Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (19 page)

In 1949 Mustargen became the first cancer chemotherapy agent approved by the FDA. In that period, proof of safety, not of effectiveness, was the standard for approval. By 1958 a full clinical investigation clarified the applications, benefits, and consequences of nitrogen mustards. Regression of tumors was often temporary, and they eventually became resistant to further treatment. Such drug resistance continued to be a vexing problem as other chemotherapeutic drugs were developed over subsequent decades. Furthermore, the agents had to be administered very conservatively, since the cure could so easily be worse than the disease.

Nitrogen mustards remain useful today in Hodgkin's disease, other lymphomas, and acute and chronic lymphocytic leukemias. They belong to a class of cancer drugs called alkylating agents. (This term is based on the fact that they add an alkyl group—a type of alcohol radical—to compounds with which they react.) They stop the multiplication of cancer cells by forming permanent cross-links between the two strands of DNA in the cell's nucleus so that the cell can't divide. Currently, four other major types of alkylating agents with actions similar to nitrogen mustard are also used in the chemo-therapy of cancer of several other organs.

The bombing at Bari was the worst Allied shipping disaster since Pearl Harbor. Yet, to this day, most World War II history books do not refer to it. The devastation at Bari was kept secret for years after the end of World War II, largely because of the presence of the deadly
chemical agents. The American and British governments released only limited announcements. The incomplete defense of Bari was certainly a major wartime blunder, but Allied secrecy was imposed for decades, particularly because they had deadly chemical agents in the field, ready for prompt offloading if the need arose. Churchill commanded that all British records be purged of any mention of mustard. In 1961 the National Academy of Sciences attempted a follow-up survey of the survivors, but the project was officially impeded and blocked.
¹³

Advances in the chemotherapy of cancers testify to the breakthrough the episode provided. The investigation of the Bari survivors’ mysterious burns and skin ailments led to the observation that alkylating agents, such as nitrogen mustard, cause marrow and lymphoid depletion, which led to their successful use in treating certain kinds of cancers. According to the American Cancer Society, “the age of cancer chemotherapy was initiated…. From this [Bari] disaster, a chemical agent with anticancer activity was serendipitously discovered.”
¹⁴
Nitrogen mustard became a model for the discovery of other classes of anticancer drugs.

It's said that every cloud has a silver lining. The cloud over Bari on that tragic day was very toxic indeed, but the silver lining that was fashioned by creative scientists led to lifesaving treatments for millions of people.

10

Antagonists to Cancer

The most common form of childhood cancer is leukemia, a cancer of the white blood cells produced in the bone marrow. Surgery is impossible and radiotherapy not very effective. In the late 1940s acute leukemia in children was an incurable and rapidly fatal disease. Patients were treated with transfusions and then sent home to await death in a few months from massive hemorrhage and infection.

Dr. Sidney Farber, a pathologist at Children's Hospital in Boston, had a particular interest in cancer in children. He based his work on an observation made halfway around the globe fifteen years earlier. In 1933 Lucy Wills, a British physician working in India, identified a type of anemia in textile workers that she attributed to their severe poverty and grossly deficient diet. She found that the anemia responded to the consumption of Marmite, a food product made from purified yeast that has been available since around 1900. It is typically slathered on toast, mainly by the British. The butt of many jokes, it has a strong odor, a saline taste, and the color and consistency of axle grease. The product derives its name from the French word for the logo pictured on the jar,
la marmite,
meaning “stewpot.” Wills inferred that Marmite must contain an unidentified nutrient or vitamin. She subsequently found that the anemia also responded to crude liver extracts.
¹

The mystery nutrient in both Marmite and liver is now known to be folic acid. The term “folic acid” was coined in 1941, following its isolation from spinach (L.
folium =
leaf), but it was not until 1946
that its chemical structure was identified. We know today that folic acid—one of the B vitamins—is a dietary essential, present especially in fresh green vegetables, liver, yeast, and some fruits. Essential for blood formation, which occurs in the bone marrow, its deficiency leads to anemia. Studies during World War II had shown that certain anemias, in which large immature cells filled the bone marrow, responded to treatment with folic acid. Farber believed a similar solution could be discovered for leukemia. At the time, there was little understanding of the role of folic acid in the normal workings of the body. The history of its biochemical isolation and clinical application to chemotherapy is a saga of clinical stumbles, misdirection, and serendipity.

In the early 1940s cancer researchers at Mount Sinai Hospital in New York were involved in an extensive screening program to find agents that could cause regression of tumors. The program involved some 18,000 mice bearing both transplanted and spontaneous malignancies. One of the agents tested was a liver extract, thought to be folic acid, provided by Lederle Laboratories. The researchers came upon dramatic and unexpected findings: The liver extract given intravenously to mice strongly inhibited the growth of tumor cells.
²
This result was both surprising and confusing, as it appeared to contradict the known attributes of folic acid. What the researchers did not recognize at the time was that the extracts contained not folic acid but rather an
antagonist
of folic acid, a slightly different substance chemically, that effectively competes with and blocks folic acid's absorption into the cell. Unbeknownst to the observers at the time, the rapidly dividing tumor cells were being deprived of folic acid in the biosynthesis of DNA.

Researchers were then tragically misled by the erroneous conclusion that the development of cancerous cells occurs because the cells lack folic acid and get out of control. Thinking that an anticancer agent had at last been found, Lederle Laboratories quickly synthesized various folic acid compounds, and Farber and colleagues arranged clinical studies of patients with advanced cancers. Farber hoped the substance would provide the cure for leukemia.

Devastation rather than triumph ensued. The most striking result
was the astonishing postmortem observation that eleven children with acute leukemia in this group showed the reverse effect of that intended—that is, their bone marrow was bursting with masses of newly formed white blood cells and their organs densely riddled with cancerous white blood cells. Since this was a totally unexpected result of these folic acid compounds, Farber termed this an “acceleration phenomenon” in the leukemia process. The sterile phrase undoubtedly hides the shock, disappointment, and guilt he must have felt.

Still, he imaginatively saw this tragedy as an opportunity: If the cells were
deprived
of folic acid, the growth of leukemia cells might be arrested. Perhaps folic acid absorption could be blocked through the use of antimetabolites. An antimetabolite, or antagonist, is a structurally similar compound that inhibits (antagonizes) the action of a metabolite by competing with it for the site of action in the body.

By 1948 Farber obtained several antagonists of folic acid. Aminopterin provided the first truly hopeful response. Out of the sixteen children treated, all of whom were suffering from acute leukemia, ten experienced unquestionable remissions.
³
The announcement of this great success was met with as much incredulity as celebration. Many observers, long inured to the futility of treatment of nonsolid tumors such as cancer of the blood cells, simply did not believe the results. Moreover, it was felt that such a breakthrough could not have been achieved by a forty-five-year-old pathologist who worked in a hospital basement laboratory with little in the way of funds, staff, or equipment.

On the other hand, practicing physicians and pediatricians were enthusiastic. Farber had achieved the first clinical remission with chemotherapy ever reported for childhood leukemia. A milestone in the history of chemotherapy had been established. With maintenance therapy, patients lived for an average of eight or nine months longer, and perhaps one in a hundred was cured.

In 1949 methotrexate was developed as a safer folic acid antagonist. By interfering with folic acid, methotrexate causes white cells to die of vitamin deficiency. By the mid-1950s it produced the first cure—not just remission but actual cure—of a solid tumor, choriocarcinoma, including, astonishingly, its lung metastases.
⁴
Choriocarcinoma
is a malignancy in women derived from the fetal part of the placenta that has a great propensity to spread to the lungs.

The success of the folic acid antagonists led to the development of other antimetabolites for different cellular metabolic pathways.
⁵
Further insight was provided by a patient who had relapsed after treatment with a folic acid antagonist but who then responded to a course of treatment with another antimetabolite. This observation provided the basis for the introduction of combination chemotherapy. The basic idea of combination drug therapy is to mix drugs, all of which attack the tumor, but each of which has different side effects. These combinations are more effective than the individual drugs. Learning to improve the drug schedule produced longer remissions and then cure after cure. With time, courses of as many as four powerful drugs at once for periods of many months yielded progressively better results. Currently, most children with acute lymphocytic leukemia, the most common malignancy of childhood, are cured.
⁶

Thus, what started as nutritional research in the 1930s led to the demonstration that antimetabolites could kill cancer cells, as well as the discovery of the effectiveness of combination chemotherapy.
⁷

11

Veni, Vidi, Vinca

The Healing Power of Periwinkle

The discovery of a totally new chemotherapeutic agent derived from a natural plant came about through fortuitous circumstances that led to an outstanding example of serendipity.

In 1952 Dr. Clark Noble of Toronto received from a patient in Jamaica a small envelope full of leaves. These were from a subtropical periwinkle plant with the botanical name
Vinca rosea,
used by the locals to make a tea that appeared to help their diabetes. A physician in Jamaica, Dr. C. D. Johnston, was convinced that drinking extracts of the periwinkle leaves helped his diabetic patients to lower their blood sugar. Indeed, teas made from periwinkle were used by diabetics in places as geographically diverse as the Philippines, South Africa, India, and Australia, following the customs of traditional folk medicine.
¹
A proprietary herbal preparation, Vinculin, was even marketed in England as a “treatment” for diabetes.

Intrigued and determined to find out if there was anything to the claims, Clark Noble decided to have the leaves analyzed. And he knew exactly where to send them: to biochemist James Collip's laboratory at the University of Western Ontario in London, Ontario. Dr. Collip had worked with Frederick Banting and Charles Best in Toronto and had distinguished himself for the extraction and purification of the hormone insulin so that it could be used in the treatment of diabetes.

Years earlier, Clark had won a coin flip against his brother
Robert for the opportunity to work with Best, who needed only one of them as an assistant. It fell to Robert Noble, an endocrinologist now working in Collip's laboratory, to investigate extracts of
Vinca.
When given orally to rabbits and diabetic rats, the extracts had no effect on blood sugar or on the disease. With the intention of increasing the possible effectiveness, Noble then injected concentrated water extracts within the abdominal cavities of the rats. “They survived about 5 days, but then died rather unexpectedly from diffuse multiple abscesses,” severe bacterial infections, as “apparently some natural barrier to infection was being depressed.” This phenomenon, observed only by chance, was shown to be due to profoundly depressed bone marrow function and gross depletion of white blood cells. Noble immediately grasped that these consequences would be beneficial to people with diseases in which bone marrow overproduced.

Dr. Johnston in Jamaica continued to send a supply of dried periwinkle leaves, collected by Boy Scouts on camping trips in the jungle. The amount, however, proved inadequate for separation and purification of active factors. But by growing the plant in greenhouses in Ontario, Noble and his coworkers were able to extract a new alkaloid in pure crystalline form, which proved highly active in experimental animals, not only causing marked depletion of bone marrow and a dramatic decrease in white blood cells but also acting to shrink transplanted tumors. Taking its origin and its effect on white blood cells into account, scientists named the alkaloid vincaleukoblastine, which was later shortened to vinblastine.

The discovery was announced at a meeting of the New York Academy of Sciences in 1958 in a report entitled “Role of chance observations in chemotherapy:
Vinca rosea.
” Few could recall any such candid title in presenting a discovery. The conference was organized to review new projects for the large-scale screening of chemicals for antitumor properties, but Noble seized upon the opportunity to underscore the value of serendipity: