be repeated almost immediately to monitor the effects of exercise and drug therapy on the heart's pumping efficiency. In European tests, the iridium generator has been successfully used in evaluating heart performance in more than 200 patients.

View a video clip on iridium-191m (QuickTime, 1.4 minutes, 2 MB)

Applications of the generator technology for producing the short-lived isotope are currently being discussed with groups with the expertise and specialized instrumentation needed to handle iridium-191m.

Spotting Early Signs of Heart Disease

In their early stages, several cardiac disorders, such as hypertensive heart disease, may have none of the symptoms traditionally associated with heart trouble--clogged arteries, restricted blood flow, or oxygen-deprived heart muscle. What they do have, ORNL researchers have determined, is a habit of altering the way affected areas of the heart muscle metabolize and absorb fatty acids. To detect these subtle changes, ORNL researchers developed a blood-borne fatty acid tagged with radioactive iodine-123, which emits photons as it decays.

The usual first step in deciding whether a problem with fatty acid metabolism exists is to use a radioisotope to produce an image of blood flow to the patient's heart muscle through the coronary arteries. If blood flow is normal, the radiolabeled fatty acids are administered to the patient. An uneven distribution of these fatty acids throughout the heart, as detected by a photon-sensitive camera, suggests that the ability of some areas of the heart muscle to metabolize fatty acids is impaired, perhaps as a result of the early stages of heart disease. The image may also enable a physician to determine which regions of a damaged heart muscle could be salvaged through treatment.

The clearest indication that the ORNL-developed agent has helped shed new light on the subtleties of cardiac metabolism is its worldwide acceptance. Studies of iodine-123 are in progress at several European clinics and at Brookhaven National Laboratory. The agent has already won approval from the Japanese Food and Drug Administration and is being marketed in the Far East by Nihon Medi-Physics Co., Inc., under the name CardiodineTM. Studies of more than 600 patients at 30 Japanese institutions were completed before the agent was approved for use.

Need more evidence? Two symposia recently held in Japan, the Third International Symposium on Radioiodinated Free Fatty Acids in Cardiac Imaging and the Thirteenth New Town Conference on Nuclear Cardiology, had a single focus--the clinical use of ORNL's iodine-123-labeled fatty acids as a gauge of the heart's metabolism.

Tracking Communication in the Brain

Alzheimer's disease, Parkinson's disease, and many other neurological disorders are characterized by abnormalities in the central nervous system. For example, normal brain cells have many receptors that receive chemical messages from other cells; in contrast, the brain cells of Alzheimer's patients often possess fewer receptors or many of their receptors are "turned off."

Other brain-centered disorders involve the message-carrying chemical compounds that interact with receptors, known as neuro-transmitters. A neurotransmitter of critical importance to normal brain function is dopamine. Its absence in the brains of patients with Parkinson's disease leads to a debilitating loss of muscle control; on the other hand, high levels of dopamine are often associated with schizophrenic behavior.

To aid in the diagnosis and treatment of these disorders, Dan McPherson is leading an effort in ORNL's Nuclear Medicine Group to develop new radiopharmaceutical agents that attach themselves chemically to the receptors involved in neurological diseases, such as Alzheimer's. Researchers have developed a simple method of producing large quantities of an iodine-123-labeled imaging agent, designated IQNP.

Because iodine-123 produces photons as it decays, its concentration and activity in the brain can be determined using photosensitive imaging techniques. A fluorine-18-labeled version of INQP is also on the drawing board and should be available in the next few months. The advantage of using fluorine-18 as a radioactive tag for INQP is that it emits positrons as it decays and, therefore, can be used in conjunction with higher-resolution positron emission tomography (PET) imaging systems.

Use of these agents will help researchers track changes in the concentration and activity of receptors and neurotransmitters in the brain. These changes mark the onset and progress of Alzheimer's and similar diseases of the brain. Initial studies in rats have demonstrated that INQP concentrates almost exclusively in the receptor-rich areas of rat brains. Further tests of INQP in primates are planned as a prelude to seeking approval for testing in human patients.

Summing Up

From the brain to the heart to the pancreas, the magic bullets developed by ORNL's Nuclear Medicine Group are finding their targets with enviable consistency. The care with which the group chooses its targets and takes aim has resulted in the development of a series of magic bullets that have shown promise in patient studies. As a result, they are now making their way into the commercial market as agents for diagnosis and treatment of a wide range of diseases.

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