Articles

The Most Promising Key To Cancer

ERIC HUTTON May 1 1953
Articles

The Most Promising Key To Cancer

ERIC HUTTON May 1 1953

The Most Promising Key To Cancer

GLUCOSAMINE

ERIC HUTTON

THE DAY before this article was written a white mouse named B-4 died of cancer in a Montreal hospital laboratory. What makes the small tragedy news is the fact that this mouse lived eighty-seven days after it contracted the disease and that an identical mouse, A-4, which developed cancer at the same time, survived just twenty-seven days. The only difference between the mice was tliis: B-4 had been given a daily injection of a substance known as glucosamine.

These two mice were not an isolated pair. They are mentioned specifically only because they bring up to date a phenomenon which has been repeating itself with fascinating consistency for the last two years. They are average members of a force of more than two hundred mice which, in squads of twenty, may well have been engaged in making medical history. The story of their lives, written tersely in a worn laboratory casebook, reads thus:

GROUP A: All with well-established cancers. Tumors increased rapidly and consistently in size. In twenty days members of this group began to die. In forty days all were dead.

GROUP B: All with well-established cancers; but at twenty days their tumors were little more than quarter the size of those in group A, the tissues of the cancer showed extensive disintegration, and only a few hardy malignant cells remained active around the edges of the growth. The first deaths in this group usually occurred after seventy days, and at one hundred days some of the mice were still alive. The normal life span of a healthy mouse of this strain is estimated at one hundred and eighty days.

The only difference in the treatment of group A and the group which, with the same fatal disease, lived up to five times longer, was this: Group B had been given glucosamine daily. That name, glucosamine, is the key word in the story of a significant Canadian medical discovery.

How significant? The first answer is that although the discovery must, of course, stand on its own feet, the reputation and past performance of the men behind the research is significant. One is Dr. J. PI. Quastel, professor of biochemistry of McGill University and director of the Montreal General Hospital Research Institute. The other is Dr. Antonio Cantero, one of Canada’s truly international medical scientists. Canadian horn and a McGill graduate, Cantero spends part of the year as head of the cancer-research laboratory of Notre Dame Hospital, Montreal, and part as co-director of the Cancer Institute of Rio de Janeiro, Brazil.

Quastel is known as a biochemist who “delivers the goods.” Working in so fundamental a field, many a biochemist completes a useful and productive career without making a single original contribution to the average man’s way of life. But Quastel has already created two minor revolutions in aspects of modern existence. He was the central figure in the research which produced 2-4-D, the compound which destroys weeds but does not harm grasses. Although Canadians know 2-4-D most familiarly as the lawn spray which is a boon to tired suburban gardeners, it plays a more vital role in increased production of sugar cane and other massgrown grasslike crops. More recently Quastel completed development of a synthetic organic compound, launched sensationally last summer under the trade name Krilium. It is a means of converting poor sterile soils into granular fertile garden loam overnight.

It is more than a coincidence that the same man should produce 2-4-D, a selective plant killer, and now a compound which has an essentially similar effect on mouse-cancer cells. Both are, in fact, results of what might he called the same scientific train of thought. Of his new discovery, glucosamine, Quastel says:

“We certainly do not claim to have discovered a ‘cure for cancer.’ What we have done is to open up a new and promising breach for the attack of science on cancer. We believe it is particularly promising because glucosamine is not a ‘foreign’ substance — it belongs in the body; because it definitely damages the cancers on which we have tried it, and, most important, because it appears to have no ill effects on the healthy organs and tissues of the body.”

This view is confirmed by the National Cancer Institute of Canada. An institute spokesman says: “The findings of Dr. Quastel and Dr. Cantero have opened a new approach to the chemotherapy of cancer. The main interest of their work lies in the fact that a substance normally found in the body, and noninjurious in the doses used, seems to have a definite inhibitory effect on the growth of a specific animal tumor. Research workers elsewhere will doubtless determine the effects of the substance on other tumors and attempt to find out more about its mechanism of action.

“The story of how glucosamine came to be used! on tumors demonstrates that cancer-research su)>port must cover all aspects of fundamental biological enquiry if we are to find the new leads so necessary for the eventual conquest of the disease.’* The British Lancet, regarded as one of the most authoritative and most conservative of medical journals, took prompt notice of the first cautious bulletin issued to the specialized world of medical science by Quastel and Cantero. Said Lancet:

The search for substances which have the power to inhibit the growth of lumors is one of the rational ways of tackling the cancer problem. Quastel and Cantero, working in Montreal, have now examined the properties of a new tumor inhibitor, glucosamine.

After detailing the findings the medical journal adds:

Before this substance could justifiably be used for human tumors, a wider variety of animal tumors must be tested and the long-term effects of glucosamine on normal tissues must be studied. Nonetheless. this type of experiment, based on reasonable theoretical grounds, should be encouraged and extended.

The layman cannot read into these cautious statements more than they say. But anyone familiar with the cancer problem and the caution of cancer authorities will recognize these early appraisals of glucosamine’s action as being as close to enthusiasm as the experts dare go.

The cancer problem is, briefly, this: Cancer is not an attack on the body by external enemies such as germs or viruses; not the deterioration of an organ or body tissues. Cancer is the unexplainable, uncontrollable growth of cells which should not. grow, cells which previously were a normal healthy part of the body. The body does not possess or acquire resistance to this sudden perversion of its normal life processes. On the contrary, the very functions which support the body’s well-being also support the cancer which will eventually destroy it.

What causes cancer, nobody knows. No certain cure has been discovered. Cancers in an accessible site, if treated before colonies of malignant cells break off and spread through the body, can often be successfully dealt with by surgery, radiation or a combination of both. Cancers more deeply seated yield to treatment less often. Survival of a patient for five years after treatment is considered one index of “successful treatment.” When colonies of malignant cells spread from the original site, treatment is almost always fruitless.

Cancer is second only to heart disease as the greatest cause of death. Every year more people die of cancer, and the only “favorable” fact concerning this melancholy statistic is that the increase is largely, perhaps almost entirely, due to the circumstance that medical science has extended the human life span, and thus saved many people from other causes of death. This is why the discovery of a cure for cancer would he the medical news event of the century; why medical authorities approach developments in the cancer field with a caution which almost banishes optimism. It is also why the story of glucosamine, hedged around with every conceivable reservation, nevertheless becomes one of extreme interest and of great potential importance. In all its details, it goes far beyond what has

The mice and men in this picture may bring Canada a fame beyond reckoning as they work together in fashioning a bright new weapon in the ceaseless war against cancer

already been said—that it keeps mice alive two to five times longer than untreated mice with similar cancers.

In the first place, the very fact that glucosamine is a substance which occurs naturally in the human body means that it can he transferred from fundamental research with mice in a laboratory to clinical tests on cancer patients without most of the long and careful tests for harmful effects required before an “unnatural” drug or compound can be used on human patients. Already the simple preliminary calculations and checks are being made in two Montreal

hospitals with a view to trying out glucosamine on patients with cancer. These include the translation of the dosage of five milligrams or less used on mice into the appropriate dosage for human beings and the determination of possible side effects such as nausea or digestive upsets which might occur even though it is apparent that there were no harmful side effects on mice.

The effects of glucosamine on human beings will, naturally, be watched with keen interest by clinicians. But, strangely enough, it is other implications of glucosamine, still to be pursued

on the laboratory research level, that are regarded more optimistically by Quastel and Cantero.

It is possible that if glucosamine has the same effect on certain human cancers as it has shown in mice, it will extend the life of cancer patients far beyond the five-year period now considered as indicative of “successful treatment.”

“But,” Cantero emphasizes, “glucosamine does not cure cancer. Even though it shows a devastating effect on the growth, in every case enough of the malignant cells remained alive to cause the eventual death of the animal. We do not know, as a matter of fact, the maximum survival of a mouse with cancer under glucosamine treatment. Some of them were still alive at one hundred days, and they were killed then because we were not primarily interested in mere survival but in getting all the information we could on what glucosamine did to cancer growth.”

Where Research May Lead

Quastel indicated the directions in which further research with glucosamine might lead: “It may be,” he said, “that glucosamine, which destroys cancer not quite completely, falls a little short because it is only fairly good at this job. The chemist following up our work may find related substances which will do the job much better. Or something else might be found, quite unrelated to glucosamine, which used in conjunction with glucosamine heightens its effect.

“The biochemist following our new approach to the cancer problem will be able to tell us what goes on in the living cell when glucosamine enters the picture. For all we know he may find that our own theory of why glucosamine damages cancer — the theory which incidentally led us to try glucosamine on cancer in the first place is entirely wrong; that glucosamine actually has quite a different method of bringing about damage to cancer cells. This would mean that we were right in trying glucosamine, but wrong in our reasons for trying it. And this would lead to a whole new series of investiga( ions.

“The physiologist will be able to tell us more about the physical reactions inside an animal when glucosamine is used. It might even be found that one effect of glucosamine on cancer growth is to prevent the dispersal of colonies of malignant cells, the worst single characteristic of cancer. If that was the case, then we would have a situation that would be almost as good as a cure. Cancer could then be handled as a benign tumor.

“It may be that the radiologist might find something of interest in glucosamine’s effect, that the injury to cancer cells may make them easier to treat by X-ray, radium and other forms of radiation.” Quastel added that this alone would be a valuable contribution to cancer treatment, since cancer cells are only slightly more vulnerable to radiation than are surrounding healthy cells and anything that tipped the scales farther in favor of healthy tissue would be valuable.

Quastel’s work on glucosamine started in 1949, not long after his career brought him to Canada from England. At the Montreal General Hospital Research Institute a young colleague, Robert Harpur, was working toward his PhD in biochemistry on a fellowship supplied by Canada Packers Ltd. While studying various biochemical aspects of brain tissue, Harpur and Quastel introduced glucosamine into one experiment.

“I had long been interested in the stuff,” said Quastel, “because it is a cross between a sugar and an amino acid. It is fairly widely distributed in the animal world, but very little was known about its behavior in the body. It is known to be present in many compounds, for example, hyaluronic acid, one of the important chemical compounds of the body, and in streptomycin, one of the so-called wonder drugs.”

Glucosamine was a hunch, the kind of hunch scientists play. But it is a strange coincidence that, if science liad thought to play a much wilder hunch— a horse-player’s type of hunch —cancer and glucosamine might have been connected long ago. Something like two thousand years ago Roman physicians thought they detected a resemblance to a crab in the malignant tumors they found in patients. So they called the tumors by the Latin name for crab: cancer. And now, in the middle of the twentieth century, the crab is being used to attack cancer. For the richest source of glucosamine is the shell of crabs and other shellfish. At present produced only in “laboratory quantities,” this extract of crab shell costs sixty-four dollars a pound. If and when glucosamine comes into wider use, Canada possesses vast supplies of raw material which now is used largely for fertilizer in the Maritimes. Quastel believes the price will come down to a point where it will not be a factor in the use of glucosamine.

Using this extract of shellfish, the senior and junior scientists made a simple finding which was soon to become of prime importance: that excessive glucosamine affected a substance called ATP in such a way that ATP became unable to do its normal job in the body, which is to prepare a food compound required by living cells.

Now it has been known that one of the small (but as it turns out, extremely significant) differences between normal cells and tumor cells is that normal cells get their energy from a variety of sources while the tumor cells, as Quastel puts it, “seem to put most of t heir eggs in one basket and depend for their nutrition largely on substances which are manufactured with the aid of ATP.”

No, They Weren’t Excited

This led Quastel to the crucial question: Would glucosamine have the same or any effect on tumor nutrition when used in the complex organism of a living animal? Would it divert ATP from its role of helping feed the tumor?

To aid in finding the answer, Quastel enlisted the collaboration of Cantero who, as research director of t he Notre Dame Hospital Cancer Laboratory, was widely experienced in screening the effects of various substances on mouse cancers. The project thus became a collaboration between a French-Canadian and an English-Carmdian institution.

In the first screening ten mice with cancer were daily injected with glucosamine; ten more, also with cancers, were left untreated as controls. But not even a day was required to show results. Two hours after the first injections some of the cancers bore visible signs of breakdown. Six to eight hours later further degeneration was seen by Cantero. In two to four days the tumors softened and hemorrhaged extensively. Finally there was general deterioration and liquefying of all the glucosamine-treated cancer tissues and cells, except a few isolated survivors.

A natural layman’s question at this point is: “Weren’t you excited?”

“No,” said Cantero. “In the last few years, in research projects all over the world, more than five thousand substances have been tested for their

effect, if any, on cancer; such unlikely things as extract of sorrel leaves, wartime poison gases and anaesthetics. At least three hundred substances have been found to affect cancer growth— but unfortunately they are just about as hard on the rest of the animal. For all I knew this was just another one of those. You see, I didn’t know what I was using ...”

Quastel smiled. “I wasn’t really holding out on my colleague,” he said, “but as a precaution against even subconscious prejudice against mv theory and the substance he was using

Cantero received it only under the code label ‘G-2.’ As a matter of fact I told him what it was only a couple of weeks ago.”

But long before that Cantero realized it was not “just another one of those” with which he was dealing. New evidence appeared to support the almost complete disintegration of cancers in mice treated with glucosamine. This was in the form of liver catalase levels. Catalase is an enzyme with a function that is not fully understood. But one of its characteristics is valuable as a test for cancer, since the

amount of catalase in the liver is apparently greatly reduced when cancer is present anywhere in the body.

In the Quastel-Cantero mice, for example, liver catalase levels in healthy animals varied from 1 to 3 units. In untreated mice with cancer it ranged from .1 to .5. In glucosamine-treated cancerous mice it averaged 1.7 units after forty days, and 1.2 units after eighty-five days. When mice had their cancers removed at forty days their liver catalase levels rose to Î .8. In other words, as far as this particular test is concerned, t he daily injection of glucosamine had approximately the same effect as the removal of the cancer.

But the most critical test was still to be made, the test which had dashed the hopes of many an investigator who had watched cancers shrivel after the injection of one hopeful substance or another: How had the rest of the animal fared? All too often the damage to delicate vital organs proved to be so devastating that the experiment was abandoned forthwith.

In the Quaslel-Cantero laboratories mouse after mouse was dissected after it had been kept alive with glucosamine injections from seventy to one hundred days. Cantero’« own notes on the findings state simply: “No abnormal effects are present in the liver, spleen, kidneys, suprarenal glands or the intestinal mucosa of the animals. Blood counts of both red and white cells of normal mice and tumor-bearing mice are unaffected by glucosamine administration.”

That is the story of glucosamine. Rather, it is the first, chapter of the story of glucosamine. But it only hints at the men behind it whose personalities have played an important part in their successful collaboration.

“If,” Quastel says, “I had not. been able to work with a collaborator as co-operative and as resourceful as Cantero the animal tests on glucosj amine could never have been carried j out. Glucosamine would still be some¡ tiling in a bottle on a laboratory shelf.”

Quastel was born to poor parents in : Sheffield, England, fifty-four years ago. He was rescued from a life of factory work by his habit of winning scholarships. “I worked my way through my entire education on scholar! ships,” he says.

He served in the British Army for the last year and a half of World War I. A dedicated scientist even in his teens, Quastel nevertheless does not begrudge the eighteen months in uniform and mud. “On the contrary,” he says, “it was very valuable. Perhaps war and army discipline make you think for yourself, make you philosophical about

hard knocks and disappointments. Certainly I have noticed since that veterans are among the best science students.”

On demobilization Quastel took up yet another scholarship and entered the Imperial College of Science in London. In 1921 he became a fellow of Trinity College, Cambridge, and spent eight years doing research in the biochemistry of micro-organisms. He became one of the youngest men ever to win a Fellowship of the Royal Society, and he also was awarded the coveted Meldola Medal, awarded to the scientist in the British Isles under the age of thirty who has contributed most to science during the year. “It was some work on the biochemistry of bacteria.” he recalls.

It was during this period that Quastel worked out what he calls the theory of “competitive inhibition.” This theory is not easy to translate into layman’s language, but in general it holds that a living cell may be deprived of nutrition if a valueless substance is substituted for a needed substance, provided the substitute is sufficiently like the original to deceive the cell. The same effect can be achieved if the valueless substance reacts with the desired substance to form a totally different compound and thus deprives the cell of a necessary nutrient.

Through all his professional career, involving countless projects in fundamental research, Quastel has kept his principle of competitive inhibition in mind, and tested its feasibility whenever possible. It provides, for example, the link between 2-4-D, a selective inhibitor of plants, and glucosamine, a selective inhibitor of cancer.

From 1929 to 1941 Quastel directed research at Cardiff City Hospital, and early in the critical period of World War II he was enlisted by the British government to become one of the nation’s top “survival scientists.” He directed the Agricultural Research Council’s unit on soil research, charged with finding ways of speeding up Britain’s self-sufficiency in foods. It was in this job that lie and his colleagues discovered “a hormone with a herbicidal action”—which became 2-4-D. Until the end of the war it remained a top secret. Obviously, enemy possession of a substance which kills plants might be disastrous to a small land where every acre of crop was precious in time of siege. During this time, too, Quastel developed the underlying principles of a synthetic soil conditioner which, after further development in Canada, has become the commercial product which at this time of year blossoms into a continent-wide advertising campaign aimed at home gardeners.

After the war Quastel’s reputation in scientific circles was such that he could just about have his pick of a professorship of biochemistry at any university in the world. He chose McGill, partly because his wife, an American girl he had met in Switzerland, wanted to return to this side of the Atlantic and partly because of the growing opportunities for scientific work in this country.

The Quastels with their two sons, aged nineteen and sixteen now, landed in Montreal in 1947, accompanied by all their worldly possessions, including a houseful of furniture. The day after their arrival Quastel “went out and bought a house.” They still live in it.

“I did not,” Quastel says now, : “realize there was anything extraordinary about buying a house in Montreal in 1947. Since then I have learned it was quite a feat.”

The laboratory which produced the I glucosamine discovery is no convenI tional temple of science. Montreal General Hospital’s Research Institute i is housed in a once-glamorous building, the home of the Morgan family of department-store owners. The highceilinged rooms with their ornate fireplaces and carved moldings are now packed, cellar to attic, with scientific equipment. It stands, surrounded by student rooming houses, across University Street from McGill’s huge modern medical building.

Quastel, medium in height, his wavy hair iron-grey, is a man of quick movement. His eyes, the intense eyes of a scientist, are seldom without a twinkle. Although the products of his research, in the form of 2-4-D and synthetic soil conditioner, sell for several millions of dollars a year, Quastel receives not a cent in royalties. “People in science,” he explained, “don’t patent their findings. They just publish them and let others do what they can with them.” He smiled. “When 1 want some 2-4-D or Krilium for my garden I buy them in a hardware store just like anybody else.”

He Summers in Brazil

Antonio Cantero was born in Sault Ste. Marie, Ont., fifty years ago. After he graduated from McGill he started his research career, literally, in an elevator shaft, with an orange crate for a laboratory. “It was,” he explains, “the only space available in the old University of Montreal building to which I was assigned. I cleared the cobwebs away and set up a research project, on the action of sex hormones on mice, in that orange crate.”

When the National Cancer Institute of Canada was founded to co-ordinate and support cancer research, Cantero organized Notre Dame’s research laboratory, with one assistant. Today the laboratory has expanded into a whole section of its own, with a staff of twenty-two.

Cantero is probably the Canadian scientist with the most widely separated research projects. Every summer he takes up his second appointment, as co-director of the Cancer Institute of Rio de Janeiro, Brazil, where lie lectures and supervises Brazil’s first fundamental cancer research project. Somehow he manages to find time for private practice as a gastro-enterologist with offices in downtown Montreal.

Quastel and Cantero are still continuing their work on glucosamine, but in addition Quastel directs a dozen more research projects, Cantero four separate enquiries, and both are responsible for a great deal of more routine work concerned with the running of laboratories attached to hospitals where human patients are treated.

“The present state of medical knowledge,” says Quastel, “teaches us one important lesson—that a very great deal more fundamental knowledge of the processes of life is vitally needed.”

Fundamental knowledge of the living cell, the basic unit of all life and the basic problem of cancer, is hard to come by. And harder still to translate into cures for the gravest ills of mankind. But the findings of these two Canadians has provided a new stimulus of hope to hundreds of research scientists the world over, and medical men everywhere are watching the outcome with an interest they reserve for the really great potential advances in the conquest of disease.