Nobel Laureates: George Hitchings and Gertrude Elion

 

The Nobel Prize in Physiology or Medicine 1988.

"for their discoveries of important principles for drug treatment"

Gertrude B. Elion (1918 - 1995) and George H. Hitchings (1905 - 1998) won the Noble Prize for their work on the treatment of disease and organ transplantation. They developed a number of drugs that interfered with nucleic acid synthesis leading to effective treatment of malaria as well as bacterial and viral infections. They are especially noted for the development of drugs that inhibit the body's ability to reject the transplant. One of the most famous of these immunosuppression drugs is azathioprine, a drug that is still used in some cases to suppress the immune response.

Elion and Hitchings worked together at the Wellcome Research Laboratories in Research Triangle Park, NC, USA. They are among a select group of Nobel Prize winners who did their prize winning research outside of academia. Elion and Hitchings shared the Nobel Prize with Sir James W. Black.

Here's what the press release said about Elion and Hitchings

THEME:
Nobel Laureates

Studies of Nucleic Acid Synthesis Result in the Discovery of New Drugs

Gertrude Elion and George Hitchings have collaborated since 1945. Their original research idea was to look for differences in nucleic acid metabolism between normal human cells, cancer cells, protozoa, bacteria and virus, which could be utilized to develop drugs that selectively block the growth of cancer cells and of noxious organisms. Over the years this research philosophy has formed the basis for the development of drugs against a variety of disorders including leukemia, malaria, virus infections and gout.

When Elion and Hitchings presented their ideas at the end of the 1940s the knowledge about nucleic acid metabolism was very limited. It was known, however, that purines and pyrimidines are incorporated into nucleic acids. Elion and Hitchings studied the growth of the Lactobacillus casei, a bacterium dependent on folic acid or a combination of purines (hypoxanthine, guanine) and pyrimidines (thymine). The purpose was twofold, to characterize the metabolic pathways involved in the biosynthesis of nucleic acids and to identify antimetabolites in the nucleic acid metabolism (Figure 3).
Figure 3.

Figure 3. Purine bases (adenine, guanine and hypoxanthine) are synthesized from simple precursors. Nucleosides are then formed by the addition of sugar moieties (deoxyribose or ribose) and subsequently converted into nucleotides by the addition of phosphate (mono-, di- and triphosphate). Nucleotides take part in cellular metabolism and are the building blocks in the synthesis of RNA and DNA. Structural analogues of the natural substances can specifically block the different metabolic steps. Some examples are given in the figure.

Already in 1948 Elion and Hitchings discovered a substance, diaminopurine, an adenine antagonist, which inhibited the growth of L. casei (Figure 3). It was also found to have an effect on experimentally induced leukemia. Clinical trials in patients were initially promising but had to be interrupted due to toxic side effects. Stimulated by this finding Elion and Hitchings continued their research which soon resulted in two new chemotherapeutic drugs, thioguanine (1950) and 6-mercaptopurine (1951). In collaboration with the Sloan-Kettering Institute 6-mercaptopurine was tried in leukemic patients who were resistant to methotrexate. About one third of the patients responded with complete remission (1953). The finding was soon confirmed, and 6-mercaptopurine (as well as thioguanine) are still used in the treatment of leukemia (Table II).

Elion and Hitchings tried to improve the therapeutic properties of 6-mercaptopurine by using sulphur-substituted compounds. The result was azathioprine (1957) which replaced mercaptopurine as an inhibitor of the immune response. For a long time azathioprine was the only drug available to prevent rejection of transplanted organs. It is still used for that purpose but also for the treatment of autoimmune diseases.

Attempts were also made to prolong the effect of 6-mercaptopurine by blocking its metabolism by xanthine oxidase which is involved in the endogenous production of uric acid (Figure 3). In 1963 this research resulted in another new drug, allopurinol, which blocks the formation of uric acid and therefore is used in the treatment of primary and secondary gout.

Hitchings and collaborators also developed pyrimethamine (1950) and trimethoprim (1956) which were found to be effective in the treatment of malara and bacterial infections, respectively. Both drugs have a strong affinity to the enzyme dihydrofolate reductase, but pyrimethamine is 2000 times more toxic to the enzyme system in the malaria parasite than in the host. Trimethoprim has 100 000 times higher affinity to the bacterial compared to the human enzyme. An important discovery was that the chemotherapeutic effects of these two compounds were markedly enhanced by sulphonamides, drugs which inhibit the synthesis of folic acid. This pharmacotherapeutic principle is used in the combination drugs trimethoprim-sulfa and pyrimethamine-sulfa which are used in the treatment of bacterial infections and malaria, respectively.

A more recent application of Elion's and Hitchings' research philosophy is acyclovir, a drug used in the treatment of infections with herpes virus. Already in the 1950s they had shown that antipurines had to be transformed into nucleotides in order to become active in the cell. The herpes virus carries information which leads to the production of a new enzyme which transforms nucleosides to nucleotides (thymidine kinase) in the infected cell. This enzyme has considerably less substrate specificity than the cell's normal enzyme. Therefore, acyclovir is transformed into its corresponding nucleotide which is the active antimetabolite and the growth of the virus is inhibited (Figure 3).

Acyclovir was described by Elion and coworkers in 1977 and is a modern example of the realization of the basic ideas from 1950. An even more recent application of these ideas is the development of azidothymidine (AZT) which was described in 1985 by other scientists from the same institute, and which is the hitherto best documented drug in the treatment of AIDS. It can be added that trimethoprim-sulfa is used in the treatment of Pneumocystis carinii, a relatively common complication to AIDS.

The clinical use of the drugs discovered by Elion and Hitchings is summarized in Table II.
Table 2.



References

G. Gahrton, B. Lundh: Blodsjukdomar. Lärobok i hematologi. Natur och Kultur, Stockholm, 1983.

Läkemedelsboken 1987/88, Apoteksbolaget, Stockholm, sid, 87-88, 150-151, 249, 625.

J.H. Shelley: Creativity in Drug Research. Trends in Pharmacological Sciences. 1983, vol. 4.

L. Stryer: Biochemistry, 3rd edition. W.H. Freeman and Company, San Francisco, 1988, chapter 25, 601-625.

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[Photo Credit: George Hitchings and Gertrude Elion (top) from Welcome Images]