Chemotherapy: here is its secret origin

The beginning of the history of chemo goes back to the fall of 1917. We are in the most sinister months of the First World War, which has already made millions of deaths for nothing. The scene takes place in the city of Ypres, in the once laughing Flemish countryside, now ravaged by trench warfare.

The artillery fire has finally stopped. More than 5,000 Allied soldiers (mostly French, Belgians and Canadians) rest. Suddenly, they see arriving on them sheets of green gas carried by the wind. They were dropped by unknown machines manipulated by the Germans, a few hundred meters away. Nobody suspects that this is a new weapon of mass destruction: the “mustard gas”, the first chemical weapon.

Moments later, it’s just a screaming concert, the abominable spectacle of thousands of live burned bodies squirming on the ground.

The mustard gas, in contact with the skin, forms huge blisters. The mucous membranes are attacked, eyes, lips and lungs burned. However, men do not die until after a few days of generalized infections and haemorrhages. As doctors will observe, mustard gas has the appalling effect of destroying the bone marrow, suppressing the immune defenses of the victims and stopping the renewal of blood cells.

This story touches me closely because my great-grandfather was present at the Battle of Ypres. Luckily, he climbed the church steeple to observe the battlefield when the mustard gas was dropped by the Germans. The gas remained at ground level, and was spared.

Forbidden by the 1925 Geneva Convention, chemical weapons will nonetheless continue to be produced and used. In 1943, the Germans sank an American ship off the Italian coast near Bari. The holds of this boat are stuffed with mustard gas that is spreading. Medical Officer Colonel Steward Alexander, examining the sailors killed by the disaster, will confirm that the lethal effect of mustard gas comes from the collapse of the number of white blood cells in their blood after a few days.

It did not take much to give a strange idea to two young scientists, Alfred Gilman and Louis Goodman of Yale University, in the United States, who contributed to the secret program of American research on chemical weapons (Chemical Warfare Service ).

Since mustard gas destroys white blood cells, could it not be used to treat children with blood cancer, or leukemia, which is characterized by an uncontrolled proliferation of white blood cells in the blood?

This is how the first chemotherapy was born. We will tell the story but we must first make a reminder about leukemia.

Leukemia, white blood disease

Acute lymphoblastic leukemia is a blood cancer that affects mostly children around the age of 4 and 5 years.

It is caused by bone marrow disease.

It’s hard to imagine that anything interesting can happen in our marrow. It seems isolated from the rest of the body by the thick, hard and seemingly impenetrable wall of the bones that surround it.

In reality, our bones are porous, and our marrow plays an indispensable role: it makes the cells of our blood. Our bones pass through blood cells made in the marrow, which join the blood stream and regenerate it.

There are three main types of blood cells made by the bone marrow:

  • Red blood cells, well known because they are the ones who give the blood its scarlet color; they are used to carry oxygen from our lungs to the cells.
  • Platelets, which serve to make the blood clot.
  • White blood cells, which are the soldiers who protect our body. White blood cells are also called leucocytes (in ancient Greek leucos means white and cyte means cell).

Unfortunately, sometimes bone marrow cells become crazy and start to proliferate: this is cancer of the blood, or leukemia.

The bone marrow begins to make so many white blood cells that the blood itself becomes whitish. Nineteenth-century doctors who observed this for the first time called this disease leukemia, which means “white blood” in Greek, leucos, white, and hemos, blood.

Leukemia, a deadly disease at 99.93%

If white blood cells multiply in case of leukemia, it is not the same for other blood cells.

The number of red blood cells falls, causing anemia that is manifested by a pale complexion and fatigue. The number of platelets also decreases, causing haemorrhage risk because the blood can no longer coagulate normally.

At least, it will be thought, the large number of white blood cells ensures maximum protection against infections. Unfortunately, it is not the case. On the contrary, these many white blood cells are immature and do not even do their job of immunity anymore. The patient is at risk for infections, especially sepsis, a deadly generalized infection.

Leukemia was partially defeated, we will see, in 1971, thanks to a chemotherapy treatment to heal 50% of cases. But until then, it was a terrible and deadly disease at 99.93%. Post-war doctors had no treatment. They did not even practice blood transfusion (giving the patient a healthy blood from another person) as this only unnecessarily prolonged the sufferings of the sick.

The medical challenge of treating leukemia is that cells that begin to proliferate in the bone marrow have only a slight difference with healthy cells. Their ability to multiply too fast comes only from a tiny mutation in the code on the hidden DNA tape inside their nucleus.

Thus, if one seeks to destroy cancer cells with a product, healthy cells will also die. The problem was thus summarized in 1945 by a great researcher on cancer, Professor WH Wolgom: “People who do not have training in chemistry or medicine may not realize how much the problem is really difficult. It is almost, not quite, but almost as hard to find a product that would dissolve the right ear but not the left ear. “

Mustard gas tested on a cancer patient

Despite this apparently insurmountable difficulty, our two researchers from the Chemical Warfare Service decided to test the effects of mustard gas in mice with lymphoma, a lymphoid lymph node cancer that also produces white blood cell (lymphocyte) proliferation.

And in fact, “after only two administrations of the compound, the tumor began to soften and regress to the point of no longer being palpable.”

The result was sufficiently encouraging, according to the two researchers, to justify tests on humans.

We are indeed in full swing at the time when medical research entered the modern era. New researchers believe that it has become ethical to put patients at risk as soon as it improves their knowledge of the disease and that there is hope to lead to treatments for the following patients, even if if this hope is weak.

This is in contradiction with the conventional vision of the doctor who committed himself, by taking the oath of Hippocrates to “first not to harm” his patient (“primum non nocere”). But was this oath respected in practice by a profession which practiced on a large scale bleeding, purging, the so-called “treatments” with mercury, arsenic and antimony (violent poisons), without the slightest scientific proof of effectiveness?

Still, Alfred Gilman and Louis Goodman decided to try their idea on a patient. It was a man, JD, 48, suffering from lymphoma. He received injections of mustard gas intravenously. It reacts at first like the mice: its tumors disappeared in ten days. A month later, they had reappeared, and he was treated again with mustard gas. In fact, as might be expected, the chemical weapon had destroyed her bone marrow at the same time as she had destroyed the lymphoma, and like the unfortunate soldiers, JD died. According to the doctors, the treatment did not slow down his illness. On the contrary, “his death was hastened by the adverse effects of the drug on his bone marrow”, ie his red blood cells and his platelets had also been destroyed.

The next patient was even less fortunate: the treatment had no effect on his tumor. On the other hand, he totally destroyed his bone marrow, causing his death.

Mustard gas was declared “far too toxic”, even for the treatment of cancer. But the experience of the mice and the first patient who had seemed to experience a remission before dying, since their cancer had actually regressed, had struck the spirits.

Chemists began to “work” on mustard gas to modify it and create slightly different molecules, one of which, it was hoped, would have the same effect on tumors while being less destructive to the bone marrow.

The Chemical Warfare Service of the US Army reconverted to a chemotherapy research center

This research took place at the Chemical Warfare Service of the US Army, under the direction of Dr. Cornelius Rhoads.

This service was closed in 1945 but the facilities and all staff were converted into a cancer treatment center. Two American philanthropists, Alfred Sloan and Charles Kettering, made a donation in 1948 to continue the work and so was born the Sloan-Kettering Institute, which is still today a reference in the treatment of cancer.

Through testing, they discovered substances derived from mustard gas that were less toxic and could be used to reduce tumors by limiting adverse effects for the patient. Thus appeared the first group of chemotherapy drugs, including thiotepa (1950), chlorambucil (1953), melphalan (1953) and cyclophosphamide (1957), still used today.

Melphalan, combined with corticosteroids, is used in the treatment of myeloma, another form of bone marrow cancer. Melphalan differs from mustard gas only because chemists have replaced a sulfur atom with a nitrogen group.

But it turned out that the treatment of leukemia would not succeed with a single category of drugs. It is the administration of a combination of products that will help overcome the disease.

Discovery of methotrexate

Shortly after the discovery of the effects of mustard gas on leukemia, a Harvard researcher, Sydney Farber, found that his young leukemia patients died faster when he gave them folic acid (vitamin B9).

Instead of immediately giving up the treatment, he had the following idea, which seems obvious today, but which was absolutely brilliant: since folic acid accelerates death, then a substance that would block the action of acid folate could perhaps cure the sick?

In collaboration with Harriett Kilte and chemists Lederle Laboratories, Farber developed aminopterin, then amethopterin (methotrexate), a substance “anti-folate” which, indeed, proved effective to block the proliferation of cancer cells .

Indeed, cells need folic acid to reproduce. By giving folate to his patients, Farber had unknowingly “fed” the cancer cells, allowing them to multiply even faster.

Other anti-leukemic drugs were discovered during this period: 6-mercaptopurine (6-mp) and an alkaloid, extracted from a tropical plant, vincristine.

However, these products alone continued to cause more harm than good to the sick. In 1967, after 20 years of testing, an investigation of 1000 children treated during the period revealed that only two of them could be considered to have been “cured”, that is, to have survived more than five years.

The fight against leukemia seemed hopeless.

Treatment of leukemia

Dr. Howard Skippper of the Sloan-Kettering Institute, a veteran of the Chemical Warfare Service, is credited with the treatment protocol that increased the 5-year survival rate for leukaemic children by 0.07%. in 1945 to 71% today.

Influenced by military culture, he understood that leukemia could only be defeated by the total eradication of the enemy: the cancerous cells in the bone marrow.

It was necessary to be ready, both in practice and psychologically, to practice on the patients a total war , using both chemical weapons (chemotherapy) and nuclear weapons (radiotherapy), by imposing only one only limit: that the treatment stops just before killing the patient.

It meant accepting to close the eyes on all the children who were going to be sacrificed so that this limit could be found, and also to accept to make the patients suffer indescribable pain: because each stage of the treatment would be followed by nausea and vomiting. so severe that most children would be malnourished and their growth interrupted. Moreover, as explained above, their healthy cells would be poisoned like their cancer cells, which would make them fall hair, fill their mouths with ulcers, and cause them chronic diarrhea and cystitis (inflammation of the urinary canal).

During all this dreadful period of seeking treatment, the adverse effects outweighed those of the disease itself, and it was more often the drugs that killed the patients than the cancer itself.

And yet, the solution ends up being found by Dr. Skipper. His innovation was to understand that the mistake of his predecessors had been to stop treatment too early.

The practice up to him had been to induce remission in the patient, then to reduce the doses to limit the toxicity of the treatment. Dr. Skipper, on the other hand, decided to increase the doses once the remission was obtained.

Indeed, he imagined correctly, the cancer cells that survived the first attack are necessarily the most resistant and the most malignant. These are the ones that must be flushed out and annihilated before they multiply and counterattack in force.

It had been observed that, during cancer recurrences, the drugs were much less effective, as if the cancer cells had developed a resistance to chemotherapy.

Doctors began to apply this principle: to begin by inducing a remission through relatively low-toxicity drugs, vincristine and prednisone (derived from cortisone). At that time, once the enemy weakened, launch the weapons of mass destruction methotrexate and 6-mp, and continue treatment for two to three years in the hope of eliminating the last surviving cancer cell.

This treatment made modest progress, but the doctors realized that cancer cells were taking refuge in the brain. Protected by the blood-brain barrier, they were like in an anti-chemotherapy bunker.

This prompted another doctor, Dr. Pinkel, to release the nuclear weapon: he decided to inflict additional treatment of radioactive radiation in the brain of leukemic children. It was a failure. He reacts on the next patient by doubling the dose of radiation.

This time, the rate of relapse was divided by twenty !!!

A giant step had been taken in the treatment of leukemia. The suffering endured by the sacrificed patients proved useful. The 5-year survival rate increased to 50% in 1971 and, by other improvements in treatment, increased to 71% in 1995 in children.

Overall, today, including adults, 50% of leukemic patients survive beyond 5 years after their diagnosis.

A terrible story, but that ends well

So it’s a terrible story, but it ends pretty well.

I say “rather” because the problem of leukemia is far from behind us. The current treatment (which remains virtually identical to that which was developed in the 1970s) continues to lead to sequelae (lower IQ, related to treatments in the brain), and especially a large increase in the risk of leukemia at age. adult, which is a side effect of treatment.

This is why research continues ardently. We would like to find a less toxic, less aggressive treatment.

Unfortunately, the spectacular progress made in the 1960s has not been re-edited. Leukemia is still treated roughly the same way. Dr. Nicole Délépine, famous for her leukemia treatment service at Garches Hospital, even considers that the new treatments that the labs are trying to test against leukemia do not even deserve to be tried. For her good old methotrexate is the only product that has proven itself in the field.

This is basically the difference between the generation of our parents, who has known the progress of post-war medicine, and ours. Their optimism, their unlimited trust came from the harvest of discoveries that took place at the time. And it is true that the spectacular progress, like the treatment of leukemia, could hope that the movement would continue more.

It was not the case.

In the fight against cancer, progress is slow, very slow. But we can nevertheless consider ourselves very happy to have this treatment against childhood leukemia. Really, it’s a good thing.

Now, we will also understand the willingness of more and more people to get involved in understanding the causes (environmental, for example) of cancers, and discover the most effective means of prevention, in the absence of really satisfactory treatments. .

Cheers !

Jean-Marc Dupuis

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