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Brave. that is how parents most frequently describe their children who cope with leukemia--the needle pokes and jabs, the tests, the frequent visits to the doctor, the medication.
According to St. Jude Children's Research Hospital, in the U.S. about 2,500 children a year are diagnosed with acute lymphoblastic leukemia. It is the most common childhood cancer and usually strikes two- to five-year-olds. As chemist Gertrude B. Elion said in her Nobel Prize acceptance lecture in 1988, the median life expectancy for children with acute leukemia in the late 1940s was between three and four months. Long-term survival rates are now around 80%.
The increase in cure rate "is entirely [associated] with drug therapy--not with radiation therapy, not with surgery," says Richard M. Weinshilboum, an internist and researcher in the department of molecular pharmacology and experimental therapeutics at the Mayo Clinic College of Medicine in Rochester, Minn.
The first effective leukemia drug was 6-mercaptopurine, developed by Elion and George H. Hitchings, who worked together for 30 years at Burroughs Wellcome Research Laboratories. They shared the Nobel Prize in 1988. The Nobel assembly said their work has "fundamental significance," as they pioneered what is now known as rational drug design: the targeted synthesis of molecules with desired structures.
THIOPURINE DRUGS, the class to which 6-mercaptopurine belongs, "are mainstays of the treatment of acute lymphoblastic leukemia, without which cure rates would be lower," explains Mary V. Relling, who chairs the pharmaceutical sciences department at St. Jude Children's Research Hospital in Memphis, Tenn. Thiopurine drugs are also "more widely used for autoimmune diseases such as Crohn's disease," she adds.
Hitchings had been intrigued by nucleic acids, the building blocks of both DNA and RNA. In the '40s, DNA structure was still a puzzle, but it was known to contain heterocyclic aromatic amines: the purines and pyrimidines.
Expanding on the way sulfonamides affected bacteria by interfering with the use of an essential nutrient, Hitchings hypothesized that it might be possible to use antagonists to stop bacterial or tumor cell growth by interfering with nucleic acid biosynthesis.
So, at a time when mass spectrometry was available in only a few laboratories and the little-studied purines were separated as copper and silver salts by fractional crystallization, Elion worked on purines and purine analogs, which were to be the focus of her entire career.
By 1951, Hitchings and Elion had tested more than 100 of their purine analogs on the bacterium Lactobacillus casei, their assay to test biological activity of synthesized compounds. The purine antagonist 6-mercaptopurine was among them. Elion found that she obtained an inhibitor of purine utilization when she substituted sulfur for the oxygen on hypoxanthine. Tests followed at Sloan Kettering Cancer Center, first in rats, then in leukemic children. Approval by the Food & Drug Administration came through in 1953--unthinkable speed by today's standards. That was a mere two years after 6-mercaptopurine was first synthesized and only 10 months after testing had begun.
The partnership between Elion and Hitchings began in 1944 and yielded a fountain of drugs for Burroughs Wellcome: for leukemia, malaria, organ transplantation, bacterial infections, gout, even paving the way for HIV drugs. When Hitchings came to the Mayo Clinic to give talks and seminars, he would often say that "the best day's work he ever did was when he hired Gertrude Elion as his technician," Weinshilboum remembers.
Elion and Hitchings shared an intense desire to use chemical knowledge to advance medicine. For Elion, the death of her favorite grandfather from cancer when she was 15 and the death of her fianc due to an infection of the heart in 1941 were career-shaping events. Hitchings had witnessed, at age 12, the death of his father after a long illness.
Joseph E. Murray, Nobel Laureate in 1990 for his work involving organ transplantation, said in his Nobel talk that Hitchings and Elion were "enthusiastic collaborators" in his experiments that involved the synthesis of the imidazole derivative of 6-mercaptopurine, which later became the immunosuppressant Imuran.
6-Mercaptopurine is now also considered a classic example for pharmacogenomics, an area of pharmacology that Weinshilboum has pioneered at the Mayo Clinic. He knew both Elion and Hitchings, who passed away in 1999 and 1998, respectively. The two scientists represent, in Weinshilboum's words, the "epitome of the scientific approach to drug development." And he adds, "I don't think you could ask for any better role models."
Name
◾ 1,7-Dihydro-6H-purine-6- thione monohydrate
CAS Registry
◾ 50-44-2
Other Names
◾ Leukerin
◾ Mercaleukin
◾ Puri-Nethol
◾ Purinethol
◾ 6-MP
Introduced
1953, Burroughs Wellcome
Sales
The global purine analogs market in 2004 was $180.9 million. Annual sales in 2004 for mercaptopurine were $44.3 million.
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