6-Mercaptopurine (Box 23-2), after its conversion to the corresponding nucleotide through salvage reactions, is a potent competitive inhibitor of IMP in the pathways for AMP and GMP biosynthesis. It is therefore a clinically useful anticancer agent. The chemotherapeutic effectiveness of 6-mercaptopurine is enhanced when it is administered with allopurinol. Explain the mechanism of this enhancement.

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Box 23-2 Pathways of Discovery Gertrude Elion and Purine Derivatives ****** Gertrude Elion (1918-1999) Gertrude Elion's choice of career was made at age 15 when she graduated from high school in New York City. As she watched her grandfather suffer and die from stomach cancer, she decided to dedicate herself to finding a cure for cancer. When she enrolled at Hunter College the next fall, she began to study chemistry. Despite her academic accomplishments, she was unable to ob- tain a scholarship for graduate school and spent the next two years as a teacher and lab assistant. She eventually obtained a master of science degree in 1941. After finding that working in an industrial chemistry laboratory bored her, Elion obtained a position with George Hitchings at the pharmaceuti- cal company Burroughs Wellcome. There, she found an intellectually stimulating environment where she was able to expand her understand- ing of chemistry as well as pharmacology, immunology, and other fields. Although she ultimately received numerous honorary degrees, Elion never formally earned a doctoral degree; after several years of attending classes at night, she was forced to choose between her work with Hitch- ings, which she loved, and full-time study. Fortunately for science and medicine, Elion kept her job and significantly advanced the development of drugs for cancer, gout, organ transplants, and infectious diseases. Hitchings asked Elion to investigate purine metabolism, with the idea that disrupting a cell's supply of nucleotides could interfere with its ability to synthesize DNA. Ideally, compounds that blocked DNA synthesis would disable rapidly growing cancer cells, bacteria, and vi- ruses, without affecting normal cells. Without knowing the structures of the relevant enzymes, or even of DNA, Elion and her colleagues used a simple bacterial growth assay to investigate the ability of various purine derivatives to act as "antimetabolites." Elion's first clinical success was 6-mercaptopurine, which was used to treat leukemia in children. Many patients showed a dramatic recov- ery, but to Elion's dismay they often relapsed and later died. Their initial improvement, however, confirmed Elion's belief that interfering with nucleotide metabolism was a sound therapeutic strategy. SH OS H 6-Mercaptopurine A related compound, azathioprine, is converted to 6-mercaptopurine intracellularly. It turned out to be effective not as an anticancer drug but as an inhibitor of the immune response. This drug helped solve the problem of rejection in organ transplants and was used for the first suc- cessful human kidney transplant in 1961. ANA SANA KAmanda KARARANASANA ARANANDA Ak HC N N HN HN- NO Azathioprine Studies aimed at improving the effectiveness of purine derivatives by preventing their degradation by xanthine oxidase led to the discovery of allopurinol which is still used to treat gout and some parasitic diseases. Elion also helped develop the antibacterial agent tri- methoprim and the widely used antiviral drug acyclovir (Zovir). HOCH, CH Acyclovir H 1 CH ARANDARANNhahahhahahahahahahahahahahaahahahaha AkNAAN dndandakakakakaka