1997 – Gertrude B. Elion

Challenges and Rewards of Pharmaceutical Research

A biochemical approach to chemotherapy based on interference with nucleic acid synthesis by purine and pyrimidine antimetabolites has led to a number of important medicinal agents. The antileukemic drugs 6-mercaptopurine and thioguanine resulted from this program. These were the first purine antimetabolites used successfully in the treatment of acute leukemia and have remained, even after 40 years, an important part of the armamentarium against leukemia.

Studies on the metabolism of 6-mercaptopurine (6-MP) led to the realization that much of the compound was converted to inactive compounds in the body. Derivatives were synthesized which could act as pro-drugs of 6-MP. One of these, azathioprine (Imuran®) proved to be the drug of choice for suppressing the immunological rejection of transplanted organs. As a result of the use of azathioprine, many thousands of kidney transplant patients have enjoyed a long-term survival of their grafts.

The studies of purine metabolism also led us to the investigation of the in vivo inhibition of the enzyme xanthine oxidase with allopurinol. This purine analog not only potentiated the activity of 6-MP, but also inhibited the formation of uric acid. Allopurinol has become a standard treatment for gout and for the prevention of uric acid kidney stones.

In the 1970’s we developed a new antiviral agent, acyclovir, for the treatment of herpes virus infections. This drug is a purine nucleoside derivative which has an acyclic side chain at the position ordinarily occupied by a deoxyribose moiety in DNA. It is non-toxic to normal cells but is activated in herpes virus-infected cells to form a compound which is toxic to the virus. The high selectivity and safety of acyclovir have made it an effective agent for treating cold sores, herpes keratitis, genital herpes, herpes encephalitis, chickenpox and shingles. It has also been successful prophylactically in preventing recurrences of genital herpes in patients who suffer from frequent recurrences. Acyclovir was a landmark in antiviral chemotherapy because it proved it was possible to have a drug with a good safety profile that was active against DNA viruses.