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Milestones in Oncology |
GlaxoSmithKline, Upper Merion, Pennsylvania, USA
Sixty-two years after Gertrude "Trudy" Elion came to work for a predecessor company of GlaxoSmithKline (GSK), 56 years after she synthesized the first of her drugs to gain regulatory approval as a cancer therapy, 23 years after she retired, 18 years after she won the Nobel Prize for Physiology or Medicine, and 7 years after she died, her legacy has wound its way to yet another medicine, this one called nelarabine.
Nelarabine (Arranon® Injection; GlaxoSmithKline, Research Triangle Park, NC), a cancer drug licensed in the U.S. just last year, is the product of many hands and minds [1]. Only through a sustained collaboration of industry, academia, and government were the clinical data produced to demonstrate that the drug has a role in treating certain rare forms of leukemia and lymphoma when patients have exhausted standard treatment options [2].
Yet look back far enough into this history, and there, yet again, you see the Elion legacy. In the early 1980s, Elion knew that among the compounds her laboratory had synthesized over the years there might be something that would work against leukemia or lymphoma originating in white blood cells known as T cells. "She gave me two little glass vials, I still remember, with black tops," says Dr. Joanne Kurtzberg, a specialist in pediatric oncology at Duke University Medical Center. In one of the vials was a precursor of nelarabine.
In time, Dr. Kurtzberg would initiate clinical studies of nelarabine. "It was Trudy working with Joanne who started the ball rolling" toward developing the drug for pediatric patients, says Dr. Thomas Krenitsky, long a colleague of Elion’s and now the head of his own research company. "It’s part of the legacy, it’s part of the continuum." At the same time, Dr. Beverly Mitchell, an oncologist then at the University of North Carolina, led the early clinical work in adults. Now at Stanford University, she recalls Elion as "one of my role models."
Elion was a member of one of the greatest drug-discovery partnerships in history. The other member was Dr. George Hitchings, a biochemist 12 years her senior, who hired her as an assistant, gave leeway to her talent, and pulled her along in his own ascent. For example, when in the 1950s Hitchings, who would share the Nobel Prize with Elion years later, successfully sponsored her before the American Society of Biological Chemists, he tried to preempt the challenges her election might face [3]. His words to the society, as Elion herself later related them, were these: "I know she has three strikes against her. She doesn’t have a Ph.D., she is a woman, and she works for industry. Nevertheless, I am going to tell you about her."
There was already much to tell about Elion, and much more to come: Personal losses that impelled her toward medical research, a chance meeting with Hitchings, encounters with bias against women in science—and the brilliant, prodigious work that spanned half a century. It never ceased; it established new methods of drug discovery; it rushed to exploit serendipity, ranging across disciplines and diseases; and it succeeded until, in a difficult domain where success is a rarity, it came to astonish.
"You look at the list of their drugs," says Dr. Kurtzberg, "and it is phenomenal."
From the laboratories of Elion, Hitchings, and their coworkers came early therapies for childhood leukemia (Purinethol® [mercaptopurine; Biogal Pharmaceutical Works Ltd., Debrecen, Hungary], often called 6-MP for 6-mercaptopurine, and Tabloid® [thioguanine; Glaxo-SmithKline]); an immunosuppressant that enabled wider use of organ transplantation (Imuran® [azathioprine; Promethius Laboratories Inc., San Diego, CA]); the first selective antiviral for herpes infection (Zovirax® [acyclovir; GlaxoSmithKline]); a treatment for gout (Zyloprim® [allopurinol; Promethius Laboratories, Inc., San Diego, CA]); an antimalarial (Daraprim® [pyrimethamine; GlaxoSmithKline]); and an antibiotic (trimethoprim, a component of Septra® [Monarch Pharmaceuticals, Bristol, TN] and Bactrim® [F. Hoffmann-La Roche AG, Basel]). Even after retirement, Elion contributed to the development of another therapy: the first AIDS drug, Retrovir® (zidovudine; GlaxoSmithKline), widely known as AZT for azidothymidine.
A CANCER DEATH
The need for medical research struck Elion at an early age. In 1933, when she was 15 years old, her grandfather developed stomach cancer. She spent time with him during his last days, this man who had followed her immigrant parents to America, had read to her, and had taken her on walks during her childhood. "I watched him die, essentially, in the hospital," she recalled long afterward, "and that made a terrific impression on me." At the time, she was about to enter college, and she was reflecting on what to study and what to do with her life. The experience with her grandfather convinced her: "I was going to do something about cancer."
Having moved precociously through the public schools of New York City, Elion entered Hunter College. It was a free school without which she may never have furthered her education, for the Great Depression had bankrupted the family. By age 19, she held a degree in chemistry, summa cum laude. Yet upon graduation she encountered the harsh reality that, no matter a woman’s high intellect, research positions were largely reserved for men. She secured a lab job only by working at first without pay, later to earn the grand sum of $20 a week.
With her savings, Elion went on to New York University. In 1941, she completed a master’s degree in chemistry there—and she lost the love of her life. Her fiancé died of a heart infection just before the dawn of the penicillin age. Her urgency about medical research—what she called "a matter of life and death"—was cruelly reinforced. She never married.
Looking for work again, Elion entered a new market. The U.S. had entered World War II, and male scientists were exchanging lab coats for military uniforms. Women in science could find their chance. Her first opportunity came in industry, but not in pharmaceuticals. She did quality control for a grocery chain, checking the acidity of pickles, the color of mayonnaise, and taking from the experience all she could learn about instrumentation. Then came a post at Johnson & Johnson, but she cooled to the work when it transpired that she would not be synthesizing medicines but rather checking the strength of sutures. As she looked for something closer to her interests, she found that Burroughs Wellcome, today merged into GSK, had a small research group in Tuckahoe, New York. Researchers there took turns interviewing job applicants. It was Hitchings’ turn the Saturday morning Elion showed up. He made the hire. She would observe later that he saw in her work a "certain intensity."
It was 1944. Hitchings was concentrating his investigative energies on the metabolism of nucleic acids, the molecular carriers of genetic information. He sought to make drug discovery more rational, less hit-and-miss, though exactly how his path would lead to medicines was hardly obvious at the time. Not until 1944 had Oswald Avery at the Rockefeller Institute published a paper suggesting, and then only cautiously, that DNA was the stuff of genes. Not until 9 years later would James Watson and Francis Crick at Cambridge University propose the double-helix structure of DNA, which revealed how the information in this master molecule might be copied during cell replication.
Hitchings figured that he could inhibit replication of rapidly dividing cells—such as cancer cells and pathogenic microbes—by making false DNA building blocks, specifically, derivatives of the chemical bases in DNA. The trick would be to make chemical bases similar enough to those in nucleic acids that they could integrate themselves into natural metabolic pathways, yet different enough that, once integrated, they would jam the works. "Rubber donuts," the researchers called these knockoff antimetabolites—they looked like the real thing but weren’t. Elion made her own specialty the bases called purines. They became not only prospective medicines but research tools, and observation of their effects helped to elucidate metabolic pathways until then only intuited. As she put it, "Let the drug lead you to the answer nature is trying to hide from you."
Cancer was the disease that had first moved Elion to become a researcher, and as it happened, cancer was the disease for which the Elion–Hitchings team first created new therapies. Working with collaborators at the Memorial Sloan-Kettering Cancer Center, in New York, they created 6-MP and thioguanine in the early 1950s. 6-MP is still a mainstay in combination therapy for patients with acute lymphoblastic leukemia. The prospect for these patients, especially children, a prospect so bleak in the 1950s, has become one of the success stories in the anticancer crusade; among children under age five, the rate of 5-year survival, sometimes deemed a cure, now exceeds 80%.
QUICK STUDIES, OPEN MINDS
Elion and Hitchings soon turned to other diseases as well. The fundamental nature of the biology they were exploring allowed them to do that. So did their appetites to learn more. Elion, for her part, had little experience outside chemistry upon arriving at the company, and she abandoned night-school pursuit of a Ph.D. when a dean insisted she give up her job to attend classes fulltime. It didn’t much matter. She devoured chemistry at work, and branched into microbiology, enzymology, pharmacology, virology, and immunology. Dr. Krenitsky recalls of the two, "They would let the compounds take them into new areas. They were quick studies. They were amazing to watch." Far from being satisfied to lob compounds "over the fence" for clinical development, they would stay involved as the compounds advanced in the pipeline, from lab bench to bedside. Dr. Krenitsky: "Everybody tried to do that, but Trudy was a master at it. She’d argue with the medical people. She’d argue with the FDA."
Sometimes Elion got lucky, smart-lucky. She gave years to fashioning a drug that would release 6-MP only after entering leukemic cells. Nothing came of the effort for cancer therapy. Yet, by the late 1950s, researchers outside the company had taken an interest in the effects of 6-MP on the immune response. Might drugs like 6-MP prevent rejection of organ transplants? At the time, rejection thwarted transplants other than those between twins. Always quick to collaborate, Elion and Hitchings began working with what was then known as the Peter Bent Brigham Hospital, in Boston. They provided compounds screened by an immunological test their lab had set up. Joseph Murray, a transplant surgeon at the Brigham then working experimentally with dogs, came to know the two chemists from Tuckahoe as "frequent visitors" who "knew most of our dogs by name."
From this effort resulted Imuran, one of the drugs Elion had synthesized while trying to improve upon 6-MP. It remained an essential drug in transplantation for 20 years. "Now, I didn’t start to make a compound that would do that," Elion pointed out late in her career. "But if you listen and keep your mind open, this is what can happen. This was the story of our lives." Surgeons first successfully used Imuran to perform a kidney transplant in 1962. In 1990, when Murray was giving his own Nobel Prize address, he noted that more than 200,000 kidney transplants had been performed worldwide.
As product followed product, the scientific contributions of Elion and Hitchings, together with those of their colleagues, merged almost indistinguishably into one another. She became head of the Department of Experimental Therapy when he moved to a higher executive rank, and she continued to make vital contributions after he retired. Her own retirement came in 1983, if retirement it can be called. A world traveler and opera buff, she took more time for interests outside her work, yet the work went on.
In 1983 the company was marshalling resources for an effort that led to the approval of AZT as the first AIDS therapy. By some accounts, Elion, with no direct hand in the accomplishment, had little to do with it. She disclaimed a part for herself. Marty St. Clair begs to differ. A virologist at GSK and an inventor of the use of AZT in treating AIDS, she says, "Trudy had everything to do with AZT. Yes, officially she was retired, but she was there working with us and counseling us. She knew exactly what we were doing" [4].
NELARABINE
It was about this time that Elion was helping to spark the long train of research that would lead to nelarabine. Her propensity to mentor young researchers had led to a position at Duke. There she got to know Dr. Kurtzberg, who had developed a way to test leukemia drugs in mice. Elion handed over the two compounds. With one of them, called arabinoside-guanine, or ara-G, Dr. Kurtzberg saw encouraging results.
It lacked characteristics it needed to be a medicine, however, such as solubility in water and capacity to reach target tissues in quantity. A group led by Dr. Krenitsky worked through the chemistry to overcome those issues and found more efficient routes of synthesis. It is his invention, known among his group as 506U78, that today is known as nelarabine. It is a prodrug of ara-G, meaning that it is broken down to ara-G in the body. Accumulation of the drug in T cells inhibits DNA synthesis, stopping rampant cell replication.
A minority of patients afflicted with acute lymphoblastic leukemia and lymphoblastic lymphoma, perhaps 1,600 new cases a year in the U.S., have the T-cell types of these cancers [5]. Thanks to medical advances, including Elion’s early work, these patients have clearly brighter prospects at the time their disease is diagnosed. If, however, they do not respond to therapy, or if, after initially encouraging results, they find their disease worsening, their prospects suddenly darken. For some patients, there is then no standard therapy.
In this grim context, nelarabine is no miracle cure. Like many other cancer drugs, this one is toxic, so physicians using it must watch carefully for side effects, especially including toxicity to nerves and blood-forming cells, which may be severe [6]. Having received accelerated approval, the drug now needs further evaluation of its clinical benefit [7].
Nelarabine provides, nevertheless, another treatment option, offering in some cases the prospect of sufficiently long remissions to allow bone-marrow transplants to go forward [7]. A transplant, though carrying its own risk, can replace blood-forming cells—it can sustain the thread of hope. Nelarabine followed by transplant was the course for a boy whose father appeared before an advisory committee of the U.S. Food and Drug Administration to say his son received the drug at age four, had now reached the age of 10, and was playing Little League baseball.
In a sense, then, nelarabine represents the final effort by Elion to help a small group of patients who desperately needed something additional to what she could offer them before. "She started with 6-MP, and you could say that with this last drug she has completed the cycle," remarks Dr. Neil Spector, an oncologist formerly on staff at GSK. "Her words still ring out to me, ‘Neil’—it’s as though she’s right next to me—‘you have to keep your eye on the patients. If you do that, the company will do fine.’" [8]
With "retirement" came more honors for Elion. In 1998, the company, which in 1970 had moved from Tuckahoe to Research Triangle Park, North Carolina, dedicated a new research center, an architectural adventure with a cubist-like façade. Its name: the Elion–Hitchings Building. The Nobel Prize had come a decade earlier. At the Stockholm awards ritual, accustomed to men in white-tie attire, Elion blazed in blue chiffon. She treated celebrity lightly, though. Arriving home, she joked about hesitantly pulling out the prize medal for a customs agent who asked her to declare any jewelry.
Such a woman leaves a legacy of spirit as well as of products. She was direct in manner and wholly unpretentious. If she was vigorous in debate, she didn’t let it get personal. Her zest, her high purpose, rubbed off on others, and she gave them the pursuit of their intellectual passions. She was generous in crediting them for what they did.
You can still hear Elion stories at GSK. There is one that goes something like this: Toward the end of her life, Elion pulls into a VIP parking space by the avant-garde structure at Research Triangle Park, an uncommon exercise of privilege by someone who typically had so little time for it. She gets out of the car, and makes her way toward an entrance. She is unknown to the parking-lot guard who now interdicts her course. She has wandered off, he suggests, and points out a parking space elsewhere. Comes the delicate reply from the seeming interloper, the inventor on 45 patents and author on more than 200 papers, the drug hunter extraordinaire and Nobel Laureate, lady of poised persistence, "Would it change your mind if I told you ... my name is on the building?" Whereupon the guard opens the door and bids her enter.
One reason Elion kept coming back was to champion nelarabine. The path of the drug was difficult, what with the need to weigh its promise against its side effects, to find the right dose and regimen, to enroll enough patients with rare cancers into trials, and to weigh its medical and commercial potential against the opportunity of other drugs in the pipeline. But then she more than most knew how hard it is to make a cancer drug.
"If you want to stay in oncology and save lives," she once wrote in a memo of unyielding advocacy, "you need patience and vision."
Trudy Elion participated in a nelarabine-project-team meeting for the last time in February of 1999. It was the week before her death. She was 81.
DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
R.K. owns stock in and is Vice President, R&D Communications, at GlaxoSmithKline.
ACKNOWLEDGMENT
Les Prix Nobel/Nobel Lectures, the Academy of Achievement, the Jewish Women’s Archive, Bella International Productions, Inc., the Chemical Heritage Foundation, the GlaxoSmithKline archives, and colleagues of Gertrude Elion all contributed information for this article.
ENDNOTES
2 Elion GB, Hitchings GH, VanderWerff H. Antagonists of nucleic acid derivatives. VI. Purines. J Biol Chem 1951;192:505–518.
3 Elion GB, Burgi E, Hitchings GH. Studies on condensed pyrimidine systems. IX. The synthesis of some 6-substituted purines. J Am Chem Soc 1952;74:411–414.[CrossRef]
4 Elion GB, Singer S, Hitchings GH. The purine metabolism of a 6-mercaptopurine-resistant Lactobacillus casei. J Biol Chem 1953;204:35–41.
5 Elion GB, Singer S, Hitchings GH. Antagonists of nucleic acid derivatives. VIII. Synergism in combinations of biochemically related antimetabolites. J Biol Chem 1954;208:477–488.
6 Elion GB, Callahan SW, Hitchings GH et al. The metabolism of 2-amino-6-[(1-methyl-4-nitro-5-imidazolyl) thio]purine (BW 57-323) in man. Cancer Chemother Rep 1960;8:47–52.[Medline]
7 Elion GB, Callahan S, Nathan H et al. Potentiation by inhibition of drug degradation: 6-substituted purines and xanthine oxidase. Biochem Pharmacol 1963;12:85–93.[Medline]
8 Elion GB, Callahan S, Rundles RW et al. Relationship between metabolic fates and antitumor activities of thiopurines. Cancer Res 1963;23: 1207–1217.
9 Elion GB, Kovensky A, Hitchings GH et al. Metabolic studies of allopurinol, an inhibitor of xanthine oxidase. Biochem Pharmacol 1966;15: 863–880.[CrossRef][Medline]
10 Elion GB. Actions of purine analogs: enzyme specificity studies as a basis for interpretation and design. Cancer Res 1969; 29:2448–2453.
11 Elion GB, Furman PA, Fyfe JA et al. Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl)guanine. Proc Natl Acad Sci U S A 1977;74:5716–5720.
12 Elion GB. Mechanism of action and selectivity of acyclovir. Am J Med 1982;73:7–13.[Medline]
13 Biron K, Fyfe JA, Noblin JE et al. Selection and preliminary characterization of acyclovir-resistant mutants of varicella zoster virus. Am J Med 1982;73:383–386.[Medline]
14 Kucera LS, Furman PA, Elion GB. Inhibition by acyclovir of herpes simplex virus type 2 morphologically transformed cell growth in tissue culture and tumor-bearing animals. J Med Virol 1983;12:119–127.[Medline]
15 Hitchings GH, Elion GB. Layer on layer: the Bruce F. Cain memorial award lecture. Cancer Res 1985;45:2415–2420.
16 Elion GB. Selectivity—key to chemotherapy: presidential address. Cancer Res 1985;45:2943–2950.
17 Elion GB. Acyclovir: discovery, mechanism of action, and selectivity. J Med Virol 1993;(supp1 1):2–6.
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