History of Science: A female chemist initially excluded from research helps develop a drug for a remarkable but short-lived recovery in a child with leukemia — December 6, 1954

In 1954, researchers reported a new drug that put children with acute leukemia into remission. This became one of the first chemotherapy drugs and would later form the basis of a new “rational” approach to drug design.

Gertrude Elion earned a master’s degree in chemistry in 1941, but was rejected from many graduate research positions that were not open to women. According to an autobiographical sketch she wrote in 1988, she worked as a high school chemistry teacher and a food quality inspector for a supermarket company.

However, by 1944 she found work in George Hitchings’ laboratory at Burroughs Wellcome Pharmaceutical Company (now GSK). Hitchings was developing a new method of manufacturing new drugs that avoided the trial-and-error approach that had previously dominated drug design.

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“One of the deciding factors may have been that my grandfather, whom I loved dearly, died of cancer when I was 15 years old. I had a strong desire to do something that might eventually lead to a cure for this terrible disease,” Elion wrote in 1988.

Hitchings and Elian reasoned that because all living cells require the nucleic acids that make up DNA in order to replicate, rapidly growing cells such as invasive bacteria or tumor cells would require even more of these compounds to fuel their insatiable growth. They discovered and rationalized that compounds that inhibit nucleic acid synthesis could suppress cancer growth.

In 1950, when Elian was 32 years old, his research team discovered a purine-derived compound called 6-mercaptopurine (6-MP). This compound can inhibit the growth of both bacterial and leukemic cells in laboratory dishes. Over the next two years, the drug was tested on animal tumors and found to slow tumor growth. In 1952, researchers began a clinical trial involving 107 patients with various types of cancer, including 45 children and 18 adults with acute leukemia. Until now, there was no good treatment for these children, and they usually died several months after diagnosis.

There have been several chemotherapy drugs in the past, but many of them were based on highly toxic compounds such as war gases. In contrast, children who took 6-MP seemed to tolerate it fairly well, with 15 children achieving complete remission within weeks to months. It wasn’t a huge increase, but it was more than what was previously possible. Elian was overjoyed when his children got better, but became depressed when they fell ill again.

Hitching and Elian decided to pursue other related compounds that could produce more durable remissions. In the late 1950s, they came up with a regimen that combined methotrexate (another chemotherapy drug developed by Dr. Jane Wright and others) and 6-MP, which produced long-term, stable remissions in some children with acute leukemia.

Elion went on to develop more drugs during its decades-long career, including the rheumatoid arthritis and transplant rejection drug azathioprine. Acyclovir, an antiviral drug that treats genital herpes, chickenpox, and shingles. AZT was the first drug to be effective against HIV/AIDS. In 1988, she shared the Nobel Prize in Physiology or Medicine with Hitchings and James Black for her work on “key principles in drug design,” including research on 6-MP.