New Tumor Treatment : Breaking the Brain Barrier

Joe Cunningham had just turned 38 when his doctor told him in early 1985 that he had only 10 months to live.

The Detroit tax attorney had a lymphoma deep in the brain behind his right ear. It was inoperable, and radiation is not very effective against such tumors.

A third alternative was chemotherapy, but that is rarely attempted because brain tumors are shielded by a mysterious phenomenon known as the blood-brain barrier. The barrier prevents most drugs and chemicals in the blood from reaching delicate brain tissues.

Cunningham’s wife, a medical technician, nevertheless refused to accept her husband’s death sentence. She “devoured the medical literature” until she found a radical, and controversial, new form of therapy to break down the barrier temporarily so that the brain can be flooded with cancer drugs.

No Trace of It

“Within a month (after treatment started), 90% of the tumor was gone,” Lydia Cunningham said, “and by the end of the year there was no trace of it. We were elated.”

Today, 19 months after the tumor was diagnosed, Joe Cunningham works 50 hours a week, coaches son Sean’s soccer team and jogs several times a week.

“In all respects, he’s leading a normal life,” she said.

Cunningham was one of the first patients to benefit from new insights about the blood-brain barrier that are emerging from research laboratories throughout the country. These insights are leading to the development of techniques and drugs that could revolutionize the treatment not only of brain tumors but also of brain infections, neurological diseases such as Tay-Sachs, and tumors that are influenced by brain hormones, such as prostate tumors.

Ways to Control Pain

Farther in the future, physicians also see new ways to control pain and safer methods of birth control.

Transporting drugs through the blood-brain barrier will be the dominant biological technology of the 1990s, said William M. Pardridge, a professor of medicine at UCLA. “If we understand how to get substances through the barrier, we will be able to treat many more . . . diseases.”

That the blood-brain barrier provides a safe haven for tumors like Cunningham’s or for viral infections like AIDS is a supreme irony: The barrier has evolved over millennia to protect the delicate tissues of animal brains from damaging materials that circulate in the blood.

Some components of food, such as certain amino acids and metal ions, can cause uncontrolled activity of brain cells that could lead to convulsion and are kept out by the barrier. In the process, it also keeps out many beneficial drugs. But the barrier is not perfect: It lets some harmful materials through, including heroin, nicotine and cancer cells.

Scientists have known of the barrier’s existence since the turn of the century when studies in animals showed that many chemicals injected into the bloodstream did not reach the brain. Until recently, however, researchers had little success in unraveling the barrier’s delicate intricacies. Only a generation ago, medical students were still told there was nothing physicians could do to affect it.

Researchers knew so little because there was no effective way to study the living brain, said UCLA neurologist William Oldendorf. The recent advances in understanding the barrier have been made possible by three separate technological developments.

Around 1970, Oldendorf pioneered the use of radioactive isotopes to measure how fast nutrients and some drugs crossed the barrier. In 1975, researchers at UCLA and other universities developed techniques for growing small blood vessels--called capillaries--in the laboratory, enabling them to tease apart the various components of the vessels and study them on a molecular level.

And in the early 1980s, Pardridge and his colleagues found that human brain capillaries are remarkably resilient and can be removed from the brain during an autopsy and kept alive for study. Based on these developments, an increasingly detailed picture of the blood-brain barrier is being assembled.

The barrier is formed by a type of cell that lines the capillaries, called endothelial cells. In capillaries elsewhere in the body, the endothelial cells are joined together loosely. Blood plasma leaks through the gaps between the cells and nourishes body cells.

Tight Junctions

But in the brain, the endothelial cells are linked together by tight junctions that “act like a zipper that seals the capillary shut and allows nothing to leak out,” Pardridge said.

Why does the barrier form only in the brain and not elsewhere in the body? The answer appears to lie in astrocytes, star-shaped cells that were once thought to serve only as a kind of scaffolding to support capillaries and brain cells. Several studies have shown that the astrocytes continuously secrete a chemical, not yet identified, that causes endothelial cells to form tight junctions.

The astrocytes also seem to regulate the passage of nutrients and hormones across the barrier, UCLA pathologist Pasquale Cancilla said, by controlling the activity of cellular transport systems that act like tiny couriers. Each of these systems, first discovered by Oldendorf, grabs onto a specific chemical--such as a sugar or an amino acid--in the bloodstream, carries it through the endothelial cells and releases it to the brain cells.

But some substances, if they have the right chemical composition, can get through without help from the transport systems. The membranes of the endothelial cells are composed primarily of lipids, fatty substances that do not dissolve in water. Chemicals that will dissolve in the fats pass readily through the blood-brain barrier. Nicotine, alcohol and heroin, for example, are all fat-soluble and can be detected in the brain within seconds after they are ingested.

With only a few exceptions, anti-cancer drugs and antibiotics are water soluble and do not pass through the barrier on their own.

One alternative is to open the barrier briefly, as was done for Cunningham. This approach was pioneered in rats and monkeys by neurophysiologist Stanley I. Rapoport of the National Institute on Aging in Bethesda, Md.

Rapoport’s technique involves infusing a concentrated solution of a sugar into the carotid artery, which leads to the brain. By a simple physical principle, this solution draws water from the endothelial cells of the barrier. As the cells lose water and shrink, they pull back from the tight junctions, allowing drugs in the bloodstream to reach the brain.

Water Absorbed

Within an hour, the cells reabsorb the lost water and the barrier is closed again.

This technique was applied to humans by neurosurgeon Edward O. Neuwelt of the Oregon Health Sciences Center in Portland, and Joe Cunningham’s treatment was typical.

The Cunninghams flew to Portland once a month for nearly a year for five to six days of therapy. Each time, Cunningham would be anesthetized and Neuwelt would insert a catheter into the carotid artery. He would then infuse the shrinking agent and the anti-cancer drugs methotrexate and cytoxan.

The process was painless--except for the tube in his nose required for the anesthesia--but Cunningham found that he had difficulty remembering things that happened on the day after the procedure. “I became accustomed to it, but I never enjoyed it,” he said.

The procedure has few side effects beyond the anemia and susceptibility to infection associated with chemotherapy, Neuwelt said. About 10% to 15% of recipients go into convulsions caused by “irritation of brain cells” by the drugs, he noted, but this can be prevented by administering anti-convulsant drugs along with the sugar.

Once in every 200 times the procedure is performed, Neuwelt added, the patient has a mild stroke, but none has been seriously impaired. This is the same incidence of stroke found when dyes are infused into the carotid artery for imaging the brain and is thought to be caused by the formation of small blood clots on the tip of the catheter.

Neuwelt has used this technique to open the barrier about 800 times in 100 humans to treat the three main types of brain tumors, he said. Such tumors are normally treated by surgery or radiation, he said, but those therapies are “only modestly effective” and the life expectancy of a victim is normally between seven and 10 months after diagnosis.

For two of the brain cancers, Neuwelt said, the infusion treatment doubled the survival time of the patients after diagnosis. Not enough data is available yet to evaluate success with the third type.

Neurosurgeon Clark Watts of the University of Missouri Medical School in St. Louis said he has performed the procedure successfully on about 50 brain tumor patients, and scientists at the University of Wisconsin and the University of Vienna are beginning to use it for that purpose. But the technique has its critics.

Treatment Questioned

Neurologist William Shapiro of Memorial Sloan-Kettering Cancer Center in New York City argues that not enough experiments have been performed in animals. He also said Neuwelt has not given the same anti-cancer drugs to patients in whom the barrier was not opened. Shapiro said one of the drugs, cytoxan, crosses the barrier to a limited extent and might have worked without using the barrier-lowering procedure.

Some studies in rats also show that opening the barrier does not sharply increase the amount of drugs that reach tumors, and Shapiro and others fear that the cancer drugs will have toxic effects on healthy brain cells without an enhanced effect on the tumors.

Neuwelt’s response: “The results speak for themselves.”

Neurosurgeon Michael Salcman of the University of Maryland Medical Center in Baltimore believes that Neuwelt’s technique will be superseded by less drastic ways of getting drugs into the brain. “Opening the barrier is a dying industry,” he said.

Salcman said one technique is to modify drugs so that they are more fat-soluble. Indian chemists inadvertently discovered this in the 1800s when they chemically converted morphine--which is water-soluble and has difficulty reaching the brain--into heroin, which reaches the brain immediately.

One promising approach was developed by chemist Nicholas S. Bodor of the University of Florida at Gainesville. Bodor found a small organic molecule that, when chemically linked to many drugs, carries them across the barrier.

In the brain, naturally occurring enzymes separate the carrier from the drug, freeing it for therapeutic activity.

In 1982, Bodor licensed the carrier technology to Pharmatec Inc., a small company in Alachua, Fla., near Gainesville. “Over the past four years, we have synthesized 15 to 20 carrier-drug combinations and then looked to see how much gets into the brain (of animals),” said Warren C. Stern, president of Pharmatec. In each case, he said, the carrier increased the amount of drug that reached the brain by 10 to 50 times.

Pharmatec began trials in July of what the company hopes will be its first commercial product, a modified form of the synthetic female hormone estradiol. It is being tested on about 20 patients in the United Kingdom.

Acts on Pituitary

The British researchers are treating prostate cancers and endometriosis, an abnormal growth of the inner lining of the uterus. In both cases, Stern said, the drug acts on the pituitary gland of the brain, causing it to stop production of hormones that promote tumor growth.

Estradiol is normally used to treat these diseases, but only a small percentage actually reaches the brain, Stern said. The rest remains in the general circulation, where it can cause undesirable side effects, such as enlargement of the breasts in men or an increased risk of heart disease or stroke in women.

Because less of the carrier-linked estradiol is required to get the same amount of estradiol into the brain and obtain the same therapeutic effect, Stern said, the side effects should be reduced. The carrier-linked estradiol might also be used for birth control, and Pharmatec is testing it for that purpose on rodents.

Pharmatec also hopes to begin human trials in 1988 with a carrier-linked drug to treat encephalitis, a brain inflammation that is difficult to treat because most antibiotics do not reach the brain, Stern said. The company is also linking AIDS drugs to the carrier.

With the exception of the drug AZT, which is not a cure, most potential AIDS drugs do not cross the barrier, according to Martin Hirsch, an infectious disease specialist at Massachusetts General Hospital in Boston. Even if the AIDS virus were cleared from the rest of the body by those drugs, the brain would serve as a reservoir for reinfection.

Other groups are doing similar research. Pardridge, for example, piggybacks drugs into the brain by linking them to a small peptide--a short chain of amino acids--that is carried across the barrier by the transport mechanisms.

One drug he has studied is beta-endorphin, a narcotic-like drug produced by the brain to control pain. Artificially produced beta-endorphin cannot cross the barrier and thus has no effect. Preliminary results in rats and rabbits indicate that the linked endorphin can reduce pain, he said.

Back in Detroit, Joe Cunningham’s prognosis looks good. He just had another brain scan that shows no evidence of a tumor, and he is rapidly approaching the two-year mark since his diagnosis. For brain tumors, physicians typically consider two years without a relapse as a cure.

Lydia Cunningham, meanwhile, is tired of the controversy about Neuwelt’s technique. “Some of the doctors don’t feel it is safe, which bugs me no end because my husband is walking around alive when he should be dead.”