George H. Hitchings (1905–1998), Gertrude B. Elion (1918–1999)
One of the great collaborations in science led to the development of highly significant and innovative drugs used for the treatment of cancer, bacterial and viral infections, malaria, and gout, as well as to prevent the rejection of transplanted organs. For these accomplishments, George Hitchings and Gertrude Elion were awarded the Nobel Prize in Physiology or Medicine in 1988.
In 1942, Elion joined Hitchings’s laboratory at Burroughs Wellcome in Tuckahoe, New York (now GlaxoSmithKline in Research Triangle Park, North Carolina). Hitchings had earned a doctorate in chemistry at Harvard; Elion had a master’s degree, but financial pressures prevented her from completing a PhD program. Over the years, Elion’s career rapidly progressed from Hitchings’s assistant to a fully equal collaborator.
TRICKING CANCER CELLS WITH COUNTERFEIT BUILDING BLOCKS. Studies by Hitchings and Elion focused on chemical modifications of natural purines and pyrimidines, building blocks in DNA synthesis. The development of their chemotherapeutic agents—medicines used to combat bacteria, viruses, and cancer—was based on the use of antimetabolite drugs. Antimetabolites are false building blocks that insert themselves into biochemical reactions. Once there, they substitute themselves for the normal purine or pyrimidine building block (the metabolite) used in the microbial or cancer cell; and because the cell cannot utilize them to synthesize DNA, the cell cannot divide and grow.
Hitchings and Elion’s first significant drug was 6-mercaptopurine (Purinethol), a purine antimetabolite that Elion synthesized in 1950. It was further evaluated in New York City at the Sloan-Kettering Institute and then clinically tested at Memorial Hospital. Mercaptopurine produced complete remissions of leukemia in children, but these victories were temporary and followed by relapses within one year. Later, with a better understanding of the biology of the cell and cancer chemotherapy, other clinicians began to treat leukemias with mercaptopurine as a component of a combination of drugs. Leukemia cure rates now approach 80 percent.
SEE ALSO Sulfanilamide (1936), Amethopterin and Methotrexate (1947), Zyloprim (1966), Acyclovir (1982).
The cell-division cycle is a series of phases that occur in a cell and lead to its division and replication. In the illustration, the outer ring shows a long interphase (I), followed by cell division (M). Following the Gap 0 resting phase (G0), the interphase consists of four phases, depicted in the inner ring: Gap 1 (G1) prepares the cell for DNA synthesis (S), then Gap 2 (G2) prepares the cell for mitosis (M). A major characteristic of cancer is the loss of normal control during cell proliferation, resulting in the growth of malignant tumors. Anticancer drugs such as mercaptopurine act at specific points in the tumor-cell cycle.