ARTICLES

Is there a drug to cure cancer?

THE SCIENTISTS are promising nothing — but, as a result of new chemical discoveries, they are cautiously hopeful that now it’s just a question of time

SIDNEY KATZ April 12 1958
ARTICLES

Is there a drug to cure cancer?

THE SCIENTISTS are promising nothing — but, as a result of new chemical discoveries, they are cautiously hopeful that now it’s just a question of time

SIDNEY KATZ April 12 1958

Is there a drug to cure cancer?

THE SCIENTISTS are promising nothing — but, as a result of new chemical discoveries, they are cautiously hopeful that now it’s just a question of time

ARTICLES

SIDNEY KATZ

Until fairly recently the doctor had only two main methods of fighting cancer: radiation and surgery. With these he was able to cure about one third of his patients. The other two thirds were often written off as “unbeatable” and doomed to an early—and probably painful— death. But today’s most exciting and cheerful medical story concerns the “unbeatable” two thirds. A new and powerful weapon against cancer is being forged. It’s called chemotherapy— treatment by the use of chemicals. There are already at least twenty such substances that prolong the life and decrease the pain of the cancer patient. While no chemical has yet been discovered that will cure cancer outright, the prospects are bright.

“I’m convinced that cancer will be completely conquered by new drugs,” says Dr. Cornelius P. Rhoads, director of the famous Sloan-Kettering institute for Cancer Research, in New York. “It’s now just a question of how soon.”

Dr. Douglas G. Cameron, physician-in-chief of the Montreal General Hospital, says, “At any time now we might stumble on a cure.” Dr. O. H. Warwick, director of the Ontario Cancer

Institute, in Toronto, declares, “Because their lives have been prolonged by the new drugs, some cancer patients are now dying of other

diseases.”

The optimism of the cancer specialists is solidly based on the achievements of chemotherapy during the last few years.

Until comparatively recently children with acute leukemia (cancer of the blood) usually died within a few months. Only five out of every hundred were alive at the end of a year. Today the records of New York’s Memorial Hospital (with which the Sloan-Kettering Institute is affiliated) show that almost sixty percent of leukemic children survive for a year or more thanks to such new chemicals as 6-MP, adrenal steroid hormones, azaserine and amethopterin. One boy has had his life prolonged by as much as seven years. “After you see a dying child back at school and play in a few weeks you become a convert to chemotherapy,” says Dr. Kenneth Endicott, director of the Cancer Chemotherapy National Service Center. This organization is part of the United States government-sponsored

National Cancer

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Is there a drug to cure cancer?

Continued from page 13

“This year one laboratory alone will test some forty thousand possible anti-cancer compounds”

Institute, at Bethesda, Maryland.

In the past the adult with chronic leukemia often spent his final months or years as an invalid, in discomfort and pain. The magic of new nitrogen mustards (Myleran, TEM, FIN2), radioactive phosphorous and a complex compound, urethane, sometimes prolong the life of the chronic leukemic. Significantly, the patient is now often fully active and in good health practically until the time he dies. Douglas Cameron of the Montreal General Hospital had as a chronic myelocytic leukemia patient, a thirty-fiveyear-old businessman. He was under medical treatment for five years. During nearly all of this time he was able to go to work every day and keep his affairs in excellent shape.

Choriocarcinoma is a highly malignant—and fortunately an uncommon— form of cancer of the uterus. It develops from the fetal placenta. It responds in a spectacular way to amethopterin. Dr. Roy Hertz, of the National Cancer Institute, and Dr. Min Chiu Li, of the Sloan-Kettering Institute, report that of fifteen patients, the tumor has disappeared in five and in another five the disease has been arrested in a remarkable fashion. The scientists are hopeful that when the usual waiting period of five years elapses, their five “cured" patients will still show no evidence of disease.

In female breast cancer, new, efficient synthetic hormones, radioactive gold and nitrogen mustards benefit as many as fifty percent of the patients. These drugs, combined with radiation and surgery, make it possible for many patients to live longer—in some cases, many years longer. In male prostate cancer similar treatment gives even better results.

Slow but definite progress is being made in discovering a vaccine against cancer. Dr. Charlotte Friend, of the Sloan-Kettering Institute, has recently produced a vaccine that protects ninety percent of mice against mouse leukemia. Dr. Friend made her immunizer by following the same process used in the development of the Salk vaccine for polio.

Fifty North American hospitals are experimenting with drugs to make surgery on lung, liver and stomach cancer more effective. Hitherto these deeply hidden cancers have been the most difficult to treat. Surgeons are now giving patients strong doses of powerful anticancer drugs at the time of surgery. "In manipulating a tumor at the time of an

operation.” explains Endicott of the Chemotherapy Center, “showers of cancer cells often get into the bloodstream, circulate and look around for another place to settle and start growing. Because the cancer cells are unsettled we believe this is a good time to use anticancer drugs—they'll do the most good. This has already been proven in surgery with cancerous animals." A new drug, TEPA, first used at the Sloan-Kettering Institute, has yielded the most promising results in this form of treatment.

Antibiotics, the family name for the wonder drugs such as penicillin and streptomycin, which cure infectious diseases, may be the source of yet another drug-—one that can destroy cancer. The Sloan-Kettering Institute has already tested twenty-seven thousand new culture filtrates that might contain new antibiotics. One in every hundred examined shows some anti-cancer activity. "And we haven't yet scratched the surface,” says Dr. Chester Stock, of the institute. “There are infinite possibilities in antibiotic preparations.” One of the most hopeful is mitomycin, which Stock recently brought back with him from Japan. “It retards the growth of a wide variety of cancers in animals," says Stock. New antibiotics—azaserine, DON, actinomycin C and actinomycin D—are already being tested clinically on a variety of cancer patients.

Another white hope for the cancer victim is a group of drugs that make normal tissue less sensitive to radiation and cancerous tissue more sensitive to radiation. With their help, according to Dr. Marvin Lougheed, radiologist at the Montreal General Hospital, it will become increasingly possible to bombard malignant tumors with massive doses of X-ray without harming the patient. Given enough radiation, all cancer cells will perish. Up to now the doses have had to be limited so as not to destroy surrounding normal tissue.

The list of effective anti-cancer drugs is almost certain to grow, month bymonth, because of the research now underway. No single disease has been assaulted by so many men, backed by so many dollars. In Canada the National Cancer Institute is spending a million dollars a year to subsidize the work of scientists in half a dozen centres. In the United States the National Cancer Institute is budgeting fifty-six million dollars a year to find cancer cures. Half

that amount is being spent by the Cancer Chemotherapy National Service Center. directed by Kenneth Endicott, a forty - two - year - old pathologist. "You might call our operation The Wall Street of Cancer Research,' ” he says. "We underwrite, direct and co-ordinate the work of a vast network of drug firms, hospitals, universities, private laboratories and individual scientists." This year the Chemotherapy Center will collect and test some forty thousand possible anticancer compounds and antibiotic preparations. "Any one of them might prove to be the magic bullet that destroys cancer," says Endicott.

The cancer scientist can approach his job from two directions. One is the "rational” approach; that is, he can study minutely the chemical processes of the birth, growth and death of the normal cell and the cancer cell. By making thousands of comparative measurements, the scientist might some day learn the secrets of the cancer cell. "With this information on hand,” says Dr. Charles S. Cameron, former medical director of the American Cancer Society, "synthesizing the anti-cancer drugs will be largely a mechanical problem for the biochemist."

The cancer scientists' other approach is the "empirical”—trying out thousands of drugs to see which ones check tumor growth. Most researchers shun this method, preferring to concentrate on an orderly, systematic investigation of the cancer cell. However, because cancer is a continuing catastrophe—twenty thousand Canadians and a quarter of a million Americans died of it last year— many scientists have thrown themselves wholeheartedly into the crash empirical program now underway.

No possibilities are overlooked. Cancerologists at the National Cancer Institute have even experimented with the juice of the needles of the juniper trees which shade their laboratories. At the Sloan-Kettering Institute, scores of sub-

stances, some familiar, some strange, some exotic, arrive each month. "We try all materials sent to us for possible anticancer properties if they meet certain requirements,” says Chester Stock. These have included milkweed, garlic, red clover, Royal Bee Jelly, lemons, mistletoe, beets, rare plants from Iran and other distant lands. A number of toadstools and mushrooms have shown interesting anti-cancer powers and are being further tested. The Brooklyn Botanical Gardens frequently ship in an assortment of molds and fungi they've grown. A rabbi recently called Stock's office claiming that the Talmud mentions taurocholic acid as a tumor cure. "By coincidence the substance is already on our research-program list," says Stock. Several times a year the institute receives packages of "grandmother’s secret remedy for warts and growths." They are usually caustic substances containing zinc chloride.

A South American suggested a complex fluid made up of jungle plants and herbs used by a primitive tribe for centuries to shrink human heads. “We got a supply of the fluid and tried it." says Stock. "It actually did shrink tumors but it was not as good as dozens of other chemicals we've got on hand."

Actually, as Warwick, of the Ontario Cancer Institute, points out. “both rational and empirical research are necessary at this time." The rational scientist is always suggesting possible cancerfighting chemicals that should be tested; the empirical scientist frequently reports on compounds that should be examined carefully in the laboratory.

It is the life cycle of the normal cell and the cancer cell that is the focal point of the rational scientist. Nobody knows precisely what causes cancer, in the fundamental sense. A cell or group of cells begins to run wild, reproducing at lightning speed, eventually crowding out the normal cells, much the same as scrub grass knocks out lawn grass. Millions of cancer cells pile up to form a malignant tumor. Later, groups of these cells may be carried to other parts of the body by the blood and lymph streams, where other tumors may start growing. This may occur in the stomach, breast, lung or any one of about sixty-five other sites. When the disease becomes spread in this manner, treatment is difficult. Until recently, it has been almost hopeless.

What the scientist is searching for is a chemical that will kill the cancer cell and at the same time do no damage to the normal cell, in somewhat the same manner as 2.4-D kills weeds without affecting lawn grass. (It is no coincidence that Dr. J. H. Quastcl, the worldrenowned biochemist who discovered 2,4-D, is now directing cancer research at the Montreal General research institute.) To accomplish this by design, the scientist would have to know exactly how normal and cancer cells differ biochemically. Penicillin is effective against pneumonia and streptomycin works against tuberculosis because they manage to knock out the offending bacteria without interfering with the normal cells. This is relatively simple because bacteria are invaders from the outside and are far different than the body’s cells. Cancer cells, on the other hand, arc produced by the body. To compound the problem they are practically identical twins of normal cells: they are built pretty much the same and require almost the same foods. "We’ve got hundreds of chemicals that destroy cancer cells,” says Warwick, "but unfortunately they are also fatal to normal tissue.”

However, after years of effort, researchers have detected subtle differences

between cancer and normal cells. Therein lies much of the hope for a powerful cancer drug or drugs. The differences lie in the metabolism. Since some cancer cells grow faster, they eat more food and cat it in different combinations than the normal cell. The scientist has therefore designed drugs that will frustrate the cancer cell in its effort to remain healthy by gobbling up such essentials as vitamins, proteins, fats and carbohydrates.

They accomplish this by pulling a kind of scientific con game on the cancer cell. They inject drugs in the body which resemble essential foods the cancer cell needs, but which, in fact, are quite different: they’re phony ersatz

foods. The cancer cell is duped into eating them and is ultimately poisoned or starved to death. It’s very much like putting large quantities of sawdust in cattle food—you'll fool the animals but ultimately they may die on you. A whole group of these chemical tricksters have been devised, known as antimetabolites because they interfere with the metabolism of the cancer cell.

The part of the cell the scientists are most anxious to fool is the nucleic acid. This lies at the heart of every cell and seems to be the lord and master of the cell. A now-popular theory is that when something goes wrong with the nucleic acid, a normal cell becomes cancerous and so do all its descendants. A close tie has been shown to exist between nucleic acid and cancer: radiation or any substance that can cause or cure cancer has a marked effect on the cell’s nucleic acid.

A number of antimetabolites are already proving their worth in treating cancer, especially leukemia.

Canadian scientists are playing an important role in cracking the mysteries of cell metabolism. At Laval University, Dr. Louis Berlinguet has devised fourteen “phony” amino acids, which, when fed to the cancer cell, will prevent it from synthesizing necessary protein. A colleague, Dr. F. Martel, is carefully charting the chemical changes that take place in the blood even before there are clinical signs of cancer. At the Montreal General Hospital Research Institute, Dr. Quastel is directing six projects delving into the diet of the cancer cell.

Ironically, other drugs that show great promise in the battle to conquer cancer are related to a compound designed to kill, not cure—mustard poison gas. The current widespread interest in HN2 (as nitrogen mustard is called by chemists) as an anti-cancer drug came about by accident. During the Italian invasion in September 1943 an allied ship carrying a hundred tons of mustard gas was hit by a bomb. Hundreds of soldiers and sailors who were forced to jump overboard came in contact with the material in the water. Medical researchers who later examined these men found that they had a greatly reduced number of white blood cells. Since this condition is characteristic of certain kinds of cancer, the scientists began to wonder whether small amounts of nitrogen mustard might not have a therapeutic effect on tumors. Their hunch paid off. One patient in an American hospital was being strangled by a huge tumor in the neck lymph glands. Given HN2, the tumor seemed to melt away and the patient could breathe again. It was also found to be beneficial in chronic leukemia. In fast-growing lung cancer forty percent of the patients were helped by HN2.

Today there are some thirty nitrogenmustardlike drugs either being used in therapy or undergoing clinical tests. HN2, TEM and Myleran (a British drug)

have been of benefit in some cases of solid tumors of the stomach, kidney, uterus and ovary. In breast and lung cancer the patient’s pleural cavity sometimes becomes filled with fluid. This is extremely uncomfortable and the draining-off process is painful. Today, when this condition appears, doctors inject the pleural cavity with a solution of salt and HN2. The results are sometimes remarkable. Douglas Cameron of the Montreal General Hospital reports that one patient formerly had to have his pleural cavity drained every month; now, thanks to HN2, once every nine months is sufficient.

At the University of Colorado, pharmacologist Richard Whitehead has combined HN2 with the anti-cancer drug urethane and is using it to treat cervix and uterus cancer in combination with radiation. At the University of Pennsylvania, Dr. Charles C. Price and Dr. Ralph Jones conceived of the idea of mixing HN2 with chloroquine, an antimalarial drug. They theorized that because chloroquine tends to concentrate in certain hard-to-reach parts of the body, it would carry along with it the anti-cancer HN2 to hitherto inaccessible tumors. The new combination drug—chloroquine mustard—is being tried on two hard-toreach cancer sites, the adrenal glands and the brain. Research in the nitrogen mustards has now assumed international proportions, with Britain, France, Hungary, Japan and Russia all preparing and testing a wide variety of compounds.

The “beer” that cures

While the nitrogen mustards show great promise, many scientists, such as Kenneth Endicott of the Chemotherapy Center, believe that new and powerful tumor-destroying antibiotics will make the biggest headlines in the months ahead. Twenty years ago, Endicott points out, antibiotic drugs were unknown; today penicillin, aureomycin. terramycin, streptomycin and other drugs are commonly used to knock out diseases that were, within our memory, unconquerable.

Antibiotics are now receiving the lion's share of the Chemotherapy Center’s time and money. Last year, thirty thousand of them were tested. The search for Huantibiotic has all the thrills of a sweepstake because it may be found in a spoonful of earth anywhere in the world. Antibiotics are grown from micro-organisms found in the soil. When the microorganisms are placed in a nourishing broth or “beer” they have the ability to manufacture compounds with unusual structures and biological activities. These beers are then tested for their anti-cancer powers.

Thousands of soil samples from all over the world are now being gathered in the hope of capturing the all-powerful micro-organism. Last summer Celia Halpern and Gwen Kamran of the Chemotherapy Center went to Europe, carrying with them several “soil sample” kits. A complete kit consists of a rectangular cardboard box containing eighteen oneounce jars and a spoon. They gathered their samples from grassy damp areas, an inch or two below the surface of the earth. Some samples were taken from the Riviera in France, others from the ruins of Pompei in Italy and Tintern Abbey in England. Nobody knows what part of the earth's surface is likely to yield the most productive soil. One official of the American Cancer Society has suggested that the soil of graveyards, because it’s rich in micro-organisms, might turn up particularly active material, but the theory hasn’t yet been tested.

Several antibiotics developed from

these soil samples are already at work fighting cancer. Amethopterin is effective in fighting a particularly malignant form of cancer of the uterus. Azaserine, in combination with other chemicals, is valuable in leukemia. Actinomycin C has been used in Germany in Hodgkin's disease, while actinomycin D is useful in treating some children with Wilms’ Tumor—a kidney cancer.

At the same time improvements are being made in hormone therapy. It’s long been known that a relationship exists between the body’s hormones and cancer. Breast cancer in the female often requires a supply of female sex hormones, estrogen, for growth. If the supply of estrogen is cut off—and this can be done by surgically removing the glands which produce it or by neutralizing its effect with androgen, the male sex hormone — the growth of the tumor is usually arrested. Similarly, prostate cancer in the male can be checked either by surgery or by the countering action of the female sex hormone, estrogen.

Day by day, the knowledge of hormones and their relationship to cancer is growing. It is now known that the hormones of the pituitary and adrenal glands are also involved in cancer growth. ACTH. cortisone and some thirty new types of synthetic hormone preparations are being studied for their influence on tumor development. What seems to be emerging is this: good health depends on the glandular system keeping the body in a state of biochemical balance. If the glandular system falls down on the job, then cancer or other diseases develop. This points the way to cancer prevention in the future. By careful tests it should be possible to establish when the body is biochemically unbalanced, and to correct this condition by hormone injections.

Perhaps the most intriguing branch of chemotherapeutic research is the one that uses human volunteers. This is the 'search to find out whether or not the human body has natural defenses against cancer, much the same as it has defenses against viruses and bacteria. If these defenses exist then they can be strengthened, perhaps by “cancer shots” or by some other method.

It is well known that some people have an amazing power to resist invasion by cancer. Recently, Dr. William Boyd, a former University of Toronto pathologist, reported on some twenty cases of spontaneous regression in cancer in which well-developed tumors stopped growing and disappeared. In one remarkable case a twenty-three-year-old Montreal woman was sent home to die after half her body was invaded by tumors. Yet four years later she was married, had three fine children and was enjoying perfect health.

Why should this be so? How did it happen? To unravel some of the mysteries of the body’s natural resistance to cancer, Sloan-Kettering scientists have been working with human volunteers— prisoners at Ohio State Penitentiary. Using a hollow needle, they implanted a cluster of five million cancer cells under the skin of the forearm of fourteen healthy volunteers. In all fourteen cases a large patch of inflammation appeared around the injection, indicating that the body was rejecting the cancer cells. Later, the cancer-cell implants were removed by surgery or disappeared by themselves. The cancer did not reappear at a later date in a single volunteer. Some weeks later the same group were again given implants of the same cancer. Their bodies destroyed the cancer even more rapidly this time, indicating that the defense reaction had increased.

The same procedure was tried on fif-

teen patients with advanced cancer at the James Ewing Hospital in New York. In thirteen of the fifteen patients the cells thrived and continued to grow until they were removed some weeks later. In four cases the cancer recurred and continued to grow. "This experiment seems to indicate that cancer patients lack some defense mechanism present in a healthy human being,” says Dr. Chester Southam of the Sloan-Kettering Institute.

Precisely what is this mechanism? Comparing the blood of the Ohio volunteers with that of the James Ewing Hospital patients, scientists put their finger on properdin, a natural defense chemical occurring in the blood. They found that the level of properdin in the blood varied directly with the ability of the person to fight cancer. It is now believed possible that properdin actually causes the destruction of implanted tumors. In simultaneous experiments conducted on animals it was discovered that zymosan, a yeast piQduct, when given in very small doses, had the ability to raise the levels of properdin in the

blood. Further studies of properdin are now underway and exciting results may come from them.

None of the scientists I spoke to in Canada or the U. S. would hazard a guess as to when an all-powerful chemical cancer cure would be discovered. They agreed, however, that probably not one drug, but many would be found, each with the power to cure a particular type of cancer. They envisaged whole new classes of cancer-fighting chemicals, now unknown.

To physicians such as Dr. David A. Karnofsky of the Sloan-Kettering Institute, who spends much of his time testing drugs on patients with runaway tumors, finding a cancer cure is a matter of urgency. "It’s a sad and frustrating experience every time you lose a patient,” he says. But, in spite of all the failures, like other cancer chemotherapists. he’s not discouraged. “Today we can help patients who were formerly abandoned: tomorrow we'll be able to help even more of them. Chemotherapy is a rewarding business.” if